· prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterial...

University of Groningen

Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterialhypertensionPloegstra, Mark-Jan

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2017

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Ploegstra, M-J. (2017). Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonaryarterial hypertension. Rijksuniversiteit Groningen.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 13-05-2021

https://research.rug.nl/en/publications/prognostic-factors-treatment-goals-and-clinical-endpoints-in-pediatric-pulmonary-arterial-hypertension(d905d8bf-542e-484a-8aa1-6f555ee2dfc1).html

Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterial hypertension

Mark-Jan Ploegstra

Mark-Jan Ploegstra

Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterial hypertension

Financial support for the publication of this thesis by the following companies / institutes is gratefully acknowledged:

Abbvie

Actelion Pharmaceuticals

Chipsoft

Graduate School of Medical Sciences

Heart Medical

Longfonds

Pfizer

Roche Diagnostics

Rijksuniversiteit Groningen

Salveo Medical

Scovas Medical

St. Jude Medical

Stichting PHA

Therabel Pharma

Universitair Medisch Centrum Groningen

Copyright © 2016, Mark-Jan Ploegstra

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by an means, without the written permission of the author.

ISBN: 978-94-6169-996-1

e-pub ISBN: 978-90-8559-243-3

Cover design, layout and printing: Optima Grafische Communicatie, Rotterdam, The Netherlands

Prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary

arterial hypertension

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de rector magnificus prof. dr. E. Sterken

en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op

woensdag 1 maart 2017 om 14.30 uur

door

Mark-Jan Ploegstra

geboren op 12 mei 1987 te Dongeradeel

PromotoresProf. dr. R.M.F. BergerProf. dr. H.L. Hillege

BeoordelingscommissieProf. dr. S.H. AbmanProf. dr. R. NaeijeProf. mr. dr. A.A.E. Verhagen Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged.

Paranimfen:

Mw. drs. W.M. PloegstraMr. J. Veninga

Van alles waarover u waakt, waak vooral over uw hart,het is de bron van uw leven. (Spreuken 4:23)

Chapter 1 General introduction and aims of this thesis 9

I. Introduction to pediatric pulmonary arterial hypertension 11

II. Current challenges in pediatric pulmonary arterial hypertension

18

Chapter 2 Current and advancing treatments for pulmonary arterial hypertension in childhoodExpert Review of Respiratory Medicine. 2014; 8: 615-628

31

Chapter 3 Prognostic factors in pediatric pulmonary arterial hypertension: A systematic review and meta-analysisInternational Journal of Cardiology. 2015; 184: 198-207

59

Chapter 4 Echocardiography in pediatric pulmonary arterial hypertension: early study on assessing disease severity and predicting outcomeCirculation Cardiovascular Imaging. 2014; 8: e000878

95

Chapter 5 Growth in children with pulmonary arterial hypertension: a longitudinal retrospective multi-registry studyThe Lancet Respiratory Medicine. 2016; 4: 281-290

119

Chapter 6 Serially measured uric acid levels predict disease severity and outcome in pediatric pulmonary arterial hypertensionAmerican Journal of Respiratory and Critical Care Medicine. 2017; 195

143

Chapter 7 Pulmonary arterial stiffness indices assessed by intravascular ultrasound in children with early pulmonary vascular disease: prediction of disease progression and mortality during 20-year follow-upEuropean Heart Journal - Cardiovascular Imaging. 2017; 18

163

Chapter 8 Identification of treatment goals in pediatric pulmonary arterial hypertension European Respiratory Journal. 2014; 44: 1616-1626

183

Contents

Chapter 9 Clinical worsening as composite study end point in pediatric pulmonary arterial hypertensionChest. 2015; 148: 655-666

207

Chapter 10 General discussion and future prospects 233

Appendices English summary 255

Nederlandse samenvatting 257

Dankwoord 263

About the author 267

List of publications 269

1

2

3

4

5

6

7

8

9

10

Chapter 1General introduction and aims of this thesis

General introduction and aims 11

1I. IntroduCtIon to PedIAtrIC PulMonAry ArterIAl hyPertensIon

Pulmonary hypertension

Under normal conditions, pulmonary arterial (PA) blood pressure is much lower than the systemic arterial pressure (SAP), despite the fact that the pulmonary circulation receives the same amount of ventricular output as the systemic circulation.1,2 Mean PA pressure (mPAP) normally ranges from 12-18 mmHg,1 about one-sixth of mean SAP. Key features of the pulmonary circulation, unique in the human body, are high-flow, low-pressure, high-compliance and low-resistance.2 Due to the high responsiveness to vasoactive mediators, the capacity to recruit unperfused vessels, and the high vascular compliance, the pulmonary vasculature has an enormous physiologic reserve to accommodate fluctuations in pulmonary blood flow, pulmonary vascular resistance (PVR), or both. The right ventricle (RV) is a crescentic- and triangularly shaped thin-walled flow generator, specifically adapted for the perfusion of this highly compliant low-pressure circulation.3 This design allows the RV to easily accommodate large changes in blood flow, but makes it less tolerable for increases in afterload.

When the physiological reserve of the pulmonary circulation is exceeded due to pathological circumstances causing a rise of PVR or pulmonary blood flow, pulmonary hypertension (PH) can result.4,5 This is a serious pathophysiological phenomenon indi-cating abnormally increased arterial pressure in the pulmonary vasculature. PH causes an afterload burden on the RV, which leads to RV failure.6 The progressive contractile dysfunction eventually leads to RV decompensation and death.7 At an international level, it has been agreed to define PH as mPAP ≥25 mmHg as assessed by right heart catheterization (RHC).8,9

The complex problem of PH can develop from several underlying diseases, which are categorized in “The World Symposium on Pulmonary Hypertension (WSPH) Clinical Classification” (Table 1).10 Disorders causing PH are categorized into 5 groups, based on similar pathological and hemodynamic characteristics and management approaches. WSPH Group 1 encompasses the various subgroups of pulmonary arterial hypertension (PAH). Groups 2-5 include PH secondary to: left heart disease (Group 2), lung disease / hypoxemia (Group 3), chronic thromboembolic disease (Group 4), and various condi-tions with unclear / multifactorial underlying mechanisms (Group 5). This thesis has a particular focus on pediatric PAH, as represented in WSPH Group 1.

12 Chapter 1

table 1. Updated Clinical Classification of Pulmonary Hypertension (Nice, 2013)

1. Pulmonary arterial hypertension (PAh)

1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug and toxin induced

1.4 Associated with:

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart diseases

1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

1’’ Persistent pulmonary hypertension of the newborn (PPhn)

2. Pulmonary hypertension due to left heart disease

2.1 Left ventricular systolic dysfunction

2.2 Left ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital / acquired left heart inflow / outflow tract obstruction and congenital cardiomyopathies

3. Pulmonary hypertension due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. Chronic thromboembolic pulmonary hypertension (CtePh)

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosingmediastinitis, chronic renal failure, segmental PH

BMPRII = Bone morphogenetic protein receptor type II, CAV1=caveolin-1, ENG=endoglin, HIV=human immuno-deficiency virus, PAH = pulmonary arterial hypertension. (Reproduced from [10])


1Pulmonary arterial hypertension

Within the context of PH, PAH can be regarded a distinct disease entity that merits spe-cial consideration. Unlike the other four WSPH Groups, PAH is a progressive disease of the precapillary pulmonary arteries, characterized by typical histopathological changes. Relief of the underlying conditions causing PH Groups 2-5 can result in regression of PH, which is generally not the case with PAH. In addition to medial hypertrophy and muscularization of arterioles, which also occurs in other forms of PH, concentric laminar intimal fibrosis and plexogenic lesions are specific hallmarks of PAH.11,12 The progressive arterial remodeling process in PAH causes increasing luminal obstruction and stiffening of the pulmonary vasculature, which leads to a rise in PVR, subsequently resulting in increased RV afterload, RV failure and death.

Although the morphological findings and presentation may be similar in patients with PAH, there is a wide variety in the underlying disease mechanisms, associated conditions, and treatment approaches. In view of this, the WSPH Clinical Classification of PH provides a further subcategorizing of this Group (Table 1). This detailed sub-categorization can roughly be summarized as the distinction between (1) PAH with an unknown or genetic cause, termed idiopathic or hereditary PAH (IPAH/HPAH), (2) PAH that occurs in association with congenital heart disease (APAH-CHD) and (3) PAH that occurs in association with other underlying conditions (APAH-other).

Idiopathic and heritable PAh

IPAH is a diagnosis per exclusionem, as this indicates the type of PAH with unknown origin. HPAH is diagnosed in case of an indisputable family history of PAH or when spe-cific PAH gene mutations have been identified. Familial cases of PAH have already been reported since 1954.13 In 2000, it was shown that in 80% of families with multiple cases of PAH, mutations of the bone morphogenic protein receptor type 2 (BMPR2) gene can be identified.14 Other mutations that have been brought into relation with the develop-ment of PAH include: ALK-1, ENG, TBX4, KCNQ3, EIF2AK4 and Caveolin-1.15–17

PAh associated with congenital heart disease

In APAH-CHD, long-standing increased pulmonary blood flow due to systemic-to-pulmonary shunting induces shear stress and circumferential stretch, which trigger the development of PAH. There are many underlying cardiac defects that can cause PAH, making APAH-CHD a very heterogeneous subgroup with regards to cardiac anatomy, physiology and the clinical presentation.18 Patients with post-tricuspid shunts such as caused by large ventricular septal defect or patent ductus arteriosus are more likely to develop advanced PAH than patients with pre-tricuspid shunts such as caused by atrial septal defects.19–22 Timely repair of the cardiac defect in a stage when the pulmonary vascular disease (PVD) is still reversible can prevent the progression to advanced PAH.

14 Chapter 1

As part of the WSPH Clinical Classification of PH, APAH-CHD is subdivided into four physiologic subtypes (Table 2). Type 1, Eisenmenger syndrome, represents the severe end-spectrum of APAH-CHD.23 In this condition, PVR becomes high enough to reverse the shunting across the defect, leading to pulmonary-to-systemic shunting with sub-sequent systemic desaturation. Although the cyanotic complications of Eisenmenger syndrome are associated with significant morbidity,24 the preserved cardiac output as a result of the pulmonary-to-systemic shunting explains the suggestions of a more favorable life-expectancy when compared to other types of PAH.25,26 Type 2 includes PAH patients with systemic-to-pulmonary shunts and normal resting saturation. Type 3 includes PAH patients that have small shunts that are not considered to cause severe PAH and are therefore regarded as “coincidental”. As the exact underlying PAH etiology of these patients is unknown, these patients are often considered and treated as IPAH patients. Type 4 includes patients that have unexpectedly developed PAH following suc-cessful correction of their cardiac shunt-defect. In contrast to the circumstances of type 1-3 where elevations of right sided pressures can be released at the level of the open cardiac defect, this is not possible when the defect has been closed, leading to a similar or even worse disease course and prognosis compared to IPAH.

Although the categorization of APAH-CHD into these four subtypes is useful and im-portant, the WSPH Clinical Classification of PH has several limitations when it comes to pulmonary vascular disease in the context of CHD. First, the four subtypes do certainly not represent homogeneous patient groups, as there still is considerable variety with re-gard to the location, size, repair status and age at repair of the defect, and the presence or absence of associated cardiac and extracardiac anomalies.18 Consequently, there is no such thing as a “typical patient” with APAH-CHD type 1, 2, 3 or 4. Second, there are CHD patients that cannot be fit in these categories, such as patients with transposition of the great arteries who have undergone a neonatal switch operation that subsequently developed PAH. Third, it has to be recognized that in the pediatric age-group, so-called

table 2. Clinical Classification of Pulmonary Arterial Hypertension As-sociated With Congenital Heart Disease

1. Eisenmenger Syndrome

2. Left to right shunts

Operable

Inoperable

3. PAH with co-incidental CHD

4. Post-operative PAH

PAH = pulmonary arterial hypertension, CHD = congenital heart disease. (Reproduced from [10])


1“flow-PAH” occurs frequently in the setting of uncorrected congenital heart defects and represents early reversible stages of PVD associated with shunts, that may resolve after correction of the cardiac defect.

PAh associated with other conditions

PAH can also occur in association with connective tissue diseases, such as systemic sclerosis and systemic lupus erythematosus. These autoimmune diseases cause fibros-ing of pulmonary vascular tissue, leading to vascular remodeling and increases in PVR. Although not very common in children, connective tissue disease is one of the main known causes of PAH in adults.27 Other conditions that can cause PAH are human immu-nodeficiency virus infection, portal hypertension and schistosomiasis. Also, a significant number of drugs and toxins have been described that are potentially associated with the development of PAH, such as aminorex and fenfluramine.28

Pulmonary veno-occlusive disease, pulmonary capillary hemangiomatosis and persistent pulmonary hypertension of the newborn are classified within WSPH group 1, but have remarkable differences in presentation and clinical course when compared to all other forms of PAH. To account for these differences in the clinical classification, these diseases are designated as separate 1’ and 1” subcategories.

Children are not small adults

Despite the same underlying disease mechanisms, there are important differences between adults and children with PAH. Pediatric PAH has specific features that preclude a simple extrapolation of adult data to a child with PAH. In children with PAH, pulmonary vascular injury occurs during susceptible periods of growth and development of the car-diopulmonary system.29 Also, important pathobiological contributing factors uniquely relate to the pediatric age group, such as perinatal hypoxia and hemodynamic stress conditions during the transition from fetal to postnatal life.

Epidemiological studies have shown that there are important differences regard-ing the distribution of etiologies between children and adults. A comparison of the adult “Registry to evaluate early and long-term pulmonary arterial hypertension disease management” (REVEAL) and the international pediatric “Tracking Outcomes and Prac-tice in Pediatric PH” (TOPP) registry shows that the proportion of IPAH/HPAH is similar, but that APAH-CHD is more frequent in children, whereas APAH-other is rare in children compared to adults (Figure 1).27,30 An explanation for the substantially larger proportion of APAH-CHD in children is the fact that pediatric PAH encompasses a broad spectrum of patients with cardiac defects, including complex heart disease, that have not always sur-vived into adulthood. APAH-CHD is also more heterogeneous in children compared to adults, and includes early disease stages of PAH where the pulmonary vascular disease can still be reversed after correction of the shunt defect.

16 Chapter 1

Children with PAH further differ from adults regarding their clinical presentation and disease course. Although dyspnea on exertion and fatigue are the most frequent presenting symptoms in both adults and children, syncope occurs twice as often in children.30 Comorbidities such as lung diseases and chromosomal and other (extra-cardiac) congenital anomalies are frequent in children with PAH, complicating diagnosis and clinical classification. Children with PAH can deteriorate very quickly and survival rates remain unsatisfactory, despite the introduction of PAH targeted drugs.26 In both diagnosis and management, the physiology of a growing and developing child needs to be taken into account.

epidemiology and prognosis

Pediatric PAH is a rare condition. In the Netherlands, Van Loon et al. have reported an-nual incidence rates of 0.7 cases of IPAH/HPAH and 2.2 cases of APAH-CHD per million children. Prevalence rates were 4.4 cases of IPAH/HPAH and 15.6 cases of APAH-CHD per million.26 In the United Kingdom, incidence and prevalence of pediatric IPAH have been estimated to be 0.48 and 2.2 cases per million, respectively.31

Before the era of PAH-targeted therapies, children with IPAH died within 1 to 2 years after diagnosis.32 Figure 2 shows survival of children from the Dutch National

12%

39%49%

b

dfe

40% 53%

7%a b c f

IPAH/HPAH APAH-other:a. CTD c. PVOD / PCH e. HIV b. Portal hypertension d. drugs / toxins f. OtherAPAH-CHD

a

Adult PAH – REVEAL registry Pediatric PAH – TOPP registry

Figure 1. Comparison of etiology in adult and pediatric pulmonary arterial hypertension. REVEAL = regis-try to evaluate early and long-term pulmonary arterial hypertension disease management, TOPP = track-ing outcomes and practice in pediatric pulmonary hypertension, IPAH = idiopathic pulmonary arterial hypertension, HPAH = hereditary pulmonary arterial hypertension, APAH = associated pulmonary arterial hypertension, CHD = congenital heart disease, CTD = connective tissue disease, PVOD = pulmonary veno-occlusive disease, PCH = pulmonary capillary hemangiomatosis, HIV = human immunodeficiency virus. (Percentages extracted from [27] and [30])


1Network for Pediatric PH that were started on PAH targeted therapy between 2000 and 2008, together with predicted survival based on the historical National Institutes of Health registry equation.33 The comparison suggests that children with PAH have benefited from the availability of PAH targeted therapies, but also demonstrates that mortality rates are still unsatisfactory. Common causes of death are RV failure, hemopty-sis, sudden death and arrhythmias.34

Clinical disease manifestation

In the initial disease stage of PAH, dyspnea on exertion and fatigue are the most fre-quently reported symptoms in children with PAH. These symptoms are non-specific and often mimic more common respiratory conditions such as asthma, which may delay diagnosis. The clear relationship with activity reflects the inability of the RV to increase cardiac output for the higher demand in workload. Chest pain as a result of ischemia can develop due to insufficient systolic right coronary artery flow in the setting of RV hy-pertrophy.35 Hemoptysis, assumed to result from rupture of frail hypertrophic bronchial arteries or from dilated pulmonary arteries,36 is not uncommon in children with PAH and has been shown to be associated with poor outcome.37 Syncope is a frequent presenting symptom specifically in children without shunts, and is the result of insufficient cardiac output. In the specific setting of Eisenmenger syndrome with systemic desaturation due to pulmonary-to-systemic shunts, cyanosis is very common.23 When the disease progresses, symptoms of RV failure can emerge, including dyspnea in rest, peripheral edema and ascites. Atrial and ventricular arrhythmias can occur and can lead to sudden

100

80

60

40

20

0

Cum

ulat

ive

surv

ival

(%)

Time from second-generation drug availability (yrs)0 2 4 6 8 10

42 27 13

Observed survival (n=45)Predicted survival using NIH registry equation

Figure 2. Observed current era survival of children with pulmonary arterial hypertension, compared to predicted survival using historical National Institutes of Health (NIH) registry equation. Dotted lines repre-sent 95% confidence interval. (Reproduced from [33])

18 Chapter 1

death. Clinical evidence of RV failure is a hallmark of the end stage of the disease and is associated with a poor prognosis.27

Clinical management

PAH is not curable with the currently available therapies. Treatment of PAH consists of supportive therapies and PAH-targeted therapies.28 Supportive therapies include diuretics, supplemental oxygen and anticoagulation. PAH-targeted therapies are subdivided in “first generation” and “second generation” agents, on the basis of their historical availability: calcium channel blockers are first generation agents and are of benefit when prescribed in high doses in patients who have shown an acute response to vasoreactivity testing during cardiac catheterization. Second generation agents have become available during the past two decades, and do not only have vasodila-tor properties but are believed to also improve pulmonary vascular remodeling. These agents target the following three molecular pathways: the nitric oxide, prostacyclin and endothelin-1 pathway. Surgical interventions that are carried out in children that do not improve despite maximal therapy include atrial septostomy, Potts shunt, and (heart-)lung transplantation. As an extension to the introduction of this thesis, the treatment of pediatric PAH is reviewed in detail in Chapter 2.

Current treatment strategies in pediatric PAH are predominantly based on the ex-perience and consensus of clinicians and extrapolation of evidence from adult studies. Controlled trials in pediatric PAH are almost non-existent, hampering an evidence-based treatment for pediatric PAH. An important reason is the lack of validated clinical end-points. In view of the improved survival rates in recent observational studies, pediatric PAH seems to have benefited from the PAH-targeted drugs that have been tested in adults. However, morbidity and mortality remain unsatisfactory.

II. Current ChAllenges In PedIAtrIC PAh

In the current era with increased availability of PAH-targeted drugs, one of the major challenges for clinicians is to tailor optimal treatment regimens for the individual pa-tient with PAH.38,39 Multiple drugs targeting different pathways are now available, but there is a paucity of data on how and when the available treatments should be used. Challenging questions are which type of drugs to start in different patient groups, or when it is better to consider upfront combination therapy targeting multiple pathways at the same time. Risk stratification is essential to allow tailoring of treatment, but there is a lack of evidence-based prognostic factors. Also, important challenges are the evaluation of treatment success, the appropriate timing of therapy escalation during follow-up, and adequate timing of surgical interventions such as Potts shunts or (heart-)


1lung transplantation. A standardized treatment strategy is much desired, but requires the identification of clinically and prognostically relevant treatment goals. The available drugs are barely tested in children as pediatric clinical trial design is challenged by a lack of appropriate clinical endpoints.

Hence, prognostic factors are required for risk stratification, treatment goals are required for defining treatment strategies, and clinical endpoints are required for the design of clinical trials. In the following sections, these three topics are introduced.

Prognostic factors for risk stratification

Children with PAH present at different stages of disease and at different levels of risk for disease progression and mortality. It appears to make sense to choose more aggressive treatment regimens (e.g. early intravenous therapy or combination therapy) for sicker and higher risk children. Thus, risk stratification is an essential first step, and this requires clinical measurements that are valid prognosticators of disease outcome.

The most widely used, but not all validated, clinical measurements in adult and pediatric PAH include the following. Functional capacity can be evaluated by World Health Organization (WHO) functional class (a scale of symptom severity and degree of functional limitation), 6-minute walk distance (6MWD) and cardiopulmonary exercise testing.27,40 These are established predictors of outcome in adults with PAH, but cur-rently available data in children are scarce and contradictory.33,41Biomarkers suggested to be associated with mortality in PAH include serum levels of N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) and uric acid.42–46 Both adult and pediatric studies have shown correlations of these biomarkers with outcome. Imaging modalities, including echocardiography and cardiac magnetic resonance imaging, have only been studied anecdotally and incompletely in pediatric PAH.47–49 However, in adults with PAH, imaging derived parameters including right atrial and RV dimensions, eccentricity index, RV frac-tional area change, RV myocardial performance index, RV dyssynchrony, the presence or absence of pericardial effusion, RV ejection fraction, and tricuspid annular plane systolic excursion have all been suggested to correlate with outcome.27,50–56Cardiac catheteriza-tion is performed to define PAH at time of diagnosis, and yields several hemodynamic characteristics with prognostic value that are currently used to tailor initial treatment. In both adults and children, among other hemodynamic measurements, mean right atrial pressure, indexed PVR (PVRi) and cardiac index have been shown to correlate with mortality in multiple observational studies.27,33,57–59 Assessment of the response to vasoreactivity testing is crucial, as responders are at lower risk and can be treated with high-dose calcium channel blockers.60 There is a need for additional diagnostic and prognostic tools that can complement hemodynamics, and that can provide more insight in the actual state of the pulmonary vasculature. Measurements that take ac-count of the pulsatile characteristics of the pulmonary vasculature, such as PA stiffness

20 Chapter 1

indices,61,62 may prove of added value in this respect, as these are not incorporated in conventional hemodynamic measurements such as PVRi and mPAP (these assume steady flow, whereas the pulmonary vasculature is a pulsatile flow system).63

With regard to risk stratification, there are specific unmet needs for the field of pediatric PAH. Studies on prognostic factors in pediatric PAH are available but limited, as these are mostly based on relatively small patient series and there are contradictory findings between the cohorts. When considering the utility of these reported prognostic factors for risk stratification in pediatric PAH, it is of utmost importance to evaluate the available literature as a whole, and to evaluate potential causes of the discrepancies. In addition, specific clinical measurements that are promising for risk stratification in children (e.g. based on adult data), have not yet been sufficiently studied in pediatric PAH. For example, the prognostic value of echocardiography and serum biomarkers requires further investigation.

To allow for clinical monitoring of the disease over time, there is a need for clinical measurements that are not only informative at time of diagnosis or time of treatment initiation, but also during follow-up. In longitudinal studies in adults with PAH, some of the aforementioned clinical measurements have been shown to remain prognostic during follow-up (e.g. hemodynamics, 6MWD).64 This supports the usefulness of such measurements for monitoring a patient over time. In children, however, there is a lack of data regarding the prognostic value of repeated measurements. Reliable disease mark-ers fluctuate according to the severity of the disease. Therefore, clinical measurements that are candidates for monitoring a child with PAH over time, require evaluation in a longitudinal fashion.

An interesting topic that exclusively applies to PAH in children, is the influence of the disease on growth. Impaired growth is a determinant of disease severity and outcome in several severe pediatric diseases. Previous data have suggested that height is also impaired in children with PAH and that Z-scores for weight and height correlate with outcome.31 These findings provide clues that also growth could have a role in risk stratification in pediatric PAH. However, to allow adequate interpretation of growth measurements, the degree of growth impairment, trends over time, subgroups at risk for growth impairment, and associated determinants need further elucidation before measurements of growth can become useful in the context of risk stratification and tailoring treatment.

With respect to risk stratification, another important topic in PVD that almost exclusively applies to children is the assessment of disease reversibility.65 In the setting of uncorrected congenital heart defects, children may present with early stages of PVD in which the disease may still be reversible. To guide clinical-decision making in these early stages, clinical measurements are needed that can predict whether the disease will reverse or progress to advanced PAH in the future. Accurate prediction of disease


1progression is important, as shunt closure in irreversible disease stages has deleterious effects.25,26

treatment goals to define treatment strategies

Previously, patients with PAH were followed according to clinical parameters, and therapy was escalated in case of clinical deterioration. As PAH can develop very progres-sively, this conventional “waiting for clinical worsening” often leads to lagging behind events. A more aggressive goal-oriented treatment strategy is now recommended, in which clinically relevant goals are predefined.66,67 When treatment goals are not met during follow-up after initiation of first treatment, more aggressive treatment regimens are installed. Therapy can be escalated by adding other PAH-targeted treatments, and intravenous therapy may be considered in an earlier stage. When treatment goals are still not met despite intensive therapy regimens, surgical options such as Potts shunt or (heart-)lung transplantation are considered early.

In pediatric PAH, the design of such a goal oriented treatment strategy is ham-pered by the lack of validated treatment goals.68 The first step in defining such goals, is the identification of clinical measurements that are either directly clinically meaningful outcomes (i.e., how a patient feels, functions or survives),69 or are surrogates for such clinically meaningful outcomes.70,71 For example, the experience of PAH symptoms like dyspnea, chest pain and syncope are directly clinically meaningful, thus striving for improvement of these symptoms is a valid treatment goal.

Improving such symptoms does not necessarily lead to prolonged longevity. When improving survival is part of the overall treatment objective, then clinical mea-surements have to be identified that qualify as surrogates for mortality; improving such measurements using treatment may potentially lead to improved survival.

A strong correlation with outcome, even when this correlation persists during follow-up, does not necessarily indicate surrogacy for survival. In addition to a strong correlation with outcome, there are two additional basic criteria for surrogacy: (1) the clinical measurement must be modifiable by treatment and (2) treatment-induced changes in the clinical measurement correlate with outcome also.70,71 As longitudinal studies in both pediatric and adult PAH are scarce, there is a lack of evidence regarding the prognostic value of treatment-induced changes in clinical measurements, which hampers the definition of valid treatment goals.

endpoints for clinical trials

Most of the drugs that are currently being used in the treatment of pediatric PAH, have not yet been tested in randomized clinical trials (RCTs) in the pediatric age group. A crucial problem is the lack of appropriate clinical endpoints to evaluate treatment ef-ficacy, which hamper the design of RCTs.38,39,72

22 Chapter 1

Figure 3 provides an overview of endpoints that are used in adult trials in PH.73 The 6MWD has most frequently been used in the pivotal trials in adult PAH. However, 6MWD is not reliable in young children or in children with mental or physical disabilities, and depends on motivational issues. Therefore 6MWD is not feasible as a pediatric endpoint. Hemodynamics are also not attractive in children, in view of the associated risks of this invasive procedure and the need for sedation or general anesthesia.74 Clinical measure-ments that are considered as clinical endpoints need evaluation regarding the way in which they are directly or indirectly (a surrogate for) clinically meaningful outcomes.

“Clinical worsening” (CW) is a patient-centered composite endpoint consisting of clinically meaningful events that indicate clinical deterioration.75 CW consists of a combi-nation of hard unambiguous events such as death and (heart-)lung transplantation, and softer events, including hospitalizations, need for additional therapy, and worsening of function. This combined morbidity/mortality endpoint is gaining increasing interest in PAH and is now being used as primary or secondary endpoint in adult RCTs.76,77 CW is applicable throughout the full pediatric age range, but requires a comprehensive evalu-ation before it can qualify as a pediatric study endpoint. Essential information that is not yet available includes the incidence of the endpoint events of CW, the relation of the soft endpoint events with mortality, and the timing of the endpoint events throughout the disease course in pediatric PAH.

Number of Trials0 50 100

PFTLaboratory values

CPEX6MWT

QOL indicesFunctional status

Cardiac MRIEchoRHC

Primary endpointSecondary endpoint

Figure 3. Outcome measures as endpoints in PH trials, 1995-2013. Number of trials (from total N = 126 identified in systematic literature review) reporting each outcome measure as a primary or secondary end-point. RHC = right heart catheterization, MRI = magnetic resonance imaging, QOL = quality of life, 6MWT = 6-minute walk test, CPEX = cardiopulmonary exercise testing, PFT = pulmonary function test. (Reproduced from [73])


1AIMs oF thIs thesIs

To address the unsatisfactory outcome in children with PAH, risk stratification, treatment strategies and clinical trial design should be improved. Therefore, the aims of this thesis were:– To identify prognostic factors, as these are essential for risk stratification and tailoring

of treatment. The identification of such prognostic factors starts with an overview of what has already been reported. We aim to evaluate the prognostic value of clini-cal measurements that have the potential to serve as prognostic factors, including echocardiography, a child’s growth, serum biomarkers, and PA stiffness indices.

– To identify treatment goals, as these are required for the design of pediatric goal-oriented treatment strategies. Therefore, we aim to investigate the prognostic value of treatment-induced changes in prognostic factors, and to identify prognostically distinctive threshold values.

– To identify clinical endpoints, as these are a prerequisite for the design of pediatric clinical trials. We aim to study clinical worsening as a candidate composite endpoint for pediatric PAH, including the evaluation of the incidence, timing and prognostic value of its endpoint components.

outlIne oF thesIs

In Chapter 2, current and advancing treatments for PAH are reviewed, as an extension to this general introduction. Potential treatment goals and strategies to guide treatment are also discussed.

In Chapter 3, currently available evidence regarding prognostic factors in pediatric PAH is systematically reviewed and combined. The available pediatric reports are scarce and sometimes contradictory, thus it is of great importance to identify, appraise, synthesize and combine the currently available data on prognostic factors in pediatric PAH. Ex-tracted data from the identified reports are combined using meta-analysis.

In Chapter 4, the potential of echocardiography in assessing disease severity and prog-nosis in children with PAH is evaluated. This widely used imaging modality is suited ideally to repeat throughout the course of the disease, but is insufficiently studied in pediatric PAH. Correlations are described between multiple transthoracic echocardiog-raphy variables and markers of disease severity and outcome.

24 Chapter 1

In Chapter 5, growth impairment in pediatric PAH is evaluated in a large longitudinal multi-registry study, together with the identification of its associated determinants. Growth is an easy and globally available indicator of a child’s health, but it is unclear how to interpret growth and its trends over time in an individual with PAH. In this chapter, the growth impairment in pediatric PAH is quantified and subgroups at risk and associated determinants are identified.

In Chapter 6, the value of serum uric acid as a prognostic biomarker is evaluated in children with PAH. Single measurements of uric acid have been shown to correlate with outcome in earlier studies, but the prognostic value of serially measured levels needs evaluation, including the clinical value of an incline over time. Associations with disease severity markers and mortality throughout the full course of the disease are described in a longitudinal fashion, and trends over time are evaluated.

In Chapter 7, a 20-year outcome study is reported that focuses not only on advanced PAH, but also on the earlier stages of PVD. In this chapter, the value of PA stiffness indices assessed by intravascular ultrasound are evaluated, with regards to prediction of future disease progression to advanced PAH and long-term mortality.

In Chapter 8, potential treatment goals in children with PAH are identified and evalu-ated, as a step towards the design of a goal oriented treatment strategy. The prognostic value of treatment-induced changes are assessed, and optimal prognostic thresholds are estimated.

In Chapter 9, clinical worsening is studied as a candidate composite study endpoint for future clinical trials in pediatric PAH. The usefulness of clinical worsening is evaluated by assessing the event incidence and prognostic value of each separate endpoint compo-nent, and of the composite clinical worsening endpoint.

In Chapter 10, a general discussion is provided together with future prospects, and the results of this thesis are summarized as part of the appendices.


1reFerenCes

1. Ehrsam RE, Perruchoud A, Oberholzer M, Burkart F, Herzog H. Influence of age on pulmonary haemodynamics at rest and during supine exercise. Clin Sci (Lond). 1983;65:653–60.

2. Naeije R. Physiology of the Pulmonary Circulation and the Right Heart. Curr Hypertens Rep. 2013;15:623–631.

3. Haddad F, Hunt SA, Rosenthal DN, Murphy DJ. Right Ventricular Function in Cardiovascular Disease, Part I: Anatomy, Physiology, Aging, and Functional Assessment of the Right Ventricle. Circulation. 2008;117:1436–1448.

4. Romberg E. Über sklerose der lungen arterie. Dtsch Arch Klin Med. 1891;48:197–206. 5. van Wolferen SA, Grünberg K, Vonk Noordegraaf A. Diagnosis and management of pulmonary

hypertension over the past 100 years. Respir Med. 2007;101:389–98. 6. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J,

Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62:D22–33.

7. Greyson CR. Pathophysiology of right ventricular failure. Crit Care Med. 2008;36:S57–65. 8. Forssmann W. Die Sondierung des Rechten Herzens. Klin Wochenschr. 1929;8:2085–2087. 9. Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D. Catheterization of the heart in

man with use of a flow-directed balloon-tipped catheter. N Engl J Med. 1970;283:447–51. 10. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA,

Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–41.

11. Dickinson MG, Bartelds B, Borgdorff MAJ, Berger RMF. The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models. Am J Physiol Lung Cell Mol Physiol. 2013;305:L1–14.

12. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2008;118:2372–2379.

13. Dresdale DT, Michtom RJ, Schultz M. Recent studies in primary pulmonary hypertension, in-cluding pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med. 1954;30:195–207.

14. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737–44.

15. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA, Soubrier F, Trembath RC, Chung WK. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S32–42.

16. Soubrier F, Chung WK, Machado R, Grünig E, Aldred M, Geraci M, Loyd JE, Elliott CG, Trembath RC, Newman JH, Humbert M. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D13–21.

17. Austin ED, Ma L, LeDuc C, Rosenzweig EB, Borczuk A, Phillips JA, Palomero T, Sumazin P, Kim HR, Talati MH, West J, Loyd JE, Chung WK. Whole exome sequencing to identify a novel gene (Caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336–343.

18. van Albada ME, Berger RMF. Pulmonary arterial hypertension in congenital cardiac disease – the need for refinement of the Evian-Venice classification. Cardiol Young. 2008;18:10–7.

26 Chapter 1

19. Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilén U, Kaemmerer H, Moons P, Meijboom F, Popelová J, Laforest V, Hirsch R, Daliento L, Thaulow E, Mulder B. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J. 2005;26:2325–33.

20. Engelfriet PM, Duffels MGJ, Möller T, Boersma E, Tijssen JGP, Thaulow E, Gatzoulis MA, Mulder BJM. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart. 2007;93:682–7.

21. Duffels MGJ, Engelfriet PM, Berger RMF, van Loon RLE, Hoendermis E, Vriend JWJ, van der Velde ET, Bresser P, Mulder BJM. Pulmonary arterial hypertension in congenital heart disease: an epide-miologic perspective from a Dutch registry. Int J Cardiol. 2007;120:198–204.

22. Gatzoulis MA, Alonso-Gonzalez R, Beghetti M. Pulmonary arterial hypertension in paediatric and adult patients with congenital heart disease. Eur Respir Rev. 2009;18:154–61.

23. Wood P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J. 1958;2:701–9.

24. Cordina RL, Celermajer DS. Chronic cyanosis and vascular function: implications for patients with cyanotic congenital heart disease. 2010;242–253.

25. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001-2006. Heart. 2009;95:312–7.

26. van Loon RLE, Roofthooft MTR, Hillege HL, ten Harkel ADJ, van Osch-Gevers M, Delhaas T, Kapusta L, Strengers JLM, Rammeloo L, Clur S-AB, Mulder BJM, Berger RMF. Pediatric pulmonary hyper-tension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124:1755–64.

27. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hyperten-sion: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–72.

28. McLaughlin V V, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65:1976–97.

29. Abman SH. Pulmonary hypertension in children: a historical overview. Pediatr Crit Care Med. 2010;11:S4–S9.

30. Berger RMF, Beghetti M, Humpl T, Raskob GE, Ivy DD, Jing Z-C, Bonnet D, Schulze-Neick I, Barst RJ. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. 2012;379:537–46.

31. Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96:1401–6.

32. Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thébaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL, American Heart Association Council on Cardiopulmonary, Critical Care, Peri-operative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young, Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgety and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037–99.

33. van Loon RLE, Roofthooft MTR, Delhaas T, van Osch-Gevers M, ten Harkel ADJ, Strengers JLM, Backx A, Hillege HL, Berger RMF. Outcome of pediatric patients with pulmonary arterial hyperten-sion in the era of new medical therapies. Am J Cardiol. 2010;106:117–24.


1 34. Tonelli AR, Arelli V, Minai OA, Newman J, Bair N, Heresi GA, Dweik RA. Causes and circumstances

of death in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188:365–9. 35. Van Wolferen SA, Marcus JT, Westerhof N, Spreeuwenberg MD, Marques KMJ, Bronzwaer JGF,

Henkens IR, Gan CTJ, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Right coronary artery flow impairment in patients with pulmonary hypertension. Eur Heart J. 2008;29:120–127.

36. Tio D, Leter E, Boerrigter B, Boonstra A, Vonk-Noordegraaf A, Bogaard HJ. Risk Factors for Hemop-tysis in Idiopathic and Hereditary Pulmonary Arterial Hypertension. PLoS One. 2013;8:1–7.

37. Roofthooft MTR, Douwes JM, Vrijlandt EJLE, Berger RMF. Frequency and prognostic significance of hemoptysis in pediatric pulmonary arterial hypertension. Am J Cardiol. 2013;112:1505–1509.

38. Beghetti M, Berger RMF. The challenges in paediatric pulmonary arterial hypertension. Eur Respir Rev. 2014;23:498–504.

39. Hopper RK, Abman SH, Ivy DD. Persistent Challenges in Pediatric Pulmonary Hypertension. Chest. 2016;150:226–36.

40. Oudiz RJ, Midde R, Hovenesyan A, Sun X-G, Roveran G, Hansen JE, Wasserman K. Usefulness of right-to-left shunting and poor exercise gas exchange for predicting prognosis in patients with pulmonary arterial hypertension. Am J Cardiol. 2010;105:1186–91.

41. Lammers AE, Munnery E, Hislop AA, Haworth SG. Heart rate variability predicts outcome in children with pulmonary arterial hypertension. Int J Cardiol. 2010;142:159–65.

42. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865–870.

43. Bendayan D, Shitrit D, Ygla M, Huerta M, Fink G, Kramer MR. Hyperuricemia as a prognostic factor in pulmonary arterial hypertension. Respir Med. 2003;97:130–133.

44. Van Albada ME, Loot FG, Fokkema R, Roofthooft MTR, Berger RMF. Biological serum markers in the management of pediatric pulmonary arterial hypertension. Pediatr Res. 2008;63:321–7.

45. Bernus A, Wagner BD, Accurso F, Doran A, Kaess H, Ivy DD. Brain natriuretic peptide levels in managing pediatric patients with pulmonary arterial hypertension. Chest. 2009;135:745–51.

46. Wagner BD, Takatsuki S, Accurso FJ, Ivy DD. Evaluation of circulating proteins and hemodynam-ics towards predicting mortality in children with pulmonary arterial hypertension. PLoS One. 2013;8:e80235.

47. Alkon J, Humpl T, Manlhiot C, McCrindle BW, Reyes JT, Friedberg MK. Usefulness of the right ven-tricular systolic to diastolic duration ratio to predict functional capacity and survival in children with pulmonary arterial hypertension. Am J Cardiol. 2010;106:430–6.

48. Moledina S, Pandya B, Bartsota M, Mortensen KH, McMillan M, Quyam S, Taylor AM, Haworth SG, Schulze-Neick I, Muthurangu V. Prognostic significance of cardiac magnetic resonance imaging in children with pulmonary hypertension. Circ Cardiovasc Imaging. 2013;6:407–14.

49. Kassem E, Humpl T, Friedberg MK. Prognostic significance of 2-dimensional, M-mode, and Dop-pler echo indices of right ventricular function in children with pulmonary arterial hypertension. Am Heart J. 2013;165:1024–31.

50. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, Chamera E, Corretti MC, Champion HC, Abraham TP, Girgis RE, Hassoun PM. Tricuspid Annular Displacement Predicts Survival in Pulmonary Hypertension. Am J Respir Crit Care Med. 2006;174:1034–1041.

51. Bustamante-Labarta M, Perrone S, De La Fuente RL, Stutzbach P, De La Hoz RP, Torino A, Favaloro R. Right atrial size and tricuspid regurgitation severity predict mortality or transplantation in primary pulmonary hypertension. J Am Soc Echocardiogr. 2002;15:1160–1164.

28 Chapter 1

52. Ghio S, Pazzano AS, Klersy C, Scelsi L, Raineri C, Camporotondo R, D’Armini A, Visconti LO. Clini-cal and prognostic relevance of echocardiographic evaluation of right ventricular geometry in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol. 2011;107:628–32.

53. Yeo TC, Dujardin KS, Tei C, Mahoney DW, McGoon MD, Seward JB. Value of a Doppler-derived in-dex combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol. 1998;81:1157–1161.

54. Grapsa I, Pavlopoulos H, Dawson D, Gibbs JS, Nihoyannopoulos P. Retrospective study of pulmo-nary hypertensive patients: is right ventricular myocardial performance index a vital prognostic factor? Hellenic J Cardiol. 2007;48:152–160.

55. Sachdev A, Villarraga HR, Frantz RP, McGoon MD, Hsiao JF, Maalouf JF, Ammash NM, McCully RB, Miller FA, Pellikka PA, Oh JK, Kane GC. Right ventricular strain for prediction of survival in patients with pulmonary arterial hypertension. Chest. 2011;139:1299–1309.

56. Lopez-Candales A, Dohi K, Rajagopalan N, Suffoletto M, Murali S, Gorcsan J, Edelman K. Right ventricular dyssynchrony in patients with pulmonary hypertension is associated with disease severity and functional class. Cardiovasc Ultrasound. 2005;3:23.

57. Clabby ML, Canter CE, Moller JH, Bridges ND. Hemodynamic data and survival in children with pulmonary hypertension. J Am Coll Cardiol. 1997;30:554–60.

58. Nakayama T, Shimada H, Takatsuki S, Hoshida H, Ishikita T, Matsuura H, Saji T. Efficacy and limitations of continuous intravenous epoprostenol therapy for idiopathic pulmonary arterial hypertension in Japanese children. Circ J. 2007;71:1785–90.

59. Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arte-rial hypertension disease management. Circulation. 2012;125:113–22.

60. Barst RJ, Maislin G, Fishman a. P. Vasodilator Therapy for Primary Pulmonary Hypertension in Children. Circulation. 1999;99:1197–1208.

61. Hunter KS, Lammers SR, Shandas R. Pulmonary Vascular Stiffness: Measurement, Modeling, and Implications in Normal and Hypertensive Pulmonary Circulations. Compr Physiol. 2011;1:1413–1435.

62. Tian L, Chesler N. In vivo and in vitro measurements of pulmonary arterial stiffness: A brief review. Pulm Circ. 2012;2:505–517.

63. Naeije R. Pulmonary vascular resistance. A meaningless variable? Intensive Care Med. 2003;29:526–9.

64. Nickel N, Golpon H, Greer M, Knudsen L, Olsson K, Westerkamp V, Welte T, Hoeper MM. The prog-nostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hyperten-sion. Eur Respir J. 2012;39:589–596.

65. Wagenvoort CA. Morphological substrate for the reversibility and irreversibility of pulmonary hypertension. 1988;9:7–12.

66. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 2005;26:858–863.

67. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noor-degraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo Badano L, Albert Barberà J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol Ç, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GYH, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel M-P, Rigau D, Rosenkranz S, Völler H, Luis Zamorano J.


12015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.

68. Ivy DD, Abman SH, Barst RJ, Berger RMF, Bonnet D, Fleming TR, Haworth SG, Raj JU, Rosenzweig EB, Schulze Neick I, Steinhorn RH, Beghetti M. Pediatric pulmonary hypertension. J Am Coll Car-diol. 2013;62:D117–26.

69. Temple R. A regulatory authority’s opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, editors. Clinical Measurement in Drug Evaluation. New York, NY: John Wiley; 1995. p. 790.

70. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605–613.

71. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med. 2012;31:2973–84.

72. Adatia I, Haworth SG, Wegner M, Barst RJ, Ivy D, Stenmark KR, Karkowsky A, Rosenzweig E, Aguilar C. Clinical trials in neonates and children: Report of the pulmonary hypertension academic research consortium pediatric advisory committee. Pulm Circ. 2013;3:252–66.

73. Parikh KS, Rajagopal S, Arges K, Ahmad T, Sivak J, Kaul P, Shah SH, Tapson V, Velazquez EJ, Douglas PS, Samad Z. Use of outcome measures in pulmonary hypertension clinical trials. Am Heart J. 2015;170:419–429.

74. Beghetti M, Berger RM, Schulze-Neick I, Day RW, Pulido T, Feinstein J, Barst RJ, Humpl T, Investiga-tors TR. Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice. Eur Respir J. 2013;42:689–700.

75. Frost AE, Badesch DB, Miller DP, Benza RL, Meltzer LA, McGoon MD. Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL Registry analysis. Chest. 2013;144:1521–1529.

76. McGlinchey N, Peacock AJ. Endpoints in PAH clinical trials in the era of combination therapy: How do we decide whether something is working without going bankrupt? Drug Discov Today. 2014;19:1236–1240.

77. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani H-A, Jansa P, Jing Z-C, Le Brun F-O, Mehta S, Mittelholzer CM, Perchenet L, Sastry BKS, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G; SERAPHIN Investigators. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013;369:809–818.

1

2

3

4

5

6

7

8

9

10

Chapter 2Current and advancing treatments for pulmonary arterial hypertension in childhood

Willemijn M.H. ZijlstraMark-Jan PloegstraRolf M.F. Berger

Expert Review of Respiratory Medicine 2014: 8: 615-28

32 Chapter 2

ABstrACt

Pulmonary arterial hypertension (PAH) is a severe and progressive intrinsic disease of the precapillary lung vasculature. Since the introduction of PAH-targeted drugs, survival of PAH patients seems to have improved. Randomized controlled trials have led to evidence-based guidelines to direct treatment in adults. However, since disease characteristics differ between adults and children, it is hazardous to simply extrapolate these guidelines to children. Moreover, pediatric data on treatment strategies and how to assess treatment response remain virtually absent. Optimal treatment strategies are highly needed to guide therapy and improve survival in children with PAH. This review provides an overview of currently available treatments of PAH and the limited efficacy and safety data in children (with the exclusion of perinatal pulmonary vascular diseases, as persistent pulmonary hypertension of the newborn). We also discuss potential treat-ment goals and how the available data can be translated into treatment strategies in pediatric PAH.

Treatment of PAH in childhood 33

2

IntroduCtIon

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg.1 PH can be classified into five subgroups, with PH group 1 being pulmo-nary arterial hypertension (PAH). In contrast to the other four subgroups of PH, PAH is a progressive intrinsic disease of the precapillary pulmonary vessels characterized by unique vascular neointimal lesions.2 These result in elevation of the mPAP and pulmo-nary vascular resistance (PVR) leading to right-sided heart failure and ultimately death. PAH has a poor prognosis with a median survival of 2.8 years in untreated adults.3 Sur-vival in children is believed to be even worse. Also, PAH is a rare disease, with estimated prevalence rates ranging from 6.6 to 26 cases per million adults and 20 cases per million children.4-6 In children, estimated incidence rates for idiopathic PAH (IPAH) are 0.48 to 0.7 cases per million children per year.6,7

Although the pathophysiology of PAH is not completely understood, it is believed that endothelial dysfunction is a key component.2,8 Endothelial dysfunction is associ-ated with a decreased production of vasodilators with antiproliferative properties and an increased production of vasoconstrictors with proliferative properties. This leads to an increased pulmonary vascular muscle tone and to proliferation of vascular smooth muscle and endothelial cells. In the past decades, three major pathways have been identified in this process.9 The prostacyclin and nitric oxide (NO) pathways both lead to vasodilatation and antiproliferation. The endothelin-1 pathway has opposite effects and leads to vasoconstriction and proliferation. Three major classes of drugs interfering with these pathways have been developed: prostanoids, substituting prostacyclin, phospho-diesterase-5 (PDE-5) inhibitors, promoting the effects of NO and endothelin receptor antagonists (ERAs), inhibiting the effects of endothelin-1.

Very recently, novel drugs that interfere at different points in these pathways have either been approved or are in the stage of a Phase III clinical trial. These include the soluble guanylate cyclase stimulator riociguat that targets the NO pathway and the oral prostacyclin receptor antagonist selexipag.10,11

Based on multiple randomized controlled trials (RCTs) in adult PAH patients, evidence-based treatment guidelines have been developed and survival seems to have improved since the introduction of PAH-targeted drugs.1,12,13 Although there are similarities between adult and pediatric PAH, important differences in pathophysiology, underlying conditions, clinical presentation and outcome exist so that adult treatment algorithms cannot simply be extrapolated to children.14-16 For instance, in around 50% of children, PAH is associated with congenital heart defects that are often more complex than those in adults. PAH associated with connective tissue disease, portal hypertension or drugs is rare in children.6,17-20 Furthermore, in IPAH, syncope occurs more often in children, while heart failure is more frequent in adults.15 However, to date, there are no

34 Chapter 2

specific guidelines for the treatment of pediatric PAH and its development is hampered by the lack of RCTs in children. Although available data on the treatment of pediatric PAH are accumulating, this predominantly includes observational data based on single-center studies, small select patient groups or registries. These have provided safety and tolerability data, but no controlled data on efficacy. The available pediatric data suggest that survival has also improved in children since the introduction of the PAH-targeted drugs.18,21-25 However, survival remains unsatisfactory (Figure 1) with 5-year survival rates ranging from 71 to 81%, illustrating the high unmet need for treatment guidelines specifically for the pediatric age group.18,21-25 Optimal treatment strategies, including adequate monitoring of treatment response, are essential to guide therapy and may improve survival in children with PAH.

This review will provide an overview of the currently available treatments for PAH and the limited data on efficacy and safety in children with PAH (with the exclusion of peri-natal pulmonary vascular diseases, such as persistent PH of the newborn). Further, it will discuss potential treatment goals and how the available data can be translated into treatment strategies in pediatric PAH.

100

80

60

40

20

0

Cum

ulat

ive

surv

ival

(%)

Time from second-generation drug availability (yrs)0 2 4 6 8 10

42 27 13

Observed survival (n=45)Predicted survival using NIH registry equation

Figure 1. Survival of children with pulmonary arterial hypertension since the introduction of pulmonary arterial hypertension-targeted drugs compared with predicted survival. Reproduced with permission from [23].


2

overvIew oF Currently AvAIlABle treAtMents

supportive treatments

In the era of PAH-targeted drugs, supportive therapies should not be forgotten. Many patients with PAH receive supportive treatments during their disease course, such as anticoagulants and oxygen. Also, several general measures and lifestyle advices are often recommended and include influenza and pneumococcal immunization.16

Calcium channel blockers

Calcium channel blockers (CCBs) have been demonstrated to improve survival in a small select proportion (7%) of adults with IPAH and this has also been suggested in children.25-27 The small proportion of IPAH patients who show a positive response to acute pulmonary vasodilator testing during cardiac catheterization will sustainably benefit from CCB therapy. For a long time, the proportion of responders has been assumed to be higher in children with IPAH than in adults. However, reported values in children vary significantly (8-56%) and appear to be highly dependent on the used response criteria.24,25,27-29 In adults, responder status is usually determined according to criteria defined by Sitbon et al.26 In children, criteria defined by Barst et al., either or not modified, are often used.24,27,29 However, using the same criteria in both adults and children revealed similar proportions of responders in both age groups.28 Responders treated with CCB therapy need frequent clinical and hemodynamic reevaluation as they may become nonresponders over time and then need more advanced therapies. Due to negative inotropic effects, CCBs are advised not to be used in children <1 year of age.30 In summary, CCBs are the drug of choice for children and adults who are identified as responders according to the Sitbon or Barst criteria.1,30,31

Prostanoids

Prostacyclin is an endogenous prostanoid which is produced by vascular endothelial cells. It is a potent vasodilator that has antiproliferative and anticoagulant effects as well. Prostacyclin production is decreased in PAH. The prostanoids are synthetic prostacyclin analogs and were the first discovered class of PAH-targeted drugs. Drug-related side effects are mainly related to systemic vasodilatation and include flushing, jaw pain, diarrhea, nausea and headache. Side effects related to the administration route are significant and include line infections for intravenous (IV), site pain for subcutaneous (SC) and bronchospasm, cough and chest pain for inhaled administration.

Epoprostenol improves clinical and hemodynamic conditions as well as survival in adults and children with PAH when compared to conventional therapies.32-38 Epopros-tenol therapy is possible at all ages, also in infants and toddlers. However, epoprostenol has a very short half-life and is unstable at room temperature, leading to several practi-

36 Chapter 2

cal disadvantages including the need to be administered continuously intravenously through a central catheter. Also, it is generally advised to cool the epoprostenol cassette with ice packs. Intravenous administration poses the risk of line thrombosis and, more importantly, line infections that could lead to severe sepsis and death. Furthermore, these may lead to systemic embolic complications in patients with PAH associated with congenital heart disease (PAH-CHD) and a right-to-left shunt. A sudden halt of adminis-tration may lead to possibly fatal rebound PH.39

Treprostinil has a longer half-life and is chemically stable at room temperature. It can thus be administered subcutaneously, inhaled and orally as well. In adults with PAH, positive effects have been shown for SC, IV and inhaled (TRIUMPH trial) trepro-stinil on exercise tolerance, clinical condition and hemodynamics.40-45 Also, (a trend toward) improved survival has been reported for IV and SC treprostinil.41-43 Oral trepro-stinil monotherapy was shown to improve exercise capacity after 12 weeks in adults (FREEDOM-M).46 However, the addition of oral treprostinil to background therapy with a PDE-5 inhibitor, an ERA or both failed to improve exercise capacity after 16 weeks of therapy (FREEDOM C1/C2 trials).47,48 Data regarding treprostinil therapy in children are limited. Because of the pain and inflammation at the puncture place, SC therapy has been thought not to be feasible in children. However, two small studies that included 8 and 29 children showed improvements in clinical condition and hemodynamics after add-on therapy with SC and inhaled treprostinil, respectively, without significant side effects. Both drugs appeared to have acceptable safety profiles.49,50

Beraprost was initially reported to improve clinical condition and hemodynam-ics in adults with PAH (ALPHABET trial), but these effects did not persist after a longer period of follow-up.51-53

Iloprost is mainly used as an inhaled prostanoid. Beneficial effects of inhaled ilo-prost as mono- or add-on therapy, which persisted until at least one year after treatment initiation, have been demonstrated in adults with PAH (AIR and STEP trials).54-56 Some clinical improvements were reported in a proportion of children in two small single-center studies.57,58 Switching to or addition of IV iloprost in adult patients, who clinically deteriorated on non-IV therapy, resulted in clinical and hemodynamic improvements only in a subgroup of these patients.59-61

endothelin receptor antagonists

Endothelin-1 serum levels are increased in PAH patients.62 Two receptors mediate en-dothelin-1 in humans: endothelin-A and endothelin-B receptors.63 Both receptors are found in pulmonary vascular smooth muscle cells, where they promote vasoconstric-tion, inflammation and proliferation. Endothelin-B, however, is also present in pulmo-nary endothelial cells, where it mediates vasodilatation and activates antiproliferative agents. ERAs block these receptors, either both of them or the endothelin-A receptor


2

selectively, and thereby inhibit the effects of endothelin-1. An advantage of selective over dual blocking or the other way around has not been demonstrated. The major side effects of ERAs are liver enzyme elevation, peripheral edema and a decrease in hemo-globin levels. ERAs for PAH are given orally and there are no major side effects related to the administration route.

Bosentan is a dual receptor antagonist that has been demonstrated to improve 6-min walk distance (6MWD), World Health Organization functional class (WHO-FC) and time to clinical worsening in adults with PAH (BREATHE-1 trial).64 Several uncontrolled pediatric studies, including 19-101 children, suggested similar effects. Importantly, bosentan appeared to be well tolerated and safe in children and a pediatric formulation is available.21,22,65-68 Elevation of liver enzymes appears to occur less frequently in children than in adults (3% versus ~10%).1,22,69,70 Nonetheless, regular testing remains necessary as elevations require dose adaptation or discontinuation of bosentan.

Ambrisentan is a selective endothelin-A receptor antagonist that has demonstrat-ed effects comparable to bosentan (ARIES trials).71-74 A retrospective study in 38 children suggested that ambrisentan may have beneficial effects in a subset of children with PAH. Furthermore, ambrisentan may have a favorable safety profile compared to bosentan, including less liver function abnormalities and less drug interactions.75

Macitentan, a dual receptor antagonist with sustained receptor binding and increased tissue penetration, was recently shown to significantly reduce morbidity when compared to placebo in 742 PAH patients aged >12 years (SERAPHIN trial).76,77 Clinical and hemodynamic parameters improved after 6 months of therapy compared to placebo. Macitentan had a favorable safety profile with little occurrence of liver enzymes elevation and peripheral edema.77 To date, no data are available in children.

Pde-5 inhibitors

PDE-5 inactivates cyclic guanosine monophosphate through which NO mediates its va-sodilatory and antiproliferative effects. The PDE-5 inhibitors inhibit the actions of PDE-5, and thus increase the effects of available NO. The most common side effects are related to systemic vasodilatation and include headache, flushing and epistaxis. In general, PDE-5 inhibitors for PAH are given orally and there are no major side effects related to the administration route.

Sildenafil has been shown to have beneficial effects in adults with PAH that persist up to 3 years after start of therapy (SUPER trials). Also, sildenafil treatment was well tol-erated.78,79 STARTS-1 was the first randomized, double-blind, placebo-controlled study ever in children with PAH. Although the beneficial effect on the primary endpoint of the study, peak oxygen consumption on cardiopulmonary exercise testing (CPET), just failed to reach statistical significance, the results showed improvements in hemodynamics in the medium- and high-dose sildenafil-treated groups.80 The recently published results

38 Chapter 2

of the subsequent STARTS-2 trial suggested worse survival in children receiving high doses of sildenafil.81 However, the data were not conclusive. This is illustrated by the fact that these data caused the United States Food and Drug Administration to recommend against the use of sildenafil in children, whereas the European Medicines Agency ap-proved the use of sildenafil in children with a warning against high doses of sildenafil. The American Pediatric Pulmonary Hypertension Network stated that ‘although we be-lieve that low doses of sildenafil are likely to be safe in pediatric PAH and we support the EMA finding, further studies should carefully examine its role in the long-term therapy of children’.82

Tadalafil has been demonstratedto improve exercise tolerance and hemodynam-ics and to lead to better quality of life and increased time to clinical worsening after 16 weeks of therapy in treated adults compared to placebo (PHIRST trial).83 Improved exer-cise tolerance was maintained after another 52 weeks.84 Tadalafil treatment was safe and well tolerated. Pediatric data regarding tadalafil are scarce. One retrospective, single-center cohort study was performed that included 33 children who either transitioned from sildenafil to tadalafil (29 patients) or received tadalafil as initial PDE-5 inhibitor therapy (4 patients). Transition to tadalafil improved mPAP, indexed PVR and pulmonary-to-systemic vascular resistance ratio, while exercise capacity, brain natriuretic peptide (BNP) and cardiac index did not significantly change. Clinical and hemodynamic condi-tions tended to improve in the 4 patients who received initial tadalafil therapy. Tadalafil appeared to be safe and well tolerated.85

Vardenafil is a new PDE-5 inhibitor that has been shown to improve exercise toler-ance and hemodynamics after 3 and 14 months when compared to baseline and after 12 and 24 weeks when compared to baseline and placebo in 45 and 66 adult PAH patients, respectively (EVALUATION trial). Side effects were mild and mostly transient.86,87 To date, no data are available in children.

novel drugs

Riociguat, a soluble guanylate cyclase stimulator, is a novel drug that acts more upstream in the NO pathway than the PDE-5 inhibitors. Riociguat increases cyclic guanosine mo-nophosphate availability by directly stimulating soluble guanylate cyclase. Its actions can be synergetic with NO, but it can also act completely independent of NO. Riociguat improved exercise capacity, clinical condition and hemodynamics in PAH patients after 12 weeks of therapy compared to baseline and placebo (PATENT trial).10 To date, no data are available in children.

Selexipag is an oral selective prostacyclin receptor agonist. A Phase II study includ-ing 43 adult PAH patients on stable background therapy showed that PVR improved after 17 weeks of addition of selexipag and that it was well tolerated.11 Phase III clinical trial results are currently pending (GRIPHON trial). To date, no data are available in children.


2

Imatinib is a tyrosine kinase inhibitor that was initially developed for the treat-ment of chronic myeloid leukemia. It inhibits vascular smooth muscle cell proliferation and hyperplasia.88 Thus, unlike the previously described drugs targeting the three major pathways, imatinib has mainly antiproliferative effects. Imatinib was shown to have beneficial effects in patients with severe PAH.89,90 However, more discontinuations and serious adverse events (including subdural hematoma) were reported in the imatinib group compared to placebo.90 Consequently, the authorization application for imatinib in PAH was withdrawn. There are no data regarding imatinib in pediatric PAH.

Several novel drugs targeting newly identified pathways in the pathogenesis of PAH are currently under investigation and may be promising drugs for the future. These include rho kinase inhibitors targeting the Rho/Rho-kinase signaling pathway, which influences many cellular actions including apoptosis, inflammation and vasoconstric-tion,91 and endothelial progenitor cells targeting regeneration and repair of damaged lung microvasculature.92,93

Combination therapies

The rationale behind combination therapy is that the PAH-targeted drugs target three different pathways and that simultaneous targeting of two or three of these pathways may lead to a greater beneficial effect than targeting only one pathway. The current guidelines for the treatment of adults with PAH summarize options for treatment initia-tion.1,31 The level of evidence and recommendation for the use of combination therapies has significantly improved since controlled data on such use are becoming increasingly available, although this evidence is almost exclusively based on adult studies.31

Since the early 2000s, various studies on the effects of combination or add-on therapy in PAH have been performed.

The combination of an ERA and a PDE-5 inhibitor has been shown to (tend to) improve exercise capacity, functional status and hemodynamics in adults compared to monotherapy with one of these drugs.83,94-98 Also, the addition of macitentan to PDE-5 inhibitor therapy improved time to the combined endpoint, including worsening of PAH, lung transplantation (LTx), escalation to IV or SC prostanoids and death (SERAPHIN trial).77 Combining both classes appeared to be safe and well tolerated in all studies. Add-on riociguat to ERA or non-IV prostanoid therapy was shown to be beneficial and safe in the PATENT trial.10

Combining prostanoids with either ERAs or PDE-5 inhibitors has been studied in different compositions. Add-on sildenafil therapy in adults receiving long-term IV epoprostenol improved clinical and hemodynamic conditions and time to clinical worsening (PACES trial).99 Add-on therapy with inhaled treprostinil or inhaled iloprost to ERA and/or PDE-5 inhibitor therapy was studied in adults who did not improve on oral therapy alone (TRIUMPH and STEP trials). Both were shown to improve exercise capacity,

40 Chapter 2

functional status and hemodynamics.44,55,100 Furthermore, inhaled iloprost was shown to prolong time to clinical worsening and the beneficial effects of inhaled treprostinil were shown to persist for 24 months.45,55 Beneficial results have also been reported for the addition of bosentan to SC treprostinil therapy.101

Thus, several studies have shown beneficial effects of add-on combination therapy in adult PAH patients who did not adequately respond to monotherapy. Little research has been done regarding this subject in children. A recently published report, including 275 children, showed that children who received combination therapy during the study period had better survival compared to children who received monotherapy, independent of disease characteristics at baseline.25 Another recent report, including 24 children, showed that the addition of sildenafil to bosentan improved WHO-FC and 6MWD in children who clinically deteriorated on bosentan mono therapy.102 Survival seemed to improve in the children who received add-on sildenafil therapy compared to those who remained on bosentan therapy alone. Add-on therapy with inhaled or SC treprostinil was shown to improve clinical and hemodynamic conditions in children with severe PAH.49,50 These results point in the same direction as those obtained in adult stud-ies, supporting the beneficial effects of add-on combination therapy in pediatric PAH.

Although combination therapy seems to be efficacious in both adults and chil-dren with PAH, it remains unclear when and how to start combination therapy and what disease characteristics could guide decisions regarding therapy escalation.

nondrug treatments

Nondrug treatments could be considered to preserve cardiac output and to reduce the right ventricular (RV) workload. They could serve as a treatment option to relieve symptoms or as a bridge to LTx.

Balloon atrial septostomy (BAS) is used in patients with IPAH and end-stage disease, recurrent syncope or both. As syncope is more frequent in the pediatric age group, BAS could be more often of use in children than in adults. BAS is believed to lead to an increase of left ventricle preload and cardiac output at the cost of a decrease in systemic arterial oxygen saturation. This overall is assumed to result in increased systemic oxygen transportation. Several small uncontrolled studies including adults and/or children reported improvements in clinical and hemodynamic conditions. BAS has been suggested to improve survival as well, increasing the chance of receiving donor lungs.103-107 BAS requires an invasive procedure, which brings concomitant risks, especially in this vulnerable population. In patients with severely elevated right atrial pressure (RAP), the mortality rate increases due to potential major right-to-left shunting with life-threatening hypoxemia. Thus, it has been advised not to wait with BAS until this hemodynamic condition develops.1,31


2

Potts shunt, a (direct) anastomosis between the left pulmonary artery and the descending aorta, forms an alternative way to create a pulmonary-to-systemic shunt and, when compared to BAS, has the advantage of directly relieving the right ventricle. This technique is suitable for patients with suprasystemic pulmonary pressures and can also be used in patients with concomitant severely elevated RAP. The decrease in oxygen saturation will only occur in the lower body half. Two case reports of both two children and one retrospective multicenter study of eight children with end-stage IPAH showed improved functional and exercise capacity, lower plasma levels of BNP and improved RV function in both the short- and longer-term.108-110 However, postoperative mortality in this early experience was reported to be 25% in the multicenter study, illustrating the high risk of invasive procedures in PAH patients. Further research including more patients is essential to evaluate the short- and long-term effects of this palliative pro-cedure.

Aortic banding is based upon the theory of ventricular-ventricular interaction, in which right heart disease alters left ventricular function and vice versa. A recent experimental study including 23 rabbits showed that aortic constriction in a model of chronic RV pressure overload resulted in improved biventricular function and myocardial remodeling.111 To date, no studies in humans exist and its possible value in (pediatric) patients with PAH remains to be elucidated.

(Heart-)LTx remains the treatment of choice for end-stage PAH despite maximal therapy. As the heart has the ability to recover and re-remodel to normal function and dimensions, bilateral LTx is most frequently performed. In children, IPAH is the second most common indication for LTx.112 Given the high risk and major consequences of the procedure, LTx is only indicated in patients with progressive and severe PAH despite maximal medical therapy. Several small studies including children with IPAH that under-went bilateral LTx showed improved WHO-FC, improved RV function and improved sur-vival, with a median survival that ranged from 45 to 70 months.113-115 Reported survival was comparable or improved compared to LTx in children with cystic fibrosis.112 Whether a child is eligible for transplantation and what the optimal timing is remains unknown and is mostly determined by the center’s expert opinion and donor organ availability. Although medical treatment options are expanding and seem to be beneficial, medical therapy should not lead to (too) late listing for LTx.

In summary,over the past 15 years, many RCTs showed that PAH-targeted drugs are efficacious in the treatment of PAH in adult patients. Although mainly uncontrolled, observational studies exist in children with PAH, the available data suggest comparable effects. The available PAH-targeted drugs appear to have acceptable safety and toler-ability profiles also in children, except for sildenafil in which this is a subject of debate. Combination therapy with PAH-targeted drugs that act on different pathways could lead to additional beneficial clinical effects, also in pediatric PAH. Novel drugs targeting exist-

42 Chapter 2

ing or newly discovered pathways in the pathogenesis of PAH are being developed and will hopefully further improve quality of life and survival in pediatric PAH. Furthermore, nondrug treatments are available for children and are believed to have a place in treat-ment strategies for children with PAH.

treAtMent strAtegIes

Although the development of novel drugs for the treatment of PAH is of great impor-tance, knowledge on how to use the various drugs combined in optimal treatment strat-egies is at least as important. To improve survival and optimize quality of life in patients with PAH, relevant considerations include choice of drugs, timing of therapy initiation and when and how to use combination therapy. For example, guidelines recommend combination therapy ‘in case of inadequate clinical response’. However, how should inadequate clinical response be defined?

A goal-oriented treatment strategy is now recommended to guide therapy in adult PAH patients.31 Instead of reacting on deterioration of a patient’s clinical condition, the physician aims to reach a predefined improvement in clinical condition.116 Thus, pa-tients who start therapy are supposed to reach certain goals.1,117,118 If these goals are not met within 3-6 months, therapy should be escalated. For such a strategy, it is essential to have reliable, validated and clinically meaningful treatment goals that are applicable in all patients and that can be obtained without disproportional risks.

The treatment of patients with PAH aims at improving quality of life and survival. Therefore, a treatment goal could be a measure that represents improved quality of life, for instance relieve of symptoms or improvement of exercise capacity. Also, a treat-ment goal could be a clinical measure that represents a decrease in the chance of an outcome event, such as death or LTx. Thus, a variable that serves as a treatment goal either directly reflects quality of life or meets the following criteria for a surrogate for outcome: has a strong correlation with outcome, values can be influenced by therapy and treatment-induced changes reflect a change in outcome.119,120 Thus, a variable that serves as treatment goal is not simply a predictor of outcome. It should additionally be influenced by therapy. To illustrate this, although patient characteristics as age and sex are reported to predict outcome, it is obvious that these are no suitable treatment goals. The third requirement for a treatment goal indicates that a treatment-induced change in the variable should reflect a change in outcome. For example, improved WHO-FC after 6 months of therapy should be associated with improved survival. Follow-up assessments are therefore necessary.

Several clinical, biochemical and hemodynamic variables have been identified as predictors of outcome both in adults and children with PAH (Table 1). However, data


2

on the predictive value of treatment-induced changes in these predictors are scarce. Few observational studies regarding treatment-induced changes in adults have been published.121-124 Very few data are currently available in children. Although the concept of goal-oriented treatment seems reasonable and beneficial, these variables should be sufficiently validated as treatment goals in the relevant patients, so also in children with PAH.

Current treatment goals in adult patients, as recently proposed at the 5th World Sympo-sium for Pulmonary Hypertension (WSPH) held in Nice 2013, to optimize prognosis in patients with PAH include WHO-FC I-II, near-normal or normal RV size and function on echocardiography or cardiac magnetic resonance (CMR), RAP <8 mmHg and cardiac in-dex >2.5 to 3.0 l/min/m² on cardiac catheterization, 6MWD >380 to 440 m, peak oxygen consumption >15 ml/min/kg on CPET and normal plasma levels of N-terminal pro brain

table 1. Evidence for the Prognostic Value of Potential Treatment Goals in Children with Pulmonary Arte-rial Hypertension

Prognostic implications at baseline (Ref.)

Prognostic implications at follow-up (Ref.)

Clinical condition

WHO-FC 7, 21-23, 25, 126, 127 160

6MWD 126 -

CPET - -

Biomarkers

(NT-pro)BNP 23-25, 36, 141-143 160

Imaging

Echocardiography 126, 146, 147 161

CMR 148 -

hemodynamics

mRAP 25, 27 -

PVRi 22, 24, 25, 27, 126, 131 -

mPAP/mSAP 23, 25, 28, 127 -

CI 23-25, 27 -

Pulsatile components of RV afterload 127, 131 -

6MWD, six-minute walk distance; CI, cardiac index; CMR, cardiac magnetic resonance imaging; CPET, cardiopul-monary exercise testing; mPAP/mSAP, mean pulmonary-to-systemic arterial pressure ratio; mRAP, mean right atrial pressure; (NT-pro)BNP, (N-terminal pro) brain natriuretic peptide; PVRi, pulmonary vascular resistance in-dex; RV, right ventricular; WHO-FC, World Health Organization functional class.

44 Chapter 2

natriuretic peptide (NT-proBNP) or BNP.117 Based on the strength of expert opinion, the pediatric task force of the 5th WSPH proposed a treatment algorithm for children with IPAH in which patients are characterized using a risk profile based on proposed pediatric treatment goals.30 An adapted version of this risk profile is shown in Table 2.

In the following section, variables that may serve as treatment goals in children with PAH will be discussed and the relevant evidence will be reviewed.

Clinical characteristics of PAH in children include symptoms, such as dyspnea at rest and/or during exercise, exercise intolerance, syncope, fatigue and chest pain, that could greatly impact quality of life. Reducing these symptoms is clinically relevant, will improve quality of life and thus can be regarded as a valid treatment goal in children with PAH. Children with PAH may show failure to thrive.6,7,17 Lower age-normalized scores for height and weight have been suggested to correlate with worse survival.7 However, this could not be confirmed in two other cohorts.24,25 Furthermore, no catch-up growth after treatment initiation was found, which potentially disqualifies growth, or age-normalized scores for height and weight, as treatment goals.7

Although a correlation between syncope and survival has not been confirmed in several pediatric studies, the occurrence of syncope or its persistence after treatment

table 2. Treatment Goals Proposed for Guiding Therapy in Children With Pulmonary Arterial Hypertension.

Lower risk Treatment Goals Higher risk

No Clinical evidence of RV failure Yes

No Progression of symptoms Yes

No Syncope Yes

Growth Failure to thrive

I, II WHO functional class III, IV

Minimally elevated Serum BNP/NT-proBNP Significantly elevated, rising level

Echocardiography Severe RV enlargement/dysfunction Pericardial effusion

Systemic CI >3.0 L/min/m2

mPAP/mSAP<0.75Acute vasoreactivity

Hemodynamics Systemic CI <2.5 L/min/m2

mPAP/mSAP>0.75RAP >10 mmHgPVRi>20 WU*m2

Stable >450 m 6MWD* ≤350 m or decreasing

*Although the 6MWD was not proposed as treatment goal by the WSPH pediatric task force, maintaining of or improving to an adequate 6MWD can be regarded as clinically meaningful in pediatric PAH, as improved exercise capacity is believed to improve quality of life. 6MWD, six-minute walk distance; BNP, brain natriuretic peptide; CI, cardiac index; mPAP/mSAP, mean pulmonary-to-systemic arterial pressure ratio; mRAP, mean right atrial pressure; NT-proBNP, N-terminal pro brain natriuretic peptide; PVRi, pulmonary vascular resistance index; RV, right ventricular.Adapted with permission from [30].


2

initiation is regarded as a serious sign of disease and according to current expert opinion requires escalation of therapy.7,24,30

WHO-FC is a non-invasive, subjective assessment of a patient’s clinical condition using the occurrence of symptoms at different levels of activities. WHO-FC, both at baseline as well as after treatment, has been shown to strongly correlate with survival in adult PAH patients.121-123 It therefore represents a useful treatment goal to guide therapy in adults. WHO-FC can be difficult to assess in infants and young children as it will be based on the observation and impression of caregivers. An age-adjusted estimation of a child’s physical activity in relation to its peers may help to accurately determine WHO-FC. Despite this apparent limitation, several pediatric studies have shown WHO-FC to be a strong predictor of outcome that could be affected by therapy.7,21-23,25,125-127 A functional classification system specifically designed for children has been proposed but has not been validated yet.128 Overall, WHO-FC is an easy and freely obtainable parameter re-flecting clinical condition also in children. As in adult PAH, the WSPH pediatric task force proposed reaching or maintaining WHO-FC I or II as a treatment goal in pediatric PAH.

Six-minute walk distance is widely used to assess clinical condition in adult PAH. It has served as primary endpoint in most RCTs. A meta-analysis recently showed that changes in 6MWD may not reflect changes in outcome.129 The use of 6MWD in children is limited due to developmental restrictions: infants do not walk, young children may be distracted during the test and developmental delays may affect the test results. In gen-eral, it is a reliable and reproducible test that can be performed from an age of 7 years.130 However, many children are younger than 7 years at diagnosis.6,7,22 The predictive value of 6MWD for outcome in children with PAH is unclear and available data from various observational studies are contradictory on this point.25,126,131 Nevertheless, as in adults, 6MWD can be improved by therapies in children with PAH.49,50,57,65,66,102 Since improved exercise capacity is believed to improve quality of life, maintaining of or improving to an adequate 6MWD can be regarded as a valid treatment goal in pediatric PAH.

Cardiopulmonary exercise testing has been shown to predict survival in adults with PAH.132,133 Treatment-induced changes have not been studied. In young children, the use of CPET is also hampered by limited feasibility due to developmental issues. Reference values are available for children from an age of 6-8 years.134,135 Peak oxygen consumption was shown to correlate with mPAP and PVR in 40 children with PAH.136 Also, CPET has been suggested to provide complimentary information to the 6MWT.137 A possible cor-relation between CPET and survival in children with PAH has not been studied. Overall, its value in a goal-oriented treatment strategy in children remains unknown.

NT-proBNP and BNP are biomarkers related to RV dysfunction, which is one of the most important predictors for survival in PAH.3 Both in adults and children, plasma levels of (NT-pro)BNP have been shown to strongly correlate with survival.23,25,36,138-143 Recently, treatment-induced changes in NT-proBNP were shown to be associated with

46 Chapter 2

a change in survival in adults, making NT-proBNP a valid treatment goal.121 In children with PAH, changes in (NT-pro)BNP levels have been correlated with changes in WHO-FC, 6MWD and hemodynamics.141-144 Although the correlation between treatment-induced changes of (NT-pro)BNP and survival has not been studied yet, the WSPH pediatric task force proposed reaching (near-)normal levels of (NT-pro)BNP as treatment goal and advised (NT-pro)BNP to be part of the regular follow-up in pediatric PAH.

Echocardiography and CMR are both noninvasive methods to assess RV function. In adults and children with PAH, echocardiographic and CMR parameters at baseline have been associated with survival.126,139,145-150 Furthermore, treatment-induced changes in CMR parameters were shown to predict survival in adult patients.149 Although data are promising, they remain currently limited and further research is necessary to determine the value of echocardiography and CMR in guiding treatment in PAH patients. According to the WSPH pediatric task force, the findings of severe or progressive RV dysfunction or pericardial effusion dictates escalation of therapy.

Hemodynamic parameters are objective and can be obtained at any age. In adults, hemodynamics at baseline have been shown to predict survival.3,121,123,139,151-153 Treatment-induced changes in cardiac index and mixed venous oxygen saturation were recently reported to correlate with changes in survival, supporting their use as treatment goals.121 Hemodynamic variables, such as RAP, indexed PVR, cardiac index and mean pulmonary-to-systemic arterial pressure ratio, have been associated with survival in the pediatric age group.22-25,27,28,126,127 Furthermore, initiation of therapy has been shown to improve hemodynamics.21,27,154,155 Recently, pulsatile components of RV afterload were shown to predict survival in children with PAH, as in adults.127,131,156 Although it seems reasonable to assume that treatment-induced improvements in hemodynamics will lead to a better outcome, this remains to be demonstrated in pediatric PAH. Further-more, obtaining invasive hemodynamics by cardiac catheterization often requires the use of sedation or general anesthesia in childhood, which comes with associated risks. Cardiac catheterizations in pediatric PAH carried out in specialized centers are reported to have a complication rate (major complications) of 4-6%.157-159 Nevertheless, the WSPH pediatric task force proposed hemodynamic variables as potential treatment goals. Many, but not all, expert centers for pediatric PAH practice a strategy of repeated cardiac catheterizations during follow-up, with the rationale that the risks of cardiac catheteriza-tion, if minimized via adequate expertise of the treatment team, will be outweighed by the benefits of optimizing therapy and improvement of outcome.

In summary, although outcome in pediatric PAH has improved since the introduc-tion of PAH-targeted drugs, survival of children with this disease is still unsatisfactory. Improvement in treatment success is highly needed and waiting for clinical deteriora-tion to escalate initiated therapy may not be the way to go. Therefore, goal-oriented treatment strategies are currently adopted in the management of pediatric PAH. Taking


2

into account the paucity of data on treatment goals in children with PAH, the WSPH pediatric task force agreed on recommending several variables to serve as treatment goals, including clinical symptoms, WHO-FC, (NT-pro)BNP, RV imaging and invasive he-modynamics. However, proper validation of these variables as treatment goals remains to be done.

exPert CoMMentAry

Although several PAH-targeted drugs have been developed and their efficacy has been demonstrated, outcome in children with PAH remains poor. Therefore, there is a high, but unmet, need for better treatment strategies specifically for children. Knowing how to adequately assess treatment response and when and how to escalate therapy is es-sential. Emerging evidence is becoming available that children with PAH may benefit from adequate monitoring of treatment response and more aggressive treatment regi-mens with escalation to combination therapy.

Ideally, pediatric data for evidence-based guidelines, that is, RCTs, should be collected. However, controlled trials in pediatric PAH were and will be hampered by difficulties. First, it is challenging to reach appropriate study sizes due to the rarity and heterogeneity of the disease. Second, the widespread pediatric use of currently available PAH-targeted drugs complicates study designs. Several PAH-targeted drugs are regarded ‘standard of care’, while not approved for children. Third, there is a lack of validated endpoints in pediatric PAH, including the nonacceptance by the regulatory authorities of invasive hemodynamics as endpoint. Therefore, much of the pediatric data will have to be derived from clinical registries and cohorts that collect patient and treatment characteristics and outcome data. A standardized follow-up, with predefined variables and timepoints, would be very helpful. Registries may be multicenter, multi-country center-based, such as the TOPP and REVEAL registries. They may also be based on national cohorts, such as the Dutch and United Kingdom national service registries. Furthermore, there are single-center registries. All these registries, each with its unique design and thereby having its own merits and disadvantages, and providing mostly observational data, will have to clearly define their aims and collect relevant data. Only then, registries will be able to contribute to the actual questions that arise in defining the optimal management of children with different types of PAH in the coming future.

One of these questions is whether children with IPAH and children with PAH-CHD should be treated equally. Most of the studies regarding PAH-specific therapies have been performed in patients with IPAH. Nevertheless, an increasing amount of data is becoming available showing that these drugs, perhaps with the exception of CCBs, have similar effects in both groups. The same holds for clinical predictors of outcome. Further-

48 Chapter 2

more, although survival of patients with PAH-CHD has long been assumed to be more favorable than survival of patients with IPAH, recent data indicate that in childhood, survival is equally poor in both types of PAH. Based on current knowledge, the authors feel that there is no indication to treat children with PAH-CHD according to different treatment algorithms than children with IPAH. Nevertheless, practical issues should be considered for the individual patient, such as the use of central catheters in patients with a right-to-left shunt.

Importantly, defining clinically relevant treatment goals that correlate with long-term outcome has emerged as one of the most critical tasks. Effort should be put in establishing and validating these treatment goals, which will help to guide therapy and improve the currently unsatisfying outcome in pediatric PAH.

FIve-yeAr vIew

In the next five years, treatment options for patients with PAH will likely expand. More drugs, targeting new pathways, will become available and have to be evaluated in RCTs. ‘Smart-design’ controlled trials should be designed to collect evidence for efficacy in the pediatric PAH population. Also, the value of nondrug treatments should be established within the setting of drug treatment. Especially the role of the Potts shunt in short- and long-term outcome of pediatric PAH will have to be investigated. Since experience in this technique is limited and patient numbers are small, a multicountry registry for this intervention could be very valuable.

In the coming years, data from newly or redesigned registries will become avail-able that will allow for the assessment and validation of the recently proposed treat-ment goals and the identification of new treatment goals. With these, evidence-based guidelines that define how to accurately monitor treatment response and escalate therapy will be developed also for children. Finally, novel therapies directed toward the reversal of RV dysfunction in PAH may become available.


2

reFerenCes

1. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-2537.

2. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arte-rial hypertension. J Am Coll Cardiol. 2004;43:13S-24S.

3. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343-349.

4. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023-1030.

5. Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S. An epidemiological study of pulmo-nary arterial hypertension. Eur Respir J. 2007;30:104-109.

6. van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Neth-erlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124:1755-1764.

7. Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96:1401-1406.

8. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2008;118:2372-2379.

9. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425-1436.

10. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.

11. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012;40:874-880.

12. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482.

13. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244-249.

14. Rosenzweig EB, Widlitz AC, Barst RJ. Pulmonary arterial hypertension in children. Pediatr Pulm-onol. 2004;38:2-22.

15. Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J. 2011;37:665-677.

16. Berger RM, Bonnet D. Treatment options for paediatric pulmonary arterial hypertension. Eur Respir Rev. 2010;19:321-330.

17. Berger RM, Beghetti M, Humpl T, et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet. 2012;379:537-546.

18. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001-2006. Heart. 2009;95:312-317.

19. Fraisse A, Jais X, Schleich JM, et al. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103:66-74.

20. van Loon RL, Roofthooft MT, van Osch-Gevers M, et al. Clinical characterization of pediatric pulmonary hypertension: complex presentation and diagnosis. J Pediatr. 2009;155:176-82.e1.

50 Chapter 2

21. Rosenzweig EB, Ivy DD, Widlitz A, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:697-704.

22. Ivy DD, Rosenzweig EB, Lemarie JC, Brand M, Rosenberg D, Barst RJ. Long-term outcomes in chil-dren with pulmonary arterial hypertension treated with bosentan in real-world clinical settings. Am J Cardiol. 2010;106:1332-1338.

23. van Loon RL, Roofthooft MT, Delhaas T, et al. Outcome of pediatric patients with pulmonary arte-rial hypertension in the era of new medical therapies. Am J Cardiol. 2010;106:117-124.

24. Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arte-rial hypertension disease management. Circulation. 2012;125:113-122.

25. Zijlstra WM, Douwes JM, Rosenzweig EB, et al. Survival differences in pediatric pulmonary arterial hypertension: clues to a better understanding of outcome and optimal treatment strategies. J Am Coll Cardiol. 2014;63:2159-2169.

26. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.

27. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197-1208.

28. Douwes JM, van Loon RL, Hoendermis ES, et al. Acute pulmonary vasodilator response in paediat-ric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria. Eur Heart J. 2011;32:3137-3146.

29. Barst RJ. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest. 1986;89:497-503.

30. Ivy DD, Abman SH, Barst RJ, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol. 2013;62:D117-26.

31. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62:D60-72.

32. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296-301.

33. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132:425-434.

34. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998;338:273-277.

35. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482.

36. Nakayama T, Shimada H, Takatsuki S, et al. Efficacy and limitations of continuous intravenous epoprostenol therapy for idiopathic pulmonary arterial hypertension in Japanese children. Circ J. 2007;71:1785-1790.

37. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999;99:1858-1865.

38. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with con-tinuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112:485-491.


2

39. Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hyper-tension? Int J Clin Pract Suppl. 2010;(168):23-32. doi:23-32.

40. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prosta-cyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:800-804.

41. Barst RJ, Galie N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28:1195-1203.

42. Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. 2006;129:1636-1643.

43. Hiremath J, Thanikachalam S, Parikh K, et al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010;29:137-149.

44. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915-1922.

45. Benza RL, Seeger W, McLaughlin VV, et al. Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension. J Heart Lung Transplant. 2011;30:1327-1333.

46. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013;127:624-633.

47. Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arte-rial hypertension in patients on background endothelin receptor antagonist and/or phospho-diesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012;142:1383-1390.

48. Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial hyper-tension in patients receiving background endothelin receptor antagonist and phosphodies-terase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144:952-958.

49. Levy M, Celermajer DS, Bourges-Petit E, Del Cerro MJ, Bajolle F, Bonnet D. Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr. 2011;158:584-588.

50. Krishnan U, Takatsuki S, Ivy DD, et al. Effectiveness and safety of inhaled treprostinil for the treat-ment of pulmonary arterial hypertension in children. Am J Cardiol. 2012;110:1704-1709.

51. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:2119-2125.

52. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496-1502.

53. Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension. J Am Coll Cardiol. 1999;34:1188-1192.

54. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322-329.

55. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257-1263.

52 Chapter 2

56. Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hyper-tension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med. 2000;342:1866-1870.

57. Alehan D, Yildirim I, Sahin M, Ozkutlu S, Ozer S, Karagoz T. Long-term inhaled iloprost use in children with pulmonary arterial hypertension. Cardiol Young. 2012;22:396-403.

58. Ivy DD, Doran AK, Smith KJ, et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51:161-169.

59. Hoeper MM, Spiekerkoetter E, Westerkamp V, Gatzke R, Fabel H. Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension. Eur Respir J. 2002;20:339-343.

60. Knudsen L, Schurawlew A, Nickel N, et al. Long-term effects of intravenous iloprost in patients with idiopathic pulmonary arterial hypertension deteriorating on non-parenteral therapy. BMC Pulm Med. 2011;11:56-2466-11-56.

61. Ewert R, Opitz CF, Wensel R, Winkler J, Halank M, Felix SB. Continuous intravenous iloprost to re-vert treatment failure of first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Clin Res Cardiol. 2007;96:211-217.

62. Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased pro-duction of endothelin in pulmonary circulation. Circulation. 1991;84:2280-2285.

63. Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004;61:227-237.

64. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.

65. Maiya S, Hislop AA, Flynn Y, Haworth SG. Response to bosentan in children with pulmonary hypertension. Heart. 2006;92:664-670.

66. Hislop AA, Moledina S, Foster H, Schulze-Neick I, Haworth SG. Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children. Eur Respir J. 2011;38:70-77.

67. Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2003;73:372-382.

68. Beghetti M, Haworth SG, Bonnet D, et al. Pharmacokinetic and clinical profile of a novel formula-tion of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study. Br J Clin Pharmacol. 2009;68:948-955.

69. Beghetti M, Hoeper MM, Kiely DG, et al. Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension: results from the European Postmarketing Sur-veillance program. Pediatr Res. 2008;64:200-204.

70. Beghetti M. Bosentan in pediatric patients with pulmonary arterial hypertension. Curr Vasc Phar-macol. 2009;7:225-233.

71. Galie N, Badesch D, Oudiz R, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:529-535.

72. Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hy-pertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117:3010-3019.

73. Oudiz RJ, Galie N, Olschewski H, et al. Long-term ambrisentan therapy for the treatment of pul-monary arterial hypertension. J Am Coll Cardiol. 2009;54:1971-1981.

74. Klinger JR, Oudiz RJ, Spence R, Despain D, Dufton C. Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension. Am J Cardiol. 2011;108:302-307.


2

75. Takatsuki S, Rosenzweig EB, Zuckerman W, Brady D, Calderbank M, Ivy DD. Clinical safety, pharma-cokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol. 2013;48:27-34.

76. Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O. Slow receptor dissociation kinetics dif-ferentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012;7:e47662.

77. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809-818.

78. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hyperten-sion. N Engl J Med. 2005;353:2148-2157.

79. Rubin LJ, Badesch DB, Fleming TR, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest. 2011;140:1274-1283.

80. Barst RJ, Ivy DD, Gaitan G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125:324-334.

81. Barst RJ, Beghetti M, Pulido T, et al. STARTS-2: Long-Term Survival With Oral Sildenafil Mono-therapy in Treatment-Naive Pediatric Pulmonary Arterial Hypertension. Circulation. 2014.

82. Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. Food and Drug Administra-tion warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med. 2013;187:572-575.

83. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119:2894-2903.

84. Oudiz RJ, Brundage BH, Galie N, et al. Tadalafil for the treatment of pulmonary arterial hyperten-sion: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol. 2012;60:768-774.

85. Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012;33:683-688.

86. Jing ZC, Jiang X, Wu BX, et al. Vardenafil treatment for patients with pulmonary arterial hyperten-sion: a multicentre, open-label study. Heart. 2009;95:1531-1536.

87. Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011;183:1723-1729.

88. Barst RJ. PDGF signaling in pulmonary arterial hypertension. J Clin Invest. 2005;115:2691-2694. 89. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients

with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182:1171-1177. 90. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial

hypertension: results of the randomized IMPRES study. Circulation. 2013;127:1128-1138. 91. Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo-controlled clinical trial with a

rho-kinase inhibitor in pulmonary arterial hypertension. Circ J. 2013;77:2619-2625. 92. Zhu JH, Wang XX, Zhang FR, et al. Safety and efficacy of autologous endothelial progenitor cells

transplantation in children with idiopathic pulmonary arterial hypertension: open-label pilot study. Pediatr Transplant. 2008;12:650-655.

93. Smadja DM, Gaussem P, Mauge L, et al. Circulating endothelial cells: a new candidate biomarker of irreversible pulmonary hypertension secondary to congenital heart disease. Circulation. 2009;119:374-381.

94. Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J. 2004;24:1007-1010.

54 Chapter 2

95. D’Alto M, Romeo E, Argiento P, et al. Bosentan-sildenafil association in patients with congenital heart disease-related pulmonary arterial hypertension and Eisenmenger physiology. Int J Cardiol. 2012;155:378-382.

96. Lunze K, Gilbert N, Mebus S, et al. First experience with an oral combination therapy using bosen-tan and sildenafil for pulmonary arterial hypertension. Eur J Clin Invest. 2006;36 Suppl 3:32-38.

97. Porhownik NR, Al-Sharif H, Bshouty Z. Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy. Can Respir J. 2008;15:427-430.

98. Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmo-nary arterial hypertension. Eur Respir J. 2007;29:469-475.

99. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epopros-tenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149:521-530.

100. Channick RN, Olschewski H, Seeger W, Staub T, Voswinckel R, Rubin LJ. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006;48:1433-1437.

101. Benza RL, Rayburn BK, Tallaj JA, Pamboukian SV, Bourge RC. Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension: long-term efficacy and com-bination with bosentan. Chest. 2008;134:139-145.

102. Douwes JM, Roofthooft MT, Van Loon RL, et al. Sildenafil add-on therapy in paediatric pulmonary arterial hypertension, experiences of a national referral centre. Heart. 2014;100:224-230.

103. Kerstein D, Levy PS, Hsu DT, Hordof AJ, Gersony WM, Barst RJ. Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension. Circulation. 1995;91:2028-2035.

104. Thanopoulos BD, Georgakopoulos D, Tsaousis GS, Simeunovic S. Percutaneous balloon dilatation of the atrial septum: immediate and midterm results. Heart. 1996;76:502-506.

105. Micheletti A, Hislop AA, Lammers A, et al. Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension. Heart. 2006;92:969-972.

106. Law MA, Grifka RG, Mullins CE, Nihill MR. Atrial septostomy improves survival in select patients with pulmonary hypertension. Am Heart J. 2007;153:779-784.

107. Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol. 1998;32:297-304.

108. Blanc J, Vouhe P, Bonnet D. Potts shunt in patients with pulmonary hypertension. N Engl J Med. 2004;350:623.

109. Labombarda F, Maragnes P, Dupont-Chauvet P, Serraf A. Potts anastomosis for children with idiopathic pulmonary hypertension. Pediatr Cardiol. 2009;30:1143-1145.

110. Baruteau AE, Serraf A, Levy M, et al. Potts shunt in children with idiopathic pulmonary arterial hypertension: long-term results. Ann Thorac Surg. 2012;94:817-824.

111. Apitz C, Honjo O, Humpl T, et al. Biventricular structural and functional responses to aortic con-striction in a rabbit model of chronic right ventricular pressure overload. J Thorac Cardiovasc Surg. 2012;144:1494-1501.

112. Benden C, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official pediatric lung and heart-lung transplantation report--2013; focus theme: age. J Heart Lung Transplant. 2013;32:989-997.

113. Lammers AE, Burch M, Benden C, et al. Lung transplantation in children with idiopathic pulmo-nary arterial hypertension. Pediatr Pulmonol. 2010;45:263-269.


2

114. Schaellibaum G, Lammers AE, Faro A, et al. Bilateral lung transplantation for pediatric idiopathic pulmonary arterial hypertension: a multi-center experience. Pediatr Pulmonol. 2011;46:1121-1127.

115. Goldstein BS, Sweet SC, Mao J, Huddleston CB, Grady RM. Lung transplantation in children with idiopathic pulmonary arterial hypertension: an 18-year experience. J Heart Lung Transplant. 2011;30:1148-1152.

116. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 2005;26:858-863.

117. McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D73-81.

118. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417-1431. 119. Boissel JP, Collet JP, Moleur P, Haugh M. Surrogate endpoints: a basis for a rational approach. Eur J

Clin Pharmacol. 1992;43:235-244. 120. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med.

2012;31:2973-2984. 121. Nickel N, Golpon H, Greer M, et al. The prognostic impact of follow-up assessments in patients

with idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;39:589-596. 122. Barst RJ, Chung L, Zamanian RT, Turner M, McGoon MD. Functional class improvement and 3-year

survival outcomes in patients with pulmonary arterial hypertension in the REVEAL Registry. Chest. 2013;144:160-168.

123. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788.

124. Henkens IR, Van Wolferen SA, Gan CT, et al. Relation of resting heart rate to prognosis in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol. 2009;103:1451-1456.

125. van Loon RL, Hoendermis ES, Duffels MG, et al. Long-term effect of bosentan in adults versus children with pulmonary arterial hypertension associated with systemic-to-pulmonary shunt: does the beneficial effect persist? Am Heart J. 2007;154:776-782.

126. Lammers AE, Munnery E, Hislop AA, Haworth SG. Heart rate variability predicts outcome in children with pulmonary arterial hypertension. Int J Cardiol. 2010;142:159-165.

127. Douwes JM, Roofthooft MT, Bartelds B, Talsma MD, Hillege HL, Berger RM. Pulsatile haemody-namic parameters are predictors of survival in paediatric pulmonary arterial hypertension. Int J Cardiol. 2013;168:1370-1377.

128. Lammers AE, Adatia I, Cerro MJ, et al. Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011. Pulm Circ. 2011;1:280-285.

129. Savarese G, Paolillo S, Costanzo P, et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials. J Am Coll Cardiol. 2012;60:1192-1201.

130. Li AM, Yin J, Au JT, et al. Standard reference for the six-minute-walk test in healthy children aged 7 to 16 years. Am J Respir Crit Care Med. 2007;176:174-180.

131. Sajan I, Manlhiot C, Reyes J, McCrindle BW, Humpl T, Friedberg MK. Pulmonary arterial capacitance in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease: relation to pulmonary vascular resistance, exercise capacity, and survival. Am Heart J. 2011;162:562-568.

132. Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation. 2002;106:319-324.

56 Chapter 2

133. Oudiz RJ, Midde R, Hovenesyan A, et al. Usefulness of right-to-left shunting and poor exercise gas exchange for predicting prognosis in patients with pulmonary arterial hypertension. Am J Cardiol. 2010;105:1186-1191.

134. Cooper DM, Weiler-Ravell D, Whipp BJ, Wasserman K. Aerobic parameters of exercise as a function of body size during growth in children. J Appl Physiol Respir Environ Exerc Physiol. 1984;56:628-634.

135. Ten Harkel AD, Takken T, Van Osch-Gevers M, Helbing WA. Normal values for cardiopulmonary exercise testing in children. Eur J Cardiovasc Prev Rehabil. 2011;18:48-54.

136. Yetman AT, Taylor AL, Doran A, Ivy DD. Utility of cardiopulmonary stress testing in assessing disease severity in children with pulmonary arterial hypertension. Am J Cardiol. 2005;95:697-699.

137. Lammers AE, Diller GP, Odendaal D, Tailor S, Derrick G, Haworth SG. Comparison of 6-min walk test distance and cardiopulmonary exercise test performance in children with pulmonary hyperten-sion. Arch Dis Child. 2011;96:141-147.

138. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865-870.

139. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hyper-tension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hyperten-sion Disease Management (REVEAL). Circulation. 2010;122:164-172.

140. Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prog-nostic parameter in patients with pulmonary hypertension. Chest. 2006;129:1313-1321.

141. Bernus A, Wagner BD, Accurso F, Doran A, Kaess H, Ivy DD. Brain natriuretic peptide levels in managing pediatric patients with pulmonary arterial hypertension. Chest. 2009;135:745-751.

142. Van Albada ME, Loot FG, Fokkema R, Roofthooft MT, Berger RM. Biological serum markers in the management of pediatric pulmonary arterial hypertension. Pediatr Res. 2008;63:321-327.

143. Lammers AE, Hislop AA, Haworth SG. Prognostic value of B-type natriuretic peptide in children with pulmonary hypertension. Int J Cardiol. 2009;135:21-26.

144. Takatsuki S, Wagner BD, Ivy DD. B-type natriuretic peptide and amino-terminal pro-B-type na-triuretic peptide in pediatric patients with pulmonary arterial hypertension. Congenit Heart Dis. 2012;7:259-267.

145. Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement predicts survival in pulmo-nary hypertension. Am J Respir Crit Care Med. 2006;174:1034-1041.

146. Alkon J, Humpl T, Manlhiot C, McCrindle BW, Reyes JT, Friedberg MK. Usefulness of the right ven-tricular systolic to diastolic duration ratio to predict functional capacity and survival in children with pulmonary arterial hypertension. Am J Cardiol. 2010;106:430-436.

147. Kassem E, Humpl T, Friedberg MK. Prognostic significance of 2-dimensional, M-mode, and Dop-pler echo indices of right ventricular function in children with pulmonary arterial hypertension. Am Heart J. 2013;165:1024-1031.

148. Moledina S, Pandya B, Bartsota M, et al. Prognostic significance of cardiac magnetic resonance imaging in children with pulmonary hypertension. Circ Cardiovasc Imaging. 2013;6:407-414.

149. van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250-1257.

150. Eysmann SB, Palevsky HI, Reichek N, Hackney K, Douglas PS. Two-dimensional and Doppler-echocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension. Circulation. 1989;80:353-360.

151. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010;36:549-555.


2

152. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorex-igen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156-163.

153. Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Survival in pulmonary arte-rial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J. 2010;35:1079-1087.

154. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110:660-665.

155. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation. 2005;111:3274-3280.

156. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arte-rial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol. 2006;47:799-803.

157. Carmosino MJ, Friesen RH, Doran A, Ivy DD. Perioperative complications in children with pul-monary hypertension undergoing noncardiac surgery or cardiac catheterization. Anesth Analg. 2007;104:521-527.

158. Hill KD, Lim DS, Everett AD, Ivy DD, Moore JD. Assessment of pulmonary hypertension in the pediatric catheterization laboratory: current insights from the Magic registry. Catheter Cardiovasc Interv. 2010;76:865-873.

159. Taylor CJ, Derrick G, McEwan A, Haworth SG, Sury MR. Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension. Br J Anaesth. 2007;98:657-661.

160. Ploegstra MJ, Douwes JM, Roofthooft MT, Zijlstra WM, Hillege HL, Berger RM. Identification of treatment goals in paediatric pulmonary arterial hypertension. Eur Respir J. 2014;44:1616-1626.

161. Ploegstra MJ, Roofthooft MTR, Douwes M, et al. The Value Of Echocardiography In Pediatric Pulmonary Arterial Hypertension: Assessing Disease Severity And Outcome Am J Respir Crit Care Med. 2014;189:A3256.

1

2

3

4

5

6

7

8

9

10

Chapter 3Prognostic factors in pediatric pulmonary arterial hypertension: a systematic review and meta-analysis

Mark-Jan PloegstraWillemijn M.H. ZijlstraJohannes M. DouwesHans L. HillegeRolf M.F. Berger

International Journal of Cardiology 2015: 184: 198-207

60 Chapter 3

ABstrACt

Background

Despite the introduction of targeted therapies in pediatric pulmonary arterial hyper-tension (PAH), prognosis remains poor. For the definition of treatment strategies and guidelines, there is a high need for an evidence-based recapitulation of prognostic factors. The aim of this study was to identify and evaluate prognostic factors in pediatric PAH by a systematic review of the literature and to summarize the prognostic value of currently reported prognostic factors using meta-analysis.

Methods and results

Medline, EMBASE and Cochrane Library were searched on April 1st 2014 to identify origi-nal studies that described predictors of mortality or lung-transplantation exclusively in children with PAH. 1053 citations were identified, of which 25 were included for further analysis. Hazard ratios (HR) and 95% confidence intervals were extracted from the pa-pers. For variables studied in at least three non-overlapping cohorts, a combined HR was calculated using random-effects meta-analysis. WHO functional class (WHO-FC, HR 2.7), (N-terminal pro) brain natriuretic peptide ([NT-pro]BNP, HR 3.2), mean right atrial pres-sure (mRAP, HR 1.1), cardiac index (HR 0.7), indexed pulmonary vascular resistance (PVRi, HR 1.3) and acute vasodilator response (HR 0.3) were identified as significant prognostic factors (p≤0.001).

Conclusions

This systematic review combined with separate meta-analyses shows that WHO-FC, (NT-pro)BNP, mRAP, PVRi, cardiac index and acute vasodilator response are consistently reported prognostic factors for outcome in pediatric PAH. These variables are useful clinical tools to assess prognosis and should be incorporated in treatment strategies and guidelines for children with PAH.

Prognostic factors in pediatric PAH 61

3

IntroduCtIon

Pulmonary arterial hypertension (PAH) is a severe progressive disease of the pulmonary vasculature, leading to increased pulmonary vascular resistance (PVR), right ventricular (RV) failure and death.1 Since the recent introduction of specific PAH-targeted drugs, quality of life and survival in both children and adults have improved, but remain unsat-isfactory.2-4

For clinical decision-making in the treatment of these patients, it is important to be able to predict survival using prognostic factors.5 In adults with idiopathic PAH, vari-ous prognostic factors have been identified and reviewed.6,7 Although data in children are limited, several pediatric studies have recently reported on survival and prognostic factors. These data, however, are mostly derived from relatively small patient series and contradictory findings have been reported. It is unclear whether contradictions that have emerged from recent pediatric studies can be explained by differences in study populations, different treatment strategies or by insufficient power of the individual studies due to small sample sizes.

There is a high clinical need to improve treatment strategies and to define guide-lines for the management of children with PAH. Therefore, it is of great importance to identify, appraise, synthesize and combine the currently available data on prognostic factors in pediatric PAH. This will help in defining current evidence and in developing supportive guidelines for the management of infants and children with PAH. Hence, the aim of this study was to identify and evaluate prognostic factors in pediatric PAH, by a systematic review of the literature and to subsequently summarize the prognostic value of currently reported prognostic factors in children with PAH using meta-analysis.

Methods

literature search

Medline, EMBASE and Cochrane Library were searched on April 1st 2014. The initial literature search focused on the overlapping part of three elements: (1) PAH, (2) children and (3) survival. To achieve this, a search string was composed and adapted to the three literature databases (Supplementary Table 1). The keyword “primary pulmonary hypertension” was also included, as this term was previously used for idiopathic PAH (IPAH). In contrast, the formerly used term “secondary pulmonary hypertension” for PH other than IPAH was not included because this group also comprised forms of PH with different etiologies and disease mechanisms than PAH. The search was limited to human studies and English language. The reference lists of all primary identified articles were hand searched for additional relevant publications.

62 Chapter 3

study selection

Titles and abstracts were screened by two independent reviewers (M.J.P and W.M.H.Z., investigators) to identify studies that described predictors of mortality in children with PAH. Eligible studies were required to report at least (1) data on mortality in pediatric PAH and (2) variables studied in relation to mortality. Studies were considered ineligible if they were animal studies or review articles, were not limited to children or when no survival analysis (Cox regression analysis or Kaplan-Meier survival analysis) was per-formed. All remaining studies underwent full-text review, with a targeted focus on the study population and survival analysis details. Studies were excluded when >20% of the study population did not meet the current PAH definition according to the updated Nice classification.8 Studies using endpoints other than death or death + lung-transplantation were also excluded. Any disagreements between the reviewers were resolved by discus-sion leading to consensus or by consulting a third-party arbitrator (H.L.H., epidemiolo-gist/statistical consultant).

data extraction

Of all studied variables, hazard ratios (HR) and 95% confidence intervals (CI) derived from univariable Cox regression analysis were extracted from the papers. When the CI was not reported, the P-value was used to estimate the CI.9 When only Kaplan-Meier analysis was performed to assess a variable’s relation with survival, HR and CI were estimated using Parmar’s survival curve method, on the condition that picture quality and description of patient numbers were sufficient.10 When individual patient data were provided in the paper in the absence of a reported HR, the HR and CI were calculated using Cox regres-sion analysis rather than estimated from the survival curve. When the HR was described for death and death + lung-transplantation, the HR for death was extracted. When analy-ses were performed for characteristics at different baseline moments (e.g. both time of diagnosis and study enrollment), the baseline with least missing values was used.

data synthesis

Multiple separate random-effects meta-analyses were conducted to calculate combined HRs for sufficiently studied candidate prognostic factors. The following methodological considerations were taken into account: (1) patient-overlap between studies, (2) suf-ficiency of number of combinable studies, (3) differences in how the HR was calculated and (4) potential between-study heterogeneity.

Patient-overlap between studies is likely to exist, since most studies on pediatric PAH are performed in a limited number of centers. When a variable was studied and reported more than once by the same center with overlapping inclusion-periods, only the HR from the largest study was included in the meta-analysis. In the case of exactly matching patient numbers, the most recent study was included. HRs from studies that


3

combined previously published cohorts in a new individual patient data level analysis were excluded, unless a HR was not available from the original cohort studies. The HRs of all excluded studies were still displayed in the meta-analysis forest plots in a different color to retain overview of the entirety and consistency of the available data.

Meta-analysis was only considered appropriate when a candidate prognostic fac-tor was studied in at least three non-overlapping cohorts. When meta-analysis was not appropriate, results were summarized in tabular form.

Differences in how the HR was calculated, such as variation in the number of units change used for HR calculation (e.g. when one study reported the HR per 1 mmHg pressure change while another reported the HR per 5 mmHg change), were addressed by recalculating the HRs using a uniform clinically applicable number of units change. HRs of dichotomized continuous variables (i.e. when patients with high values were compared to patients with low values), could not be recalculated and were left unad-justed. HRs based on dichotomized variables were not combined with HRs based on continuous variables, but were displayed separately. The choice of including HRs based on dichotomized or continuous variables in meta-analyses depended on how often the methods were applied: studies with the least applied method were excluded from the meta-analysis but were still displayed in the forest plot in a different color to retain overview of the entirety and consistency of the available data.

Heterogeneity was assessed using both Cochran’s Q-test and the I2 quantity. In view of the small number of studies to be compared, a Q-test p-value <0.10 or an I2 quantity >50% were considered indicative of substantial heterogeneity. In the case of a statistically significant combined weighted HR in combination with substantial evidence for heterogeneity, the methodological characteristics and study populations were compared and exploratory sub-group analysis and meta-regression were conducted to identify potential causes of heterogeneity. Analyses were performed using STATA 11.0 (STATA corp., College Station, Texas, USA).

64 Chapter 3

results

Identified studies

In total, 1053 citations were identified (Figure 1). With screening titles and abstracts, 989 citations were excluded, leaving 64 articles for full-text review (references are provided as Supplementary Material). Screening full articles identified 27 articles that described prognostic factors for survival exclusively in pediatric PAH (Supplementary Table 2). Exclusion reasons per publication are shown in Supplementary Table 3. Additionally, two primarily identified studies were excluded from further data analysis because of inconsistency in data reporting within the paper,11 and because of demonstrable 100% patient-overlap with a previously published report.12 The main characteristics of the remaining 25 studies are outlined in Table 1.

1053 unique publications identified

64 full text review

989 publications excluded during abstract review

148 Not English 13 Animal studies 308 Not original article 87 Case reports 110 PH not main topic 250 Not paediatric study 73 No described survival

25 publications eligible for inclusion

40 publications excluded during full text review 6 PAH not main topic (PH group 1, Nice classification) 4 Not paediatric study or analysis not restricted to children 1 No described survival 24 No survival analysis performeda 3 Endpoint other than death or death + transplantation 2 Other reasonsb

1 publication added during reference list hand search

14/25 HR and CI reported in paper

1/11 HR and CI lacking, individual

patient data in paper

Reported HR and CI used in meta-analysis

746 MEDLINE 705 EMBASE 9 The Cochrane Library

2/11 HR and P-value available,

CI lacking

Calculated HR and CI used in meta-analysis

CI estimated using P-valuec HR and CI estimated using Parmar’s survival curve methodd

Exact HR and CI calculated using Cox regression analysis

8/11 HR and CI lacking, Survival curves available

Reported HR and estimated CI used in meta-analysis

Estimated HR and CI used in meta-analysis

11/25 HR and / or CI not reported in paper

Figure 1. Flow chart showing study selection and data extraction. PH = pulmonary hypertension; PAH = pulmonary arterial hypertension; HR = hazard ratio; CI = 95% confidence interval. aSurvival analysis in which a candidate prognostic factor is evaluated using Cox regression analysis or Kaplan Meier analysis (not: comparison of treatment group survival). bOther reasons included: inconsistency in data reporting within the paper and demonstrable 100% patient overlap with another included paper. cSee Altman et al. 2011 [9]. dSeeParmar et al. 1998 [10].


3

tabl

e 1.

Stu

dy C

hara

cter

istic

s

Stud

y [R

efer

ence

]

Patient number

Study baseline

Type of survival analysis

Endpoint

IPAH / HPAH / Primary PH (%)

APAH-CHD (%)

APAH-non-CHD (%)

Other types of PH (%)

Sex male (%)

Age (yrs)

WHO-FC

NT-proBNP (pg/mL)

BNP (pg/mL)

mRAP (mmHg)

mPAP (mmHg)

Cardiac Index (L/min/m2)

PVRi (WU*m2)

Acute vasodilator responsee (%)

Sand

oval

199

5 [1

4]18

DCo

xD

t10

00

00

399.

92.

85.

4 d

66.0

d4.

1 d

18.4

d59

d

Clab

by 1

997

[26]

50D

Cox

Dt

3070

00

358.

36.

162

.03.

622

.0

Bars

t 199

9 [1

5]77

DCo

xD

t10

00

00

357.

02.

95.

065

.03.

122

.042

d

Nak

ayam

a 20

07 [2

4]31

TKM

Dt/

LTx

100

00

052

10.7

3.3

511

9.2

d84

.1 d

2.3

d32

.4

Van

Alb

ada

2008

[22]

29P

KMa

Dt

6238

00

387.

0 c

1065

Bern

us 2

009

[23]

78O

KMD

t33

538

646

9.3

c36

c6.

0c d

38.0

c d

3.5

c d

6.5

c d

Haw

orth

200

9 [4

9]21

6P

KMD

t28

484

2046

7.7

3.1

52.4

d17

.4 d

Lam

mer

s 20

09 [2

5]50

PKM

Dt/

LTx

5434

210

648.

42.

714

49.

1 d

62.4

d19

.5 d

Van

Loon

201

0 [3

]52

DCo

xD

t56

440

037

3.1

c2.

950

17.

055

.02.

820

.515

Lam

mer

s 20

10 [2

7]47

OCo

xD

t/LT

x45

450

1057

11.4

2.7

8.3

58.4

22.1

Alk

on 2

010

[50]

47O

Cox

Dt/

LTx

3664

00

325.

5 c

1.8

Mol

edin

a 20

10 [1

7]64

PCo

xD

t10

00

00

376.

5 c

3.1

7.1

d58

.0 d

2.9

d19

.7 d

9 d

Ivy

2010

[21]

86T

Cox

Dt

4256

20

4311

.02.

37.

0 d

63.0

d3.

6 d

20.0

d

His

lop

2011

[19]

101

TKM

Dt

4258

00

429.

72.

87.

6 d

56.4

d21

.1 d

Mol

edin

a 20

11 [2

0]31

OCo

xD

t39

450

1642

10.3

2.6

6.0

c d

42.0

c d

13.2

c d

Van

Loon

201

1 [5

1]15

4D

KMD

t23

725

049

2.2

c2.

5 d

7.0

d51

.0 d

2.7

d17

.8 d

Bars

t 201

2 [1

6]21

6E

Cox

Dt

5636

80

3615

.0 c

2.1

7.0

56.0

3.7

17.0

27 d

Chid

a 20

12 [5

2]54

OCo

xD

t10

00

00

448.

557

c d

6.8

d64

.3 d

3.2

d19

.1 d

66 Chapter 3

tabl

e 1.

(con

tinue

d)

Stud

y [R

efer

ence

]

Patient number

Study baseline

Type of survival analysis

Endpoint

IPAH / HPAH / Primary PH (%)

APAH-CHD (%)

APAH-non-CHD (%)

Other types of PH (%)

Sex male (%)

Age (yrs)

WHO-FC

NT-proBNP (pg/mL)

BNP (pg/mL)

mRAP (mmHg)

mPAP (mmHg)

Cardiac Index (L/min/m2)

PVRi (WU*m2)

Acute vasodilator responsee (%)

Api

tz 2

012

[53]

43D

KMD

t/LT

x10

00

00

4410

.42.

467

.13.

023

.549

Dou

wes

201

3 [1

8]52

PCo

xD

t/LT

x64

360

040

7.1

c2.

86.

0 c

51.0

2.8

c14

.6 c

Mol

edin

a 20

13 [4

1]10

0D

Cox

Dt/

LTx

6022

?b?b

3910

.4 c

2.3

Kass

em 2

013

[54]

54E

KMD

t/LT

x33

670

035

8.0

18.5

Wag

ner 2

013

[13]

83O

Cox

Dt

4357

00

518.

3 c

6.0

c d

40.0

c d

4.0

c d

7.9

c d

Chid

a 20

14 [5

5]59

OCo

xD

t10

00

00

4411

.33.

016

697.

365

.53.

121

.3

Zijls

tra

2014

[4]

275

DCo

xD

t/LT

x52

426

041

6.4

c2.

670

8 d

81 d

6.0

d55

.03.

6 d

15.8

25 d

Dat

a ar

e pr

esen

ted

as p

erce

ntag

e or

mea

n, u

nles

s sta

ted

othe

rwis

e. P

AH =

pul

mon

ary

arte

rial h

yper

tens

ion;

PH

= p

ulm

onar

y hy

pert

ensi

on; I

PAH

= id

iopa

thic

PAH

; APA

H =

as-

soci

ated

PAH

; CH

D =

con

geni

tal h

eart

dis

ease

; WH

O-F

C =

WH

O fu

nctio

nal c

lass

, NT-

proB

NP

= N

-ter

min

al-p

ro b

rain

nat

riure

tic p

eptid

e; B

NP

= br

ain

natr

iure

tic p

eptid

e; m

RAP

= m

ean

right

atr

ial p

ress

ure;

mPA

P =

mea

n pu

lmon

ary

arte

ry p

ress

ure;

PVR

i = in

dexe

d pu

lmon

ary

vasc

ular

resi

stan

ce; D

= d

iagn

osis

; T =

trea

tmen

t sta

rt; P

= p

rese

ntat

ion;

E =

en

rollm

ent;

O =

oth

er, C

ox =

Cox

regr

essi

on a

naly

sis;

KM =

Kap

lan-

Mei

er a

naly

sis;

Dt =

dea

th; D

t/LT

x =

deat

h or

lung

-tra

nspl

anta

tion.

a Als

o in

divi

dual

pat

ient

dat

a av

aila

ble

in p

aper

, allo

win

g fo

r haz

ard

ratio

cal

cula

tion.

b The

dia

gnos

is o

f 18%

of t

he p

atie

nts i

n th

is st

udy

was

des

crib

ed a

s ‘m

isce

llane

ous c

ause

s of P

H’, w

hich

cou

ld b

e in

terp

rete

d as

ei

ther

APA

H-n

on-C

HD

or o

ther

type

s of P

H. c M

edia

n (m

ean

not r

epor

ted

in p

aper

). d C

alcu

late

d w

ithin

a su

bgro

up o

f the

coho

rt. e T

ype

of v

asod

ilato

rs a

nd d

efini

tions

of a

favo

r-ab

le re

spon

se d

iffer

ed th

roug

hout

the

stud

ies.


3

tabl

e 2.

Var

iabl

es A

ssoc

iate

d W

ith S

urvi

val,

Per S

tudy

Sandoval 1995 [14]

Clabby 1997 [26]

Barst 1999 [15]

Nakayama 2007 [24]

Van Albada 2008 [22]

Bernus 2009 [23]

Haworth 2009 [49]

Lammers 2009 [25]

Van Loon 2010 [3]

Lammers 2010 [27]

Alkon 2010 [50]

Moledina 2010 [17]

Ivy 2010 [21]

Hislop 2011 [19]

Moledina 2011 [20]

Van Loon 2011 [51]

Barst 2012 [16]

Chida 2012 [52]

Apitz 2012 [53]

Douwes 2013 [18]

Moledina 2013 [41]

Kassem 2013 [54]

Wagner 2013 [13]

Chida 2014 [55]

Zijlstra 2014 [4]

N times studied

N times significant

N extractable HRsa

N HRs from non-overlapping cohorts

dem

ogra

phic

Age

✗✗

✓✗

✗✗

✗✗

✓✗

102

65

Sex

✗✗

✓✗

✓✗

✗✗

✗✗

102

55

Clin

ical

Dia

gnos

is✗

✗✗

✗✗

✓✗

✗✓

92

73

WH

O-F

C✗

✓✓

✓✓

✗✗

✓✓

✓✓

118

104

6MW

T✗

✓✗

✗✗

✗6

12

1

Hea

rtra

te✗

✗✓

✓✗

52

22

Syst

olic

RR

✓✗

✗✓

42

32

Dia

stol

ic R

R✓

✓2

22

1

Hei

ght

✓✗

✗✗

41

22

Wei

ght

✗✓

✗✗

41

22

BSA

✓1

11

1

Hea

rtra

te v

aria

bilit

y✓

11

11

peak

VO

2✓

11

11

VE/V

CO2

slop

e✓

11

11

BMPR

2 m

utat

ion

✓1

11

1

68 Chapter 3

tabl

e 2.

(con

tinue

d)

Sandoval 1995 [14]

Clabby 1997 [26]

Barst 1999 [15]

Nakayama 2007 [24]

Van Albada 2008 [22]

Bernus 2009 [23]

Haworth 2009 [49]

Lammers 2009 [25]

Van Loon 2010 [3]

Lammers 2010 [27]

Alkon 2010 [50]

Moledina 2010 [17]

Ivy 2010 [21]

Hislop 2011 [19]

Moledina 2011 [20]

Van Loon 2011 [51]

Barst 2012 [16]

Chida 2012 [52]

Apitz 2012 [53]

Douwes 2013 [18]

Moledina 2013 [41]

Kassem 2013 [54]

Wagner 2013 [13]

Chida 2014 [55]

Zijlstra 2014 [4]

N times studied

N times significant

N extractable HRsa

N HRs from non-overlapping cohorts

Bioc

hem

ical

(NT-

pro)

BNP

✓✓

✓✓

✓✓

✗✓

✓9

88

4

Uric

Aci

d✓

✓✓

33

32

Hb

✗✓

21

11

Nor

epin

ephr

ine

✓1

11

1

Apo

-A1

✓1

11

1

TIM

P-1

✓1

11

1

sST2

✓1

11

1

hem

odyn

amic

mRA

P✗

✓✓

✗✗

✗✗

✗✓

93

63

mPA

P✗

✓✓

✗✗

✗✗

✗✗

✓✗

113

74

mPA

P/m

SAP

✗✓

✓✓

✗✓

64

42

PVRi

✗✓

✓✗

✓✗

✓✗

✓✗

✓✓

127

94

Card

iac

inde

x✗

✗✓

✓✗

✗✓

✗✗

✓10

47

4

Qp(

i)✓

✗✗

31

22

SvO

2✓

✓2

22

2

PAC(

i)✓

✗2

11

1

PVR/

SVR

✗✓

21

22


3

Acut

e re

spon

se✗

✓✗

✗✗

✓✓

73

44

PVR

durin

g VR

T✓

✓2

22

1

mPA

P du

ring

VRT

✓✓

22

22

PFR

durin

g VR

T✓

11

11

mRA

P x

PVRi

✓1

11

1

PSVi

✓1

11

1

Imag

ing

Echo

card

iogr

aphy

b✓

✓✓

✗✓

✓6

56

3

CMRc

✓1

11

1

CT,

frac

tal d

im.

✓1

11

1

‘✓’ =

sig

nific

ant a

ssoc

iatio

n w

ith s

urvi

val;

‘✗’ =

no

sign

ifica

nt a

ssoc

iatio

n w

ith s

urvi

val;

shad

ed in

dica

tes

that

suffi

cien

t sur

viva

l ana

lysi

s re

sults

wer

e pr

ovid

ed in

the

pape

r to

be in

clud

ed in

met

a-an

alys

is; H

R =

haza

rd ra

tio; W

HO

-FC

= W

HO

func

tiona

l cla

ss; 6

MW

T =

6-m

inut

e w

alk

test

; RR

= bl

ood

pres

sure

; BSA

= b

ody

surf

ace

area

; VO

2 =

oxyg

en

cons

umpt

ion;

VE/

VCO

2 =

vent

ilato

ry-e

ffici

ency

slo

pe; B

MPR

2 =

bone

mor

phog

enet

ic p

rote

in re

cept

or ty

pe II

; (N

T-pr

o)BN

P =

(N-t

erm

inal

pro

) bra

in n

atriu

retic

pep

tide;

Hb

= he

mog

lobi

n; A

po-A

1 =

apol

ipop

rote

in-A

-1; T

IMP-

1 =

met

allo

pept

idas

e-in

hibi

tor-

1; sS

T2 =

solu

ble

ST2;

mRA

P =

mea

n rig

ht a

tria

l pre

ssur

e; m

PAP

= m

ean

pulm

onar

y ar

tery

pre

s-su

re; m

PAP/

mSA

P =

pulm

onar

y-to

-sys

tem

ic a

rter

ial p

ress

ure

ratio

; PVR

i = in

dexe

d pu

lmon

ary

vasc

ular

resi

stan

ce; Q

p(i)

= pu

lmon

ary

bloo

d flo

w (i

ndex

); Sv

O2

= m

ixed

ven

ous

oxyg

en sa

tura

tion;

PAC

(i) =

pul

mon

ary

arte

rial c

apac

itanc

e (in

dex)

; PVR

/SVR

= p

ulm

onar

y-to

-sys

tem

ic v

ascu

lar r

esis

tanc

e ra

tio; V

RT =

vas

orea

ctiv

ity te

stin

g; P

FR =

pul

mon

ary

flow

rese

rve;

PSV

i = p

ulm

onar

y st

roke

vol

ume

inde

x; C

MR

= ca

rdia

c m

agne

tic re

sona

nce

imag

ing;

CT

= co

mpu

ted

tom

ogra

phy.

a HR

was

onl

y ex

trac

tabl

e w

hen

suffi

cien

t sur

-vi

val a

naly

sis r

esul

ts w

ere

prov

ided

in th

e pa

per.

b Ech

ocar

diog

raph

ic v

aria

bles

onc

e sh

own

to b

e as

soci

ated

with

surv

ival

incl

ude:

sem

i-qua

ntita

vely

ass

esse

d RV

-hyp

ertr

ophy

, RV

-dila

tatio

n an

d RV

-func

tion

(sco

re 1

-4),

syst

olic

to d

iast

olic

dur

atio

n ra

tio, m

axim

um tr

icus

pid

regu

rgita

tion

velo

city

, RV-

fract

iona

l are

a ch

ange

, Z-s

core

of t

ricus

pid

annu

lar

plan

e sy

stol

ic e

xcur

sion

, Z-s

core

of R

V en

d-di

asto

lic a

rea,

RV

end

syst

olic

are

a in

dex

and

right

to le

ft v

entr

icul

ar d

imen

sion

ratio

. c CM

R va

riabl

es o

nce

show

n to

be

asso

ciat

ed

with

surv

ival

incl

ude:

RV

end-

dias

tolic

vol

ume

inde

x, R

V en

d-sy

stol

ic v

olum

e in

dex,

RV

ejec

tion

fract

ion,

RV

mas

s ind

ex, L

V st

roke

vol

ume

inde

x, tr

icus

pid

regu

rgita

tion

fract

ion,

rig

ht a

tria

l are

a in

dex,

and

mid

righ

t ven

tric

le d

iam

eter

inde

x.

70 Chapter 3

Identified candidate prognostic factors

Table 2 summarizes a total of 40 variables that have been shown to be significantly re-lated to survival in one or more studies. The availability of HRs (either directly reported or indirectly calculable) is also shown in Table 2. For 10 of the 40 identified variables, there were HRs available from at least three non-overlapping cohorts. For these 10 candidate prognostic factors, a combined HR and accompanying P-value could be calculated using meta-analysis (Table 3). The corresponding forest plots are displayed in Figures 2-4. The meta-analysis results of the 10 candidate prognostic factors are detailed below.

Age was investigated in 10 studies, with HRs available from 6/10 studies (Table 2). One of these 6 was omitted from meta-analysis to prevent duplicate patient inclusion (Figure 2).13 Combining the remaining 5 non-overlapping cohorts representing 426 patients yielded a HR (CI) of 1.01 (0.92-1.10) per year increase (Figure 2, p=0.866), indicating no significant association with survival. North-American studies (Sandoval, Barst 1999, Barst 2012 and Wagner13-16) and European studies (Moledina and Douwes17,18) reported contradictory findings.

table 3. Combined Prognostic Value of Candidate Prognostic Factors

Predictor N HR (CI) P-value

demographic

Age, per year 426 1.01 (0.92-1.10) 0.866

Sex, male compared to female 428 1.38 (0.55-3.43) 0.495

Clinical / biochemical

Diagnosis, APAH compared to IPAH 585 0.70 (0.41-1.19) 0.191

WHO-FC (high compared to low) 307 2.67 (1.49-4.80) 0.001

(NT-pro)BNP (high compared to low) 351 3.24 (1.76-6.02) <0.001

hemodynamic

mRAP, per mmHg 404 1.12 (1.05-1.20) 0.001

mPAP, per 10 mmHg 254 1.18 (0.99-1.40) 0.056

Cardiac index, per 1 L/min/m2 360 0.66 (0.52-0.84) 0.001

PVRi, per 10 WU*m2 353 1.32 (1.17-1.48) <0.001

Acute vasodilator response 312 0.27 (0.14-0.54) <0.001

Data is presented as hazard ratio (95% confidence interval). HR = hazard ratio; CI = 95% confidence interval; APAH = associated pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; WHO-FC = WHO functional class; (NT-pro)BNP = (N-terminal-pro) brain natriuretic peptide; mRAP = mean right atrial pressure; mPAP = mean pulmonary arterial pressure; PVRi = (indexed) pulmonary vascular resistance; WU = wood units.


3

Sex was investigated in 10 studies, with HRs available from 5/10 studies (Table 2). Combining these 5 non-overlapping cohorts representing 428 patients yielded a HR (CI) of 1.38 (0.55-3.43) for male compared to female (Figure 2, p=0.495), indicating no significant association with survival.

Diagnosis was investigated in 9 studies, with HRs available from 2 studies and survival curves available from 5 studies (Table 2). Four of these 7 were omitted from meta-analysis to prevent duplicate patient inclusion (Figure 3).3,4,18,19 Combining the remaining 3 non-overlapping cohorts representing 585 patients yielded a HR (CI) of 0.70 (0.41-1.19) for associated PAH (APAH) compared to IPAH (Figure 3, p=0.191), indicating no significant association with survival.

World Health Organization functional class (WHO-FC) was investigated in 11 stud-ies, with HRs available from 10/11 studies (Table 2). Since WHO-FC was mostly studied as a dichotomized variable, 3 studies that reported HRs based on WHO-FC as a continuous variable were omitted from meta-analysis (Figure 3).3,17,20 An additional 3 studies were omitted to prevent duplicate patient inclusion.4,13,21Combining the remaining 4 non-overlapping cohorts representing 307 patients yielded a HR (CI) of 2.67 (1.49-4.80), for high compared to low WHO-FC (Figure 3, p=0.001), without substantial heterogeneity-evidence (p=0.452, I2=0.0%).

HR per year increase

Sandoval 1995, n=18

Barst 1999, n=77

Moledina 2010, n=64

Barst 2012, n=215

Douwes 2013, n=52

Wagner 2013, n=83

COMBINED, n=426 (p=0.866) Heterogeneity: p=0.011, I2=69.5%

Age

HR of male compared to female

Sandoval 1995, n=18

Barst 1999, n=77

Moledina 2010, n=64

Barst 2012, n=215

Chida 2012, n=54


Sex

HR (95% CI)

1.09 (0.78-1.53)

1.14 (1.03-1.26)

0.92 (0.81-1.05)

1.04 (1.00-1.07)

0.89 (0.79-1.00)

1.13 (1.02-1.24)

1.01 (0.92-1.10)

HR (95% CI)

3.33 (0.51-20.0)

2.69 (1.18-6.13)

0.11 (0.01-0.85)

0.76 (0.35-1.67)

2.62 (0.87-8.73)

1.38 (0.55-3.43)

0.67 1 1.5

0.05 1 20

10 . 6 7

12 00 . 0 5

Figure 2. Forest plots showing demographic candidate prognostic factors. HR = hazard ratio; CI = confi-dence interval. HRs displayed as diamonds ◆ are based on dichotomized variables, HR’s displayed as dots ● are based on continuous variables. Area of each diamond / dot is proportional to the sample size of the studied cohort. Only HRs in blue are non-overlapping and included in meta-analysis.

72 Chapter 3

HR of high compared to low WHO-FC or per FC increase

Sandoval 1995, n=18 (III/IV vs. I/II)

Van Loon 2010, n=52 (per FC)

Lammers 2010, n=47 (III/IV vs. I/II)

Moledina 2010, n=64 (per FC)

Ivy 2010, n=81 (III/IV vs. I/II)

Moledina 2011, n=31 (per FC)

Barst 2012, n=190 (III/IV vs. I/II)

Douwes 2013, n=52 (IV vs. I/II/III)

Wagner 2013, n=83 (III/IV vs. I/II)

Zijlstra 2014, n=236 (III/IV vs. I/II)


HR (95% CI)

2.30 (0.21-24.4)

3.00 (1.19-7.65)

10.8 (1.44-81.0)

2.35 (1.04-5.30)

5.40 (1.20-24.6)

6.80 (0.92-50.3)

1.98 (0.92-4.26)

3.41 (1.11-10.4)

6.73 (1.20-37.8)

2.23 (1.09-4.58)

2.67 (1.49-4.80)

HR of high compared to low (NT-pro)-BNP or per unit increase

Nakayma 2007, n=27 (400 pg/mL)a,d

Van Albada 2008, n=24 (per ng/mL)b,e

Bernus 2009, n=78 (180 pg/mL)a,d

Lammers 2009, n=50 (130 pg/mL)a,d

Van Loon 2010, n=52 (per 10-Log value)e

Barst 2012, n=215 (50/[300] pg/mL)f

Chida 2014, n=59 (537 pg/mL)e

Zijlstra 2014, n=41 (per 10-Log value)e

COMBINED, n=351 (p<0.001) Heterogeneity: p=0.664, I2=0.0%

HR (95% CI)

3.57 (0.82-15.6)

1.97 (1.10-3.71)

11.4 (2.55-50.9)

2.60 (0.89-7.65)

9.17 (2.03-41.5)

2.86 (1.11-7.69)

10.9 (1.40-85.3)

4.04 (1.17-13.9)

3.24 (1.76-6.02)

WHO-FC

(NT-pro)BNPc

0.02 1 50

0.02 1 50

15 00 . 0 2

15 00 . 0 2

HR of APAH compared to IPAH

Haworth 2009, n=216a

Van Loon 2010, n=52a

Hislop 2011, n=101a

Van Loon 2011, n=154a

Barst 2012, n=215

Douwes 2013, n=52a

Zijlstra 2014, n=275


Diagnosis HR (95% CI)

0.71 (0.36-1.41)

0.71 (0.27-1.87)

1.06 (0.35-3.22)

0.49 (0.32-0.76)

1.24 (0.58-2.66)

0.81 (0.22-2.99)

0.47 (0.23-0.97)

0.70 (0.41-1.19)

0.2 1 5 150 . 2

Figure 3. Forest plots showing clinical and biochemical candidate prognostic factors. HR = hazard ratio; CI = confidence interval; APAH = associated pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; FC = functional class; (NT-pro)BNP = (N-terminal-pro) brain natriuretic peptide. HRs displayed as diamonds ◆ are based on dichotomized variables, HRs displayed as dots ● are based on con-tinuous variables. Area of each diamond / dot is proportional to the sample size of the studied cohort. Only HRs in blue are non-overlapping and included in meta-analysis. aHR estimated from survival curve. bHR calculated from reported individual patient data. cBetween brackets are the cut-off values used in dichoto-mization or the number of units increase at which the HR calculation was based. dStudied biomarker was BNP. eStudied biomarker was NT-proBNP. fBoth BNP and NT-proBNP were studied.


3

(N-Terminal-pro) brain natriuretic peptide ([NT-pro]BNP) was investigated in 9 stud-ies (Table 2, 4x BNP, 3x NT-proBNP, 2x both) and the results of these studies were com-bined. HRs, survival curves and individual patient data were available from 4, 3 and 1 studies, respectively (Figure 3). Since (NT-pro)BNP was mostly studied as a dichotomized

HR per 1 mmHg increase in mRAP

Sandoval 1995, n=18 (>7 mmHg)b

Clabby 1997, n=50

Barst 1999, n=77

Lammers 2010, n=47

Moledina 2010, n=58



HR (95% CI)

8.41 (0.99-71.0)

1.36 (1.15-1.60)

1.21 (1.07-1.38)

0.71 (0.42-1.10)

1.02 (0.85-1.23)

1.11 (1.04-1.18)

1.12 (1.05-1.20)

HR per 10 mm Hg increase

Sandoval 1995, n=18 (>66 mmHg)

Clabby 1997, n=50

Barst 1999, n=77

Lammers 2010, n=47

Moledina 2010, n=58

Douwes 2013, n=52

Wagner 2013, n=67


HR (95% CI)

1.28 (0.18-8.84)

1.34 (1.00-1.97)

1.22 (1.00-1.48)

1.10 (0.90-1.34)

1.00 (0.82-1.34)

1.10 (0.82-1.48)

1.63 (1.10-2.37)

1.18 (0.99-1.40)

HR per 10 WU.m2 increase in indexed PVR

Sandoval 1995, n=18 (>23 WU.m2)

Clabby 1997, n=50

Barst 1999, n=77

Lammers 2010, n=47

Moledina 2010, n=58

Ivy 2010, n=66 (>20 WU.m2)

Barst 2012, n=166

Douwes 2013, n=52

Wagner 2013, n=67


COMBINED, n=353 (p<0.001) Heterogeneity: p=0.731, I2=0.0%

HR (95% CI)

2.17 (0.30-15.6)

1.97 (1.34-2.59)

1.48 (1.10-1.97)

1.79 (1.10-2.84)

1.10 (0.74-1.79)

5.40 (1.10-26.8)

1.30 (1.12-1.49)

1.34 (0.90-1.97)

4.05 (1.79-10.1)

1.40 (1.12-1.74)

1.32 (1.17-1.48)

HR of responders compared to non-responders

Sandoval 1995, n=18c

Barst 1999, n=77d

Barst 2012, n=174e

Apitz 2012, n=43f,g

COMBINED, n=312 (p<0.001) Heterogeneity: p=0.801, I2=0.0%)

HR (95% CI)

0.34 (0.03-3.75)

0.15 (0.03-0.47)

0.29 (0.07-1.24)

0.35 (0.13-0.97)

0.27 (0.14-0.54)

HR per 1 L/min/m2 increase

Sandoval 1995, n=18 (>3 L/min/m2)

Barst 1999, n=77

Van Loon 2010, n=52

Moledina 2010, n=58

Barst 2012, n=173

Douwes 2013, n=52



HR (95% CI)

0.30 (0.04-2.13)

0.59 (0.39-0.91)

0.48 (0.23-0.98)

0.92 (0.50-1.66)

0.65 (0.45-0.94)

0.62 (0.32-1.21)

0.73 (0.58-0.94)

0.66 (0.52-0.84)

mPAPa

mRAPa

PVRia

Cardiac Indexa

Responsiveness To Acute Vasodilator Testing

0.02 1 50

0.2 1 5

0.2 1 5

0.5 1 2

0.5 1 2 1

20 . 5

15 00 . 0 2

11 00 . 1

150 . 2

120 . 5

11 0 00 . 0 10.01 100

Figure 4. Forest plots showing hemodynamic candidate prognostic factors. mRAP = mean right atrial pres-sure; HR = hazard ratio; CI = confidence interval; mPAP = mean pulmonary artery pressure; PVRi = indexed pulmonary vascular resistance; WU = wood units. HRs displayed as diamonds ◊ are based on dichotomized variables, HRs displayed as dots • are based on continuous variables. Area of each diamond / dot is pro-portional to the sample size of the studied cohort. Only HRs in blue are non-overlapping and included in meta-analysis. aBetween brackets are the cut-off values used in dichotomization of the variable at which the HR calculation was based. bBecause of the high HR and wide 95% CI, this study is shown on a different scale. cResponse defined as (1) >20% decrease in mPAP or PVRi, (2) decrease in pulmonary / systemic vascu-lar resistance ratio and (3) absence of a deleterious effect on pulmonary gas exchange. dResponse defined as (1) ≥20% decrease in mPAP, (2) no decrease in cardiac index and (3) no increase in pulmonary / systemic vascular resistance ratio. eResponse defined as (1) ≥20% decrease in mPAP, (2) no decrease in cardiac index <2.5 L/min/m2 and (3) no increase in pulmonary / systemic vascular resistance ratio. fResponse defined as >20% reduction of mean pulmonary artery pressure / mean systemic artery pressure ratio. gHR estimated from survival curve.

74 Chapter 3

variable, 3 studies that reported HRs based on (NT-pro)BNP as a continuous variable were omitted from meta-analysis.3,4,22 One additional study was omitted to prevent duplicate patient inclusion.23 Combining the 4 remaining non-overlapping cohorts representing 351 patients yielded a HR (CI) of 3.24 (1.76-6.02) for high levels compared to low (Figure 3, p<0.001), without substantial heterogeneity-evidence (p=0.664, I2=0.0%).

To be able to selectively analyze BNP instead of analyzing BNP and NT-proBNP together, we performed a sensitivity analysis. In the studies of Nakayama et al., Bernus et al., and Lammers et al., BNP was studied exclusively.23-25 Combining these 3 non-overlapping cohorts representing 155 patients yielded a HR (CI) of 4.24 (1.80-9.96) for high levels compared to low (Supplementary Figure 1, p=0.001), without substantial heterogeneity-evidence (p=0.284, I2=20.5%). A similar separate analysis for NT-proBNP was hampered by the low number of non-overlapping cohorts in which NT-proBNP was studied exclusively (n=2).

Mean right atrial pressure (mRAP) was investigated in 9 studies, with HRs available from 6/9 studies (Table 2). Since mRAP was mostly studied as a continuous variable, 1 study that reported a HR based on dichotomized mRAP was omitted from meta-analysis (Figure 4).14 An additional 2 studies were omitted to prevent duplicate patient inclu-sion.26,27 Combining the remaining 3 non-overlapping cohorts representing 404 patients yielded a HR (CI) of 1.12 (1.05-1.20) per mmHg increase (Figure 4, p=0.001), without substantial heterogeneity-evidence (p=0.289, I2=19.3%).

Mean pulmonary artery pressure (mPAP) was investigated in 11 studies, with HRs available from 7/11 studies (Table 2). Since mPAP was mostly studied as a continuous variable, 1 study that reported a HR based on dichotomized mPAP was omitted from meta-analysis (Figure 4).14 An additional 2 studies were omitted to prevent duplicate patient inclusion.26,27 Combining the remaining 4 non-overlapping cohorts representing 254 patients yielded a HR (CI) of 1.18 (0.99-1.40) per mmHg increase (Figure 4, p=0.056), indicating no significant association with survival.

Cardiac index was investigated in 10 studies, with HRs available in 7/10 studies (Table 2). Since cardiac index was mostly studied as a continuous variable, 1 study that reported a HR based on dichotomized cardiac index was omitted from meta-analysis (Figure 4).14 An additional 2 studies were omitted to prevent duplicate patient inclu-sion.3,4 Combining the remaining 4 non-overlapping cohorts representing 360 patients yielded a HR (CI) of 0.66 (0.52-0.84) per L/min/m2 increase (Figure 4, p=0.001), without substantial heterogeneity-evidence (p=0.685, I2=0.0%).

Indexed pulmonary vascular resistance (PVRi) was investigated in 12 studies, with HRs available in 10/12 studies (Table 2). Since PVRi was mostly studied as a continuous variable, 2 studies that reported a HR based on dichotomized PVRi were omitted from meta-analysis (Figure 4).14,21 An additional 4 studies were omitted to prevent duplicate patient inclusion.4,13,26,27 Combining the remaining 4 non-overlapping cohorts represent-


3

ing 353 patients yielded a HR (CI) of 1.32 (1.17-1.48) per 10 WU*m2 increase (Figure 4, p<0.001), without substantial heterogeneity-evidence (p=0.731, I2=0.0%).

Acute vasodilator response was investigated in 7 studies, with HRs and survival curves available from 3 and 1 studies, respectively (Table 2). It must be noted that the used vasodilators and definitions of a favorable response differed in these studies (Figure 4). Still, combining these 4 non-overlapping cohorts representing 312 patients yielded a HR (CI) of 0.27 (0.14-0.45) for responders compared to non-responders (Figure 4, p<0.001), without substantial heterogeneity-evidence (p=0.801, I2=0.0%).

Other variables. Table 2 shows that imaging modalities have also been studied more than once (5x echocardiography, 1x cardiac magnetic resonance imaging [CMR]). None of the investigated echo-variables has been studied more than once in the same way, hampering further comparison or meta-analysis.

dIsCussIon

To our knowledge, this is the first study systematically reviewing and meta-analyzing all currently available prognostic factors in pediatric PAH. Separate meta-analyses for candidate prognostic factors showed convincing evidence for the prognostic value of the following six variables: WHO-FC, (NT-pro)BNP, mRAP, PVRi, cardiac index and acute vasodilator response.

Systematic reviews combined with meta-analyses are powerful methods for sum-marizing and synthesizing data and are the building blocks of evidence-based practice. The highest level of evidence is reached when only randomized studies are included in a systematic review, but the available systematic reviews in adults show that this is not possible in a rare disease like PAH.6,28 As stated by the Cochrane Collaboration, a system-atic review of non-randomized observational studies is justified when the question of interest cannot be answered by a review of randomized trials.29 As only one randomized trial has been performed in children with PAH, this justification especially applies to the field of pediatric PAH.30,31

Prognostic factors have also been systematically reviewed in adult PAH.6,7,28 Well-established predictors of mortality in adults include: WHO-FC, heart rate, 6-minute walk distance (6MWD), (NT-pro)BNP, pericardial effusion, tricuspid annular plane systolic excursion, mPAP, mRAP, cardiac index, stroke volume index, PVR, acute vasodilator re-sponse and mixed venous oxygen saturations. The six prognostic factors identified in the current study are highly in line with adult evidence. However, an important difference between adult and pediatric PAH is the available evidence for 6MWD as a prognostic factor. Whereas 6MWD has repeatedly and consistently been shown to predict survival in adults2,32, the prognostic value of 6MWD in children has been questioned because of

76 Chapter 3

its limited feasibility at young age and the lack of available data (Table 2). More pediatric research is needed on this topic, and might focus on the prognostic value of 6MWD in older children (e.g. ≥7 years).

Several recommendations regarding the clinical assessment of prognosis have been made in current adult treatment guidelines.5 Since the results from the current systematic review provide an overview of evidence for prognostic factors specifically in pediatric PAH, such recommendations are now also possible for children.

Prognostic factors with moderate to high level of evidence

WHO-FC. The applicability of WHO-FC in young children has been questioned in the past, because it is mainly based on the observation and impression of caregivers. Despite this apparent limitation, the current study shows WHO-FC to be one of the strongest prognostic factors in pediatric PAH, also in the relatively younger pediatric cohorts. Not all studies on WHO-FC could be included in meta-analysis because of potential patient overlap, but combining 4 non-overlapping cohorts showed a strong association with survival which was consistent with the results of the 6 excluded studies. The results support the recent consensus statement from the Pediatric Task Force of the 5th World Symposium for Pulmonary Hypertension (WSPH) held in Nice 2013, which proposes to strive for WHO-FC I or II as a treatment goal in pediatric PAH.33 Treatment-induced changes in WHO-FC carry prognostic value in both adults and children, which further underscores its usefulness and validity as a pediatric treatment goal.34-36

(NT-pro)BNP. Pediatric studies that evaluated the prognostic value of (NT-pro)BNP differed regarding the biomarker under study (BNP, NT-proBNP or both), the used cut-off values and the analysis techniques. Nevertheless, there was a high degree of consis-tency and a strong association with survival in the combined meta-analysis. A sensitivity analysis with solely inclusion of studies that studied BNP, also showed a significant as-sociation with survival. It has recently been shown that children who stay on NT-proBNP levels below 1200 ng/L during treatment have significantly better survival rates, which is in line with adult findings regarding this topic.34,36 This suggests that a low NT-proBNP level is not only a strong predictor of survival, but is also a valid treatment goal to be used in pediatric goal-oriented treatment strategies.

Hemodynamic variables. Cardiac catheterization in childhood often requires seda-tion or general anesthesia and has been reported to be accompanied by a complication rate of 4-6%.37 However, the fact that 4 of the 6 identified prognostic factors in this study are hemodynamic measures underlines the importance of cardiac catheterization, at least to assess disease severity and prognosis at time of diagnosis.


3

Prognostic factors with low level of evidence

Although not statistically significant, APAH appeared to have a slightly more favorable prognosis compared to IPAH. Importantly, it must be noted that the meta-analysis concerning diagnosis was based upon HRs that were predominantly estimated from survival curves using Parmar’s survival curve method.10,38 This method is known to lead to underestimations of the HRs in smaller sample sizes, which subsequently could have led to an underestimation of the combined HR.39 In addition, all subtypes of APAH were analyzed together, while differences in prognostic value might exist within this group.

Other biomarkers than (NT-pro)BNP have also been shown to correlate with survival in pediatric PAH. The current systematic literature search showed that uric acid was a significant prognostic factor in 3 separate studies based on 2 non-overlapping cohorts (Table 2). Although uric acid was not frequently enough studied to be combined in meta-analysis, this indicates at least a low level of evidence for this prognostic factor.

Although meta-analysis could not be performed for echocardiography, this im-aging modality has repeatedly been shown to yield important measures for prognosis (Table 2). Echocardiography is a generally accessible follow-up tool without the need for sedation or anesthesia and its role in assessing prognosis is already well established in adults.40 Five pediatric studies showed echocardiographic variables to be associated with survival (Table 2), which makes this modality a promising tool in managing pedi-atric PAH. Further research is needed to enhance the body of evidence regarding these prognostic factors with low level of evidence.

Potential prognostic factors requiring further study

Other variables that were reported not sufficiently frequent to be meta-analyzed but may be potential prognostic factors include heart rate, blood pressure, height and weight, body surface area, heart rate variability, peak oxygen consumption, ventilatory-efficiency slope, genetic mutations, hemoglobin, norepinephrine, Apolipoprotein-A-1, metallopeptidase-inhibitor-1 and soluble ST2 (Table 2). Future research should reveal which role these variables could play in assessing prognosis in pediatric PAH.

The prognostic value of CMR has only been studied incidentally in children and the accessibility to required infrastructure and expertise may not be widely available.41 However, the well-established role of CMR in adults makes this a promising future imag-ing modality in addition to echocardiography also in pediatric PAH.42

Of special future interest in relation to survival are measures of pulmonary artery capacitance, pulmonary artery distensibility, RV stroke work, and ventricular-vascular coupling, which to date have only been studied incidentally and anecdotally in relatively small cohorts.11,18,43-45The feasibility and potential prognostic value of combining imag-ing modalities and cardiac catheterization are also under study and are expected to yield valuable insights in pulmonary arterial wall dynamics.44

78 Chapter 3

strengths and limitations

This recapitulation of published evidence for prognostic factors in pediatric PAH pro-vides a unique clinical overview. Combining only randomized controlled trials would have been the most ideal way to identify prognostic factors. However, such trials report-ing on prognostic factors are unavailable in this field. This could have led to a certain degree of heterogeneity, which was addressed in the current study by combining only studies with similar methodologies and providing a detailed description of the study characteristics (Table 1). Heterogeneity was tested for every meta-analyzed candidate prognostic factor, and revealed no substantial heterogeneity-evidence for the six identi-fied statistically significant prognostic factors.

When HRs were not available, these were estimated using Parmar’s survival curve method, which is known to lead to underestimations of the hazard ratios in smaller sample sizes.39 HRs of statistically insignificant associations were sometimes not reported and could in those cases not be included in meta-analysis. Since this could potentially have led to an overrepresentation of significant results in the combined HR, these excluded studies are shown in tabular form to avoid bias within the current paper (Table 2).

We aimed to prevent duplicate patient representation in the meta-analyses. This was accomplished by restricting study inclusion to non-overlapping cohorts. Overlap was suspected in case of overlapping inclusion periods in studies performed at the same center. Although conservative and accompanied by the risk of also excluding non-overlapping patients, this method ensured a pure and unbiased combined HR.

Considerations regarding future research

This study demonstrates the usefulness of the currently available literature on pediatric PAH. Nevertheless, available data are limited by relatively small sample sizes, insuf-ficiently explained discrepancies and inevitable potential duplicate patient inclusion. Current international collaborative initiatives aim to overcome these limitations. The ongoing Tracking Outcomes and Practice in Pediatric PH (TOPP) registry encompasses the largest cohort of children with PAH to date and is expected to yield important new insights in survival and prognostic factors in pediatric PAH.46 Although a powerful tool with regard to sample size, the usefulness of any registry depends on the predefined aims and might be hampered by the fact that frequency and mode of follow-up are often not dictated.47

To be able to further investigate reported discrepancies and to increase sample size and statistical power, it could also be considered to merge existing patient cohorts on an individual patient level. Recently, a direct comparison has been made between three major pediatric PAH referral centers, which allowed for analyzing differences in survival rates between centers.4 Such initiatives could be further expanded in the future.


3

To provide transparency in the degree of duplicate patient inclusion throughout differ-ent reports, it could be considered to publish lists of unique patient codes with every paper.

To be able to identify which prognostic factors could also qualify in defining treatment goals, future research should also focus on assessing the prognostic value of treatment-induced changes in these variables.34,48

ConClusIons

This systematic review combined with separate meta-analyses shows that WHO-FC, (NT-pro)BNP, mRAP, PVRi, cardiac index and acute vasodilator response are consistently reported prognostic factors in pediatric PAH. These variables are validated and useful clinical tools to assess prognosis. The current recapitulation of scientific evidence will provide an important basis for defining treatment strategies and developing practice guidelines for children with PAH. This systematic review does not preclude the potential of the other reported candidate prognostic factors, but rather identifies directions for further research to address gaps in current evidence.

80 Chapter 3

reFerenCes

1. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol. 2011;8:443–55.



4. Zijlstra WMH, Douwes JM, Rosenzweig EB, Schokker S, Krishnan U, Roofthooft MTR, Miller-Reed K, Hillege HL, Ivy DD, Berger RMF. Survival differences in pediatric pulmonary arterial hypertension: clues to a better understanding of outcome and optimal treatment strategies. J Am Coll Cardiol. 2014;63:2159–69.

5. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery J-L, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30:2493–537.

6. Swiston JR, Johnson SR, Granton JT. Factors that prognosticate mortality in idiopathic pulmonary arterial hypertension: a systematic review of the literature. Respir Med. 2010;104:1588–607.

7. McCrory DC, Coeytaux RR, Schmit KM, Kraft B, Kosinski AS, Mingo AM, Vann LM, Gilstrap DL, Hargett CW, Lugogo NL, Heidenfelder BL, Posey R, Irvine RJ, Wing L, Pendergast K DR, McCrory DC, Coeytaux RR, Schmit KM, Kraft B, Kosinski AS, Mingo AM, Vann LM, Gilstrap DL, Hargett CW, Lugogo NL, Heidenfelder BL, Posey R, Irvine RJ, Wing L, Pendergast K, Dolor RJ. Pulmonary Arterial Hypertension: Screening, Management and Treatment, Comparative Effectiveness Review No. 117. Rockville (MD): Agency for Healthcare Research and Quality; 2013.

8. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–41.

9. Altman DG, Bland JM. How to obtain the confidence interval from a P value. BMJ. 2011;343:d2090. 10. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the

published literature for survival endpoints. Stat Med. 1998;17:2815–2834. 11. Sajan I, Manlhiot C, Reyes J, McCrindle BW, Humpl T, Friedberg MK. Pulmonary arterial capacitance

in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease: relation to pulmonary vascular resistance, exercise capacity, and survival. Am Heart J. 2011;162:562–8.

12. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110:660–5.


14. Sandoval J, Bauerle O, Gomez A, Palomar A, Martinez Guerra ML, Furuya ME. Primary pulmonary hypertension in children: clinical characterization and survival. J Am Coll Cardiol. 1995;25:466–474.

15. Barst RJ, Maislin G, Fishman AP. Vasodilator Therapy for Primary Pulmonary Hypertension in Children. Circulation. 1999;99:1197–1208.


3



18. Douwes JM, Roofthooft MTR, Bartelds B, Talsma MD, Hillege HL, Berger RMF. Pulsatile haemody-namic parameters are predictors of survival in paediatric pulmonary arterial hypertension. Int J Cardiol. 2013;168:1370–7.

19. Hislop AA, Moledina S, Foster H, Schulze-Neick I, Haworth SG. Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children. Eur Respir J. 2011;38:70–7.

20. Moledina S, de Bruyn A, Schievano S, Owens CM, Young C, Haworth SG, Taylor AM, Schulze-Neick I, Muthurangu V. Fractal branching quantifies vascular changes and predicts survival in pulmo-nary hypertension: a proof of principle study. Heart. 2011;97:1245–9.

21. Ivy DD, Rosenzweig EB, Lemarié J-C, Brand M, Rosenberg D, Barst RJ. Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical set-tings. Am J Cardiol. 2010;106:1332–8.




25. Lammers AE, Hislop AA, Haworth SG. Prognostic value of B-type natriuretic peptide in children with pulmonary hypertension. Int J Cardiol. 2009;135:21–6.



28. Lefevre G, Dauchet L, Hachulla E, Montani D, Sobanski V, Lambert M, Hatron PY, Humbert M, Lau-nay D. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 2013;65:2412–2423.

29. Reeves BC, Deeks JJ, Higgins JPT WG. Chapter 13: Including non-randomized studies. In: Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration; 2011.

30. Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BKS, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125:324–34.

31. Barst RJ, Beghetti M, Pulido T, Layton G, Konourina I, Zhang M, Ivy DD, STARTS-2 Investigators. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014;129:1914–23.

32. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161:487–492.

82 Chapter 3


34. Ploegstra M-J, Douwes JM, Roofthooft MTR, Zijlstra WMH, Hillege HL, Berger RMF. Identification of treatment goals in paediatric pulmonary arterial hypertension. Eur Respir J. 2014;44:1616–26.

35. Barst RJ, Chung L, Zamanian RT, Turner M, McGoon MD. Functional Class Improvement and 3-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry. Chest. 2013;144:160–168.



38. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating sum-mary time-to-event data into meta-analysis. Trials. 2007;8:16.

39. Hirooka T, Hamada C, Yoshimura I. A note on estimating treatment effect for time-to-event data in a literature-based meta-analysis. Methods Inf Med. 2009;48:104–112.

40. Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, Ettinger NA, Hill NS, Sum-mer WR, de Boisblanc B, Schwartz T, Koch G, Clayton LM, Jobsis MM, Crow JW, Long W. Echocar-diographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214–1219.


42. van Wolferen SA, Marcus JT, Boonstra A, Marques KMJ, Bronzwaer JGF, Spreeuwenberg MD, Post-mus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250–7.

43. Ivy DD, Neish SR, Knudson OA, Nihill MR, Schaffer MS, Tyson RW, Abman SH, Shaffer EM, Valdes-Cruz L. Intravascular ultrasonic characteristics and vasoreactivity of the pulmonary vasculature in children with pulmonary hypertension. Am J Cardiol. 1998;81:740–748.

44. Berger RMF, Cromme-Dijkhuis AH, Hop WCJ, Kruit MN, Hess J. Pulmonary arterial wall distensibil-ity assessed by intravascular ultrasound in children with congenital heart disease: an indicator for pulmonary vascular disease? Chest. 2002;122:549–57.

45. Di Maria MV, Younoszai AK, Mertens L, Landeck BF, Ivy DD, Hunter KS, Friedberg MK. RV stroke work in children with pulmonary arterial hypertension: estimation based on invasive haemody-namic assessment and correlation with outcomes. Heart. 2014;100:1342–7.


47. Berger RMF. Pulmonary hypertension: smaller kids, smaller steps. Lancet Respir Med. 2014;2:348–50.

48. Ventetuolo CE, Gabler NB, Fritz JS, Smith KA, Palevsky HI, Klinger JR, Halpern SD, Kawut SM. Are hemodynamics surrogate endpoints in pulmonary arterial hypertension? Circulation. 2014;130:768–75.



3



52. Chida A, Shintani M, Yagi H, Fujiwara M, Kojima Y, Sato H, Imamura S, Yokozawa M, Onodera N, Horigome H, Kobayashi T, Hatai Y, Nakayama T, Fukushima H, Nishiyama M, Doi S, Ono Y, Yasukou-chi S, Ichida F, Fujimoto K, Ohtsuki S, Teshima H, Kawano T, Nomura Y, Gu H, Ishiwata T, Furutani Y, Inai K, Saji T, Matsuoka R, Nonoyama S, Nakanishi T. Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. Am J Cardiol. 2012;110:586–93.

53. Apitz C, Zimmermann R, Kreuder J, Jux C, Latus H, Pons-Kühnemann J, Kock I, Bride P, Kreymborg KG, Michel-Behnke I, Schranz D. Assessment of pulmonary endothelial function during invasive testing in children and adolescents with idiopathic pulmonary arterial hypertension. J Am Coll Cardiol. 2012;60:157–64.


55. Chida A, Sato H, Shintani M, Nakayama T, Kawamura Y, Furutani Y, Inai K, Saji T, Matsuoka R, Nonoyama S, Nakanishi T. Soluble ST2 and N-terminal pro-brain natriuretic peptide combination. Useful biomarker for predicting outcome of childhood pulmonary arterial hypertension. Circ J. 2014;78:436–442.

84 Chapter 3

HR of high compared to low BNP

Nakayma 2007, n=27 (400 pg/mL)

Bernus 2009, n=78 (180 pg/mL)

Lammers 2009, n=50 (130 pg/mL)


HR (95% CI)

3.57 (0.82-15.6)

11.4 (2.55-50.9)

2.60 (0.89-7.65)

4.24 (1.80-9.96)

BNPa

0.02 1 50 1

5 00 . 0 2

supplementary Figure 1. Forest plot showing combined prognostic value of brain natriuretic peptide. Area of each diamond ◆ is proportional to the sample size of the studied cohort. a HRs are estimated from survival curve. Between brackets are the cut-off values used in dichotomizing BNP. BNP = brain natriuretic peptide; HR = hazard ratio; CI = confidence interval.


3

supp

lem

enta

ry t

able

1.

Sear

ch S

trin

gs U

sed

and

Num

ber o

f Ide

ntifi

ed A

bstr

acts

per

Lite

ratu

re D

atab

ase

MED

LIN

En

hits

EMBA

SEn

hits

Coch

rane

Lib

rary

n hi

ts

Com

pone

nt ‘P

Ah

’#1

“Pul

mon

ary

arte

rial

hype

rten

sion

”[tit

le/a

bstr

act]

O

R “p

rimar

y pu

lmon

ary

hype

rten

sion

”[tit

le/a

bstr

act]

O

R “IP

AH

”[tit

le/a

bstr

act]

O

R “p

edia

tric

pul

mon

ary

hype

rten

sion

”[tit

le/a

bstr

act]

8419

(‘Pul

mon

ary

arte

rial

hype

rten

sion

’:ti,a

b O

R ‘p

rimar

y pu

lmon

ary

hype

rten

sion

’:ti,a

b O

R ‘IP

AH

’:ti,a

b O

R ‘p

edia

tric

pu

lmon

ary

hype

rten

sion

’:ti,a

b)

AN

D [e

mba

se]/

lim

1073

8“P

ulm

onar

y ar

teria

l hy

pert

ensi

on”:t

i,ab

OR

“prim

ary

pulm

onar

y hy

pert

ensi

on”:t

i,ab

OR

“IPA

H”:t

i,ab

OR

“ped

iatr

ic

pulm

onar

y hy

pert

ensi

on”:t

i,ab

419

Com

pone

nt ‘C

hild

ren’

#2“P

edia

tric

s”[M

esh]

O

R “C

hild

”[M

esh]

OR

“Ado

lesc

ent”

[Mes

h]

OR

“Inf

ant”

[Mes

h] O

R Pe

diat

ric[t

itle/

abst

ract

] OR

Pedi

atric

s [t

itle/

abst

ract

] OR

Paed

iatr

ic[t

itle/

abst

ract

] OR

Paed

iatr

ics[

title

/abs

trac

t]

OR

child

[titl

e/ab

stra

ct] O

R ch

ildre

n[tit

le/a

bstr

act]

OR

child

hood

[titl

e/ab

stra

ct]

OR

kids

[titl

e/ab

stra

ct] O

R ad

oles

cent

[titl

e/ab

stra

ct] O

R ad

oles

cent

s[tit

le/a

bstr

act]

OR

adol

esce

nce[

title

/abs

trac

t]

OR

infa

nt[t

itle/

abst

ract

] O

R in

fant

s[tit

le/a

bstr

act]

O

R in

fanc

y[tit

le/a

bstr

act]

O

R ba

by[t

itle/

abst

ract

] OR

babi

es[t

itle/

abst

ract

]

3119

773

((‘Pe

diat

rics’/

exp

OR

‘Chi

ld’/e

xp

OR

‘Ado

lesc

ent’/

exp

OR

‘Infa

nt’/

exp)

OR

(Ped

iatr

ic:ti

,ab

OR

Pedi

atric

s:ti,

ab O

R Pa

edia

tric

:ti,a

b O

R Pa

edia

tric

s:ti,

ab O

R ch

ild:ti

,ab

OR

child

ren:

ti,ab

O

R ch

ildho

od:ti

,ab

OR

kids

:ti,a

b O

R ad

oles

cent

:ti,a

b O

R ad

oles

cent

s:ti,

ab O

R ad

oles

cenc

e:ti,

ab O

R in

fant

:ti,a

b O

R in

fant

s:ti,

ab O

R in

fanc

y:ti,

ab

OR

baby

:ti,a

b O

R ba

bies

:ti,a

b))

AN

D [e

mba

se]/

lim

1928

580

((MeS

H d

escr

ipto

r Ped

iatr

ics

expl

ode

all t

rees

) OR

(MeS

H

desc

ripto

r Chi

ld e

xplo

de a

ll tr

ees)

OR

(MeS

H d

escr

ipto

r Ad

oles

cent

exp

lode

all

tree

s) O

R (M

eSH

des

crip

tor I

nfan

t exp

lode

al

l tre

es))

OR

(Ped

iatr

ic:ti

,ab

OR

Pedi

atric

s:ti,

ab O

R Pa

edia

tric

:ti,a

b O

R Pa

edia

tric

s:ti,

ab O

R ch

ild:ti

,ab

OR

child

ren:

ti,ab

O

R ch

ildho

od:ti

,ab

OR

kids

:ti,a

b O

R ad

oles

cent

:ti,a

b O

R ad

oles

cent

s:ti,

ab O

R ad

oles

cenc

e:ti,

ab O

R in

fant

:ti,a

b O

R in

fant

s:ti,

ab O

R in

fanc

y:ti,

ab O

R ba

by:ti

,ab

OR

babi

es:ti

,ab)

7715

4

86 Chapter 3

supp

lem

enta

ry t

able

1. (

cont

inue

d)

MED

LIN

En

hits

EMBA

SEn

hits

Coch

rane

Lib

rary

n hi

ts

Com

pone

nt ‘ s

urvi

val’

#3“S

urvi

val”[

Mes

h] O

R “S

urvi

val A

naly

sis”

[Mes

h]

OR

“Sur

viva

l Rat

e”[M

esh]

O

R “M

orta

lity”

[Mes

h] O

R “O

utco

me

Ass

essm

ent

(Hea

lth C

are)

”[M

esh]

OR

“Tre

atm

ent O

utco

me”

[Mes

h]

OR

“Pro

gnos

is”[

Mes

h] O

R Su

rviv

al[t

itle/

abst

ract

] OR

mor

talit

y[tit

le/a

bstr

act]

OR

Prog

nosi

s[tit

le/a

bstr

act]

O

R de

ath[

title

/abs

trac

t] O

R de

aths

[titl

e/ab

stra

ct] O

R ou

tcom

e[tit

le/a

bstr

act]

OR

outc

omes

[titl

e/ab

stra

ct]

2792

649

((‘Su

rviv

al’/e

xp O

R ‘P

ropo

rtio

nal

Haz

ards

Mod

el’/e

xp O

R ‘S

urvi

val

Rate

’/exp

OR

‘Mor

talit

y’/e

xp

OR

‘Out

com

e A

sses

smen

t’/ex

p O

R ‘T

reat

men

t Out

com

e’/

exp

OR

‘Pro

gnos

is’/e

xp) O

R (S

urvi

val:t

i,ab

OR

mor

talit

y:ti,

ab

OR

Prog

nosi

s:ti,

ab O

R de

ath:

ti,ab

O

R de

aths

:ti,a

b O

R ou

tcom

e:ti,

ab

OR

outc

omes

:ti,a

b)) A

ND

[e

mba

se]/

lim

2918

321

((MeS

H d

escr

ipto

r Sur

viva

l exp

lode

al

l tre

es) O

R (M

eSH

des

crip

tor

Surv

ival

Ana

lysi

s ex

plod

e al

l tre

es)

OR

(MeS

H d

escr

ipto

r Sur

viva

l Ra

te e

xplo

de a

ll tr

ees)

OR

(MeS

H

desc

ripto

r Mor

talit

y ex

plod

e al

l tre

es) O

R (M

eSH

des

crip

tor

Out

com

e A

sses

smen

t (H

ealth

Ca

re) e

xplo

de a

ll tr

ees)

OR

(MeS

H

desc

ripto

r Tre

atm

ent O

utco

me

expl

ode

all t

rees

) OR

(MeS

H

desc

ripto

r Pro

gnos

is e

xplo

de

all t

rees

)) O

R (S

urvi

val:t

i,ab

OR

mor

talit

y:ti,

ab O

R Pr

ogno

sis:

ti,ab

O

R de

ath:

ti,ab

OR

deat

hs:ti

,ab

OR

outc

ome:

ti,ab

OR

outc

omes

:ti,a

b)

1501

97

Com

bine

d se

arch

#4#1

AN

D #

2 A

ND

#3

746

#1 A

ND

#2

AN

D #

370

5#1

AN

D #

2 A

ND

#3

9

Valu

es re

pres

ent t

he n

umbe

r of i

dent

ified

abs

trac

ts fo

r eve

ry se

para

te se

arch

strin

g at

Apr

il 1st

201

4. C

ombi

ning

the

final

MED

LIN

E, E

MBA

SE a

nd C

ochr

ane

sear

ches

yie

lded

105

3 un

ique

abs

trac

ts. P

AH =

pul

mon

ary

arte

rial h

yper

tens

ion.


3

supplementary table 2. Studies Included During Full Text Review

First author Abbreviated Journal Title Year Study Site N Inclusion period

Sandoval [1] J Am CollCardiol 1995 Mexico City 18 1977 - 1991

Clabby [2] J Am CollCardiol 1997 US multicenter 50 1982 - 1992

Barst [3] Circulation 1999 New York 77 1982 - 1995

Yung [4] Circulation 2004 New York 44 1982 - 1995

Nakayama [5] Circ J 2007 Tokyo 31 1999 - 2004

Van Albada [6] Pediatr Res 2008 Netherlands 29 1997 - 2005

Bernus [7] Chest 2009 Denver 78 2005 - 2008

Haworth [8] Heart 2009 London 216 2001 - 2006

Lammers [9] Int J Cardiol 2009 London 50 2004 - 2006

Van Loon [10] Am J Cardiol 2010 Netherlands 52 1993 - 2008

Lammers [11] Int J Cardiol 2010 London 47 Not reported

Alkon [12] Am J Cardiol 2010 Toronto 47 1999 - 2008

Moledina [13] Heart 2010 London 64 2001 - 2007

Ivy [14] Am J Cardiol 2010 NY and Denver 86 2001 - 2003

Hislop [15] EurRespir J 2011 London 101 2002 - 2008

Moledina [16] Heart 2011 London 31 2007 - 2009

Sajan [17] Am Heart J 2011 Toronto 47 1996 - 2007

Van Loon [18] Circulation 2011 Netherlands 154 1991 - 2006

Barst [19] Circulation 2012 US multicenter 216 2006 - 2009

Chida [20] Am J Cardiol 2012 Japan/China multicenter 54 1995 - 2011

Apitz [21] J Am CollCardiol 2012 Giessen 43 Not reported

Douwes [22] Int J Cardiol 2013 Netherlands 52 1993 - 2010

Moledina [23] CircCardiovasc Imaging 2013 London 100 2007 - 2012

Kassem [24] Am Heart J 2013 Toronto 54 2004 - 2011

Wagner [25] Plos One 2013 Denver 83 2001 - 2008

Chida [26] Circ J 2014 Tokyo 59 Not reported

Zijlstra [27] J Am Coll Cardiol 2014 NL+Denver+NY 275 2000 - 2010

Citations are listed in Supplementary References section. US = United States; NL = Netherlands.

88 Chapter 3

supplementary table 3. Studies Excluded During Full Text Review

First author Abbreviated Journal Title Year Reason for exclusion

Houde [28] Br Heart J 1993 PAH not main topic

Kerstein [29] Circulation 1995 No survival analysis performeda

Darlow [30] N Z Med J 1998 PAH not main topic

Rosenzweig [31] Circulation 1999 No survival analysis performeda

Manzar [32] J Coll Physicians Surg Pak 2004 PAH not main topic

Humpl [33] Circulation 2005 No survival analysis performeda

Rosenzweig [34] J Am CollCardiol 2005 Endpoint other than Dt or Dt/LTx

Simpson [35] J Heart Lung Transplant 2006 No survival analysis performeda

Lammers [36] Heart 2007 No survival analysis performeda

Duffels [37] Int J Cardiol 2007 Analysis not restricted to children

Taylor [38] Br J Anaesth 2007 No survival analysis performeda

Van Loon [39] Am Heart J 2007 Analysis not restricted to children

Fasnacht [40] Swiss Med Wkly 2007 No survival analysis performeda

Joshi [41] Perinatology 2007 PAH not main topic

Ivy [42] J Am CollCardiol 2008 No survival analysis performeda

Kim [43] Korean Circ J 2008 No survival analysis performeda

Dickinson [44] J Heart Lung Transplant 2009 Analysis not restricted to children

Fraisse [45] Arch Cardiovasc Dis 2010 No survival analysis performeda

Barst [46] PediatrCardiol 2010 No survival analysis performeda

Melnick [47] Am J Cardiol 2010 No survival analysis performeda

Goldstein [48] J Heart Lung Transplant 2011 PAH not main topic

Schaellibaum [49] PediatrPulmonol 2011 PAH not main topic

Douwes [50] Eur Heart J 2011 Analysis not restricted to children

Takatsuki [51] PediatrCardiol 2012 No survival analysis performeda

Yeager [52] Proteomics ClinAppl 2012 No survival analysis performeda

Baruteau [53] Ann ThoracSurg 2012 No survival analysis performeda

Takatsuki [54] J Pediatr 2012 Endpoint other than Dt or Dt/LTx

Krishnan [55] Am J Cardiol 2012 No described survival

Duncan [56] Mediators Inflamm 2012 No survival analysis performeda

Siehr [57] J Heart Lung Transplant 2013 No survival analysis performeda

Kömhoff [58] Pediatrics 2013 No survival analysis performeda

Roofthooft [59] Am J Cardiol 2013 Endpoint other than Dt or Dt/LTx

Rausch [60] Int J Cardiol 2013 No survival analysis performeda

Maxey [61] PediatrCardiol 2013 No survival analysis performeda

Aiello [62] PediatrPulmonol 2014 No survival analysis performeda

Douwes [63] Heart 2014 No survival analysis performeda

Waruingi [64] World J Pediatr 2014 No survival analysis performeda

Barst [65] Circulation 2014 No survival analysis performeda

Citations are listed in Supplementary References section.a Survival analysis in which a candidate prognostic fac-tor is evaluated using Cox regression analysis or Kaplan Meier analysis (not: comparison of treatment group survival). Dt = death; Dt/Ltx = death or lung-transplantation.


3

suPPleMentAry reFerenCes

1. Sandoval J, Bauerle O, Gomez A, Palomar A, Martinez Guerra ML, Furuya ME. Primary pulmonary hypertension in children: clinical characterization and survival. J Am Coll Cardiol. 1995;25:466–474.


3. Barst RJ, Maislin G, Fishman AP. Vasodilator Therapy for Primary Pulmonary Hypertension in Children. Circulation. 1999;99:1197–1208.













16. Moledina S, de Bruyn A, Schievano S, Owens CM, Young C, Haworth SG, Taylor AM, Schulze-Neick I, Muthurangu V. Fractal branching quantifies vascular changes and predicts survival in pulmo-nary hypertension: a proof of principle study. Heart. 2011;97:1245–9.

17. Sajan I, Manlhiot C, Reyes J, McCrindle BW, Humpl T, Friedberg MK. Pulmonary arterial capacitance in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease: relation to pulmonary vascular resistance, exercise capacity, and survival. Am Heart J. 2011;162:562–8.

18. van Loon RLE, Roofthooft MTR, Hillege HL, ten Harkel ADJ, van Osch-Gevers M, Delhaas T, Kapusta L, Strengers JLM, Rammeloo L, Clur S-AB, Mulder BJM, Berger RMF. Pediatric pulmonary hyper-

90 Chapter 3

tension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124:1755–64.


20. Chida A, Shintani M, Yagi H, Fujiwara M, Kojima Y, Sato H, Imamura S, Yokozawa M, Onodera N, Horigome H, Kobayashi T, Hatai Y, Nakayama T, Fukushima H, Nishiyama M, Doi S, Ono Y, Yasukou-chi S, Ichida F, Fujimoto K, Ohtsuki S, Teshima H, Kawano T, Nomura Y, Gu H, Ishiwata T, Furutani Y, Inai K, Saji T, Matsuoka R, Nonoyama S, Nakanishi T. Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. Am J Cardiol. 2012;110:586–93.

21. Apitz C, Zimmermann R, Kreuder J, Jux C, Latus H, Pons-Kühnemann J, Kock I, Bride P, Kreymborg KG, Michel-Behnke I, Schranz D. Assessment of pulmonary endothelial function during invasive testing in children and adolescents with idiopathic pulmonary arterial hypertension. J Am Coll Cardiol. 2012;60:157–64.





26. Chida A, Sato H, Shintani M, Nakayama T, Kawamura Y, Furutani Y, Inai K, Saji T, Matsuoka R, Non-oyama S, Nakanishi T. Soluble ST2 and N-terminal pro-Brain Natriuretic Peptide Combination. Circ J. 2014;78:436–442.


28. Houde C, Bohn DJ, Freedom RM, Rabinovitch M. Profile of paediatric patients with pulmonary hypertension judged by responsiveness to vasodilators. Br Heart J. 1993;70:461–468.

29. Kerstein D, Levy PS, Hsu DT, Hordof AJ, Gersony WM, Barst RJ. Blade Balloon Atrial Septostomy in Patients with Severe Primary Pulmonary-Hypertension. Circulation. 1995;91:2028–2035.

30. Darlow B, Kempthorne P, Knight D, Wong M. Audit of early experience with inhaled nitric oxide in New Zealand neonatal intensive care units. N Z Med J. 1998;111:474–477.

31. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999;99:1858–1865.

32. Manzar S, Nair AK, Pai MG, Al Khusaiby SM. Pulmonary hypertension in neonates: does the cause influence the outcome? J Coll Physicians Surg Pak. 2004;14:612–614.

33. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension - Twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation. 2005;111:3274–3280.


3

34. Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ. Effects of Long-Term Bosentan in Children With Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2005;46:697–704.

35. Simpson CM, Penny DJ, Cochrane AD, Davis AM, Rose ML, Wilson SE, Weintraub RG. Preliminary experience with bosentan as initial therapy in childhood idiopathic pulmonary arterial hyperten-sion. J Heart Lung Transplant. 2006;25:469–473.

36. Lammers AE, Hislop AA, Flynn Y, Haworth SG. Epoprostenol treatment in children with severe pulmonary hypertension. Heart. 2007;93:739–743.

37. Duffels MGJ, Engelfriet PM, Berger RMF, van Loon RLE, Hoendermis E, Vriend JWJ, van der Velde ET, Bresser P, Mulder BJM. Pulmonary arterial hypertension in congenital heart disease: an epide-miologic perspective from a Dutch registry. Int J Cardiol. 2007;120:198–204.

38. Taylor CJ, Derrick G, McEwan A, Haworth SG, Sury MRJ. Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension. Br J Anaesth. 2007;98:657–661.

39. van Loon RLE, Hoendermis ES, Duffels MGJ, Vonk-Noordegraaf A, Mulder BJM, Hillege HL, Berger RMF. Long-term effect of bosentan in adults versus children with pulmonary arterial hyperten-sion associated with systemic-to-pulmonary shunt: Does the beneficial effect persist? Am Heart J. 2007;154:776–782.

40. Fasnacht MS, Tolsa JF, Beghetti M, Hypertension SS for PA. The Swiss registry for pulmonary arte-rial hypertension: the paediatric experience. Swiss Med Wkly. 2007;137:510–513.

41. Joshi R, Patil SS, Dominic S, Pratap U, Rajhans AP, Devaskar UP. Is inhaled nitric oxide therapy in neonates with primary pulmonary hypertension in developing countries like India feasible? Perinatology. 2007;9:101–105.

42. Ivy DD, Doran AK, Smith KJ, Mallory GB, Beghetti M, Barst RJ, Brady D, Law Y, Parker D, Claussen L, Abman SH. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51:161–169.

43. Kim HW, Kim GB, Je HG, Beak JS, Bae EJ, Noh CI, Choi JY, Yun YS. Pulmonary arterial hypertension in children: A single center experience. Korean Circ J. 2008;38:644–650.

44. Dickinson MG, Scholvinck EH, Boonstra A, Vonk-Noordegraaf A, Snijder RJ, Berger RM. Low com-plication rates with totally implantable access port use in epoprostenol treatment of pulmonary hypertension. J Heart Lung Transplant. 2009;28:273–279.

45. Fraisse A, Jais X, Schleich J-M, di Filippo S, Maragnès P, Beghetti M, Gressin V, Voisin M, Dauphin C, Clerson P, Godart F, Bonnet D, Maragnes P, Beghetti M, Gressing V, Voisin M, Dauphin C, Clerson P, Godark F, Bonnet D. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103:66–74.

46. Barst RJ, Agnoletti G, Fraisse A, Baldassarre J, Wessel DL, NO Diagnostic Study Group. Vasodilator testing with nitric oxide and/or oxygen in pediatric pulmonary hypertension. Pediatr Cardiol. 2010;31:598–606.

47. Melnick L, Barst RJ, Rowan CA, Kerstein D, Rosenzweig EB. Effectiveness of transition from intrave-nous epoprostenol to oral/inhaled targeted pulmonary arterial hypertension therapy in pediatric idiopathic and familial pulmonary arterial hypertension. Am J Cardiol. 2010;105:1485–1489.

48. Goldstein BS, Sweet SC, Mao J, Huddleston CB, Grady RM. Lung transplantation in children with idiopathic pulmonary arterial hypertension: an 18-year experience. J Heart Lung Transplant. 2011;30:1148–52.

49. Schaellibaum G, Lammers AE, Faro A, Moreno-Galdo A, Parakininkas D, Schecter MG, Solomon M, Boyer D, Conrad C, Frischer T, Wong J, Boehler A, Benden C. Bilateral Lung Transplantation

92 Chapter 3

for Pediatric Idiopathic Pulmonary Arterial Hypertension: A Multi-Center Experience. Pediatr Pulmonol. 2011;46:1121–1127.

50. Douwes JM, van Loon RLE, Hoendermis ES, Vonk-Noordegraaf A, Roofthooft MTR, Talsma MD, Hillege HL, Berger RMF. Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria. Eur Heart J. 2011;32:3137–3146.

51. Takatsuki S, Darst JR, Das BB, Fagan TE, Wolfe R, Ivy DD. Clinical manifestations and long-term follow-up in pediatric patients living at altitude with isolated pulmonary artery of ductal origin. Pediatr Cardiol. 2012;33:775–781.

52. Yeager ME, Colvin KL, Everett AD, Stenmark KR, Ivy DD. Plasma proteomics of differential outcome to long-term therapy in children with idiopathic pulmonary arterial hypertension. Proteomics Clin Appl. 2012;6:257–267.

53. Baruteau A-E, Serraf A, Levy M, Petit J, Bonnet D, Jais X, Vouhe P, Simonneau G, Belli E, Humbert M. Potts Shunt in Children With Idiopathic Pulmonary Arterial Hypertension: Long-Term Results. Ann Thorac Surg. 2012;94:817–824.

54. Takatsuki S, Nakayama T, Jone PN, Wagner BD, Naoi K, Ivy DD, Saji T. Tissue Doppler imaging predicts adverse outcome in children with idiopathic pulmonary arterial hypertension. J Pediatr. 2012;161:1126–1131.

55. Krishnan U, Takatsuki S, Ivy DD, Kerstein J, Calderbank M, Coleman E, Rosenzweig EB. Effective-ness and Safety of Inhaled Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Children. Am J Cardiol. 2012;110:1704–1709.

56. Duncan M, Wagner BD, Murray K, Allen J, Colvin K, Accurso FJ, Ivy DD. Circulating cytokines and growth factors in pediatric pulmonary hypertension. Mediators Inflamm. 2012;2012:143428.

57. Siehr SL, Ivy DD, Miller-Reed K, Ogawa M, Rosenthal DN, Feinstein JA. Children with pulmonary arterial hypertension and prostanoid therapy: long-term hemodynamics. J Heart Lung Transplant. 2013;32:546–552.

58. Komhoff M, Roofthooft MT, Westra D, Teertstra TK, Losito A, van de Kar NC, Berger RM. Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency. Pediatrics. 2013;132:e540–4.

59. Roofthooft MTR, Douwes JM, Vrijlandt EJLE, Berger RMF. Frequency and prognostic significance of hemoptysis in pediatric pulmonary arterial hypertension. Am J Cardiol. 2013;112:1505–1509.

60. Rausch CM, Taylor AL, Ross H, Sillau S, Ivy DD. Ventilatory efficiency slope correlates with func-tional capacity, outcomes, and disease severity in pediatric patients with pulmonary hyperten-sion. Int J Cardiol. 2013;169:445–448.

61. Maxey DM, Ivy DD, Ogawa MT, Feinstein JA. Food and drug administration (FDA) postmarket reported side effects and adverse events associated with pulmonary hypertension therapy in pediatric patients. Pediatr Cardiol. 2013;34:1628–1636.

62. Aiello VD, Thomaz AM, Pozzan G, Lopes AA. Capillary hemangiomatosis like-lesions in lung biop-sies from children with congenital heart defects. Pediatr Pulmonol. 2014;49:E82–5.

63. Douwes JM, Roofthooft MTR, Van Loon RLE, Ploegstra M-J, Bartelds B, Hillege HL, Berger RMF. Sildenafil add-on therapy in paediatric pulmonary arterial hypertension, experiences of a na-tional referral centre. Heart. 2014;100:224–30.

64. Waruingi W, Mhanna MJ. Pulmonary hypertension in extremely low birth weight infants: charac-teristics and outcomes. World J Pediatr. 2014;10:46–52.


3

65. Barst RJ, Beghetti M, Pulido T, Layton G, Konourina I, Zhang M, Ivy DD, STARTS-2 Investigators. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014;129:1914–23.

1

2

3

4

5

6

7

8

9

10

Chapter 4Echocardiography in pediatric pulmonary arterial hypertension: early study on assessing disease severity and predicting outcome

Mark-Jan Ploegstra*

Marcus T.R. Roofthooft*

Johannes M. DouwesBeatrijs BarteldsNynke J. ElzengaDick van de WeerdHans L. HillegeRolf M.F. Berger*Contributed equally

Circulation Cardiovascular Imaging 2014: 8: e000878

96 Chapter 4

ABstrACt

Background

The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH.

Methods and results

Forty-three consecutive children (median age, 8.0 years; range 0.4-21.5) with idio-pathic/hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18)were enrolled in aprospective single-center observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal-pro-B-type natriuretic peptide, hemodynamics) and lung-trans-plantation-free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics (P<0.05), whereas left ventricular dimensions correlated with hemodynamics and survival (P<0.05). Right-to-left ventricular dimension ratio cor-related with WHO-FC, hemodynamics and survival (P<0.05). Right ventricular ejection time correlated with hemodynamics and survival (P<0.05) and tended to correlate with WHO-FC (P=0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival (P<0.05).

Conclusions

This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding manage-ment in children with PAH.

Echocardiography in pediatric PAH 97

4

IntroduCtIon

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease and often progresses rapidly towards right ventricular (RV) failure and death if left untreated.1,2 Although the disease shares similarities in children and adults, several epidemiological features, clinical characteristics and the feasibility of diagnostic modalities differ between these groups.3–5 The introduction of PAH-targeted medical therapies has improved qual-ity of life and life expectancy in both adult and pediatric patients with PAH.6,7

Current guidelines advocate goal-oriented treatment strategies to improve outcome.5,8,9 To assess disease severity and prognosis and to guide treatment strategies in both adult and pediatric patients with PAH, various variables have been proposed. These include invasive hemodynamics such as indexed pulmonary vascular resistance, cardiac index or mean right atrial pressure, and also noninvasive variables, including World Health Organization functional class (WHO-FC), 6-minute-walk-distance (6MWD), cardiac MRI (cMRI) and N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP).6,7,10–15

Owing to its widespread availability, echocardiography is used as first-line tool to detect PAH, to provide clues for differential diagnoses, and to assess RV function.16,17 The role of echocardiography in guiding treatment of patients with PAH, however, is less well defined. In adult patients with PAH, the predictive value of several echo-variables for outcome has been studied.7,18–24 Pericardial effusion, right atrial (RA) and RV dimen-sions, eccentricity index, RV fractional area change, RV myocardial performance (Tei) index, RV-free wall systolic strain, RV dyssynchrony and tricuspid annular plane systolic excursion (TAPSE) are all suggested to be associated with outcome in adults with PAH and such predictors now gain an increasing role in therapeutic decision-making.18,19,22–33

In pediatric PAH, however, the value of echocardiography in assessing prognosis and therapeutic decision-making has been studied only anecdotally and incom-pletely.34–39 Isolated echocardiographic measurements in children with PAH, such as RV systolic to diastolic duration ratio or tissue Doppler measurement of early diastolic myocardial relaxation velocity or tricuspid annular peak systolic velocity (S’), have been reported to be associated with clinical outcome.34–36

Because many diagnostic tools used to guide management in adult PAH may be not or less feasible in children (e.g. 6MWD, right heart catheterization [RHC] requiring sedation or anesthesia), the need for noninvasive tools that are feasible also in young children is urgent. Recently, cMRI has been suggested as a promising tool for guiding management in pediatric PAH, but accessibility to required infrastructure and expertise is not (yet) widely available to physicians treating children with PAH.11–13

In contrast, echocardiography is noninvasive and easily obtainable also in small children, allowing for repetitive measurements and thus longitudinal follow-up. Quality of echocardiographic windows is known to be superior in children compared to adults.

98 Chapter 4

In this early study, we evaluate the value of conventional transthoracic echocardiogra-phy in children with PAH, by describing correlations between multiple echo variables and disease severity and outcome.

Methods

study design and population

Between 2004 and 2010, 43 consecutive children with idiopathic PAH and PAH associated with congenital heart disease (PAH-CHD), confirmed by RHC, were enrolled in a registry-based prospective observational study. In The Netherlands, all children with PAH are referred to the University Medical Center Groningen, the national referral center of the Dutch National Network for Pediatric Pulmonary Hypertension.6 In this ongoing registry, all patients have standardized follow-up visits at least twice a year. Data on RHC, 6MWD, echocardiography and serum markers are prospectively collected with written informed consent from the parents or caregivers and institutional review board approval.

echocardiographic measurements

In 2004, a study protocol for transthoracic echocardiography, including predefined 2D-anatomic variables, color Doppler flow variables and tissue Doppler imaging variables, was designed and since then performed in all children with PAH who visited the referral center. The echo-study was performed by two specifically trained echocardiographers, using a Vivid 7 ultrasound scanner (GE-Vingmed Ultrasound AS, Benelux, Brussels, Bel-gium). In each patient, the first echo-study according to this protocol was used for the baseline analysis. The second echo-study, obtained during follow-up, was used for fol-low-up analysis. The echo-protocol included 41 echo-variables (Supplementary Table 1). 2D-anatomic measurements and (tissue-) Doppler measurements were performed ac-cording to the pediatric guidelines of the American Society of Echocardiography.40 Three consecutive cardiac cycles were recorded during expiration and were analyzed using offline quantification software (General Electric, Echopac, Benelux, Brussels, Belgium). The off-line measurements were performed by a trained echocardiographer (D.v.d.W.) blinded for clinical data.

disease severity and outcome

Echo variables at baseline were correlated with disease severity and outcome. Disease severity correlates were performed using WHO-FC and NT-pro-BNP, which were assessed within a period of 2 weeks from the echo-study. WHO-FC was determined by 2 pediatric cardiologists, who were responsible for the daily medical care of the patients. NT-pro-BNP was measured by electrochemiluminescence (Elecsys, Roche Diagnostics, Basel,


4

Switzerland). Outcome was defined as death or lung-transplantation (transplant-free survival). The follow-up time was calculated from the echo-study until death, lung-transplantation or the last follow-up visit before October 2013.

hemodynamics: a subgroup analysis

Patients in whom RHC was performed within 2 months from the baseline echo-study were included in a subgroup analysis to evaluate the correlation between echocardiog-raphy and invasively obtained hemodynamic measures, previously reported to predict prognosis in pediatric PAH: mean right atrial pressure, indexed pulmonary vascular resistance, cardiac index and mean pulmonary-to-systemic arterial pressure ratio.15,41

statistical analysis

Data analysis was performed using IBM SPSS 22.0 (Armonk, NY). Data were presented as number (percentage) for dichotomous or categorical data, mean±SD for normally distributed continuous data or median (interquartile range [IQR]) for not-normally distributed continuous data. The distribution of the data was visually inspected using quantile-quantile plots in which quantiles from the data were plotted against expected quantiles from the standard normal distribution.42,43 Sample skewness and kurtosis statistics were assessed for every studied variable. These were generated in IBM SPSS by calculating adjusted Fisher-Pearson standardized moment coefficients, which is the standard skewness/kurtosis calculating method in most statistical software packages.43 Only variables with both skewness and kurtosis coefficient values between -2 and 2 were considered acceptably normally distributed. Log-transformation was used to normalize the distribution of NT-pro-BNP. The multiple imputation functionality in IBM SPSS with fully conditional specification was used to impute missing values for variables with <50% missing data which met the ‘missing at random’ assumption. Pooled analyses were performed on 15 imputed datasets, generated using multiple imputation with 20 iterations.44

Categorical variables were compared using χ2 test or Fisher exact test in case of expected cell frequencies <5. Continuous variables were compared using t test or ANOVA (normally distributed variables) and Mann-Whitney U test or Kruskal-Wallis (not-normally distributed variables). Correlations involving not-normally distributed or ordinal variables were assessed using Spearman correlation analysis. Pearsons correla-tion analysis was used to assess correlations between normally distributed continuous variables.

Survival of the full cohort was depicted with Kaplan-Meier curves stratified by WHO-FC and survival differences were compared by means of a log-rank test. Cox proportional hazard analysis was used in the assessment of the correlation of echo vari-ables with transplant-free survival. A separate Cox regression analysis was performed

100 Chapter 4

table 1. Clinical, Hemodynamic and Echocardiographic Baseline Characteristics Stratified by Diagnosis

IPAH PAH-CHD Original† Imputed‡

n N=25 n N=18 P-value P-value

Clinical characteristics

Female, n (%) 13 (52%) 13 (72%) 0.181 N.A.

Incident case, n (%) 15 (60%) 9 (50%) 0.515 N.A.

Age at baseline, y 25 8.0 (5.8-14.0) 18 6.9 (2.8-12.3) 0.257 N.A.

Follow-up, y 25 5.9 (1.9-9.2) 18 5.0 (3.1-8.8) 0.694 N.A.

BSA, m2 24 1.0 ± 0.5 18 0.9 ± 0.4 0.147 N.A.

Mortality, n (%) 9 (36%) 7 (39%) 0.847 N.A.

WHO-FC 25 18 0.917* N.A.

I+II, n (%) 7 (28%) 4 (22%)

III, n (%) 13 (52%) 11 (61%)

IV, n (%) 5 (20%) 3 (17%)

NT-pro-BNP, log-value 14 3.0 ± 0.9 11 2.7 ± 0.6 0.398 0.383

hemodynamic characteristics

mRAP, mmHg 15 7.7 ± 5.4 6 7.5 ± 3.7 0.924 N.A.

mPAP, mmHg 15 55 ± 20 6 56 ± 9 0.978 N.A.

PVRi, WU*m2 15 23 ± 13 6 25 ± 14 0.710 N.A.

CI, L/min/m2 15 2.4 ± 0.6 6 2.5 ± 0.6 0.718 N.A.

2d-anatomical echocardiographic characteristics

RA area, mm2 25 1045 (829-1572) 16 1089 (865-1537) 0.915 0.813

RA length, mm 25 42 ± 14 16 42 ± 11 0.846 0.793

RA width, mm 25 38 ± 12 16 38 ± 12 0.798 0.804

RV 4ch, mm 24 38 ± 11 16 35 ± 10 0.456 0.636

RV sax, mm 25 30 ± 12 16 27 ± 9 0.353 0.369

RV lax, mm 15 30 ± 10 14 23 ± 7 0.044 0.033

RV/LV 4ch 19 1.3 ± 0.4 14 1.3 ± 0.4 0.844 0.920

RV/LV sax 25 1.1 ± 0.6 16 1.1 ± 0.6 0.661 0.893

RV/LV lax 15 1.0 ± 0.4 14 0.8 ± 0.3 0.092 0.115

Ecc index 24 1.4 (1.2-1.8) 16 1.4 (1.1-1.6) 0.508 0.751

LV 4ch, mm 19 29 ± 7 14 28 ± 7 0.691 0.670

LV sax, mm 24 41 ± 10 16 37 ± 8 0.233 0.313

LV perp sax, mm 25 28 ± 7 16 28 ± 8 0.856 0.659

LV lax, mm 15 30 ± 9 14 30 ± 8 0.862 0.861

rv-functional echocardiographic characteristics

RV ejection time, ms 20 258 ± 35 16 219 ± 67 0.048 0.044

RV acceleration time, ms 19 67 (50-83) 16 66 (43-80) 0.529 0.610

TAPSE, mm 24 16 ± 4 18 14 ± 3 0.115 0.119


4to assess the correlation of the first follow-up echo-study with transplant-free survival, in which transplant-free survival was calculated from the follow-up echo-study. P<0.05 was considered statistically significant.

results

Patient characteristics and echo variables

Forty-three children with PAH were included: 26 patients (60%) were girls and 24 patients (56%) were newly diagnosed ones (incident patients). The median age at the baseline echo-study was 8.0 years (IQR, 4.4-13.7; range, 0.4-21.5), with a median follow-up of 5.8 years (IQR, 3.1-8.8; range 0.02-10.8). Twenty-five patients had idiopathic PAH and 18 had PAH-CHD. Supplementary Table 1 provides an overview of all echo variables according to the echo-protocol, including the number of patients in which these measures turned out to be feasible (variables that were considered eligible to include in analyses are marked with an asterisk). Baseline characteristics, measures of disease severity, hemody-namics and echo-variables eligible for analysis are shown in Table 1, stratified by type of PAH. The congenital heart defects of the patients with PAH-CHD are detailed in Table 2.

disease severity

At time of the first echo-study, 74% of the patients were in WHO-FC III or IV. Treatment was according to the evolving treatment algorithm for PAH during the study period. Thirty patients (70%) were treatment naive at the start of the study. Thirteen were already on targeted PAH-treatment: calcium channel blockers (n=5), bosentan (n=5), beraprost (n=1), epoprostenol (n=1), and calcium channel blockers in combination with epoprostenol (n=1).

Clinical, hemodynamic and echocardiographic baseline-characteristics, stratified by WHO-FC are shown in Table 3. RA and RV dimensions, right-to-left ventricular dimen-sion ratio (RV/LV-ratio), RV ejection time and TAPSE differed significantly among patients in different WHO-FC. Table 4 shows correlations between echo variables and WHO-FC

Values are presented as median (interquartile range), mean ± standard deviation, or as numbers (percentage). IPAH indicates idiopathic pulmonary arterial hypertension; PAH-CHD, pulmonary arterial hypertension associ-ated with congenital heart disease; N.A.: not applicable; BSA, body surface area; WHO-FC, World Health Orga-nization Functional Class; NT-pro-BNP, N-terminal-pro-B-type natriuretic peptide; mRAP, mean right atrial pres-sure; mPAP, mean pulmonary arterial pressure; PVRi, indexed pulmonary vascular resistance; CI, cardiac index; RA, right atrium; RV, right ventricle; RV/LV, right-to-left ventricular dimension ratio; 4ch, four chamber view; Ecc, eccentricity; LV left ventricle; sax, short axis; lax, long axis; perp sax, perpendicular short axis; TAPSE, tricuspid an-nular plane systolic excursion. *: Fisher’s Exact test used to calculate P-value. †: P-value from analysis on original dataset, before imputation of missing values. ‡: P-value from pooled analysis on 15 imputed datasets generated using multiple imputation with 20 iterations.

102 Chapter 4

and NT-pro-BNP. RA and RV dimensions, RV/LV-ratio, eccentricity index and TAPSE were significantly associated with WHO-FC. Although RV/LV-ratio, left ventricular (LV) dimen-sions, RV acceleration time and TAPSE tended to correlate with NT-pro-BNP (P<0.100), these correlations did not reach statistical significance.

In a subgroup of 21 patients, RHC had been performed within 2 months from the baseline echo-study. Table 5 shows correlations between echo variables and he-modynamics.RA and RV dimensions correlated with mean right atrial pressure, indexed pulmonary vascular resistance and cardiac index; RV/LV ratio (short axis), eccentricity index, and RV ejection time correlated with indexed pulmonary vascular resistance and mean pulmonary-to-systemic arterial pressure ratio; LV dimension (short axis) correlated

table 2. Demographic and Diagnostic Characteristics of Patients With PAH-CHD

Diagnosis Eisenm Age, yrs Sex F-up time, yrs Died

Pre-tricuspid shunt

ASD Y 2.9 F 0.7 Y

ASD Y 5.0 M 5.6 N

corr VSD/PDA, created ASD Y 13.4 M 4.3 Y

Post-tricuspid shunt

PDA Y 11.8 F 8.7 N

PDA N 2.0 F 1.1 Y

PDA Y 17.9 F 4.5 Y

PDA Y 10.1 F 6.4 N

PDA, corr VSD, ASD Y 4.8 F 3.1 Y

VSD Y 6.9 F 9.3 N

VSD Y 4.4 M 9.2 N

VSD N 7.0 F 3.5 N

VSD, ASD Y 0.6 F 6.2 N

VSD, PDA Y 14.4 F 9.0 N

VSD, PDA, ASD Y 0.7 F 3.3 Y

Corrected congenital heart defect

corr AVSD N 15.2 F 6.3 N

corr TA N 11.9 F 0.7 Y

corr TGA N 9.2 M 10.3 N

corr TGA N 2.6 M 3.1 N

ASD indicates atrial septal defect; AVSD, atrio-ventricular septal defect; corr, corrected; Eisenm, Eisenmenger physiology; F, female; F-up, follow-up; N, no; PAH-CHD, pulmonary arterial hypertension associated with con-genital heart disease; M, male; PDA, persistent arterial duct; TA, truncusarteriosus; TGA, transposition of the great arteries; VSD, ventricular septal defect; yrs, years and Y, yes.


4

tabl

e 3.

Clin

ical

, Hem

odyn

amic

and

Ech

ocar

diog

raph

ic B

asel

ine

Char

acte

ristic

s St

ratifi

ed b

y W

HO

Fun

ctio

nal C

lass

WH

O-F

C I +

IIW

HO

-FC

IIIW

HO

-FC

IVO

rigin

al†

Impu

ted‡

nN

=11

nN

=24

nN

=8P-

valu

eP-

valu

e

Clin

ical

cha

ract

eris

tics

Fem

ale,

n (%

)6

(55%

)16

(67%

)4

(50%

)0.

702*

N.A

.

Inci

dent

cas

e, n

(%)

5 (4

5%)

13 (5

4%)

6 (7

5%)

0.45

8*N

.A.

Age

at b

asel

ine,

y11

7.2

(3.2

-9.2

)24

10.0

(4.7

-14.

9)8

9.4

(1.8

-13.

6)0.

515

N.A

.

Follo

w-u

p, y

115.

8 (3

.5-1

0.3)

246.

1 (2

.4-9

.0)

82.

3 (0

.2-6

.2)

0.07

8N

.A.

BSA

, m2

110.

9 ±

0.4

241.

1 ±

0.5

70.

8 ±

0.4

0.51

7N

.A.

Mor

talit

y, n

(%)

2 (1

8%)

9 (3

8%)

5 (6

3%)

0.15

1*N

.A.

NT-

pro-

BNP,

log

valu

e5

2.5

± 0.

814

2.7

± 0.

76

3.6

± 0.

70.

022

0.09

5

hem

odyn

amic

cha

ract

eris

tics

mRA

P, m

mH

g5

6.8

± 2.

311

5.7

± 3.

65

12.8

± 6

.20.

015

N.A

.

mPA

P, m

mH

g5

47 ±

13

1153

± 1

65

70 ±

15

0.05

6N

.A.

PVRi

, WU

*m2

515

± 5

1120

± 1

05

40 ±

90.

001

N.A

.

CI, L

/min

/m2

52.

5 ±

0.3

112.

5 ±

0.6

52.

0 ±

0.7

0.21

5N

.A.

2d-a

nato

mic

al e

choc

ardi

ogra

phic

cha

ract

eris

tics

RA a

rea,

mm

211

907

(638

-104

6)22

1227

(874

-156

3)8

2126

(661

-328

3)0.

037

0.03

9

RA le

ngth

, mm

1134

± 5

2243

± 1

18

50 ±

20

0.03

10.

029

RA w

idth

, mm

1131

± 6

2239

± 9

846

± 1

90.

017

0.01

9

RV 4

ch, m

m11

31 ±

721

36 ±

10

844

± 1

40.

031

0.03

2

RV s

ax, m

m11

25 ±

922

29 ±

12

837

± 1

00.

069

0.06

9

RV la

x, m

m8

22 ±

316

28 ±

10

529

± 1

10.

299

0.27

9

RV/L

V 4c

h9

1.1

± 0.

317

1.2

± 0.

37

1.7

± 0.

40.

002

0.00

3

RV/L

V sa

x11

0.9

± 0.

322

1.0

± 0.

58

1.7

± 0.

50.

001

0.00

3

104 Chapter 4

tabl

e 3.

(con

tinue

d)

WH

O-F

C I +

IIW

HO

-FC

IIIW

HO

-FC

IVO

rigin

al†

Impu

ted‡

nN

=11

nN

=24

nN

=8P-

valu

eP-

valu

e

RV/L

V la

x8

0.8

± 0.

316

0.9

± 0.

45

1.2

± 0.

20.

130

0.13

8

Ecc

inde

x10

1.3

(1.2

-1.4

)22

1.3

(1.1

-1.8

)8

1.5

(1.4

-2.0

)0.

069

0.08

3

LV 4

ch, m

m9

28 ±

717

29 ±

77

26 ±

80.

550

0.50

1

LV s

ax, m

m10

37 ±

822

41 ±

10

838

± 1

10.

470

0.51

0

LV p

erp

sax,

mm

1130

± 9

2229

± 5

823

± 9

0.06

50.

084

LV la

x, m

m8

33 ±

11

1630

± 6

525

± 8

0.21

70.

229

rv-f

unct

iona

l ech

ocar

diog

raph

ic c

hara

cter

isti

cs

RV e

ject

ion

time,

ms

924

8 ±

5021

254

± 46

618

4 ±

620.

015

0.01

8

RV a

ccel

erat

ion

time,

ms

969

(53-

82)

2065

(51-

85)

655

(34-

77)

0.54

80.

538

TAPS

E, m

m11

16 ±

523

16 ±

38

12 ±

30.

037

0.03

9

Valu

es a

re p

rese

nted

as m

edia

n (in

terq

uart

ile ra

nge)

, mea

n ±

stan

dard

dev

iatio

n or

as n

umbe

rs (p

erce

ntag

e). W

HO

-FC

indi

cate

s Wor

ld H

ealth

Org

aniz

atio

n fu

nctio

nal c

lass

; N

.A.,

not a

pplic

able

; BSA

, bod

y su

rfac

e ar

ea; N

T-pr

o-BN

P, N

-ter

min

al-p

ro-B

-typ

e na

triu

retic

pep

tide;

mRA

P, m

ean

right

atr

ial p

ress

ure;

mPA

P, m

ean

pulm

onar

y ar

teria

l pre

ssur

e;

PVRi

, pul

mon

ary

vasc

ular

resi

stan

ce; C

I, ca

rdia

c in

dex;

RA,

righ

t atr

ium

; RV,

righ

t ven

tric

le; R

V/LV

, rig

ht-t

o-le

ft v

entr

icul

ar d

imen

sion

ratio

; 4ch

, fou

r cha

mbe

r vie

w; E

cc, e

ccen

-tr

icity

; LV

left

ven

tric

le; s

ax, s

hort

axi

s; la

x, lo

ng a

xis;

perp

sax,

per

pend

icul

ar sh

ort a

xis;

TAPS

E, tr

icus

pid

annu

lar p

lane

syst

olic

exc

ursi

on. *

: Fis

her’s

Exa

ct te

st u

sed

to c

alcu

late

P-

valu

e. †

: P-v

alue

from

ana

lysi

s on

orig

inal

dat

aset

, bef

ore

impu

tatio

n of

mis

sing

val

ues.

‡: P

-val

ue fr

om p

oole

d an

alys

is o

n 15

impu

ted

data

sets

, gen

erat

ed u

sing

mul

tiple

im

puta

tion

with

20

itera

tions

.


4

with cardiac index and mean pulmonary-to-systemic arterial pressure ratio, and TAPSE correlated with mean right atrial pressure.

outcome

Over a median follow-up period of 5.8 (IQR, 3.1-8.8; range, 0.02-10.8) years, 15 patients died and 3 underwent lung-transplantation. Overall cumulative survival stratified by WHO-FC is shown in Figure 1. Univariable Cox regression analysis showed that higher WHO-FC was associated with a higher risk of death or lung-transplantation (Figure 2).

table 4. Correlation of Baseline Echocardiography with WHO Functional Class and N-terminal-pro-B-type Natriuretic Peptide†

WHO-FC Log NT-proBNP

Correlation P-value Correlation P-value

2d-anatomical

RA area 0.366* 0.016 -0.089* 0.622

RA length 0.352* 0.021 -0.146 0.446

RA width 0.340* 0.026 -0.050 0.780

RV 4ch 0.372* 0.014 -0.015 0.928

RV sax 0.335* 0.028 0.048 0.780

RV lax 0.213* 0.211 0.088 0.614

RV/LV 4ch 0.441* 0.004 0.210 0.220

RV/LV sax 0.439* 0.003 0.310 0.076

RV/LV lax 0.387* 0.019 0.326 0.108

Eccentricity index 0.327* 0.038 0.211* 0.356

LV 4ch -0.074* 0.648 -0.295 0.120

LV sax 0.063* 0.700 -0.160 0.433

LV perp sax -0.294* 0.055 -0.382 0.067

LV lax -0.226* 0.176 -0.324 0.095

rv-functional

RV ejection time -0.280* 0.071 -0.243 0.193

RV acceleration time -0.168* 0.298 -0.321* 0.090

TAPSE -0.331* 0.030 -0.346 0.071

Values are presented as Pearson’s correlation coefficient with accompanying P-value, unless otherwise indicat-ed. WHO-FC indicates World Health Organization functional class; Log NT-pro-BNP, log-transformed N-termi-nal-pro-B-type natriuretic peptide; RA, right atrium; RV, right ventricle; RV/LV, right-to-left ventricular dimension ratio; 4ch, four chamber view; Ecc, eccentricity; LV left ventricle; sax, short axis; lax, long axis; perp sax, perpen-dicular short axis; TAPSE, tricuspid annular plane systolic excursion; *: Spearman’s correlation used instead of Pearson’s correlation, because of non-normality. †: Results are from pooled analysis on 15 imputed datasets, generated using multiple imputation with 20 iterations.

106 Chapter 4

Smaller LV dimensions, higher RV/LV ratio, lower TAPSE and lower RV ejection time were also associated with death or lung-transplantation (Figure 3). Follow-up echocardiog-raphy was performed at a median follow-up time of 3.6 months (IQR, 2.7-5.4; range, 0.2-13.1) and revealed similar echo variables to be associated with outcome (Figure 3).

table 5. Correlation of Baseline Echocardiography with Hemodynamics: Subgroup Analysis†

mRAP (N=21) PVRi (N=21) CI (N=21) mPAP/mSAP (N=21)

Correlation P-value Correlation P-value Correlation P-value Correlation P-value

2d-anatomical

RA area 0.298* 0.192 0.717* <0.001 -0.583* 0.005 0.220* 0.342

RA length 0.557 0.008 0.753 <0.001 -0.612 0.003 0.186 0.425

RA width 0.639 0.001 0.798 <0.001 -0.723 <0.001 0.136 0.562

RV 4ch 0.525 0.013 0.762 <0.001 -0.599 0.003 0.180 0.439

RV sax 0.463 0.033 0.748 <0.001 -0.644 0.001 0.311 0.172

RV lax 0.362 0.122 0.455 0.043 -0.436 0.052 -0.032 0.895

RV/LV 4ch 0.295 0.210 0.625 0.002 -0.382 0.091 0.441 0.050

RV/LV sax 0.317 0.164 0.593 0.004 -0.307 0.178 0.584 0.005

RV/LV lax 0.310 0.202 0.337 0.148 -0.227 0.338 0.114 0.636

Ecc index 0.128* 0.585 0.583* 0.005 -0.342* 0.131 0.442* 0.044

LV 4ch 0.210 0.384 0.120 0.611 -0.271 0.247 -0.406 0.077

LV sax 0.087 0.712 0.336 0.138 -0.617 0.002 -0.112 0.634

LV perp sax 0.008 0.971 -0.214 0.357 -0.148 0.528 -0.665 0.001

LV lax -0.062 0.810 -0.033 0.891 -0.201 0.403 -0.301 0.221

rv-functional

RV ejection time -0.351 0.121 -0.445 0.043 0.062 0.794 -0.471 0.030

RV acceleration time -0.188* 0.422 -0.208* 0.373 -0.078* 0.741 -0.226* 0.333

TAPSE -0.481 0.026 -0.006 0.981 -0.101 0.668 -0.180 0.441

Values are presented as Pearson’s correlation coefficient with accompanying P-value, unless otherwise indicat-ed. mRAP indicates mean right atrial pressure; PVRi, indexed pulmonary vascular resistance; CI, cardiac index; mPAP/mSAP, mean pulmonary-to-systemic arterial pressure ratio; PVR/SVR, pulmonary-to-systemic vascular resistance ratio; RA, right atrium; RV, right ventricle; RV/LV, right-to-left ventricular dimension ratio; 4ch, four chamber view; Ecc, eccentricity; LV left ventricle; sax, short axis; lax, long axis; perp sax, perpendicular short axis; TAPSE, tricuspid annular plane systolic excursion. *: Spearman’s correlation used instead of Pearson’s correlation, because of non-normality. †: Results are from pooled analysis on 15 imputed datasets, generated using multiple imputation with 20 iterations in which missing echo values were imputed. As hemodynamic data were not im-puted, the presented results are from a subgroup of 21 patients.


4

dIsCussIon

This early descriptive study demonstratesthat conventional transthoracic echo variables, including RA-, RV- and LV dimensions and RV-functional variables correlate with disease severity and outcome in pediatric PAH. Previous studies on the use of echocardiography in pediatric PAH mostly focused on detection of elevated pulmonary artery pressure in patients suspected for pulmonary hypertension and its use as screening tool in popula-tions at risk. However, only few focused on the potential role of echocardiography in guiding patient management in pediatric PAH.34–36,39

For decision-making in the management of patients with PAH, several diagnostic tools are used. In adults, goal-oriented treatment strategies are recommended, using 6MWD, WHO-FC, RHC and NT-pro-BNP to guide treatment. Also, RV-function has been demon-strated to be an important determinant of prognosis in PAH, where cMRI is currently considered to be the gold standard to evaluate RV function.16 Its potential to assess disease severity, predict prognosis and guide management in PAH has recently been advocated.11–13,45

Figure 1. Cumulative survival stratified by baseline World Health Organization functional class. WHO-FC indicates World Health Organization functional class.

108 Chapter 4

In children with PAH, however, the use of such recommended tools is hampered, due to reasons of insufficient validation in pediatric PAH or lack of feasibility in young children. For instance, the prognostic value of 6MWD in young children is not clear, and only a minority of children is able to perform a reliable 6-minute-walk-test. This was illustrated in the TOPP registry, where 6MWD was available in only 38 % of children in a global cohort.3 Also, the use of WHO-FC has been claimed to be limited in young children due

HR (95% CI) P

Male 0.77 (0.29-2.06) 0.605

Prevalent case 0.62 (0.24-1.63) 0.336

CHD 0.88 (0.34-2.28) 0.793

Age at baseline echo, per 5 year 0.81 (0.50-1.32) 0.398

BSA, per m2 0.39 (0.11-1.35) 0.137

WHO-FC at baseline, per FC 2.74 (1.29-5.84) 0.009

NT-pro-BNP, per log value 2.30 (0.92-5.78) 0.075

0.01 0.1 1 10 100

HR

Figure 2. Association of clinical characteristics with death or lung-transplantation. HR indicates hazard ratio; CI, confidence interval; CHD, congenital heart disease; BSA, body surface area; WHO-FC, WHO func-tional class; NT-pro-BNP, N-terminal-pro-B-type natriuretic peptide.

First echo (baseline), univariable Cox regression Second echo (follow-up), univariable Cox regression HR (95% CI) P HR (95% CI) P

RV/LV 4ch, per 0.5 units 1.82 (0.93-3.60) 0.082 1.82 (1.11-2.97) 0.017

RV/LV sax, per 0.5 units 1.55 (1.02-2.37) 0.041 1.68 (1.23-2.28) 0.001

RV/LV lax, per 0.5 units 2.00 (1.02-3.90) 0.043 1.99 (1.03-3.84) 0.040

LV 4 ch, per 10mm 0.41 (0.20-0.85) 0.017 0.44 (0.22-0.86) 0.016

LV sax, per 10 mm 0.53 (0.29-0.98) 0.041 0.51 (0.29-0.89) 0.018

LV perp sax, per 10 mm 0.42 (0.23-0.78) 0.006 0.26 (0.13-0.52) <0.001

LV lax, per 10 mm 0.37 (0.18-0.77) 0.008 0.36 (0.18-0.72) 0.004

RV ejection time, per 50 ms 0.65 (0.43-0.97) 0.037 0.55 (0.29-1.01) 0.054

TAPSE, per 5 mm 0.34 (0.17-0.68) 0.002 0.46 (0.23-0.95) 0.036

0.01 0.1 1 10 100 0.01 0.1 1 10 100

HR HR

Figure 3. Association of echocardiography with death or lung-transplantation at baseline and follow-up. HR indicates hazard ratio; CI, confidence interval; RV/LV, right-to-left ventricular dimension ratio; 4ch, four chamber view; sax, parasternal short axis view; lax, parasternal long axis view; LV, left ventricle; perp sax, perpendicular to septum short axis view; RV, right ventricle; TAPSE, tricuspid annular plane systolic excur-sion.


4

to its subjective nature and limited applicability, although several pediatric studies have now shown WHO-FC to be a useful predictor of outcome also in pediatric PAH.6,46 An adapted functional classification for children has been proposed, but has not been validated yet.47 RHC has been shown to yield prognostically important measures, but its feasibility is hampered by the frequent need for sedation or general anesthesia and the relatively high major complication rate in children.3 Recently, cMRI-derived RV ejec-tion fraction and LV stroke volume index were demonstrated to be strong predictors of survival in 100 children with idiopathic PAH or PAH-CHD.12 However, the value of cMRI as diagnostic tool may be restricted by reduced feasibility in young children without sedation or general anesthesia and limited accessibility to required infrastructure and expertise on a global scale.

In view of the drawbacks of these currently available follow-up modalities, fea-sible, validated and easily accessible tools to assess disease severity and prognosis in pediatric PAH are urgently needed and conventional echocardiography may thus be such a tool. Previous studies in adults and children with PAH, often studying a single echo variable, have suggested echo variables to be associated with outcome in PAH. This study, however, provides a comprehensive overview of multiple conventional echo variables within the perspective of the patient’s clinical setting and shows that several echo variables correlate with disease severity and outcome. In clinical practice, echo-cardiography may, therefore, function as an adjuvant to WHO-FC and NT-pro-BNP in the subjective and often difficult clinical assessment of disease severity in children with PAH.

Survival in PAH is hypothesized to be closely related with RV function.2 In congru-ence with adults with PAH, this study showed echocardiographic measures of RV func-tion, including TAPSE and RV ejection time, to be associated with outcome in pediatric PAH. An important finding in the current study is that echo variables that were identified at baseline were also predictive when collected at follow-up visits. Although the effect of treatment-initiation on specific variables was not evaluated, the persistence of their predictive value during follow-up underscores the potential value of echocardiography in defining treatment strategies in children with PAH.

In addition to RV-functional echo variables, LV dimensions also showed corre-lations with survival. This is in line with previous cMRI studies in children and adults, demonstrating the prognostic significance of LV dimensions and LV function in PAH.12,45 It is debated whether the reduced LV dimensions in advanced PAH-disease are merely a result of an imbalanced RV/LV-ratio due to compression by a dilated high-pressure RV and prolonged systolic RV contraction or whether these reduced LV dimensions could also be due to ventricular interdependence-related failure of the LV structure and func-tion. Because previous studies investigating echocardiography in PAH predominantly focused on right heart variables, more studies are needed to gain more insight in this.

110 Chapter 4

Recently, a study on echocardiography in adults with PAH identified reduced systolic strain of the LV free wall as a predictor of early mortality.48

The observed correlation of echocardiography with both disease severity and outcome is supported by our finding, in a subgroup, that the echo variables were also associated with hemodynamic measures. The relationship of echocardiographic charac-terization of the RV with hemodynamics was recently further supported by Di Maria et al,10 who showed TAPSE and RV-fractional-area-change to be associated with RV stroke work, which is a hemodynamic measure integrating information on RV performance and ventricular-vascular coupling.

Our main observations are highly in line with adult findings. RA dimensions,22 ventricular dimensions,27 RV/LV-ratio,49 and TAPSE,18,50 have already been shown to carry prognostic value in adults. RV-myocardial performance (Tei) index,28 eccentricity index,18 and the presence of pericardial effusion,23,24 carry prognostic value in adults but were not able to be identified as potential predictors of outcome in this pediatric study. Also, a reduced tricuspid annular peak systolic velocity (S’), or reduced tissue Doppler imaging velocities (systolic myocardial velocity and early diastolic myocardial relaxation velocity), as reported in previous pediatric studies, could not be identified as predictors of outcome.38 This might be because of lack of power in this study, since pericardial ef-fusion was rare in the studied children, whereas tissue Doppler variables and Tei-index, although prescribed by the echo-protocol, could often not be appropriately assessed in our population. This not only prohibits robust conclusions on the prognostic value of these variables in pediatric PAH, but may also question the feasibility of collecting accurate measurements for these variables in all children. To illustrate, the prognostic value of increased ratio of RV-systolic/diastolic phase, as reported by Alkon et al,34 could not be confirmed in our study. These investigators assessed the RV systolic to diastolic duration ratio, from the Doppler flow signal of tricuspid valve regurgitation. In our study 31 patients (76%) had tricuspid regurgitation ≤ grade I, making this echo-variable less feasible for analysis in our population.

Newer techniques may further enhance the value of echocardiography as a bedside tool in children with PAH. Recently, speckle tracking echocardiography, an angle-independent technique to quantify myocardial motion, demonstrated decreased RV and LV longitudinal systolic strain in adults with PAH and serial measures have been suggested to predict therapy effect and outcome in these patients.48


This study was part of the Dutch nationwide registry for PH in childhood which en-compasses all diagnosed children with PAH in The Netherlands. The use of a consistent observational registry approach with a high level of methodological standardization in a well-described representative study population allows for observational studies as


4

the current. However, this approach does not replace a prospective (multicenter) study design and is inevitably associated with important limitations.

We studied a high number of echo-variables in a relatively small cohort, which may have led to overestimation of found correlations. Also, heterogeneity in patients’ diagnosis, (idiopathic/heritable PAH versus PAH-CHD) may limit the interpretation of the findings. During follow-up, treatment strategies might have changed according to evolving treatment guidelines, which could not be accounted for in survival analyses. The diagnostic approach including the echo-protocol remained unchanged during the observation time. Data of tissue Doppler imaging variables were incomplete and, there-fore, not included in the analyses. These limitations will limit confidence and preclude robust conclusions. Nevertheless, the results of the current study are highly in line with reports on echocardiographic predictors in adult patients.18,22,27,49,50 Therefore, and in view of the preliminary nature of the current data, this study should be considered an early exploratory pediatric study supporting the potential use of echocardiography in children with PAH.

suggestions for future research

To increase confidence and to be able to perform multivariable analyses, a prospective, multicenter study should be designed, including a high number of children with PAH. Then, a multivariable approach could yield insight in which of the identified parameters are independent predictors of outcome. In addition, longitudinal studies are needed to determine the prognostic value of treatment-induced changes, to identify which echo-variables could be used in defining treatment goals.

ConClusIons

This early descriptive study shows that easily acquired and widely available conventional echocardiographic characteristics, from both the right and left ventricle, correlate with disease severity and outcome in children with PAH. These characteristics include RA-, RV- and LV dimensions, RV/LV ratio’s and RV-functional variables. Recognizing the current, unmet need for goal-oriented treatment strategies in pediatric PAH, echocardiography might play an adjuvant role in the assessment of disease severity and in guiding treat-ment in young children.

112 Chapter 4

reFerenCes


2. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62:D22–33.





7. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G, Sildenafil Use in Pulmonary Arterial Hyperten-sion (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–57.

8. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery J-L, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmo-nary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493–537.

9. McLaughlin V V, Gaine SP, Howard LS, Leuchte HH, Mathier M a, Mehta S, Palazzini M, Park MH, Tap-son VF, Sitbon O. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D73–81.

10. Di Maria M V, Younoszai AK, Mertens L, Landeck BF, Ivy DD, Hunter KS, Friedberg MK. RV stroke work in children with pulmonary arterial hypertension: estimation based on invasive haemody-namic assessment and correlation with outcomes. Heart. 2014;100:1342–7.

11. Blalock S, Chan F, Rosenthal D, Ogawa M, Maxey D, Feinstein J. Magnetic resonance imaging of the right ventricle in pediatric pulmonary arterial hypertension. Pulm Circ. 2013;3:350–355.


13. Pandya B, Quail MA, Steeden JA, McKee A, Odille F, Taylor AM, Schulze-Neick I, Derrick G, Moledina S, Muthurangu V. Real-time magnetic resonance assessment of septal curvature accurately tracks acute hemodynamic changes in pediatric pulmonary hypertension. Circ Cardiovasc Imaging. 2014;7:706–13.


4



16. Mertens LL, Friedberg MK. Imaging the right ventricle - current state of the art. Nat Rev. 2010;7:551–563.

17. Koestenberger M, Friedberg MK, Ravekes W, Nestaas E, Hansmann G. Non-Invasive Imaging for Congenital Heart Disease: Recent Innovations in Transthoracic Echocardiography. J Clin Exp Cardiolog. 2012;Suppl 8:2.

18. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, Chamera E, Corretti MC, Champion HC, Abraham TP, Girgis RE, Hassoun PM. Tricuspid Annular Displacement Predicts Survival in Pulmonary Hypertension. Am J Respir Crit Care Med. 2006;174:1034–1041.

19. Bustamante-Labarta M, Perrone S, De La Fuente RL, Stutzbach P, De La Hoz RP, Torino A, Favaloro R. Right atrial size and tricuspid regurgitation severity predict mortality or transplantation in primary pulmonary hypertension. J Am Soc Echocardiogr. 2002;15:1160–1164.

20. Bossone E, Bodini BD, Mazza A, Allegra L. Pulmonary arterial hypertension: the key role of echo-cardiography. Chest. 2005;127:1836–1843.

21. Bossone E, Citro R, Blasi F, Allegra L. Echocardiography in pulmonary arterial hypertension: An essential tool. Chest. 2007;131:339–341.



24. Hinderliter AL, Willis 4th PW, Barst RJ, Rich S, Rubin LJ, Badesch DB, Groves BM, McGoon MD, Tap-son VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Koch G, Li S, Clayton LM, Jobsis MM, Blackburn Jr SD, Crow JW, Long WA. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation. 1997;95:1479–1486.

25. Vonk-Noordegraaf A, Galie N. The role of the right ventricle in pulmonary arterial hypertension. Eur Respir Rev. 2011;20:243–253.

26. Zhang R, Dai LZ, Xie WP, Yu ZX, Wu BX, Pan L, Yuan P, Jiang X, He J, Humbert M, Jing ZC. Survival of Chinese patients with pulmonary arterial hypertension in the modern treatment era. Chest. 2011;140:301–309.

27. Ghio S, Pazzano AS, Klersy C, Scelsi L, Raineri C, Camporotondo R, D’Armini A, Visconti LO. Clini-cal and prognostic relevance of echocardiographic evaluation of right ventricular geometry in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol. 2011;107:628–32.

28. Yeo TC, Dujardin KS, Tei C, Mahoney DW, McGoon MD, Seward JB. Value of a Doppler-derived in-dex combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol. 1998;81:1157–1161.

114 Chapter 4

29. Grapsa I, Pavlopoulos H, Dawson D, Gibbs JS, Nihoyannopoulos P. Retrospective study of pulmo-nary hypertensive patients: is right ventricular myocardial performance index a vital prognostic factor? Hellenic J Cardiol. 2007;48:152–160.

30. Sachdev A, Villarraga HR, Frantz RP, McGoon MD, Hsiao JF, Maalouf JF, Ammash NM, McCully RB, Miller FA, Pellikka PA, Oh JK, Kane GC. Right ventricular strain for prediction of survival in patients with pulmonary arterial hypertension. Chest. 2011;139:1299–1309.

31. Lopez-Candales A, Dohi K, Rajagopalan N, Suffoletto M, Murali S, Gorcsan J, Edelman K. Right ventricular dyssynchrony in patients with pulmonary hypertension is associated with disease severity and functional class. Cardiovasc Ultrasound. 2005;3:23.

32. Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of random-ized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30:394–403.

33. Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J, Kahan A, Cabane J, Frances C, Launay D, Mouthon L, Allanore Y, Tiev KP, Clerson P, de Groote P, Humbert M. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multi-center study. Arthritis Rheum. 2005;52:3792–3800.


35. Takatsuki S, Nakayama T, Jone PN, Wagner BD, Naoi K, Ivy DD, Saji T. Tissue Doppler imaging predicts adverse outcome in children with idiopathic pulmonary arterial hypertension. J Pediatr. 2012;161:1126–1131.


37. Sarnari R, Kamal RY, Friedberg MK, Silverman NH. Doppler assessment of the ratio of the systolic to diastolic duration in normal children: relation to heart rate, age and body surface area. J Am Soc Echocardiogr. 2009;22:928–932.

38. Koestenberger M, Nagel B, Ravekes W, Avian A, Heinzl B, Fandl A, Rehak T, Sorantin E, Cvirn G, Gamillscheg A. Tricuspid annular peak systolic velocity (S’) in children and young adults with pul-monary artery hypertension secondary to congenital heart diseases, and in those with repaired tetralogy of Fallot: echocardiography and MRI data. J Am Soc Echocardiogr. 2012;25:1041–1049.

39. Jone P-N, Hinzman J, Wagner BD, Ivy DD, Younoszai A. Right ventricular to left ventricular diam-eter ratio at end-systole in evaluating outcomes in children with pulmonary hypertension. J Am Soc Echocardiogr. 2014;27:172–8.

40. Lai WW, Geva T, Shirali GS, Frommelt PC, Humes RA, Brook MM, Pignatelli RH, Rychik J; Task Force of the Pediatric Council of the American Society of Echocardiography; Pediatric Council of the American Society of Echocardiography. Guidelines and standards for performance of a pediatric echocardiogram: a report from the Task Force of the Pediatric Council of the American Society of Echocardiography. J Am Soc Echocardiogr. 2006;19:1413–1430.


42. Wilk MB, Gnanadesikan R. Probability plotting methods for the analysis of data. Biometrika. 1968;55:1–17.


4

43. Joanes DN, Gill CA. Comparing measures of sample skewness and kurtosis. J Roy Stat Soc. 1998;47:183–189.

44. van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specifica-tion. Stat Methods Med Res. 2007;16:219–242.

45. van Wolferen S a, Marcus JT, Boonstra A, Marques KMJ, Bronzwaer JGF, Spreeuwenberg MD, Post-mus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250–7.


47. Cerro MJ, Abman S, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S, Haworth SG, Ivy D, Lopes AA, Raj JU, Sandoval J, Stenmark K, Adatia I. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ. 2011;1:286–298.

48. Hardegree EL, Sachdev A, Fenstad ER, Villarraga HR, Frantz RP, McGoon MD, Oh JK, Ammash NM, Connolly HM, Eidem BW, Pellikka PA, Kane GC. Impaired left ventricular mechanics in pulmonary arterial hypertension: identification of a cohort at high risk. Circ Fail. 2013;6:748–755.

49. Zeng WJ, Sun YJ, Xiong CM, Gu Q, He JG. Prognostic value of echocardiographic right/left ven-tricular end-diastolic diameter ratio in idiopathic pulmonary arterial hypertension. Chin Med J (Engl). 2011;124:1672–1677.

50. Brierre G, Blot-Souletie N, Degano B, Tetu L, Bongard V, Carrie D. New echocardiographic prognos-tic factors for mortality in pulmonary arterial hypertension. Eur J Echocardiogr. 2010;11:516–522.

116 Chapter 4

supplementary table 1. Echocardiographic Variables as Defined in Study Protocol and Number of Pa-tients in Which This Was Feasible

Echocardiographic variables Code Echo window N=43

2d-anatomical measures

*Right atrial area RA area Apical four chamber 41

*Right atrial length RA length Apical four chamber 41

*Right atrial width RA width Apical four chamber 41

*RV-diameter (end-diastolic)

basal 4-chamber RV 4ch Apical four chamber 40

short-axis RV sax Parasternal short-axis 41

long-axis RV lax Parasternal long-axis 29

*Ratio of end-diastolic basal RV-diameter and LV-diameter

basal four chamber RV/LV 4ch Apical four chamber 33

short-axis view RV/LV sax Parasternal long-axix 41

long-axis RV/LV lax Parasternal short-axis 29

*LV eccentricity index (Ryan’s method) Ecc index Parasternal short-axis 40

*LV-diameter (end-diastolic)

basal 4-chamber LV 4ch Apical four chamber 33

short-axis LV sax Parasternal short-axis 40

short-axis perpendicular to the IVS LV perp sax Parasternal short-axis 41

long-axis LV lax Parasternal long-axis 29

rv-functional measures

*RV ejection time RV ejection time Parasternal short-axis 36

*RV acceleration time RV acceleration time Parasternal short-axis 35

Ratio IVRT/RV ejection time IVRT/ET Parasternal short-axis 13

Ratio IVRT/RV acceleration time IVRT/AT Parasternal short-axis 12

Ratio acceleration/ejection time ACC/EJE Parasternal short-axis 35

Isovolumetric relaxation time IVRT Parasternal short-axis 13

Isovolumetric contraction time IVCT Parasternal short-axis 12

Systolic duration Dur syst Apical four chamber 42

Diastolic duration Dur diast Apical four chamber 42

Ratio systolic/diastolic duration Syst/diast Apical four chamber 42

Pulmonary valve regurgitation (colourdoppler) PR (grade) Parasternal short-axis 41

PR maximum velocity PR Vmax Parasternal short-axis 24

PR end-diastolic velocity PR Ved Parasternal short-axis 19

*Tricuspid annular plane systolic excursion TAPSE Apical four chamber 42

Tricuspid valve regurgitation (colourdoppler) TR (grade 0-3) Apical four chamber 41

TR maximum velocity TR Vmax Apical four chamber 29

Tei-index (TVI) Teitvi Apical four chamber 33

Tricuspid valve early diastolic e-wave TVe Apical four chamber 26

Tricuspid valve diastolic a-wave TVa Apical four chamber 25


4

Tricuspid valve e deceleration time TVedec Apical four chamber 25

E’/A’ Tissue Doppler (TVI) Ea TVI Apical four chamber 23

E/E’ = e top pulsed / e-top tissue doppler ee Apical four chamber 17

Tricuspid valve systolic velocity (TVI) TVs Apical four chamber 31

Tricuspid valve systolic duration TVs duration Apical four chamber 11

E/A ratio pulsed Doppler Tricuspid valve Ea pulsed Apical four chamber 24

Pericardial effusion (yes/no) PE (y/n) Subcostal 43

Pericardial effusion (mm fluid) PE (mm) Subcostal 43

Echo-variables considered eligible to include in further analyses are marked with an asterisk. All anatomical dimensions were measured using either 2D-imaging or M-Mode, as described and recommended in the guide-lines from the task force of the pediatric council of the American Society of Echocardiography.40 RV indicates right ventricle; LV, left ventricle; IVS, interventricular septum; IVRT, isovolumetric relaxation time; PR, pulmonary regurgitation; TR, tricuspid regurgitation; TVI, tissue velocity imaging.

1

2

3

4

5

6

7

8

9

10

Chapter 5Growth in children with pulmonary arterial hypertension: a longitudinal retrospective multiregistry study

Mark-Jan PloegstraD. Dunbar IvyJeremy G. WheelerMonika BrandMaurice BeghettiErika B. RosenzweigTilman HumplXavier IriartErwan Muros-Le RouzicDamien BonnetRolf M.F. Berger

The Lancet Respiratory Medicine 2016: 4: 281-90

120 Chapter 5

ABstrACt

Background

To enable adequate interpretation of growth measurements in the management of chil-dren with pulmonary arterial hypertension (PAH), we assessed growth and its associated determinants in children with PAH.

Methods

We did a retrospective longitudinal study of height and body-mass-index (BMI) in refer-ence to WHO growth standards by pooling four contemporary prospective registries of paediatric PAH representing 53 centres in 19 countries.The main outcome measures were median height for age and body-mass index for age percentiles and longitudinal deviation of height for age and body-mass index for age Z scores from WHO standards.

Findings

601 children were followed up for a median of 2.9 years (IQR 1.5-4.4). Baseline median height for age percentile was 26 (4-54) and baseline median body-mass index for age percentile was 41 (IQR 12-79). Mean height for age Z score was significantly lower than the reference (0.81, 95% CI -0.93 to -0.69; p<0.0001), as was body-mass index for age Z score (-0.12, -0.25 to -0.01; p=0.047). Height for age Z score was particularly decreased in young patients (aged ≤5 years) with idiopathic or hereditary PAH and in all patients with PAH associated with congenital heart disease. Although Z scores increased in some patients and decreased in others, we detected no significant trend in height for age Z score (p=0.57) or body mass index for age Z score (p=0.48) before taking account of covariates. Multivariable linear mixed effects modelling showed that age, cause of PAH, ex-prematurity, WHO functional class, Trisomy 21, and time since diagnosis were associ-ated with height for age Z score, whereas age, ethnicity, and Trisomy 21 were associated with body-mass index for age Z score. A favourable WHO functional class course was independently associated with increases in height for age Z score.

Interpretation

PAH is associated with impaired growth, especially in younger children and those with pulmonary arterial hypertension associated with congenital heart disease. The degree of impairment is independently associated with cause of PAH and comorbidities, but also with disease severity and duration. Because a favourable clinical course was as-sociated with catch-up growth, height for age could serve as an additional and globally available clinical parameter to monitor patients’ clinical condition.

Growth in children with PAH 121

5

IntroduCtIon

Pulmonary arterial hypertension (PAH) is a life-threatening disease of the pulmonary vasculature, characterised by pulmonary vasoconstriction and vascular remodelling leading to increased pulmonary vascular resistance, right ventricular failure, and death.1 It can be idiopathic or heritable, or can occur in association with various conditions such as congenital heart disease, connective tissue disease or portal hypertension. Despite major advances in the treatment of adults in the past decades, PAH remains a devastating disease without a cure.2 Moreover, paediatric data on treatment options and therapeutic strategies are scarce.3 Although PAH in adults and children are similar, important differences exist with regards to cause of PAH, rate of disease progression, and prognosis.4 The effect of PAH on growth applies exclusively to children.

Impaired growth is an important determinant of morbidity and mortality in sev-eral severe paediatric conditions. For instance, children with congenital heart disease are at increased risk for growth impairment for reasons such as feeding difficulties, increased caloric expenditure, and potential effects of cardiac lesions on growth regula-tion.5–7 Data about growth in paediatric PAH are limited, but previous findings8 suggest that growth is impaired such children, evidenced by decreased Z-scores for weight and height in a national cohort study of 64 children with idiopathic disease. Moreover, Z scores for weight and height have been suggested to correlate with survival.8–10 These findings have prompted the Paediatric Task Force of the 5th World Symposium on Pulmo-nary Hypertension (WSPH) to consider whether growth might be a useful parameter for monitoring disease progression and guiding treatment decisions.11

To adequately interpret growth measurements in the clinical management of children with PAH, a longitudinal description of growth in a large contemporary cohort is needed. Because concomitant conditions that also affect growth are common in children with PAH, extensive evaluation of associated determinants is also needed. We describe growth in children with PAH, in reference to World Health Organisation (WHO) growth standards, and identify its associated determinants.

Methods

study design and participants

We performed a pooled longitudinal study using data from four prospective clinical registries of pulmonary hypertension: Tracking Outcomes and Practice in Paediatric Pulmonary Hypertension, an international registry;12 (2) the Registry to Evaluate Early and Long-term PAH Disease Management, a multicentre registry of the USA;9 (3) the Dutch National Network for Paediatric Pulmonary Hypertension, a national registry;13

122 Chapter 5

and ItinérAIR-Pediatrie, a French registry.14–16 These registries together represent 53 expert centres for paediatric pulmonary hypertension in 19 countries.

In all four registries, children diagnosed with pulmonary hypertension were enrolled, predominantly on the basis of right heart catheterisation. Patients with mean pulmonary artery pressure of at least 25 mmHg and mean pulmonary capillary wedge pressure of no more than 12 mmHg (in Tracking Outcomes and Practice in Paediatric Pulmonary Hypertension) or no more than 15 mmHg (in other registries) were enrolled when diagnosed at age 1 month and older (Dutch and French registry) or at age 3 months and older (other registries). Despite small differences between the registries, these enrollment criteria ensured a cohort of patients with PAH compliant with guidelines from EU and US scientific professional associations with the exclusion of patients with pulmonary venous congestion or persistent pulmonary hypertension of the newborn. Ethical approval for the registries was obtained from the institutional review boards and the subjects and/or their guardians provided written informed consent at enrollment.

In the present study, we included children with PAH (World Symposium on Pulmonary Hypertension classification group I pulmonary hypertension) as recorded in the registry, who were diagnosed and enrolled when younger than age 18 years.17,18 Children were assigned to three groups, in agreement with contemporary clinical clas-sification guidelines: idiopathic or hereditary PAH, PAH associated with congenital heart disease (APAH-CHD), or PAH associated with other conditions (APAH-other), including connective tissue disease and portal hypertension. APAH-CHD could include patients with open shunts regarded inoperable because of advanced pulmonary vascular dis-ease and repaired shunts with persisting PAH at least 6 months after repair. Patients with fewer than two measurements of height and body-mass index could not be assessed for longitudinal growth and were excluded.

Patient follow-up and data collection

We retrieved data from the registries on Sept 15, 2013. The data were managed by an independent contract organisation. Patient records were de-identified and registry-specific characteristics were removed.19 Because patients could be entered in more than one registry, duplication was identified on the basis of date of birth, date of diagnosis, sex and site. Data were included from the registry in which the most follow-up data were recorded.

We retrieved all available height and weight measurements from the first mea-surement after diagnosis (defined as baseline) until the last measurement before the patient’s 19th birthday. In addition, we retrieved the following data at baseline: age, sex, cause of PAH, ethnicity, ex-prematurity (born before 37 weeks of gestation), Trisomy 21, concomitant diseases, time since diagnosis, and WHO functional class. The presence of concomitant disease potentially affecting growth (other than Trisomy 21 and ex-


5

prematurity) was determined a priori by two experienced paediatric cardiologists (DDI and RMFB) by independent review of all recorded concomitant diseases (Supplemen-tary Table 1). Furthermore, WHO functional class at last measurement and survival status were collected at follow-up. To summarise the course of functional class during the study, we compared functional class at baseline and at the last growth measurement. A favourable course was defined as stable course in functional class I or II, or improvement from higher functional class at baseline to class I, II or III at the last growth measurement.

Procedures

Decreases of height of more than 5 cm were deemed implausible and were omitted from further analysis. We plotted individual growth trajectories to enable visual assess-ment of data inaccuracies before the analysis. Extreme outliers were removed when they were likely to be implausible, on the basis of comparison with adjacent measurements within the individual growth trajectory.

We used WHO 2006 growth standards of height for age and body-mass index for age to assess growth.20,21 For each measurement of height and body-mass index, we calculated the growth percentile relative to WHO standards. WHO standards consist of sex-specific estimates of the distribution of height and body-mass index for each month for age 0-19 years, described by a normal approximation after a Box-Cox transformation with model parameters L, M and S.22 For each measurement, height for age Z score and body-mass index for age Z score were calculated by using the parameters L, M and S to standardise the measurement to the estimated distribution.

statistical analysis

We present the results of the analyses as estimates and 95% CIs. Categorical variables were compared with Χ2 tests, or if assumptions were violated because of small cell values, Fisher’s exact tests. Continuous variables were compared with Kruskal-Wallis tests. The statistical analyses were done by an independent contract organisation using SAS (version 9.3). All tests were two-sided and p values less than 0.05 were considered statistically significant.

To describe the cohort’s growth and allow visual comparison with WHO standards, median height and body-mass index within seven predefined incremental age groups were plotted against WHO percentile curves. In addition, mean height for age Z score and body-mass index for age Z score were plotted in reference to the WHO Z 0 reference reference (representing the WHO 50th percentile), stratified by incremental age groups. Plots were repeated for the subgroups of patients with idiopathic or hereditary PAH and those with APAH-CHD.

Height for age Z score and body-mass index for age Z score over time were ana-lysed with linear mixed effects models with random parameters for patient intercept

124 Chapter 5

and slope. This modelling strategy makes allowance for patient-level correlation in the growth trajectory. Height for age Z score and body-mass index for age Z score were defined as dependent variables and observation time, defined as time since first growth measurement, as the independent variable. Non-linear observation time variables were added to test for departure from linear growth.

To identify associated determinants of height for age Z score or body-mass index for age Z score, individual covariates were separately added to a starting base model consisting of at least intercept and observation time and also age at first measurement when significant. Covariates to be added separately included: sex, cause of PAH, ethnicity, ex-prematurity, Trisomy 21, growth-affecting concomitant disease, time since diagnosis (log-transformed) and WHO functional class at baseline, and favourable functional class course during follow-up. To identify determinants of longitudinal changes in height for age Z score and body-mass index for age Z score, the interaction of each of the covariates with time was added and retained in the model when significant. Statistically significant determinants in these models were considered eligible for inclusion in a multivariable model consisting of at least intercept, observation time, age at first measurement, and cause of PAH, but were only retained in case of sustained significance.

In addition to the multivariable models, height for age Z score and body mass index for age Z score intercepts and slopes were compared between survivors and non-survivors by adding survival status interaction terms to the base models, to enable an exploratory comparison of growth patterns between these outcome subgroups (see Supplementary Material).

We also did post-hoc stratification. On the basis of the results from statistical mod-elling, the following three subgroups were defined: patients with conditions that affect growth (group A), patients with idiopathic or hereditary PAH without such conditions (group B) and patients with APAH-CHD without such conditions (group C). Growth plots were repeated within these subgroups and sensitivity analyses were done to inform the degree of deviation from WHO standards within group B and group C.

role of the funding source

MBr and EM-LR are employees of the funder (Actelion Pharmaceuticals Ltd.) and were involved in the design of the study, analysis, and interpretation of data. The correspond-ing author (RMFB) had full access to all the data in the study and had final responsibility for the decision to submit for publication.


5

results

Patient characteristics

After removal of 32 duplicates and exclusion of 290 patients with fewer than two growth measurements, 601 patients were included. 337 (56%) of 601 had idiopathic or heredi-tary PAH, 229 (38%) of 601 had APAH-CHD, and 35 (6%) of 601 had APAH-other. During data cleaning before analysis, 63 measurements of height and body-mass index from 28 patients were removed. Age, ethnicity, Trisomy-21, and baseline height for age varied by cause of PAH (Table 1). Baseline median height for age percentile was 26 (IQR 4-54) and baseline body-mass index for age percentile was 41 (IQR 12-79). The proportion of patients below the 5th percentile for height and body-mass index also varied by cause of PAH (Table 1).

Median follow-up was 2.9 years (IQR 1.5-4.4). 333 (72%) of 462 patients with data available had a favourable course of WHO functional class during follow-up and 86 (14%) of 601 patients died. 4726 measurements of height and 4932 measurements of weight were included in longitudinal analyses.

longitudinal description of growth

Plots of median height and body-mass index within seven incremental age groups superimposed to WHO percentile curves show that median height, more than median body-mass index, deviated from the WHO 50th percentile standard (Figures 1 and 2). To enable more precise inference about the degree of deviation from WHO standards, Figure 3 shows mean height for age Z scores and body-mass index for age Z scores com-pared with the WHO Z0 reference. Height for age Z score was significantly decreased in both the total cohort and the cause of PAH subgroups (Figure 3A). Height for age Z score was particularly decreased in young patients (aged ≤5 years) with idiopathic or hereditary PAH and in all patients with APAH–CHD. Body-mass index for age Z score was also decreased compared with the WHO Z 0 reference (figure 3B). Body-mass index for age Z score was lower than the reference for patients with APAH–CHD up to age 15 years. In the idiopathic or hereditary pulmonary arterial hypertension subgroup, body-mass index for age Z score was lower than the reference predominantly in the youngest patients (age <2 years).

126 Chapter 5

tabl

e 1.

Cha

ract

eris

tics

of P

atie

nts,

Stra

tified

by

Caus

e of

Pul

mon

ary

Art

eria

l Hyp

erte

nsio

n

Tota

l coh

ort

IPA

H/H

PAH

APA

H-C

HD

APA

H-o

ther

nN

=601

nN

=337

nN

=229

nN

=35

P-va

lue*

Base

line

char

acte

rist

ics†

Age

(yea

rs)

601

9·1

(5·1

-13·

6)33

79·

6 (5

·5-1

3·7)

229

7·9

(4·4

-13·

1)35

11·6

(6·3

-15·

5)0·

023

Fem

ale

sex

601

342/

601

(57%

)33

719

7/33

7 (5

8%)

229

129/

229

(56%

)35

16/3

5 (4

6%)

0·34

Ethn

icity

585

327

224

340·

0029

Cauc

asia

n41

6/58

5 (7

1%)

232/

327

(71%

)16

7/22

4 (7

5%)

17/3

4 (5

0%)

Blac

k22

/585

(4%

)19

/327

(6%

)2/

224

(1%

)1/

34 (3

%)

Asi

an99

/585

(17%

)52

/327

(16%

)38

/224

(17%

)9/

34 (2

6%)

Oth

er48

/585

(8%

)24

/327

(7%

)17

/224

(8%

)7/

34 (2

1%)

Ex-p

rem

atur

ity47

148

/471

(10%

)26

422

/264

(8%

)17

921

/179

(12%

)28

5/28

(18%

)0·

20

Tris

omy-

2160

165

/601

(11%

)33

75/

337

(1%

)22

959

/229

(26%

)35

1/35

(3%

)<0

·000

1

Gro

wth

-affe

ctin

g co

ncom

itant

dis

ease

601

38/6

01 (6

%)

337

17/3

37 (5

%)

229

18/2

29 (8

%)

353/

35 (9

%)

0·34

Tim

e-si

nce-

diag

nosi

s (y

ears

)60

10·

8 (0

·2-2

·8)

337

0·6

(0·2

-2·8

)22

91·

0 (0

·3-3

·2)

350·

6 (0

·1-2

·2)

0·07

WH

O-F

C53

330

519

731

0·72

I10

0/53

3 (1

9%)

62/3

05 (2

0%)

33/1

97 (1

7%)

5/31

(16%

)

II26

2/53

3 (4

9%)

150/

305

(49%

)97

/197

(49%

)15

/31

(48%

)

III14

4/53

3 (2

7%)

77/3

05 (2

5%)

59/1

97 (3

0%)

8/31

(26%

)

IV27

/533

(5%

)16

/305

(5%

)8/

197

(4%

)3/

31 (1

0%)

Hei

ght f

or a

ge p

erce

ntile

601

25·7

(3·7

-54·

0)33

732

·0 (1

0·4-

61·6

)22

99·

1 (0

·9-4

2·3)

3538

·8 (2

·5-7

1·5)

<0·0

001

Hei

ght f

or a

ge b

elow

5th

%ile

601

164/

601

(27%

)33

758

/337

(17%

)22

996

/229

(42%

)35

10/3

5 (2

9%)

<0·0

001

Body

-mas

s in

dex

for a

ge p

erce

ntile

601

40·8

(12·

1-79

·4)

337

43·5

(14·

8-79

·4)

229

34·0

(8·3

-79·

2)35

46·5

(27·

2-86

·1)

0·17

Body

-mas

s in

dex

for a

ge b

elow

5th

%ile

601

103/

601

(17%

)33

747

/337

(14%

)22

951

/229

(22%

)35

5/35

(14%

)0·

032


5

Follo

w-u

p ch

arac

teri

stic

s

Dur

atio

n of

follo

w-u

p60

12·

9 (1

·5-4

·4)

337

2·9

(1·5

-4·4

)22

93·

1 (1

·8-4

·7)

351·

7 (0

·9-3

·8)

0·00

14

Hei

ght m

easu

rem

ents

per

per

son

(n)

601

6 (4

-11)

337

6 (4

-11)

229

6 (3

-10)

355

(3-8

)0·

050

Wei

ght m

easu

rem

ents

per

per

son

(n)

601

7 (4

-11)

337

7 (4

-11)

229

7 (4

-10)

356

(3-9

)0·

17

Favo

urab

le W

HO

-FC

cour

se‡

462

333/

462

(72%

)26

118

5/26

1 (7

1%)

173

129/

173

(75%

)28

19/2

8 (6

8%)

0·63

Die

d du

ring

follo

w-u

p60

186

/601

(14%

)33

750

/337

(15%

)22

929

/229

(13%

)35

7/35

(20%

)0·

47

Dat

a ar

e n/

N(%

) or m

edia

n (IQ

R). I

PAH

=idi

opat

hic

pulm

onar

y ar

teria

l hyp

erte

nsio

n. H

PAH

=her

edita

ry p

ulm

onar

y ar

teria

l hyp

erte

nsio

n. A

PAH

=ass

ocia

ted

pulm

onar

y ar

teria

l hy

pert

ensi

on. C

HD

=con

geni

tal h

eart

dis

ease

. WH

O-F

C=W

orld

Hea

lth O

rgan

isat

ion

func

tiona

l cla

ss. B

MI=

body

mas

s in

dex.

%ile

=per

cent

ile. *

Com

paris

on o

f cau

se o

f PAH

gr

oups

. † B

asel

ine

defin

ed a

s tim

e of

firs

t gro

wth

mea

sure

men

t. ‡

Favo

urab

le W

HO

-FC

cour

se d

efine

d as

stab

le c

ours

e in

FC

I or I

I or i

mpr

ovem

ent f

rom

hig

her F

C at

bas

elin

e to

FC

I, II

or I

II at

last

gro

wth

mea

sure

men

t.

128 Chapter 5

Age categories (years) Age categories (years) Age categories (years)

Hei

ght (

cm)

Hei

ght (

cm)

Total cohort IPAH/HPAH APAH-CHD

Figure 1. Median height within incremental age categories superimposed to WHO percentile curves. Blue figures represent boys and pink figures represent girls. IPAH=idiopathic pulmonary arterial hypertension. HPAH=hereditary pulmonary arterial hypertension. APAH=associated pulmonary arterial hypertension. CHD=congenital heart disease.


5


Bod

y m

ass

inde

x (k

g/m

2)B

ody

mas

s in

dex

(kg/

m2)

Total cohort IPAH/HPAH APAH-CHD

Figure 2. Median body mass index within incremental age categories superimposed to WHO percentile curves. Blue figures represent boys and pink figures represent girls. IPAH=idiopathic pulmonary arterial hypertension. HPAH=hereditary pulmonary arterial hypertension. APAH=associated pulmonary arterial hypertension. CHD=congenital heart disease.

130 Chapter 5

In all final mixed models, the covariates for squared time and cubic time were not significant, so the linear model was maintained. Modelling of height for age Z score with no other covariates than observation time, yielded a mean baseline Z score of -0.81 (95% CI -0.93 to -0.69; p<0.0001) for the total cohort, significantly below the WHO Z 0 reference. Although height for age Z score increased in some patients and decreased in others, there was no significant longitudinal increase or decrease over time in the total cohort before taking account of patient covariates (-0.01 per year, p=0.57). Similar modelling of body-mass index yielded a mean baseline Z score of -0.12 (95% CI -0.25 to -0.01; p=0.047) for the total cohort, with no significant longitudinal change over time (0.01 per year, p=0.48).

Younger age, APAH–CHD or APAH–other, ex-prematurity, Trisomy 21, longer time since diagnosis, and higher WHO functional class were associated with lower height for age Z score (figure 4A). Although height for age Z score did not change significantly for

-2.0

-1.5

-1.0

-0.5

0

+0.5

+1.0

-2.0

-1.5

-1.0

-0.5

0

+0.5

+1.0

Total cohort IPAH/HPAH APAH-CHDA

Total cohort APAH-CHDB IPAH/HPAH

<2 2-5

5-8

8-11

11-1

5

15-1

7

>17

<2 2-5

5-8

8-11

11-1

5

15-1

7

>17

<2 2-5

5-8

8-11

11-1

5

15-1

7

>17

Age categories (years)

<2 2-5

5-8

8-11

11-1

5

15-1

7

>17

<2 2-5

5-8

8-11

11-1

5

15-1

7

>17

<2 2-5

5-8

8-11

11-1

5

15-1

7

>17

Age categories (years)

Hei

ght-f

or-a

ge Z

-sco

reB

MI-f

or-a

ge Z

-sco

re

Figure 3. Mean Z-scores for height and body mass index. Panel A: Plots of mean height-for-age Z-score, Panel B: plots of mean BMI-for-age Z-score. Error bars represent 95% confidence intervals. BMI= body mass index. IPAH=idiopathic pulmonary arterial hypertension. HPAH=hereditary pulmonary arterial hyperten-sion. APAH=associated pulmonary arterial hypertension. CHD=congenital heart disease.


5

A

)IC %59( etamitsE)IC %59( etamitsEZAFH fo stnanimreteD Age at first measurement**†

)44·0- ot 54·1-( 49·0-)76·0- ot 85·1-( 21·1-sraey 2< )00·0 ot 48·0-( 24·0-)91·0- ot 89·0-( 85·0-sraey 5-2 )34·0 ot 44·0-( 00·0)35·0 ot 72·0-( 31·0sraey 11-8 )72·0 ot 64·0-( 01·0-)42·0 ot 44·0-( 01·0-sraey 51-11 )04·0 ot 05·0-( 50·0-)43·0 ot 94·0-( 80·0-sraey 71-51 )46·0 ot 87·0-( 70·0-)48·0 ot 54·0-( 91·0sraey 71>

Aetiology**‡)91·0- ot 67·0-( 84·0-)95·0- ot 60·1-( 28·0-DHC-HAPA )93·0 ot 86·0-( 41·0-)91·0 ot 08·0-( 13·0-rehto-HAPA

)93·0 ot 80·0-( 61·0xes elameF Ethnicity§

)90·1 ot 41·0-( 74·0kcalB )64·0 ot 81·0-( 41·0 naisA )83·0 ot 84·0-( 50·0-rehtO

Ex-prematurity -** 0·88 (-1·32 to -0·44) -0·59 (-1·01 to -0·18)

ledom elbairavitluMledom esaB

Ex-prematurity -0·88 (-1·32 to -0·44) -0·59 (-1·01 to -0·18))56·0- ot 65·1-( 11·1-)30·1- ot 77·1-( 04·1-**12-ymosirT

)70·0 ot 88·0-( 14·0-esaesid .cnoc .ffa htworG Time since diagnosis** )20·0- ot 62·0-( 41·0-)50·0- ot 52·0-( 51·0- WHO-FC**#

)15·0 ot 81·0-( 61·0)85·0 ot 70·0-( 62·0 II CF-OHW )10·0- ot 08·0-( 04·0-)21·0 ot 16·0-( 52·0- III CF-OHW )63·0 ot 09·0-( 72·0-)26·0 ot 95·0-( 10·0VI CF-OHW )32·0 ot 83·0-( 70·0-)72·0 ot 53·0-( 40·0-¶esruoc CF-OHW elbaruovaF

)IC %59( etamitsE)IC %59( etamitsEegnahc ZAFH fo stnanimreteD)10·0- ot 12·0-( 11·0-)10·0- ot 51·0-( 80·0-**12-ymosirT

)71·0 ot 30·0( 01·0)61·0 ot 20·0( 90·0¶**esruoc CF-OHW elbaruovaF

B)IC %59( etamitsE)IC %59( etamitsEZAFIMB fo stnanimreteD

Age at first measurement**†)61·0 ot 08·0-( 23·0-)44·0 ot 05·0-( 30·0-sraey 2< )13·0 ot 05·0-( 01·0-)25·0 ot 92·0-( 21·0sraey 5-2

8-11 years 0·48 (0·07 to 0·88) 0·52 (0·12 to 0·93)

ledom elbairavitluMledom esaB

8-11 years 0 48 (0 07 to 0 88) 0 52 (0 12 to 0 93))06·0 ot 90·0-( 62·0)65·0 ot 41·0-( 12·0sraey 51-11 )56·0 ot 2·0-( 32·0)36·0 ot 22·0-( 02·0sraey 71-51 )75·1 ot 52·0( 19·0)55·1 ot 32·0( 98·0sraey 71>

Aetiology‡)40·0- ot 75·0-( 13·0-)60·0 ot 34·0-( 91·0-DHC-HAPA )63·0 ot 86·0-( 61·0-)05·0 ot 35·0-( 10·0-rehto-HAPA

)42·0 ot 42·0-( 00·0xes elameF Ethnicity**§

)64·1 ot 71·0( 28·0)15·1 ot 12·0( 68·0kcalB )31·0- ot 18·0-( 74·0-)31·0- ot 08·0-( 64·0- naisA

)18·0 ot 80·0-( 73·0)38·0 ot 70·0-( 83·0rehtO )91·0 ot 07·0-( 52·0-ytirutamerp-xE

)81·1 ot 23·0( 57·0)78·0 ot 90·0( 84·0**12-ymosirT Growth aff. conc. disease* -0·49 (-0·97 to -0·01) Time since diagnosis )80·0 ot 41·0-( 30·0-)90·0 ot 11·0-( 10·0- WHO-FC#

)50·0- ot 37·0-( 93·0- II CF-OHW )40·0- ot 97·0-( 24·0- III CF-OHW )04·0 ot 58·0-( 22·0-VI CF-OHW

Favourable WHO-FC course¶ -0·03 (-0·32 to 0·27)

Determinants of BMIFAZ change Estimate (95% CI) Estimate (95% CI)Determinants of BMIFAZ change Estimate (95% CI) Estimate (95% CI) Ethnicity**§

)80·0 ot 32·0-( 80·0-)50·0 ot 72·0-( 11·0-kcalB )10·0 ot 61·0-( 80·0-)30·0- ot 02·0-( 11·0-naisA )30·0- ot 42·0-( 41·0-)30·0- ot 52·0-( 41·0-rehtO

)62·0 ot 70·0( 71·0)72·0 ot 90·0( 81·0**12-ymosirT Time since diagnosis**# )10·0- ot 60·0-( 40·0-)20·0- ot 70·0-( 40·0-

Figure 4. Candidate determinants of Z-scores for height and body mass index tested in linear mixed ef-fects models.Panel A: HFAZ models, Panel B: BMIFAZ models. Data are effect estimates (95% confidence intervals). Significant associations with HFAZ (Panel A, base model): age (p<0.0001), APAH (p<0.0001), ex-

132 Chapter 5

the total cohort, it did change in individual patients. Trisomy-21 and favourable WHO functional class course were significant determinants of longitudinal changes in height for age Z score; Trisomy 21 predicted a decrease, and favourable course predicted an increase over time. All determinants of height for age Z score remained significant in the multivariable model.

Trisomy-21 was associated with higher body-mass index for age Z scores, Asian ethnicity and growth-affecting concomitant disease were associated with lower Z scores, and black ethnicity was associated with higher Z scores (figure 4B). In addition, ethnicity, Trisomy-21, and time since diagnosis were significant determinants of longitu-dinal changes in body-mass index for age Z score; ethnicity other than white and longer time since diagnosis predicted decreases, and Trisomy-21 predicted increases over time. Growth-affecting concomitant disease was not significant on inclusion in the multivari-able model (p=0.0540) and was therefore omitted from the final multivariable model. The other identified determinants remained significant in the multivariable model.

We did an exploratory comparison of growth patterns in survivors and non-survivors (see Supplementary Material). Height for age Z score slopes of non-survivors tended to differ significantly from slopes of survivors, but not significantly (p=0.06).

Trisomy-21, ex-prematurity and growth-affecting concomitant disease were significant determinants of growth in one or more of the multivariable models. There-fore, the subgroups of patients with and without other conditions that affect growth were defined as follows: patients with Trisomy-21, ex-prematurity, or growth-affecting concomitant disease (group A, n=134), patients with idiopathic or hereditary PAH who did not have such conditions (group B, n=297), and patients with APAH-CHD without such conditions (group C, n=143). Plots of median height and body-mass in-dex superimposed to WHO standards within these groups are shown in the appendix (Supplementary Figures 1 and 2). The linear mixed models sensitivity analysis showed that height for age Z score was significantly below the WHO Z0 reference in both group

prematurity (p<0.0001), Trisomy-21 (p<0.0001), time-since-diagnosis (p=0.0046), and WHO-FC (p=0.0076). Associations with longitudinal HFAZ changes: Trisomy-21 (p=0.0308) and favourable WHO-FC course (p=0.0140). Associations with BMIFAZ (Panel B, base model): Trisomy-21 (p=0.0166), ethnicity (p=0.0002) and growth-affecting concomitant disease (p=0.0441). Associations with longitudinal BMIFAZ changes: Ethnicity (p=0.0060), Trisomy-21 (p=0.0001), and time-since-diagnosis (p=0.0005). HFAZ=height-for-age Z-score. BMIFAZ=body mass index-for-age Z-score. CI=confidence interval. APAH=associated pulmonary arterial hypertension. CHD=congenital heart disease. WHO-FC=World Health Organisation functional class. Growth aff. conc. disease=growth-affecting concomitant disease. * Significant variable in the base model only. ** Significant variable in the multivariable model. † Reference group is 5-8 years. ‡ Reference group is IPAH/HPAH. § Reference group is Caucasian. # Reference group is WHO-FC I. || Natural-log transformed variable because of skewed distribution.¶ Defined as stable course in FC I or II or improvement from higher FC at baseline to FC I, II or III at last growth measurement.


5

B and C (p<0.0001), whereas body-mass index for age Z score was significantly below the reference in group C only (p<0.0007, see Supplementary Material).

dIsCussIon

The results of this pooled longitudinal multiregistry study show that height is impaired in children with PAH, especially in younger children and those with APAH–CHD. Body-mass index is impaired to a lesser extent than height. Children with Trisomy 21, ex-prematurity, and growth-affecting concomitant diseases are more likely to have growth deficits, but children without these comorbidities also had significant impairment in height. Severity and duration of disease were important determinants of impaired growth. A favourable course of WHO functional class over time was associated with catch-up growth. The growth impairment in children with PAH underscores the severity of this disease and warrants the attention and action of physicians caring for these children.

Our results accord with previous preliminary findings of a decreased height in children with PAH,8,23–25 and that body-mass index is decreased to a lesser extent than height.24,25 Two reports8,23 from the United Kingdom Service for Pulmonary Hypertension in Children showed no catch-up growth despite PAH targeted treatment. In the present study, we did not detect catch-up growth for the total cohort; however catch-up growth was independently associated with a favourable WHO functional class course over time. This finding could indicate that catch-up growth is possible in children with PAH in whom functional class can be improved with effective treatment and therefore sup-ports the suggestion of the 5th World Symposium on Pulmonary Hypertension Paediatric Taskforce that growth can be a valuable adjunct parameter to monitor disease severity and treatment efficacy in paediatric PAH.8,11,23

Congenital heart disease, Trisomy 21, and ex-prematurity are all well known de-terminants of growth and are common comorbidities in children with PAH. Our findings underscore the role of these comorbidities in impaired growth in children with PAH. However, we also show, for the first time, that significant growth impairment occurs in children with idiopathic or hereditary PAH without associated comorbidities and that growth impairment in children with PAH is thus not driven solely by comorbidities. Growth impairment in patients with idiopathic or hereditary PAH was prominent in the youngest children compared with those older than age 5 years in whom median height deviation from the reference was 2–3 cm. Nevertheless, a substantial proportion (17%) of children with idiopathic or hereditary PAH had height below the 5th reference percentile (Table 1). This growth impairment seems to be clinically relevant because the occurrence of catch-up growth was correlated with clinical improvement.

134 Chapter 5

Patients with APAH-CHD had the most severe impairment in growth. Previous studies5–7 in children with CHD have shown that the degree of growth impairment depends on the type of cardiac lesion, the timing of surgical repair, and the presence of shunts, congestive heart failure or pulmonary hypertension. Cardiac and respiratory work are increased in congenital heart disease, increasing metabolic demands. However, dyspnoea, tachypnoea and fatigue negatively affect caloric intake. Also, hypoxaemia as occurs in congenital heart disease has been shown to be associated with reduced levels of endocrinological factors, potentially contributing to growth failure.26 Furthermore, malabsorption might be present in the context of cardiac cachexia due to congestive heart failure. In the heterogeneous subgroup of patients with APAH-CHD these poten-tial underlying mechanisms vary from patient to patient, which emphasises the need for a special focus on this subgroup in future research.

We speculate that increased caloric expenditure has an important role in the underlying mechanism of growth impairment in all subgroups of patients with PAH, but neither caloric intake nor expenditure have been systematically studied in children with PAH. The efficacy of dietary interventions, PAH treatment or supportive heart fail-ure drugs on growth has also not yet been studied. This is an important area of future research that requires a prospective and preferably randomised controlled design.

To our knowledge, this is the largest published study on paediatric PAH and growth to date. The representation of all paediatric age groups and the use of real-world data from 53 centres, 19 countries, and five continents enhances the generalisability of the findings. Other strengths of this study include the collection of individual patient data in one common database, the longitudinal design, the large number of growth measurements, and the advanced modelling approach. This study is limited by slight differences between the four registries regarding collection of data and duration of follow-up. Nevertheless, the registry enrollment criteria were very similar and stringent criteria were used to define PAH. The raw data did not include a set of full childhood growth trajectories (age 0-18 years) but various trajectory-lengths at various ages in childhood (median follow-up duration 3 years) and mixed effects models were used to analyse the data. In this way, the large number of measurements and the wide range of ages enable broad applicability throughout the paediatric age range. Because we also included prevalent patients (in whom the diagnosis of PAH was made >3 months before enrolment in the registry), a survivor bias might be present, potentially leading to an underestimation of growth impairment. Heterogeneity relating to disease characteris-tics and comorbidity is inherent to paediatric PAH. This limitation particularly applies to APAH-CHD, consisting of both patients with open shunts and shunts repaired at least 6 months before registry enrollment. Few patients had APAH-other, hampering addi-tional analyses to assess whether associations were consistent throughout the cause of PAH subgroups. This study was not designed to determine the prognostic value of


5

longitudinal height for age or body-mass index for age Z scores in this cohort, but our preliminary finding that height for age Z score slopes tended to differ between survivors and non-survivors might be considered hypothesis-generating. Individual data on inva-sive haemodynamics or 6-minute walk tests were not collected, precluding evaluation of its correlations with growth.

ConClusIon

This study quantifies growth impairment in children with PAH and identifies important determinants, including associated comorbidities and duration and severity of the disease. A favourable clinical course appeared independently associated with catch-up growth. These findings suggest that growth - an easy and globally available clinical measurement - can be used to assess and monitor children with PAH throughout the disease course. The mechanism of growth impairment and the prognostic value of growth patterns in paediatric PAH require further investigation.

136 Chapter 5

reFerenCes


2. Humbert M, Lau EMT, Montani D, Jaïs X, Sitbon O, Simonneau G. Advances in therapeutic inter-ventions for patients with pulmonary arterial hypertension. Circulation. 2014;130:2189–208.

3. Zijlstra WMH, Ploegstra M-J, Berger RMF. Current and advancing treatments for pulmonary arte-rial hypertension in childhood. Expert Rev Respir Med. 2014;8:615–28.

4. Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J. 2011;37:665–77.

5. Varan B, Tokel K, Yilmaz G. Malnutrition and growth failure in cyanotic and acyanotic congenital heart disease with and without pulmonary hypertension. Arch Dis Child. 1999;81:49–52.

6. Polat S, Okuyaz C, Hallioğlu O, Mert E, Makharoblidze K. Evaluation of growth and neurodevelop-ment in children with congenital heart disease. Pediatr Int. 2011;53:345–9.

7. Daymont C, Neal A, Prosnitz A, Cohen MS. Growth in children with congenital heart disease. Pediatrics. 2013;131:e236–42.



10. Ploegstra M, Zijlstra WMH, Douwes JM, Hillege HL, Berger RMF. Prognostic factors in pedi-atric pulmonary arterial hypertension: A systematic review and meta-analysis. Int J Cardiol. 2015;184:198–207.



13. van Loon RLE, Roofthooft MTR, van Osch-Gevers M, Delhaas T, Strengers JLM, Blom NA, Backx A, Berger RMF. Clinical characterization of pediatric pulmonary hypertension: complex presentation and diagnosis. J Pediatr. 2009;155:176–82.e1.

14. Fraisse A, Godart F, Bonnet D, Gressin V, Voisin M, Dauphin C, Schleich J-M, Clerson P, Beghetti M, Simonneau G. The French registry of pulmonary arterial hypertension in children: rationale and design. Curr Med Res Opin. 2007;23:S27–S33.

15. Fraisse A, Jais X, Schleich J-M, di Filippo S, Maragnès P, Beghetti M, Gressin V, Voisin M, Dauphin C, Clerson P, Godart F, Bonnet D, Maragnes P, Beghetti M, Gressing V, Voisin M, Dauphin C, Clerson P, Godark F, Bonnet D. Characteristics and prospective 2-year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103:66–74.

16. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier J-F, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simon-neau G. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–30.

17. Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S–12S.


5

18. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–41.

19. El Emam K, Rodgers S, Malin B. Anonymising and sharing individual patient data. BMJ. 2015;350:h1139–h1139.

20. WHO Multicentre Growth Reference Study Group. WHO child growth standards. Geneva: World Health Organization; 2006.

21. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr Suppl. 2006;450:76–85.

22. Rigby RA, Stasinopoulos DM. Smooth centile curves for skew and kurtotic data modelled using the Box-Cox power exponential distribution. Stat Med. 2004;23:3053–76.




26. Surmeli-Onay O, Cindik N, Kinik ST, Ozkan S, Bayraktar N, Tokel K. The effect of corrective surgery on serum IGF-1, IGFBP-3 levels and growth in children with congenital heart disease. J Pediatr Endocrinol Metab. 2011;24:483.

138 Chapter 5

suPPleMentAry MAterIAl

explorative comparison of growth patterns between survivors and non-survivors

The present study was not designed to determine the prognostic value of growth: the main outcome measurements of this study were longitudinal Height-for-age Z-score (HFAZ) and BMI-for-age Z-score (BMIFAZ), not time to death. Therefore, the results below should be interpreted within the context of the limitations of the analytical approach.

Analytical approach and limitationsIn order to enable an explorative comparison of growth patterns between survivors and non-survivors, the following interaction analysis was performed: the variable “survival status at end of follow-up” was added to the HFAZ and BMIFAZ base models, as described in the methods section of the main manuscript. This approach yields separate intercepts and slopes for survivors and non-survivors, with the ability to evaluate the statistical significance of the difference between these. Important limitations of this approach are the absence of a “time-to-event” dimension (no censoring options), and the limited options to identify and adjust for confounding factors.

Results– HFAZ intercepts of non-survivors did not significantly differ from intercepts of survi-

vors (Estimate -0.16, 95% confidence interval [CI] -0.49 to 0.17, p=0.34).– HFAZ slopes of non-survivors tended to differ significantly from slopes of survivors,

but not below the predefined alpha cut-off (Estimate -0.08, 95% CI -0.16 to 0.00, p=0.06).

– BMIFAZ intercepts of non-survivors did not significantly differ from intercepts of survivors (Estimate -0.20, 95% CI -0.53 to 0.14, p=0.26).

– BMIFAZ slopes of non-survivors did not significantly differ from slopes of non-survivors (Estimate -0.07, 95% CI -0.17 to 0.04, p=0.21).

InterpretationThe result that HFAZ slopes tended to differ between survivors and non-survivors is a hypothesis-generating finding. Taken together with the fact that absolute HFAZ have been demonstrated to correlate with outcome in previous studies in pediatric PAH, one might speculate that both absolute values and longitudinal patterns of HFAZ carry prognostic value.


5

sensitivity analysis results group B and C

Group BThe sensitivity analysis in group B of the HFAZ model with no covariates other than ob-servation time, yielded a mean (95% CI) baseline HFAZ of -0.36 (-0.50 to -0.21, p<0.0001), without a significant longitudinal increase or decrease over time (0.00 per year, p=0.98). The BMI sensitivity analysis yielded a mean (95% CI) baseline BMIFAZ of 0.02 (-0.14 to 0.18, p=0.80) for this subgroup, without a significant longitudinal increase or decrease over time (-0.01 per year, p=0.60).

Group CThe sensitivity analysis in group C of the HFAZ model yielded a mean (95% CI) baseline HFAZ of -0.94 (-1.20 to -0.68, p<0.0001), without a significant longitudinal increase or decrease over time (0.03 per year, p=0.16). The BMI sensitivity analysis yielded a mean (95% CI) baseline BMIFAZ of -0.47 (-0.74 to -0.20, p=0.0007) for this subgroup, without a significant longitudinal increase or decrease over time (-0.01 per year, p=0.60).

supplementary table 1. Concomitant Diseases Potentially Affecting Growth

Biliary atresia, s/p Kasai Cystic fibrosis Pulmonary hypoplasia

Bronchopulmonary dysplasia Fanconi syndrome S/p kidney transplantation

Cerebral palsy Hemolytic anemia Short bowel syndrome

Chronic lung disease Hemolytic uremic syndrome Silver-Russell syndrome

Chronic renal failure Jacobsen syndrome Trisomy 9 mosaicism

Coeliac disease Necrotizing enterocolitis Unclassified syndrome

Congenital alveolar hypoplasia Neurofibromatosis VACTERL/VATER association

Congenital diaphragmatic hernia NOMID syndrome Velocardiofacial syndrome

Cushing’s syndrome Noonan syndrome 22q11 deletion syndrome

Listed are all recorded concomitant diseases other than Trisomy-21 or ex-prematurity that were considered to have a potential effect on growth. S/p=status post. NOMID=neonatal onset multisystem inflammatory disease.

140 Chapter 5


Hei

ght (

cm)

Hei

ght (

cm)

Group A Group B Group C

supplementary Figure 1. Median height within incremental age categories superimposed to WHO per-centile curves, stratified by patients with and without other conditions that influence growth. Blue fig-ures represent boys and pink figures represent girls. Group A: patients with one or more of the follow-ing other conditions that influence growth: Trisomy-21, ex-prematurity or growth affecting concomitant disease (n=134). Group B: Idiopathic / hereditary pulmonary arterial hypertension patients without other conditions that influence growth (n=297). Group C: congenital heart disease associated pulmonary arte-rial hypertension patients without other conditions that influence growth (n=143). The representation of Trisomy-21, ex-prematurity and growth affecting concomitant disease in group A was 48%, 36% and 27%, respectively.


5


Bod

y m

ass

inde

x (k

g/m

2)B

ody

mas

s in

dex

(kg/

m2)

Group A Group B Group C

supplementary Figure 2. Median body mass index within incremental age categories superimposed to WHO percentile curves, stratified by patients with and without other conditions that influence growth. Blue figures represent boys and pink figures represent girls. Group A: patients with one or more of the follow-ing other conditions that influence growth: Trisomy-21, ex-prematurity or growth affecting concomitant disease (n=134). Group B: Idiopathic / hereditary pulmonary arterial hypertension patients without other conditions that influence growth (n=297). Group C: congenital heart disease associated pulmonary arte-rial hypertension patients without other conditions that influence growth (n=143). The representation of Trisomy-21, ex-prematurity and growth affecting concomitant disease in group A was 48%, 36% and 27%, respectively.

1

2

3

4

5

6

7

8

9

10

Chapter 6Serially measured uric acid levels predict disease severity and outcome in pediatric pulmonary arterial hypertension

Lynn J. LeberkühneMark-Jan PloegstraJohannes M. DouwesBeatrijs BarteldsMarcus T.R. RoofthooftHans L. HillegeRolf M.F. Berger

American Journal of Respiratory and Critical Care Medicine 2017; 195

(Published as Research Letter, see Supplementary Material)

144 Chapter 6

ABstrACt

Background

Optimal clinical decision-making in the treatment of paediatric pulmonary arterial hypertension (PAH) requires a reliable and non-invasive biomarker. Uric acid has been suggested to be such a candidate. We aimed to evaluate the association of serum uric acid with disease severity and outcome during the full disease course of paediatric PAH.

Methods and results

Eighty-one consecutive children from the Dutch National Network for Paediatric Pulmo-nary Hypertension underwent prospective follow-up in accordance with a standardized protocol. During a median follow-up of 3.9 years, 860 serum uric acid measurements were collected. Uric acid levels differed significantly from healthy controls (p<0.001). Taking into account all measurements during follow-up, higher uric acid levels were associated with higher WHO functional class, N-terminal pro brain natriuretic peptide, lower tricuspid annular plane systolic excursion and higher mortality (p=0.007, p<0.001, p<0.001 and p<0.001, respectively). Non-survivors showed a significantly steeper increase in uric acid levels during follow-up (p=0.001) and increases of ≥50% were as-sociated with a 3.9 times higher risk of death or lung-transplantation (p=0.005).

Conclusion

This study demonstrates that higher serum uric acid levels are associated with disease severity and mortality in children with PAH, throughout the full disease course. Monitor-ing absolute values and changes of uric acid levels provides valuable information and could help guide decisions in the management of paediatric PAH.

Serum uric acid in pediatric PAH 145

6

IntroduCtIon

Pulmonary arterial hypertension (PAH) is a serious disease, ultimately causing an early death of affected individuals.1 As a consequence of vascular remodelling processes, the pulmonary vascular resistance increases and pulmonary hypertension develops. Over time, the attempt to compensate for the increased resistance overwhelms the capacity of the right ventricle, resulting in right heart failure and premature death.2,3

To ensure optimal monitoring and clinical decision-making, reliable markers of disease severity and outcome are needed. For a delicate patient population such as chil-dren, there is a preference for non-invasive and easily obtainable biomarkers.4,5 Previous observations have provided clues that serum uric acid could fulfil such a role.6–8 Uric acid is the end product of purine degradation by xanthine oxidase and high levels have been implicated in many cardiovascular diseases.9,10 In clinical states of tissue hypoxia, such as chronic heart failure,11 and cyanotic congenital heart disease,12 high levels of uric acid have been observed. Hyperuricemia is likely to reflect impairment in energy generation, which might be linked to the severity of the disease.6,11 Besides its value as a disease marker, uric acid might also provide a contributing factor to the progression of cardio-vascular diseases.13 In high-risk patients with acute coronary syndrome and heart failure, hyperuricemia is a known risk factor for mortality, through its incitement of endothelial dysfunction and impaired vasodilation.14–16 In adult PAH studies, it has been confirmed that baseline acid levels correlate with disease severity and outcome.6,7,17,18 Also in cross-sectional observations in children with PAH, baseline levels of uric acid have previously been shown to correlate with outcome.8,19,20 However, associations with serial uric acid values collected during long-time follow-up to evaluate the time-dependent relation-ship with outcome are lacking.

A reliable biomarker should reflect the disease process and is expected to fluctu-ate according to the severity of the disease. Candidate biomarkers require extensive longitudinal evaluation in well-defined cohorts prior to incorporation in clinical prac-tice. Therefore, the aim of this study was to evaluate the association of uric acid levels, measured both at baseline and longitudinally during the course of the disease, with disease severity and outcome in children with PAH.

Methods


This is a longitudinal study of data from a prospective clinical registry. In the Nether-lands, all children with PAH are referred to the University Medical Center Groningen (UMCG), the expert center of the Dutch National Network for Paediatric Pulmonary

146 Chapter 6

Hypertension.21 All patients are followed and registered prospectively according to a standardized protocol. Ethical approval for this ongoing registry was obtained from the Institutional Review Board and informed consent was obtained from the patients and/or their guardians. In the current study, all children with PAH who were enrolled between July 1997 and March 2015 and who had at least one uric acid value available were in-cluded. Diagnosis of PAH was confirmed with heart catheterization and defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg, pulmonary vascular resistance index (PVRi) ≥3 WU*m2 and mean pulmonary capillary wedge pressure ≤15 mmHg.21,22 In cases of clinical instability, diagnosis was made by echocardiography, defined as either the presence of right-to-left shunting in the case of congenital heart defects or a maximum systolic tricuspid regurgitant velocity >2.8 m/s accompanied by septal flattening and/or right ventricular hypertrophy.23

data collection

Diagnostic work-up included full hemodynamic evaluation with vasoreactivity testing. Diagnostic evaluation and standardized clinical follow-up every 3-12 months, further included assessment of WHO functional class (WHO-FC), 6-minute walking distance (6MWD), echocardiographic evaluation including measurement of tricuspid annular plane systolic excursion (TAPSE), and blood sampling including uric acid, creatinine and NT-proBNP.

As part of standardized clinical practice, venous blood samples were collected in lithium- and heparin-containing tubes. Serum uric acid concentrations were measured using the MEGA clinical chemistry analyzer (Merck, Darmstadt, Germany), the VITROS chemistry system (Ortho-Clinical Diagnostics, Inc., Johnson & Johnson Co., Raritan, NJ, USA) or the Modular analyzer (Roche Diagnostics, Mannheim, Germany). All three types of analyzers use the indirect equilibrium uricase method. This colorimetric uricase-catalyzed reaction causes uric acid to transform into hydrogen peroxide (amongst other products), which can then be quantified by measuring its absorbance with spectropho-tometry.

Outcome was defined as death/lung-transplantation. The observation time was calculated from the first measurement of uric acid until death/lung-transplantation or until the last follow-up visit before March 2015.

data analysis

Statistical analysis was conducted using IBM SPSS 20.0 (Armonk, NY, USA), STATA 11.0 (StataCorp., College Station, Texas, USA) and RStudio (www.rstudio.com). Normally dis-tributed continuous variables are presented as mean ± standard deviation. Continuous non-normally distributed variables were normalized using log-transformation. Categori-cal variables are presented as absolute numbers (percentage). P-values of ≤0.05 were


6

considered statistically significant. As uric acid levels have been shown to depend on age and sex,24 and renal excretion,9 analyses were repeated with adjustment for age, sex and creatinine.

Disease severity analyses.To determine the association of baseline uric acid levels with disease severity markers, correlation coefficients were calculated. To evaluate this association during the course of the disease, including all longitudinal data, the predictive value of uric acid for three clinical markers (WHO-FC, NT-proBNP or TAPSE Z-score), which have an important prog-nostic value in PAH,25was separately analysed using linear mixed effects modelling with random intercept and slope.

Outcome analyses.To determine the association of baseline uric acid levels with outcome, Cox regression analysis was performed. Kaplan Meier analysis with log-rank testing was performed to compare transplantation-free survival of patients with high or low baseline uric acid levels. To evaluate this association during the course of the disease, the predictive value of time-varying uric acid levels was analysed using time-dependent Cox regression. Two outcome models were created: one including all follow-up levels uric acid as time-varying covariate, and another one with the occurrence of a ≥50% increase in uric acid since baseline as a dichotomous time-varying covariate. As a ceiling effect could distort the latter analysis, with uric acid barely being able to increase further because of already high levels, all hazard ratios derived from this model were adjusted for baseline uric acid.

Furthermore, the linear development of uric acid over time was compared be-tween survivors and non-survivors using linear mixed effects modelling. A model was created with random patient intercepts, with uric acid as dependent variable and obser-vation time, transplantation-free survival and the interaction of observation time with survival status at last visit as independent variables. This yielded separate intercepts and slope estimates for the survivors and non-survivors, with the ability to evaluate the statistical significance of the difference of the intercepts and slopes between these respective groups.

results

Patient characteristics at baseline

Eighty-one patients (35 males and 46 females) diagnosed with PAH were included in this study. 46 patients (57%) had either idiopathic or heritable PAH, while 27 (33%) had PAH associated with congenital heart disease and 8 (10%) other types of PAH (Table 1). Uric

148 Chapter 6

acid levels were significantly higher compared to levels healthy controls (mean Z-score deviation +1.36, 95% CI 0.91-1.82, one-sample T-test p<0.001).41

Association of uric acid levels with disease severity

Table 2 shows the correlations between disease severity markers and baseline uric acid values. Serum uric acid levels measured at baseline showed significant positive correla-tions with age (r=0.29; p=0.009), creatinine (r=0.45; p<0.001), WHO-FC (r=0.31; p=0.005), NT-proBNP (r=0.31; p=0.014), mean right atrial pressure (r=0.41; p=0.003), mean pul-monary arterial pressure (r=0.31; p=0.025), the ratio between mean pulmonary and systemic arterial pressure (r=0.39; p=0.004) and pulmonary vascular resistance index

table 1. Patient Characteristics at Baseline

n (%) or mean (SD)

n N=81

Sex (female) 81 46 (57)

Age (yr) 81 8.3 (5.7)

Etiology 81

Idiopathic / hereditary PAH 46 (57)

Associated PAH - CHD 27 (33)

Associated PAH - other 8 (10)

Treatment status at baseline 81

Treatment naive 55 (68)

Calcium channel blocker therapy 6 (7)

PAH-targeted mono therapy 15 (19)

PAH-targeted dual therapy 4 (5)

PAH-targeted triple therapy 1 (1)

WHO functional class 80

I 4 (5)

II 17 (21)

III 40 (50)

IV 19 (24)

Uric acid (mmol/L) 81 0.31 (0.11)

Creatinine (µmol/L) 71 50 (20)

NT-proBNP (Log-10 value) 61 2.9 (0.9)

TAPSE (Z-score) 54 -3.1 (2.3)

Mean pulmonary artery pressure (mmHg) 52 53 (19)

Pulmonary vascular resistance index (WU*m2) 51 19 (13)

Cardiac index (L/min/m2) 51 3.3 (2.3)

Definition of abbreviations: PAH = pulmonary arterial hypertension; CHD = congenital heart disease; WHO-FC = World Health Organization functional class; NT-proBNP = N-terminal pro B-type natriuretic peptide; TAPSE = tricuspid annular plane systolic excursio. Data presented as n (%) or mean (SD).


6

(r=0.41; p=0.003) and negative correlations with TAPSE Z-score (r=-0.30; p=0.027) and mixed venous saturation (r=-0.37; p=0.008). With the exception of mPAP, these associa-tions tended to remain significant after adjusting for age, sex and creatinine.

During a median (IQR) follow-up of 3.9 (0.8-7.5) years, serum uric acid levels were measured repeatedly, yielding a total of 860 uric acid measurements from 81 patients. The results of linear mixed effects modelling involving all follow-up time points are shown as three disease severity models in Table 3, with WHO-FC, NT-proBNP and TAPSE Z-scores as the respective dependent outcome variables. Higher uric acid levels were significantly associated with higher WHO-FC (p=0.007), higher NT-proBNP (p<0.001) and lower TAPSE Z-scores (p<0.001). These associations tended to remain significant after adjusting for age, sex and creatinine.

table 2. Correlations of Uric Acid With Disease Severity Markers at Baseline

Univariable Analysis Adjusted for Age, Sex and Creatinine

n r p value n r p value

Clinical Characteristics

IPAH/HPAH (vs.associated PAH)+ 81 0.04 0.714 71 0.05 0.660

Female+ 81 -0.10 0.381 N.A.

Age at baseline 81 0.29 0.009 N.A.

WHO-FC§ 80 0.31 0.005 70 0.36 0.002

Creatinine 71 0.45 <0.001 N.A.

Log NT-proBNP 61 0.31 0.014 54 0.27 0.050

TAPSE Z-score 54 -0.30 0.027 52 -0.26 0.067

hemodynamic Characteristics

Mixed venous oxygen saturation 50 -0.37 0.008 46 -0.41 0.006

Mean right atrial pressure 52 0.41 0.003 48 0.40 0.006

Mean pulmonary artery pressure 52 0.31 0.025 48 0.21 0.159

mPAP/mSAP 52 0.39 0.004 48 0.34 0.020

PVR index 51 0.41 0.003 47 0.29 0.055

PVR/SVR 51 0.25 0.072 47 0.22 0.146

Cardiac index 51 -0.02 0.875 47 0.00 0.999

Qp/Qs 51 -0.22 0.128 47 -0.16 0.306

Data presented as Pearson correlation coefficient r (univariable analysis) or partial correlation coefficient r (ad-justed analysis), unless otherwise indicated. Definition of abbreviations: PAH = pulmonary arterial hyperten-sion; IPAH = idiopathic PAH; HPAH = hereditary PAH; WHO-FC = World Health Organization functional class; NT-proBNP = N-terminal pro brain natriuretic peptide; TAPSE = tricuspid annular plane systolic excursion; mPAP/mSAP = pulmonary-to-systemic arterial pressure ratio; PVR/SVR = pulmonary-to-systemic vascular resistance ratio; Qp/Qs = pulmonary-to-systemic flow ratio; N.A. = not applicable. +Point-Biserial Correlation, §Spearman correlation coefficient.

150 Chapter 6

tabl

e 3.

Ass

ocia

tion

of S

eria

lly M

easu

red

Uric

Aci

d w

ith D

isea

se S

ever

ity M

arke

rs a

nd O

utco

me.

Uni

varia

ble

Ana

lysi

sAd

just

ed fo

r Age

, Sex

, Cre

atin

ine

n*β/

HR

(95%

CI)

P va

lue

n*β/

HR

(95%

CI)

P va

lue

dis

ease

sev

erit

y m

arke

rs

WH

O-F

C†78

5/80

0.09

(0.0

3 to

0.1

6)0.

007

762/

700.

09 (0

.01

to 0

.16)

0.02

8

NT-

proB

NP,

log-

tran

sfor

med

†75

1/61

0.19

(0.1

4 to

0.2

4)<0

.001

748/

540.

20 (0

.14

to 0

.26)

<0.0

01

TAPS

E, Z

-sco

re†

563/

54-0

.46

(-0.6

9 to

-0.2

3)<0

.001

560/

52-0

.26

(-0.5

3 to

0.0

1)0.

057

out

com

e

Pred

ictiv

e va

lue

of ti

me-

vary

ing

UA

for d

eath

/LTx

‡86

0/81

1.78

(1.4

0 to

2.2

6)<0

.001

831/

791.

52 (1

.13

to 2

.04)

0.00

6

Pred

ictiv

e va

lue

of ≥

50%

UA

incr

ease

for d

eath

/LTx

§86

0/81

3.94

(1.5

1 to

10.

27)

0.00

583

1/71

3.63

(1.2

2 to

10.

77)

0.02

0

Defi

nitio

n of

abb

revi

atio

ns: H

R =

haza

rd ra

tio; C

I = c

onfid

ence

inte

rval

; UA=

uric

aci

d; W

HO

-FC

= W

orld

Hea

lth O

rgan

izat

ion

func

tiona

l cla

ss; N

T-pr

oBN

P =

N-t

erm

inal

pro

B-

type

nat

riure

tic p

eptid

e; TA

PSE

= tr

icus

pid

annu

lar p

lane

syst

olic

exc

ursi

on; L

Tx =

lung

-tra

nspl

anta

tion.

Dat

a pr

esen

ted

as β

or H

R (h

azar

d ra

tio) w

ith re

spec

tive

95%

confi

denc

e in

terv

als p

er 0

.1 u

nit c

hang

e of

uric

aci

d. P

-val

ues ≤

0.05

wer

e co

nsid

ered

stat

istic

ally

sign

ifica

nt. *

Num

ber o

f uric

aci

d m

easu

rem

ents

invo

lved

in a

naly

sis/

num

ber o

f pat

ient

s in

volv

ed in

ana

lysi

s. † Al

l fol

low

-up

mea

sure

men

ts o

f the

pat

ient

s wer

e an

alyz

ed u

sing

line

ar m

ixed

effe

cts m

odel

ing

with

cor

rect

ing

for r

epea

ted

mea

sure

men

ts. U

ric a

cid

was

ad

ded

as p

redi

ctor

var

iabl

e to

sepa

rate

star

ting

mod

els c

onsi

stin

g of

dis

ease

seve

rity

mar

kers

as d

epen

dent

var

iabl

e, w

ith ra

ndom

inte

rcep

ts. ‡ Ti

me-

depe

nden

t Cox

regr

essi

on

anal

ysis

with

long

itudi

nally

colle

cted

uric

aci

d as

tim

e-va

ryin

g pr

edic

tor o

f out

com

e. § Se

gmen

ted

time-

depe

nden

t Cox

regr

essi

on w

ith th

e oc

curr

ence

of a

≥ 5

0% in

crea

se in

uric

ac

id si

nce

base

line

test

ed a

s tim

e-va

ryin

g pr

edic

tor o

f out

com

e, a

djus

ted

for l

evel

of u

ric a

cid

at b

asel

ine.


6

Association of uric acid levels with outcome

Baseline uric acid was significantly associated with death or lung-transplantation (HR=1.81, 95% CI 1.35-2.43, p<0.001), also after adjusting for age, sex and creatinine (HR 1.63, 95% CI 1.17-2.28, p=0.004). Figure 1 panel A illustrates that patients with higher uric acid levels at baseline (≥0.41 mmol/L) had a significantly worse transplantation-free survival rate when compared to patients with lower uric acid levels at baseline (log rank, p<0.001). The cut-off of 0.41 mmol/L was identified as a threshold with high specificity

Observation time (months)

0 24 48 72 96 120

Uric

aci

d (m

mol

/L)

0,10

0,20

0,30

0,40

0,50

0,60

0,70

Observation time (months)

0 24 48 72 96 120

Uric

aci

d (m

mol

/L)

0,10

0,20

0,30

0,40

0,50

0,60

0,70Survivors Non-survivors

Slope: 0.0043 mmol/L per year Slope: 0.0148 mmol/L per year

C D

Observation time (months)0 24 48 72 96 120

Cum

ulat

ive

surv

ival

0,0

0,2

0,4

0,6

0,8

1,0

Uric acid <0.41 mmol/LUric acid >=0.41 mmol/L

Log rank p<0.001

Patients at risk63 45 33 24 14 1218 8 4 3 1 1

1 - Specificity0,0 0,2 0,4 0,6 0,8 1,0

Sen

sitiv

ity

0,0

0,2

0,4

0,6

0,8

1,0

AUC = 0.78

A B

Figure 1. (A) Lung transplantation-free survival of patients with baseline uric acid levels above or below 0.41 mmol/L. (B) Time-dependent receiver operating characteristics analysis of uric acid levels for survival status at 10-year follow-up (analyzed with the TimeROC package in R). Area under the curve: 0.78 (SE 0.07). The optimal threshold value when maximizing specificity and positive predictive value was estimated at 0.41 mmol/L. Sensitivity: 0.34 (SE 0.08), Specificity: 0.92 (SE 0.07), Positive predictive value: 0.85 (SE 0.13), Negative predictive value: 0.53 (SE 0.08). (C and D) Development of uric acid levels over time stratified by survival status at end of follow-up. Estimates of intercepts and slopes are derived from random linear mixed effects modelling of uric acid over time, with transplantation-free survival tested as time-interaction. Uric acid intercept and slope were significantly higher in non-survivors compared with survivors (P=0.003 and P=0.035, respectively).

152 Chapter 6

for distinguishing survivors from non-survivors at 10 year follow-up (determined using receiver operating characteristics analysis, see Figure 1 panel B).

Table 3 additionally shows the results of the time-dependent Cox regression analysis, with all uric acid measurements collected during follow-up as time-varying co-variate. The serially measured uric acid values were significantly associated with death or lung-transplantation (HR=1.78, p≤0.001), also after adjusting for age, sex and creatinine. Increases of ≥50% in uric acid compared to baseline, occurred in 18 of 81 (22%) cases after a median follow-up time of 2.99 (1.44 - 7.21) years. An event of ≥50% increase, independent of time point of occurrence, was associated with an almost 4-times higher chance of adverse outcome (HR= 3.94, p=0.005), also when adjusted for age, sex and creatinine.

Based on the results from linear mixed effects modelling, there was a significant positive linear trend in uric acid levels over time in the total cohort during the full ob-servation period (0.0081mmol/L per year increase, p=0.003). Panels C and D of Figure 1 depict the intercepts and regression coefficient derived from the linear mixed effect modelling of uric acid development over time, stratified by survival status at end of follow-up. The longitudinal development of uric acid levels differed significantly be-tween transplant-free survivors and non-survivors (p=0.035). Non-survivors had higher baseline values and a steeper increase (0.3377 mmol/L at baseline and +0.0148 mmol/L per year increase) compared to survivors (0.2689 mmol/L at baseline and +0.0043 mmo/L per year increase).

effects of treatment

An exploratory before-after comparison was conducted in a subgroup of 53 children in whom therapy was started or escalated during the study period. Uric acid measured at a median (IQR) duration of 1.7 (1.2-3.1) months after therapy onset, was significantly lower than uric acid levels measured just before therapy onset (0.29±0.09 mmol/L compared to 0.31±0.10 mmol/L, paired samples T-test p=0.035).

dIsCussIon

This study demonstrates that in children with PAH, uric acid serum levels correlate with disease severity markers (including WHO-FC, NT-proBNP levels and TAPSE Z- score), both at baseline as well as throughout the course of the disease. Moreover, absolute serum levels of uric acid at baseline and, importantly, also changes in uric acid serum levels during the disease course are associated with transplant-free survival.

Previous studies have demonstrated that hyperuricemia is common in pulmonary hypertension.26 Increases of serum uric acid levels can result from several mecha-


6

nisms,27,28 with increased activation of xanthine oxidase caused by oxidative stress or lo-cal or systemic tissue hypoxia being the most likely in the setting of vascular and cardiac dysfunction.10,11,29 Interestingly, it has been speculated that elevated uric acid levels are not only a consequence of pulmonary hypertension, but may also have a secondary role in the pathogenesis, contributing to progression of the disease.30 Chronic hyperuricemia has been shown to directly induce endothelial dysfunction, thereby facilitating vascular remodeling,31,32 and to stimulate vasoconstrictive,33 and proinflammatory effects.34 Its role in the pathophysiology, irrespective of whether or not being pathogenic, makes uric acid a suitable candidate in the quest for prognostic biomarkers in PAH.35

A cross-sectional association of uric acid levels with disease severity and outcome has been demonstrated in various PAH populations including children.6–8,17–20 Recently, Wagner et al. evaluated the prognostic value of 27 candidate biomarkers in children with PAH, and found uric acid among the strongest predictors of outcome.19 The current longitudinal analysis confirms the previously reported correlations and extends these by revealing the prognostic value of serially measured uric acid levels throughout the course of the disease. This is the first study to provide evidence that the rate of increases of uric acid levels over time, obtained by repeated measurements, is predictive for the disease severity status and predictive for disease outcome. The potential of uric acid as a prognostic biomarker is further reinforced by our observation that patients in whom uric acid values increased by more than 50% during follow-up had an almost 4-times higher risk of adverse outcome compared to those who did not show such increases.

Uric acid has been suggested to be a potentially modifiable risk factor in pulmo-nary hypertension.30,36 Our preliminary finding that treatment may influence uric acid levels is in line with adult reports showing that PAH-targeted therapies may reduce serum uric acid levels.6,37 In chronic heart failure, but also in PAH, treatment-induced reduction of serum uric acid values have been demonstrated to improve endothelial function and correlate with better outcome.37–39 Our data, showing that deterioration of uric acid serum levels were associated with worse outcome, support this concept of uric acid as a treatable prognostic factor or marker in PAH.

The fact that not only absolute values, at any time during the disease, but also changes in serum levels of uric acid carry prognostic value, indicates that uric acid is not only a useful prognostic biomarker, but may also qualify as a treatment target for the guidance of clinical management or as a surrogate endpoint in clinical trials.

Clinical implications

The available data provides evidence that serum uric acid is a valuable marker for esti-mating disease severity and prediction of outcome in the management of children with PAH. Uric acid values are predictive at baseline and at any time point of measurement throughout the disease course. Moreover, higher rates of increase of uric acid levels

154 Chapter 6

over time correlate with PAH disease progression and increased risk for death or lung-transplantation. Closely monitoring the uric acid levels and especially their course over time in patients with PAH provides clues to understanding and predicting the state of the disease. Therefore, uric acid level monitoring may form a valuable addition to the current management of children with PAH and could improve clinical decision-making.


A strong feature of this study is the standardized collection of data in this cohort dur-ing a substantial period of time, as well as the consistent and complete follow-up. Also, the prospective collection of the data allowed evaluating changes over time, giving it a robust explanatory power. In the adult population serum uric acid levels are influenced by various comorbidities such as metabolic syndrome or renal disease.16,30 These co-morbidities are much less likely to play a role in children, making uric acid levels less vulnerable to bias in the paediatric population.

The sample size of the current study hampered extensive multivariable model-ling. However, the number of included patients is not small for a rare disease such as paediatric PAH. In view of the invasiveness and associated risks of heart catheteriza-tion,40 the collection of hemodynamic data, additional to those collected at diagnosis, was limited to follow up catheterizations that were regarded to be clinically indicated in the individual patients. Therefore the relationship of uric acid with hemodynamics could not be evaluated in a longitudinal fashion.

ConClusIon

This study demonstrates that the longitudinal development of serial serum uric acid levels is consistently associated with disease severity markers and clinical outcome in children with PAH. Higher serum uric acid levels at baseline, as well as increases dur-ing the course of the disease correspond to more serious disease severity and poorer prognosis in children with PAH. Closely monitoring uric acid levels and especially their course over time provides important information on the state of the disease and may aid in clinical decision-making in the management of children with PAH.


6

reFerenCes



3. Galiè N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J. 2010;31:2080–6.

4. Colvin KL, Dufva MJ, Delaney RP, Ivy DD, Stenmark KR, Yeager ME. Biomarkers for Pediatric Pulmo-nary Arterial Hypertension - A Call to Collaborate. Front Pediatr. 2014;2:7.

5. Lohani O, Colvin KL, Yeager ME. Biomarkers for pediatric pulmonary arterial hypertension: chal-lenges and recommendations. Paediatr Respir Rev. 2015;16:225–31.

6. Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T, Miyatake K. Serum uric acid levels correlate with the severity and the mortality of primary pulmo-nary hypertension. Am J Respir Crit Care Med. 1999;160:487–92.

7. Bendayan D, Shitrit D, Ygla M, Huerta M, Fink G, Kramer MR. Hyperuricemia as a prognostic factor in pulmonary arterial hypertension. Respir Med. 2003;97:130–133.


9. Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2015;213:8–14.

10. Feig DI, Kang D-H, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:1811–21. 11. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ. Serum

uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J. 1997;18:858–865.

12. Hayabuchi Y, Matsuoka S, Akita H, Kuroda Y. Hyperuricaemia in cyanotic congenital heart disease. Eur J Pediatr. 1993;152:873–6.

13. Baker JF, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease: recent developments, and where do they leave us? Am J Med. 2005;118:816–26.

14. Jeemon P, Prabhakaran D. Does uric acid qualify as an independent risk factor for cardiovascular mortality? Clin Sci (Lond). 2013;124:255–7.

15. Filiopoulos V, Hadjiyannakos D, Vlassopoulos D. New insights into uric acid effects on the progres-sion and prognosis of chronic kidney disease. Ren Fail. 2012;34:510–20.

16. Johnson RJ, Kang D-H, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M. Is there a pathogenetic role for uric acid in hypertension and cardio-vascular and renal disease? Hypertension. 2003;41:1183–90.

17. Oya H, Nagaya N, Satoh T, Sakamaki F. Haemodynamic correlates and prognostic significance of serum uric acid in adult patients with Eisenmenger syndrome. Heart. 2000;53–58.

18. Voelkel MA, Wynne KM, Badesch DB, Groves BM, Voelkel NF. Hyperuricemia in severe pulmonary hypertension. Chest. 2000;117:19–24.


156 Chapter 6




23. McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation. 2001;104:2797–2802.

24. Kuzuya M, Ando F, Iguchi A, Shimokata H. Effect of aging on serum uric acid levels: longitudinal changes in a large Japanese population group. J Gerontol A Biol Sci Med Sci. 2002;57:M660–4.


26. Hoeper MM, Hohlfeld JM, Fabel H. Hyperuricaemia in patients with right or left heart failure. Eur Respir J. 1999;682–685.

27. Mace SE, Newman AJ, Liebman J. Impairment of urate excretion in patients with cardiac disease. Am J Dis Child. 1984;138:1067–70.

28. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla C, Davos CH, Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ, Leyva F, Hetzer R, Ponikowski P, Coats AJS. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation. 2003;107:1991–7.

29. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985;312:159–63.

30. Zharikov SI, Swenson ER, Lanaspa M, Block ER, Patel JM, Johnson RJ. Could uric acid be a modifi-able risk factor in subjects with pulmonary hypertension? Med Hypotheses. 2010;74:1069–1074.

31. Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, Patel J. Uric acid decreases NO produc-tion and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol. 2008;295:C1183–90.

32. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67:1739–42.

33. Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens. 2008;26:269–75.

34. Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003;41:1287–93.


36. Castillo-Martínez D, Marroquín-Fabián E, Lozada-Navarro AC, Mora-Ramírez M, Juárez M, Sánchez-Muñoz F, Vargas-Barrón J, Sandoval J, Amezcua-Guerra LM. Levels of uric acid may predict the


6

future development of pulmonary hypertension in systemic lupus erythematosus: a seven-year follow-up study. Lupus. 2016;25:61–6.

37. Dhaun N, Vachiery J-L, Benza RL, Naeije R, Hwang L-J, Liu X, Teal S, Webb DJ. Endothelin antago-nism and uric acid levels in pulmonary arterial hypertension: Clinical associations. J Hear Lung Transplant. 2014;33:521–527.

38. Farquharson CAJ, Butler R, Hill A, Belch JJF, Struthers AD. Allopurinol improves endothelial dys-function in chronic heart failure. Circulation. 2002;106:221–6.

39. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJS, Anker SD, Hambrecht R. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation. 2002;105:2619–24.

40. Beghetti M, Schulze-Neick I, Berger RMF, Ivy DD, Bonnet D, Weintraub RG, Saji T, Yung D, Mallory GB, Geiger R, Berger JT, Barst RJ, Humpl T. Haemodynamic characterisation and heart catheteri-sation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension). Int J Cardiol. 2016;203:325–330.

41. Loh TP, Metz MP. Trends and physiology of common serum biochemistries in children aged 0-18 years. Pathology. 2015;47:452-61.

158 Chapter 6

suPPleMentAry MAterIAl

To the Editor:

Pediatric pulmonary arterial hypertension (PAH) is a serious disease, ultimately caus-ing an early death of affected individuals.1 To ensure optimal monitoring and clinical decision-making, reliable markers of disease severity and outcome are highly needed. Previous observations have suggested that serum uric acid, a degradation product of purine metabolism,2 has potential as a non-invasive, inexpensive and easily obtainable biomarker in PAH.3,4 Uric acid is increased in oxidative stress conditions such as vascular and cardiac dysfunction, including chronic heart failure, cyanotic congenital heart dis-ease, and also PAH.2–5 In cross-sectional observations in children with PAH, baseline levels of uric acid have previously been shown to correlate with outcome in two independent pediatric cohorts.6–8 Since a reliable biomarker should reflect the disease process and fluctuate according to the course of the disease, additional long-term follow-up data on longitudinal trends and time-dependent associations are required. In this study, we therefore evaluated the association of serially measured uric acid levels, with disease severity and outcome in children with PAH.

We analyzed longitudinal uric acid data from 81 children who were consecutively enrolled in the prospective clinical registry of the National Referral Center for Pediatric Pulmonary Hypertension in The Netherlands. In this ongoing registry, all Dutch children with PAH are followed and registered prospectively according to a standardized proto-col, with ethical approval from the Institutional Review Board of the University Medical Center Groningen and informed consent obtained from the children and/or their guard-ians.9 The inclusion criteria for this study were: confirmation of PAH diagnosis by heart catheterization (n=74) or echocardiography (n=7) according to current international guidelines, availability of a minimum of one uric acid measurement within three months of diagnosis and enrollment between July 1997 and March 2015.

Baseline characteristics of the cohort are shown in Table 1. During a median (IQR) follow-up of 3.9 (0.8-7.5) years, serum uric acid levels were measured repeatedly, yielding a total of 860 uric acid measurements. World Health Organization functional class (WHO-FC), N-terminal Pro-B-type natriuretic peptide (NT-proBNP) and tricuspid an-nular plane systolic excursion (TAPSE) were serially and concurrently collected and were defined as markers of disease severity on the basis of previous research.9 The outcome endpoint was defined as death or lung-transplantation, which occurred in 41 children (32 [40%] died, 9 [11%] underwent lung-transplantation). As uric acid levels have been shown to depend on age, sex and renal excretion,2,3 we adjusted significant results for age, sex and creatinine.

Uric acid levels differed significantly from healthy controls (mean Z-score devia-tion +1.36, 95% CI 0.91-1.82, one-sample T-test p<0.001).10 Higher baseline levels of uric


6

acid correlated with higher WHO-FC (n=80, r=0.31, p=0.005), higher NT-proBNP (n=61, r=0.31, p=0.014), and lower TAPSE Z-scores (n=54, r=-0.30, p=0.027), and were predictive of adverse outcome (HR=1.81, p<0.001, and see Kaplan Meier analysis Figure 1A). The adjustment analysis yielded similar results. Uric acid at baseline also correlated with hemodynamic characteristics. To evaluate whether uric acid also correlated with disease severity markers throughout the course of the disease, associations with WHO-FC, NT-proBNP or TAPSE Z-score were analyzed separately using linear mixed effects modeling with random intercept and slope. These analyses, involving all longitudinally collected uric acid and disease severity data, for the first time confirm the association of uric acid with disease severity throughout the disease course (Table 3). In order to evaluate the association of serially measured uric acid with outcome, time-dependent Cox regres-sion was performed, which showed a significant association with outcome throughout the disease course, independent of age, sex and creatinine (831 measurements from 79 patients, adjusted HR 1.52, p=0.006). Time-dependent receiver operating characteristics analysis yielded an area under the curve [AUC] of 0.78 for the predictive accuracy of uric acid (compared to an AUC of 0.81 for NT-proBNP in this cohort). A level of 0.41 mmol/L was identified as a threshold with high specificity for distinguishing survivors from non-survivors at 10-year follow-up (Figure 1B). The positive and negative predictive values of this threshold were 0.85 and 0.53, indicating that mortality was observed in a very high proportion of patients above the threshold, but that patients below the threshold were not excluded from the risk of death either. Thus, uric acid ≥0.41 mmol/L could be considered as a red flag, warranting immediate attention and action of caregivers, bear-ing in mind that levels <0.41 mmol/L are no guarantee of survival.

To evaluate potential effects of PAH-targeted treatment on uric acid levels, an exploratory before-after comparison was conducted in a subgroup of 53 children in whom therapy was started or escalated during the study period. Uric acid measured at a median (IQR) duration of 1.7 (1.2-3.1) months after therapy onset, was significantly lower than uric acid levels measured just before therapy onset (0.29±0.09 mmol/L compared to 0.31±0.10 mmol/L, paired samples T-test p=0.035).

Of particular interest in the quest for biomarkers, is the prognostic value of longi-tudinal changes over time. We evaluated this in two ways. First, the prognostic value of the occurrence of a ≥50% increase in uric acid since baseline was tested as dichotomous time-varying covariate in a Cox regression model. Increases of ≥50% in uric acid, oc-curred in 18 of 81 (22%) cases after a median (IQR) follow-up time of 2.99 (1.44 - 7.21) years. An event of such an increase, independent of time point of occurrence, was as-sociated with an almost 4-times higher chance of death or lung-transplantation (HR= 3.94, p=0.005), and remained significant after adjustment for age, sex and creatinine. Second, the patients were stratified for survival status at the end of follow-up and then their linear development of uric acid levels over time was compared using interaction

160 Chapter 6

analysis in a linear mixed effects model. Figures 1C and 1D depict the individual uric acid trajectories together with the intercepts and regression coefficient derived from this model, and show that non-survivors not only had significantly higher baseline values (intercept 0.34 mmol/L versus 0.27 mmol/L, p=0.003) but also a significantly steeper in-crease in uric acid over time compared to survivors (slope 0.014 mmol/L/year compared to 0.004 mmol/L/year, p=0.035). These results provide the interesting new insight that the rate of uric acid increases over time carries important prognostic information and that a gradual incline is an ominous sign associated with poor outcome.

This study demonstrates that uric acid is associated with disease severity and outcome, not only at baseline but throughout the full disease course in pediatric PAH, and that changes in serum uric acid levels correspond to changes in outcome. Our data suggest that treatment may influence uric acid levels.

The retrospective analyses of patients followed and data collected prospectively in this study, as well as the limited sample size due to the rareness of the disease form potential limitations to the study, which should be taken into account. Purine metabo-lism and its degradation products are interesting candidate biomarkers in PAH, in view of their suggested role in vascular remodeling and inflammation.2 It has been specu-lated that elevated uric acid levels are not only a consequence of PAH, but may also play a secondary role in the pathogenesis, contributing to the progression of the disease.4 As purine metabolism is involved in many other mechanisms, hyperuricemia can occur in other conditions not directly related to PAH, such as gout, renal dysfunction, and insulin resistance. The lack of specificity of uric acid in these settings may reduce its clinical value in the adult population. Nevertheless, as these comorbidities are rare in childhood, uric acid holds promise as a useful and valuable biomarker for pediatric PAH. Closely monitoring uric acid levels and especially their course over time provides impor-tant information on the state of the disease and may aid in clinical decision-making in the management of children with PAH.


6

suPPleMentAry reFerenCes


2. Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8–14.






8. Ploegstra MJ, Zijlstra WMH, Douwes JM, Hillege HL, Berger RMF. Prognostic factors in pedi-atric pulmonary arterial hypertension: a systematic review and meta-analysis. Int J Cardiol. 2015;184:198–207.


10. Loh TP, Metz MP. Trends and physiology of common serum biochemistries in children aged 0-18 years. Pathology. 2015;47:452-61.

1

2

3

4

5

6

7

8

9

10

Chapter 7Pulmonary arterial stiffness indices assessed by intravascular ultrasound in children with early pulmonary vascular disease: prediction of disease progression and mortality during 20-year follow-up

Mark-Jan PloegstraJody BrokelmanJolien W. Roos-HesselinkJohannes M. DouwesLenny M. van Osch-GeversElke S. HoendermisAnnemien E. van den BoschMaarten WitsenburgBeatrijs BarteldsHans L. HillegeRolf M.F. Berger

European Heart Journal - Cardiovascular Imaging 2017; 18 (accepted)

164 Chapter 7

ABstrACt

Aims

Prognosis in children with pulmonary vascular disease (PVD) is closely linked to right ventricular (RV) failure due to increased RV-afterload. Pulmonary arterial (PA) stiffening is known to occur early in the course of PVD and constitutes a main component of RV-afterload. This study aimed to evaluate the clinical value of PA-stiffness in children with early or advanced PVD, by determining its association with long-term disease progres-sion and mortality.

Methods and results

Forty-one children with arterial PVD in early or more advanced stages, defined as mean PA pressure ≥20mmHg and/or pulmonary-to-systemic flow ratio ≥1.2, and mean pul-monary capillary wedge pressure <15mmHg, underwent cardiac catheterization with intravascular ultrasound (IVUS) imaging between 1994 and 1997 with follow-up until 2015. The indices of PA-stiffness evaluated were compliance and distensibility. During follow-up, PVD reversal or progression was determined by transthoracic echocardiogra-phy and cardiac catheterization. During a median follow-up of 19 years, 31 (76%) cases of PVD had reversed and 10 (24%) progressed. Six (15%) patients died due to PVD. In ad-dition to conventional haemodynamics, compliance and distensibility were significantly associated with PVD progression (adjusted OR [95% CI] 0.56 [0.37-0.85] and 0.52 [0.31-0.86]), and mortality (adjusted HR [95% CI] 0.60 [0.41-0.87] and 0.67 [0.49-0.90]). Also in the subgroup of patients with favorable haemodynamics, baseline compliance and distensibility were significantly lower in patients whose PVD subsequently progressed (p=0.002/p=0.030).

Conclusions

PA-stiffness indices assessed by IVUS predict long-term disease progression and mortal-ity in children with PVD and may complement to conventional haemodynamic evalua-tion, particularly in early disease stages.

Pulmonary arterial stiffness in children with PVD 165

7

IntroduCtIon

Children with congenital heart disease (CHD) and abnormal pulmonary haemodynam-ics are at risk for developing pulmonary arterial hypertension (PAH).1–3 This progressive disease is characterized by a typical remodeling of small pulmonary arterioles, leading to increased pulmonary vascular resistance (PVR), but also by remodeling of the larger pulmonary conduit arteries, resulting in increased pulmonary arterial (PA) stiffness.4,5 Both contribute to the increased right ventricular (RV) afterload in PAH that ultimately leads to RV failure and death.6 In children with CHD, increased pulmonary blood flow due to systemic-to-pulmonary shunting induces early changes in the pulmonary vasculature that precede the development of advanced PAH, which include endothelial dysfunction and vascular smooth muscle cell proliferation.7–10 The continuum from these early pul-monary vascular changes to advanced PAH is referred to as pulmonary vascular disease (PVD).

PVR and mean PA pressure (mPAP) are important haemodynamic measurements in the evaluation of PVD, and are used to define PAH and guide therapy decisions such as whether and when a cardiac defect should be repaired or when PAH-targeted therapy should be initiated.11–15 However, in the early disease stage these measurements lack sensitivity in predicting either progression or reversibility of disease.15–18 Alterations in pulsatile flow due to PA stiffening have substantial effects on RV-afterload, but are not taken into account in these conventional haemodynamic measurements that assume steady flow.19–21

Assessment of pulsatile characteristics of the pulmonary vasculature such as PA-stiffness may complement the haemodynamic evaluation of PVD and RV-afterload.22 It has been suggested that concomitant measurement of PA stiffness indices could al-low for more accurate prediction of disease progression, adverse implications of shunt closure and mortality, especially in the early stage of the disease.8,23,24 To explore this, the current long-term follow-up study aims to correlate PA stiffness indices with late outcome, defined as PVD progression or reversal as well as survival, in children with early CHD-associated arterial PVD.

Methods


Between April 1994 and July 1997, 47 consecutive young patients with CHD-associated PVD were prospectively enrolled in a study to investigate the clinical value of pulsatile PA-characteristics obtained by intravascular ultrasound (IVUS) in the assessment of PVD.25,26 Patients were <20 years of age and PVD was confirmed with right heart cath-

166 Chapter 7

eterization. At that time, PVD was defined as increased PA pressure (mPAP ≥20 mmHg) and/or increased pulmonary blood flow (pulmonary-to-systemic blood flow ratio [Qp/Qs] ≥1.2). The originally used inclusion cut-off value of 20 mmHg for mPAP thus implies the inclusion of patients with mPAP between 20-25 mmHg who according to the guide-lines are to be carefully followed especially in populations at risk for developing PAH.15

As the current study focuses on the development of PAH over time, 6 patients with PVD due to pulmonary venous congestion, defined as mean pulmonary capillary wedge pressure (mPCWP) ≥15 mmHg, that were included in the original cohort, were excluded for this study. The remaining 41 patients were followed in two centers in the Netherlands. Ethical approval for this study was obtained from the institutional review boards and subjects and/or their guardians provided written informed consent at enrol-ment.

In order to stratify for baseline haemodynamics, patients were categorized into four haemodynamic baseline profiles: (A) Early non-flow related PVD, defined as mPAP 20-25 mmHg and Qp/Qs <1.2; (B) Early flow-related PVD, defined as mPAP <25 mmHg and Qp/Qs≥1.2; (C) Early PAH, defined as mPAP ≥25 mmHg and PVRi <3 WU*m2 and (D) Advanced PAH, defined as mPAP≥25 mmHg and PVRi ≥3 WU*m2. The cut-off values used in these definitions are in line with contemporary consensus within the field.11–13 Profiles A, B and C were together referred to as early PVD.

Cardiac catheterization and Ivus imaging

Details regarding haemodynamic evaluation and IVUS-imaging have been reported previously.25,26 In short, complete haemodynamic evaluation was performed by cardiac catheterization. Additionally, IVUS-imaging of pulmonary arteries was performed using a Sonos Intravascular Imaging-System (Hewlett Packard; Andover, MA) and a Sonicath 3.5F or Spy 3.0F ultrasound catheter with a 30-MHz transducer at the tip (Boston Scientific; Watertown, MA). The ultrasound catheter was directed through a 6F sheath along the pulmonary branch at consecutive sites in proximal, segmental and peripheral arteries. For the current follow-up study, each most proximally obtained measurement was used for analysis.

PA luminal diameter and area were measured offline at end-diastolic and peak-systolic dimension, with averaging over three cardiac cycles and over two independent observers. PA pulsatility, reflecting the relative change in arterial cross-sectional area, was calculated as (peak-systolic – end-diastolic luminal area) / (end-diastolic area). PA-stiffness was characterized by calculating the indices compliance and distensibility, which can be regarded as the conceptual inverse of stiffness.21,27 Compliance is the absolute change in arterial cross-sectional area for a given pressure change and was calculated as: (peak systolic – end-diastolic luminal area) / pulse pressure. Distensibility


7

is the relative change in arterial cross-sectional area for a given pressure change and was calculated as: (pulsatility / pulse-pressure)*100%.

long-term outcome

After baseline haemodynamic evaluation and IVUS-imaging, patients were treated at distinction of the treating physician. Treatment could include either surgical or inter-ventional closure of a systemic-to-pulmonary shunt, or treatment for advanced PAH, the latter having evolved over time in accordance with the available treatment strategies and guidelines.28–32 All patients were followed long-term, until March 1st 2015. Outcome parameters were defined as progression of PVD and mortality.

1. Progression of PVD.During follow-up, serial transthoracic echocardiography was performed as part of routine clinical practice. Follow-up echocardiography reports were scrutinized to deter-mine whether the established PVD had reversed or progressed. Evidence of progressive PVD was defined as either (1) the presence of pulmonary-to-systemic shunting or (2) maximum systolic tricuspid regurgitant velocity >2.8 m/s accompanied by one or more of the following signs of RV overload: moderate to severe RV hypertrophy or dilatation, septal flattening or pericardial effusion.33 Follow-up cardiac catheterization reports, when available, were used to confirm the PVD status, with progressed PVD defined as mPAP ≥25 mmHg, mPCWP ≤15 mmHg and PVRi ≥3 WU*m2.

2. Mortality.All cases of death were independently evaluated by three clinical investigators (authors M.J.P., J.B., and R.M.F.B) to adjudicate whether death was PVD related or unrelated.

data analysis

Data are presented as median (interquartile range) or frequencies (percentage). Statisti-cal analysis was performed using IBM-SPSS 22.0. In the regression analyses, logarithmic transformation was used to normalize the distribution of variables that were not nor-mally distributed. All statistical tests were two-sided and p-values <0.05 were considered statistically significant.

Continuous variables were compared using Mann-Whitney-U test or Kruskal-Wallis test. Geometric means were compared by conducting unpaired t-tests of logarithmically transformed variables. Categorical variables were compared using Fisher’s exact test. Binary logistic regression analysis was used to evaluate the association of PA-stiffness indices with PVD status, defined as either reversed or progressed, as established at last follow-up. Cox regression analysis was used to evaluate the association of PA-stiffness indices with PVD-related mortality. The follow-up time was calculated from the IVUS-

168 Chapter 7

study until March 1st 2015 or until date of death when applicable. In the logistic and Cox regression models, statistically significant variables were adjusted for age, sex and PA cross-sectional end-diastolic luminal area. In addition, the effect sizes were compared between patients with early and advanced baseline PVD, by testing the interaction of early PVD with significant variables.

Receiver-operating-characteristics (ROC)-analysis was performed to determine the most optimal threshold value of baseline PA compliance, distensibility and PVRi to distinguish between reversed and progressed PVD during follow-up. Kaplan-Meier analysis was used to visualize survival of patients above and below the identified thresh-old values. Survival differences were compared by means of a log-rank test.

results

Baseline characteristics

Forty-one children with arterial PVD were followed during a median (interquartile range) time of 19 (18-20) years. Median (interquartile range) age at time of the IVUS-study was 2.1 (0.6-6.4) years. The profiling according to haemodynamics at baseline is shown in the upper section of Figure 1. Table 1 shows the clinical characteristics, stratified by hae-modynamic baseline profiles. Inherent to the categorization based on haemodynamics, the profiles differed significantly with regards to haemodynamic variables. In addition, PA pulsatility (p=0.026) and distensibility (p=0.003) varied significantly according to the profiles. Details regarding congenital heart defect status at baseline are provided as Supplementary Material (Supplementary Table 1).

long-term outcome

All patients were available for follow-up. Following cardiac catheterization at baseline, 27 (66%) patients underwent shunt closure.

1. Progression of PVD.During follow-up, in 31 (76%) cases PVD had reversed and in 10 (24%) cases PVD had pro-gressed (Figure 1). In addition to repeated echocardiographic confirmation, progressed PVD was confirmed with a follow-up cardiac catheterization in 8/10 cases. Despite an initially favorable haemodynamic baseline profile (A, B or C, early PVD), PVD progressed during follow-up in 3 out of 27 patients (11%). None of the patients who had undergone shunt closure after IVUS-imaging developed progressed PVD.

In the total cohort, patients that showed progressed PVD at follow-up had less favorable conventional haemodynamics at baseline and also lower PA compliance and distensibility (Table 2). Patients with progressed PVD had significantly lower geometric


7

41 p

atie

nts

with

arte

rial P

VD

(Qp/

Qs≥

1.2

or m

PA

P≥2

0 m

mH

g, a

nd m

PC

WP

<15

mm

Hg)

3 P

rofil

e A

(Q

p/Q

s<1.

2)

E

arly

non

-flow

-rel

ated

PV

D 19 E

arly

abn

orm

al h

emod

ynam

ics

(mPA

P<25

mm

Hg)

2 re

vers

ed

22 P

AH

(mPA

P≥25

mm

Hg)

16 P

rofil

e B

(Q

p/Q

s≥1.

2)

E

arly

flow

-rel

ated

PV

D

8 P

rofil

e C

(P

VRi<

3 W

U*m

2 )

Ear

ly P

AH

14 P

rofil

e D

(P

VRi≥

3 W

U*m

2 )

Adv

ance

d P

AH

15 re

vers

ed

7 re

vers

ed

7 re

vers

ed

1 pr

ogre

ssed

(1

/1 d

ecea

sed)

PVD

REV

ERSE

D IN

31

PVD

PR

OG

RES

SED

IN 1

0

H A

E M

O D

Y N

A M

I C

P

R O

F I

L I N

G

A T

B A

S E

L I

N E

L O

N G

– T

E R

M

F O

L L

O W

– U

P

1 pr

ogre

ssed

(0

/1 d

ecea

sed)

1

prog

ress

ed

(0/1

dec

ease

d)

7 pr

ogre

ssed

(5

/7 d

ecea

sed)

Figu

re 1

. Fl

owch

art

of p

atie

nt c

ateg

oriz

atio

n ac

cord

ing

to h

aem

odyn

amic

bas

elin

e pr

ofile

and

long

-ter

m c

linic

al o

utco

me.

mPA

P, m

ean

pulm

onar

y ar

tery

pre

ssur

e;

mPC

WP,

mea

n pu

lmon

ary

capi

llary

wed

ge p

ress

ure;

PA

H, p

ulm

onar

y ar

teria

l hyp

erte

nsio

n; P

VD, p

ulm

onar

y va

scul

ar d

isea

se; P

VRi,

inde

xed

pulm

onar

y va

scul

ar re

sis-

tanc

e; Q

p/Q

s, pu

lmon

ary

to s

yste

mic

flow

ratio

.

170 Chapter 7

tabl

e 1.

Pat

ient

Cha

ract

eris

tics

of To

tal C

ohor

t and

Sub

grou

ps A

ccor

ding

to H

aem

odyn

amic

Bas

elin

e Pr

ofile

All

patie

nts

n=41

Profi

le A

aPr

ofile

BPr

ofile

CPr

ofile

D

Early

PVD

,no

n-flo

w re

late

dEa

rly P

VD,

flow

rela

ted

Early

PA

HAd

vanc

ed P

AH

n=3

n=16

n=8

n=14

p-va

lue

Clin

ical

cha

ract

eris

tics

Age

(yea

rs)

2.1

(0.6

-6.4

)6.

0 (0

.2-1

0.9)

5.7

(0.8

-8.7

)0.

5 (0

.3-1

.3)

2.5

(0.9

-3.7

)0.

100

Mal

e se

x18

(44)

2 (6

7)7

(44)

5 (6

3)4

(29)

0.40

3

Card

iac

inte

rven

tions

aft

er IV

US

Shun

t sur

gery

27 (6

6)0

(0)

14 (8

8)7

(88)

6 (4

3)0.

002

Valv

e su

rger

y8

(20)

2 (6

7)3

(19)

0 (0

)3

(21)

0.11

3

BSA

0.51

(0.2

9-0.

77)

0.69

(0.2

9-0.

81)

0.77

(0.3

0-1.

09)

0.32

(0.2

6-0.

38)

0.54

(0.3

6-0.

64)

0.08

3

hae

mod

ynam

ics

mPA

P (m

mH

g)25

(15-

39)

23 (2

0-23

)15

(12-

18)

32 (2

7-40

)46

(32-

54)

<0.0

01

Puls

e pr

essu

re (m

mH

g)26

(13-

35)

23 (1

5-26

)12

(10-

18)

34 (2

7-45

)35

(31-

40)

<0.0

01

mPC

WP

(mm

Hg)

9 (8

-10)

12 (9

-12)

8 (6

-9)

10 (9

-11)

9 (8

-11)

0.01

5

Qsi

(L/m

in/m

2 )3.

1 (2

.6-3

.9)

2.6

(2.4

-4.4

)3.

1 (2

.4-3

.4)

3.2

(2.7

-3.8

)3.

6 (2

.9-4

.1)

0.26

3

PVRi

(WU

*m2 )

2.3

(1.2

-5.3

)3.

1 (1

.6-5

.8)

1.2

(0.6

-1.6

)2.

3 (1

.4-2

.3)

7.4

(4.4

-12.

0)<0

.001

Qp/

Qs

2.0

(1.2

-3.2

)1.

0 (1

.0-1

.0)

2.3

(1.4

-3.5

)3.

7 (2

.9-4

.7)

1.2

(1.0

-1.6

)<0

.001

Ivu

s ch

arac

teri

stic

s

ESA

(mm

2 )25

.6 (1

1.9-

45.4

)12

.7 (3

.8-3

1.6)

24.7

(10.

0-47

.8)

39.4

(12.

0-54

.6)

24.5

(11.

9-36

.9)

0.51

9

EDA

(mm

2 )21

.0 (9

.0-3

4.4)

11.0

(3.4

-21.

0)21

.1 (8

.7-4

1.9)

29.6

(9.5

-35.

1)20

.7 (9

.1-3

0.3)

0.49

8

PA p

ulsa

tility

0.25

(0.1

2-0.

30)

0.16

(0.1

2-0.

51)

0.23

(0.1

2-0.

26)

0.33

(0.2

8-0.

56)

0.19

(0.1

1-0.

27)

0.02

6

PA c

ompl

ianc

e (m

m2 /m

mH

g)0.

18 (0

.08-

0.43

)0.

12 (0

.02-

0.41

)0.

31 (0

.11-

0.70

)0.

34 (0

.07-

0.49

)0.

11 (0

.05-

0.19

)0.

122

PA d

iste

nsib

ility

(%/m

mH

g)0.

95 (0

.6-1

.54)

1.07

(0.5

1-1.

95)

1.36

(0.8

9-2.

24)

1.1

(0.7

7-1.

47)

0.56

(0.3

5-0.

91)

0.00

3

Dat

a ar

e pr

esen

ted

as m

edia

n (in

terq

uart

ile ra

nge)

or n

umbe

r (pe

rcen

tage

), un

less

oth

erw

ise

indi

cate

d. B

SA, b

ody

surf

ace

area

; ED

A, e

nd-d

iast

olic

cro

ss-s

ectio

nal p

ulm

onar

y ar

teria

l lum

inal

are

a; E

SA, e

nd-s

ysto

lic c

ross

-sec

tiona

l pul

mon

ary

arte

rial l

umin

al a

rea;

IVU

S, in

trav

ascu

lar u

ltras

ound

; mPA

P, m

ean

pulm

onar

y ar

tery

pre

ssur

e; m

PCW

P, m

ean

pulm

onar

y ca

pilla

ry w

edge

pre

ssur

e; P

A, p

ulm

onar

y ar

teria

l; PA

H, p

ulm

onar

y ar

teria

l hyp

erte

nsio

n; P

VD, p

ulm

onar

y va

scul

ar d

isea

se; P

VRi,

inde

xed

pulm

onar

y va

scul

ar re

-si

stan

ce; Q

p/Q

s, pu

lmon

ary-

to-s

yste

mic

flow

ratio

; Qsi

, sys

tem

ic fl

ow in

dex.

a Profi

le A

: min

-max

rang

es a

re re

port

ed in

stea

d of

inte

rqua

rtile

rang

es fo

r con

tinuo

us v

aria

bles

(s

ubgr

oup

size

<4)

.


7

means of PA compliance and distensibility and significantly higher PVRi at baseline com-pared to those with reversed PVD (Figure 2) and this remained the case within the sub-group of patients with early PVD, after exclusion of patients who already had advanced PAH (profile D) at baseline. Logistic regression analysis confirmed that lower baseline PA compliance and distensibility both correlated significantly with progressed PVD at end of follow-up (p=0.007 and p=0.009), as did higher PVRi (p=0.002), also after adjusting for age, sex and PA end-diastolic luminal area (Table 3). The interaction analysis showed that these identified associations did not differ between early and advanced PVD. PA-pulsatility did not correlate with progression of PVD at long-term follow-up (p=0.324)

ROC-analysis yielded an optimal cut-off value for PA compliance of 0.08 mm2/mmHg to distinguish between long-term reversal and progression of PVD. The optimal cut-off value for distensibility was 0.95%/mmHg and for PVRi 4 WU*m2. In the subgroup of patients with early PVD, all 3 patients whose PVD progressed during follow-up had PA compliance and distensibility values that were below the identified cut-off values.

2. Mortality.During follow-up, death occurred in 7 (17%) patients, of which 6 were regarded PVD related. Causes of death were sudden death (n=2), progressive RV-failure (n=2) and massive hemoptysis (n=2). One patient died as a consequence of severe neurological complications due to Trisomy 18, considered unrelated to PVD. In the analyses, this patient was regarded a survivor, with censoring from the time of death. There were no patients who underwent heart- or lung-transplantation.

Cox regression analysis showed that lower PA compliance and distensibility cor-related significantly with mortality (p=0.018 and p=0.013), as did higher PVRi (p=0.005), also after adjusting for age, sex and end-diastolic luminal area (Table 3). The interaction analysis showed that these identified associations did not differ significantly between early and advanced PVD. PA pulsatility did not correlate with mortality during follow up (p=0.204). Figure 3 shows survival of PVD patients with values of PA-compliance, PA-distensibility and PVRi above versus below the respective identified cut-off values. Patients with PA-compliance ≤0.08 mm2/mmHg, distensibility ≤0.95 %/mmHg or PVRi ≥4 WU*m2 showed significantly worse survival (logrank p=0.011, p=0.009 and p<0.001, respectively).

dIsCussIon

This long-term follow-up study in a series of young patients with PVD demonstrates that both PA-stiffness indices and PVRi predict progression of PVD and long-term mortality. In a subgroup of patients with early PVD not meeting current PAH criteria, 11% developed

172 Chapter 7

table 2. Comparison of Reversed and Progressed PVD

Reversed PVD Progressed PVD

n=31 n=10 p-value


Age (years) 1.2 (0.6-6.5) 3.1 (1.8-6.2) 0.412

Male sex 13 (42) 5 (50) 0.724

Hemodynamic baseline profile

A. Early non-flow related PVD 2 (7) 1 (10) >0.999

B. Early flow related PVD 15 (48) 1 (10) 0.059

C. Early PAH 7 (23) 1 (10) 0.653

D. Advanced PAH 7 (23) 7 (70) 0.017

Cardiac interventions after IVUS

Shunt surgery 27 (87) 0 (0) <0.001

Valve surgery 8 (26) 0 (0) 0.165

BSA 0.38 (0.29-0.81) 0.63 (0.47-0.69) 0.354

haemodynamics

mPAP (mmHg) 20 (14-32) 45 (25-54) 0.005

Pulse pressure (mmHg) 19 (11-34) 34 (30-35) 0.023

mPCWP (mmHg) 9 (8-11) 9 (6-9) 0.293

Qsi (L/min/m2) 3.1 (2.6-3.7) 3.3 (2.7-3.9) 0.595

PVRi (WU*m2) 1.6 (1.1-3.0) 10.2 (5.4-13.5) <0.001

Qp/Qs 2.4 (1.5-3.6) 1.0 (1.0-1.3) <0.001

Ivus characteristics

ESA (mm2) 29.5 (14.5-47.3) 14.4 (6.1-26.4) 0.036

EDA (mm2) 23.2 (12.5-35.5) 12.3 (5.4-22.7) 0.031

PA pulsatility 0.25 (0.13-0.35) 0.19 (0.11-0.28) 0.316

PA compliance (mm2/mmHg) 0.30 (0.09-0.49) 0.06 (0.03-0.17) 0.002

PA distensibility (%/mmHg) 1.26 (0.73-1.78) 0.53 (0.35-0.83) 0.002

Data are presented as median (interquartile range) or number (percentage), unless otherwise indicated. BSA, body surface area; EDA, end-diastolic cross-sectional pulmonary arterial luminal area; ESA, end-systolic cross-sectional pulmonary arterial luminal area; IVUS, intravascular ultrasound; mPAP, mean pulmonary artery pres-sure; mPCWP, mean pulmonary capillary wedge pressure; PA, pulmonary arterial; PAH, pulmonary arterial hy-pertension; PVD, pulmonary vascular disease; PVRi, indexed pulmonary vascular resistance; Qp/Qs, pulmonary to systemic flow ratio; Qsi, systemic flow index.


7Dis

tens

ibili

ty (%

/mm

Hg)

Reversed Progressed0.1

0.2

0.4

0.8

1.6

n=31 n=10

p=0.002

Com

plia

nce

(mm

/mm

Hg)


0.02

0.04

0.08

0.16

0.32

n=31 n=10

p=0.001

PVR

i (W

U*m

2 )

Reversed Progressed1

2

4

8

16

n=31 n=10

p<0.001

Reversed Progressed1

2

4

8

16

n=24 n=3

p=0.003


0.02

0.04

0.08

0.16

0.32

n=24 n=3

p=0.002


0.2

0.4

0.8

1.6

n=24 n=3

p=0.030

TOTAL COHORT Profile A+B+C+D (n=41)

EARLY PVD Profile A+B+C (n=27)

A

B

C

Figure 2. Comparison of geometric means of baseline pulmonary arterial compliance (A), distensibility (B) and indexed pulmonary vascular resistance (C) between patients with reversed and progressed pulmonary vascular disease at long-term follow-up. PVD, pulmonary vascular disease; PVRi, indexed pulmonary vascu-lar resistance. Error bars represent geometric standard errors of the mean.

174 Chapter 7

tabl

e 3.

Pre

dict

ive

Valu

e fo

r Pro

gres

sed

PVD

and

Mor

talit

y D

urin

g Fo

llow

-up

Uni

varia

ble

anal

ysis

Adju

sted

for A

ge, S

ex a

nd E

DA

Inte

ract

ion

anal

ysis

a Ear

ly /

Adva

nced

PVD

OR/

HR

(95%

CI)

p-va

lue

OR/

HR

(95%

CI)

p-va

lue

p-va

lue

Pred

ictiv

e va

lue

for p

rogr

esse

d PV

D:

PA p

ulsa

tility

0.86

(0.6

4-1.

16)

0.32

4-

--

PA c

ompl

ianc

e0.

75 (0

.61-

0.92

)0.

007

0.56

(0.3

7-0.

85)

0.00

70.

140

PA d

iste

nsib

ility

0.63

(0.4

4-0.

89)

0.00

90.

52 (0

.31-

0.86

)0.

011

0.18

5

PVRi

2.06

(1.3

0-3.

25)

0.00

22.

50 (1

.29-

4.84

)0.

007

0.67

5

Pred

ictiv

e va

lue

for m

orta

lity:

PA p

ulsa

tility

0.80

(0.5

7-1.

13)

0.20

4-

--

PA c

ompl

ianc

e0.

81 (0

.68-

0.96

)0.

018

0.60

(0.4

1-0.

87)

0.00

70.

629

PA d

iste

nsib

ility

0.72

(0.5

5-0.

93)

0.01

30.

67 (0

.49-

0.90

)0.

009

0.43

9

PVRi

1.71

(1.1

8-2.

48)

0.00

51.

69 (1

.15-

2.49

)0.

008

0.60

9

Resu

lts a

re fr

om lo

gist

ic re

gres

sion

or C

ox re

gres

sion

ana

lysi

s and

dat

a ar

e pr

esen

ted

as o

dds r

atio

s or h

azar

d ra

tios p

er 0

.1 10

Log

unit

incr

ease

. CI,

confi

denc

e in

terv

al; E

DA,

end

di

asto

lic c

ross

-sec

tiona

l pul

mon

ary

arte

rial l

umin

al a

rea;

HR,

haz

ard

ratio

; PA,

pul

mon

ary

arte

rial;

PVD

, pul

mon

ary

vasc

ular

dis

ease

; PVR

i, in

dexe

d pu

lmon

ary

vasc

ular

resi

s-ta

nce.

a Early

PVD

inte

ract

ion

anal

ysis

: P<0

.05

wou

ld in

dica

te a

sign

ifica

nt e

ffect

size

diff

eren

ce b

etw

een

early

and

adv

ance

d PV

D.


7

Time since IVUS (years)0 5 10 15 20

Cum

ulat

ive

surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

Compliance > 0.08 mm/mmHgCompliance ≤ 0.08 mm/mmHg Logrank p=0.011

Patients at risk: 31 30 29 29 7 10 9 8 7 3

Time since IVUS (years)

Cum

ulat

ive

surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

Distensibility > 0.95 %/mmHgDistensibility ≤ 0.95 %/mmHg Logrank p=0.009

Patients at risk: 21 20 20 20 5 20 19 17 16 5

Time since IVUS (years)

Cum

ulat

ive

surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

PVRi < 4 WU*m2

PVRi ≥ 4 WU*m2 Logrank p<0.001

Patients at risk: 28 27 27 27 6 13 12 10 9 4

A

B

C

0 5 10 15 20

0 5 10 15 20

Figure 3. Comparison of survival of patients with high and low pulmonary arterial compliance (A), disten-sibility (B), and indexed pulmonary vascular resistance (C). Cut-off values are derived from receiver oper-ating characteristic analysis. IVUS, intravascular ultrasound; PVRi, indexed pulmonary vascular resistance.

176 Chapter 7

advanced PAH during follow-up, despite favorable haemodynamics at baseline. In these patients, PA-stiffness indices showed to be highly sensitive regarding the prediction of future PVD progression. The results indicate that PA-stiffness indices and conventional haemodynamics, such as PVRi, are mutually complementary in providing insight in the state and dynamics of the pulmonary vasculature both in early and advanced stages of PVD.

Based on data from the current cohort, our group previously demonstrated that IVUS derived PA stiffness indices differ significantly between cases and controls, independently of PA-pressure, and correlate with disease severity in children with PVD.26 Also in adults, indices of PA wall stiffness have been found to differ between patients with PAH and controls, when obtained either by cardiac catheterization combined with CMR,23,34 or by IVUS.24,35 Moreover, Rodés-Cabau et al. previously showed, in a cohort of 20 adults with PAH, that in non-survivors pulmonary arteries had a higher, thus impaired, IVUS-obtained pressure/strain elastic modulus (= the mathematical inverse of distensibility) compared to survivors.36 Also PA-pulsatility has been suggested to cor-relate with survival in patients with PAH,34,36 however the current data do not support this. Pulsatility reflects the relative change in luminal area not taking into account the accompanying pressure change and is thus not a measure of intrinsic wall properties. Although its potential for non-invasive measurement may be clinically appealing, to assess arterial wall properties in a viscoelastic pulmonary artery, the systolic-diastolic area should be adjusted for pulse pressure. Relative area changes are merely an indirect measure of wall stretch and more a surrogate for PA pressure.

PVR is a cornerstone in the clinical diagnosis of PVD and the prognostication of disease progression and mortality, especially in the advanced stages of PAH.11–13,37,38 The current results confirm the prognostic value of an increased PVR and show that in the studied children the optimal cut-off value for predicting progression or mortality was ≥ 4 WU*m2. This observation is in line with the current PVR-based recommendations for correction of CHD in the presence of PAH.12 The most important result from the current study is that measures of PA-stiffness indices carry prognostic value regarding disease progression and outcome in PVD, also in the setting of favorable haemodynamics where PVR may still be relatively low. PA stiffness measurements may be complementary to conventional haemodynamics and of particular benefit in early disease stages, as evidenced by the observation that all patients whose PVD progressed during follow-up despite favorable baseline haemodynamics could be identified using PA-stiffness cut-off values, whereas this was not possible using PVRi cut-off values of 3 or 4 WU*m2. Of note, conclusions regarding independence or superiority of PA stiffness indices over PVRi cannot be drawn from this study, as the sample size hampered extensive multivariable modeling.


7


The current 20-year follow-up data of a cohort of children with early and advanced PVD associated with CHD, meticulously characterized at diagnosis by both conventional pulmonary haemodynamics and PA-stiffness indices, are unique and provide important information on the development of PVD over time in this population. Strengths of this study include the complete data without any loss to follow-up, the highly standardized and predefined protocol for haemodynamic assessment and IVUS-imaging and the simultaneous measurement of PA luminal area and pressure changes.

The sample size obviously limited the analyses. In the present cohort, there were no patients whose PVD did not reverse after correction of a cardiac shunt, which hampered conclusions regarding the role of PA stiffness indices in predicting adverse effects of shunt closure. The cohort consisted of patients with different haemodynamic baseline profiles and associated types of CHD, with inherent heterogeneity. Important areas of future research are the evaluation of serial measurements over time and the development of interventions that specifically target PA-stiffness.

ConClusIons

PA stiffness indices assessed by IVUS correlate with long-term disease progression and mortality in children with early and advanced arterial PVD. Especially in patients with early stages of PVD, assessment of intrinsic PA-stiffness indices can be complementary to conventional haemodynamic assessment and appears a valuable tool that may en-hance the prognostication of disease progression and survival.

178 Chapter 7

reFerenCes

1. Hoffman J, Rudolph A, Heymann M. Pulmonary vascular disease with congenital heart lesions: pathologic features and causes. Circulation. 1981;64.

2. Duffels MGJ, Engelfriet PM, Berger RMF, van Loon RLE, Hoendermis E, Vriend JWJ, Van der Velde ET, Bresser P, Mulder BJM. Pulmonary arterial hypertension in congenital heart disease: an epide-miologic perspective from a Dutch registry. Int J Cardiol. 2007;120:198–204.

3. Menting ME, Cuypers JA, Opić P, Utens EM, Witsenburg M, Van den Bosch AE, van Domburg RT, Meijboom FJ, Boersma E, Bogers AJJC, Roos-Hesselink JW. The unnatural history of the ventricular septal defect: outcome up to 40 years after surgical closure. J Am Coll Cardiol. 2015;65:1941–1951.


5. Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ. Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am J Respir Crit Care Med. 1994;149:1317–26.

6. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013;62:D22–33.

7. Dickinson MG, Bartelds B, Borgdorff MAJ, Berger RMF. The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models. Am J Physiol Lung Cell Mol Physiol. 2013;305:L1–14.

8. Berger RM. Possibilities and impossibilities in the evaluation of pulmonary vascular disease in congenital heart defects. Eur Heart J. 2000;17–27.

9. Gatzoulis MA, Beghetti M, Landzberg MJ, Galiè N. Pulmonary arterial hypertension associated with congenital heart disease: recent advances and future directions. Int J Cardiol. 2014;177:340–7.

10. McLaughlin V V, Shah SJ, Souza R, Humbert M. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65:1976–97.


12. Galiè N, Humbert M, Vachiery J-L, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noor-degraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, Vaz Carneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo Badano L, Albert Barberà J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol Ç, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GYH, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel M-P, Rigau D, Rosenkranz S, Völler H, Luis Zamorano J. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsod by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.

13. Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thébaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL, American Heart Association Council on Cardiopulmonary, Critical Care, Peri-operative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease


7

in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037–99.

14. Lopes AA, Barst RJ, Haworth SG, Rabinovitch M, Al Dabbagh M, Del Cerro MJ, Ivy D, Kashour T, Kumar K, Harikrishnan S, D’Alto M, Thomaz AM, Zorzanelli L, Aiello VD, Mocumbi AO, Santana MVT, Galal AN, Banjar H, Tamimi O, Heath A, Flores PC, Diaz G, Sandoval J, Kothari S, Moledina S, Gonçalves RC, Barreto AC, Binotto MA, Maia M, Al Habshan F, Adatia I. Repair of congenital heart disease with associated pulmonary hypertension in children: what are the minimal investigative procedures? Consensus statement from the Congenital Heart Disease and Pediatric Task Forces, Pulmonary Vascular Research Institute (PVRI). Pulm Circ. 2014;4:330–41.

15. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D42–D50.

16. Rabinovitch M, Keane JF, Norwood WI, Castaneda AR, Reid L. Vascular structure in lung tissue obtained at biopsy correlated with pulmonary hemodynamic findings after repair of congenital heart defects. Circulation. 1984;69:655–667.

17. van Riel AC, Blok IM, Zwinderman AH, Wajon EM, Sadee AS, Bakker-de Boo M, van Dijk AP, Hoen-dermis ES, Riezebos RK, Mulder BJ, Bouma BJ. Lifetime Risk of Pulmonary Hypertension for All Patients After Shunt Closure. J Am Coll Cardiol. 2015;66:1084–6.

18. Van Loon RL, Roofthooft MT, Hillege HL, ten Harkel AD, van Osch-Gevers M, Delhaas T, Kapusta L, Strengers JL, Rammeloo L, Clur SA, Mulder BJ, Berger RM. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124:1755–64.

19. Naeije R. Pulmonary vascular resistance. A meaningless variable? Intensive Care Med. 2003;29:526–9.

20. Hunter KS, Lammers SR, Shandas R. Pulmonary Vascular Stiffness: Measurement, Modeling, and Implications in Normal and Hypertensive Pulmonary Circulations. Compr Physiol. 2011;1:1413–1435.

21. Tian L, Chesler N. In vivo and in vitro measurements of pulmonary arterial stiffness: A brief review. Pulm Circ. 2012;2:505–517.

22. Schäfer M, Ivy DD, Barker AJ, Kheyfets V, Shandas R, Abman SH, Hunter KS, Truong U. Characteriza-tion of CMR-derived haemodynamic data in children with pulmonary arterial hypertension. Eur Heart J Cardiovasc Imaging. 2016;jew152.

23. Sanz J, Kariisa M, Dellegrottaglie S, Prat-González S, Garcia MJ, Fuster V, Rajagopalan S. Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance. JACC Cardiovasc Imaging. 2009;2:286–95.

24. Shen J, Cai Z, Sun L, Yang C, He B. The Application of Intravascular Ultrasound to Evaluate Pulmo-nary Vascular Properties and Mortality in Patients with Pulmonary Arterial Hypertension. J Am Soc Echocardiogr. 2015;1–9.

25. Berger RM, Cromme-Dijkhuis AH, Van Vliet AM, Hess J. Evaluation of the pulmonary vascula-ture and dynamics with intravascular ultrasound imaging in children and infants. Pediatr Res. 1995;38:36–41.

26. Berger RMF, Cromme-Dijkhuis AH, Hop WCJ, Kruit MN, Hess J. Pulmonary arterial wall distensibil-ity assessed by intravascular ultrasound in children with congenital heart disease: an indicator for pulmonary vascular disease? Chest. 2002;122:549–57.

180 Chapter 7

27. Rhee MY, Lee HY, Park JB. Measurements of Arterial Stiffness: Methodological Aspects. Korean Circ J. 2008;38:343–350.

28. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW, Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–301.

29. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903.

30. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G, Sildenafil Use in Pulmonary Arterial Hyperten-sion (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.

31. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery J-LJ-L, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, McGregor K, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas P, Widimsky P, Sechtem U, Al Attar N, Andreotti F, Aschermann M, Asteggiano R, Benza R, Berger R, Bonnet D, Delcroix M, Howard L, Kitsiou AN, Lang I, Maggioni A, Nielsen-Kudsk JE, Park M, Perrone-Filardi P, Price S, Domenech MTS, Vonk-Noordegraaf A, Zamorano JL. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J.2009;30:2493–2537.

32. Barst RJ, Gibbs JSR, Ghofrani HA., Hoeper MM, McLaughlin VV, Rubin LJ, Sitbon O, Tapson VF, Galiè N. Updated Evidence-Based Treatment Algorithm in Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2009;54:S78–S84.


34. Gan CT-J, Lankhaar J-W, Westerhof N, Marcus JT, Becker A, Twisk JWR, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Noninvasively assessed pulmonary artery stiffness predicts mortality in pulmonary arterial hypertension. Chest. 2007;132:1906–12.

35. Lau EMT, Iyer N, Ilsar R, Bailey BP, Adams MR, Celermajer DS. Abnormal pulmonary artery stiff-ness in pulmonary arterial hypertension: in vivo study with intravascular ultrasound. PLoS One. 2012;7:e33331.

36. Rodes-Cabau J, Domingo E, Roman A, Majo J. Intravascular ultrasound of the elastic pulmonary arteries: a new approach for the evaluation of primary pulmonary hypertension. Heart. 2003;311–317.

37. Gabriels C, Lancellotti P, Van De Bruaene A, Voilliot D, De Meester P, Buys R, Delcroix M, Budts W. Clinical significance of dynamic pulmonary vascular resistance in two populations at risk of pulmonary arterial hypertension. Eur Heart J Cardiovasc Imaging. 2015;16:564–70.



7

supplementary table 1. Congenital Heart Defect Status of Study Patients, Stratified By Haemodynamic Baseline Profile

Description of congenital heart defect n

Profile A - Early non-flow-related PVD 3

Repaired left sided obstructive lesionsa 3

Profile B - Early flow related PVD 16

Open VSD ± ASD ± PDA 10

Open ASD 4

Open PDA 1

Uncorrected DORV + corr CoA + corr PDA + open ASD 1

Profile C - Early PAH 8


corr ASD/PAPVR + corr PAS + open PDA 1

Profile D - Advanced PAH 14


Open PDA 1

corr AVSD + corr PDA (no residual shunt) 1

corr TGA (neonatal arterial switch operation, no residual shunt) 1

No congenital heart defects (IPAH patients) 2

Repaired left sided obstructive lesionsa 1

Total 41

ASD, atrial septal defect; AVSD, atrioventricularseptal defect; corr, corrected; DORV, double outlet right ventricle; IPAH, idiopathic pulmonary arterial hypertension; mPCWP, mean pulmonary capillary wedge pressure; PAH, pulmonary arterial hypertension; PAPVR, partial anomalous pulmonary venous return; PAS, pulmonary artery stenosis; PDA, patent ductusarteriosus; PVD, pulmonary vascular disease; TGA, transposition of the great ar-teries; VSD, ventricular septal defect.aNormalized pulmonary capillary wedge pressure (<15 mmHg) after aorta stenosis or coarctatio aortae repair.

1

2

3

4

5

6

7

8

9

10

Chapter 8Identification of treatment goals in paediatric pulmonary arterial hypertension

Mark-Jan PloegstraJohannes M. DouwesMarcus T.R. RoofthooftWillemijn M.H. ZijlstraHans L. HillegeRolf M.F. Berger

European Respiratory Journal 2014: 44: 1616-26

184 Chapter 8

ABstrACt

Introduction

To be able to design goal-oriented treatment strategies in paediatric pulmonary arterial hypertension (PAH), we aimed to identify treatment goals by investigating the prog-nostic value of treatment-induced changes in non-invasive predictors of transplant-free survival.

Methods

66 consecutive, treatment-naïve paediatric PAH patients in the Dutch National Network for Paediatric Pulmonary Hypertension who started with PAH-targeted drugs between January 2000 and April 2013 underwent prospective, standardised follow-up. Clinical, biochemical and echocardiographic measures were longitudinally collected at treat-ment initiation and at follow-up, and their respective predictive values for transplant-free survival were assessed. Furthermore, the predictive values of treatment-induced changes were assessed.

results

From the identified set of baseline predictors, the variables World Health Organization functional class (WHO-FC), N-terminal pro-brain natriuretic peptide (NT-proBNP) and tri-cuspid annular plane systolic excursion (TAPSE) were identified as follow-up predictors, in which treatment-induced changes were associated with survival. Patients in whom these variables improved after treatment showed better survival (p<0.002).

Conclusion

WHO–FC, NT-proBNP and TAPSE are not only predictors of transplant-free survival in paediatric PAH, but can also be used as treatment goals, as treatment-induced improve-ments in these variables are associated with improved survival. The identification of these variables allows for the introduction of goal-oriented treatment strategies in paediatric PAH.

Treatment goals in pediatric PAH 185

8

IntroduCtIon

Pulmonary arterial hypertension (PAH) is a severe, progressive disease of the precapillary pulmonary vessels, leading to increased pulmonary vascular resistance (PVR), right ven-tricular (RV) failure and death.1,2 Since the recent introduction of specific PAH-targeted drugs, quality of life and survival in both children and adults have been improved but remain unsatisfactory.3–11 In adult PAH-patients, a goal-oriented treatment strategy is recommended, in which validated clinical and laboratory variables are used to guide the clinician in the timing of therapy escalations or lung transplantation.12,13 In children, such a strategy is hampered by the of a lack of validated treatment goals.14

The first step in defining such treatment goals is assessing which variables qualify as surrogates for survival. A true surrogate meets at least the following criteria: 1) A strong correlation with survival; 2) values can be influenced by treatment; and 3) treatment-induced changes reflect changes in survival.15,16 Ideally, intra- and interob-server variability is low and the surrogate is part of the causal pathway of the disease.15 A treatment goal could subsequently be defined using a clinically and prognostically relevant threshold value for such a variable.

Several simple predictors of survival have been identified in both adults and chil-dren, but validated survival surrogates are scarce. Predictors of survival include World Health Organization functional class (WHO-FC), 6-min walking distance (6MWD), resting heart rate, serum levels of brain natriuretic peptide or its precursor N-terminal pro-brain natriuretic peptide (NT-proBNP), noradrenaline, uric acid, troponin-T and haemodynam-ic variables, such as cardiac index, mixed venous oxygen saturation, mean right atrial pressure and PVR index.4–11,17–27 In addition, measures derived by echocardiography and cardiac magnetic resonance imaging (CMR) are shown to have prognostic value, includ-ing tricuspid annular plane systolic excursion (TAPSE), ratio of right- to-left ventricular dimensions (RV/left ventricular (LV) ratio) and the presence of pericardial effusion.28–32 Nevertheless, such predictors of survival can only be used as treatment goals when treatment-induced changes are correlated with survival as well.15,16 It has recently been demonstrated in adults that improvements in WHO-FC, NT-proBNP, cardiac index and mixed venous oxygen saturation are associated with improvements in survival, support-ing their role as treatment goals in adults.33,34

No such treatment goals have yet been identified in children with PAH. Because of the drawbacks of serial follow-up catheterisations in children (need for anesthesia and relatively high complication rate), there is a particular need for noninvasive treatment goals.35 The current study aimed to identify noninvasive treatment goals in paediatric PAH by investigating the prognostic value of treatment-induced changes of noninvasive predictors of transplant-free survival.

186 Chapter 8

Methods

We performed a registry-based, prospective, observational study. In The Netherlands, all children with PAH are referred to the University Medical Center Groningen, the national referral centre of the Dutch National Network for Paediatric Pulmonary Hypertension.5 Patients are followed and registered prospectively according to a standardised protocol. Ethical approval for this ongoing registry has been obtained from the Medical Ethics Review Board of the University Medical Center Groningen and the subjects (and/or their guardians) provided written informed consent at enrolment.

Patients

All consecutive, treatment-naïve children with PAH who were started on PAH-targeted drugs between January 2000 and April 2013 were included. PAH-targeted therapies con-sisted of endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostacyclin analogues or a combination of these. Diagnosis of PAH was confirmed with cardiac cath-eterisation and defined as mean pulmonary artery pressure ≥ 25 mmHg with a mean pulmonary capillary wedge pressure ≤ 15 mmHg and PVR index ≥ 3 Wood units*m2. In case of clinical instability, diagnosis was made by echocardiography, defined as either the presence of right-to-left shunting in case of congenital heart defects or a maximum systolic tricuspid regurgitant velocity >2.8 m*s-1 accompanied by septal flattening and/or RV hypertrophy.36 Exclusion criteria were the presence of LV dysfunction or the start of PAH-targeted therapy >3 months before confirmation of diagnosis.

Baseline and clinical follow-up

Treatment initiation was defined as baseline and treatment effect was assessed at the follow-up visit ≥2 months after treatment initiation. WHO-FC, 6MWD, blood pressure, heart rate, NT-proBNP, creatine kinase, creatine kinase-MB fraction, uric acid, adrenaline, noradrenaline, (high-sensitivity) troponin-T, echocardiography, including TAPSE, RV/LV ratio (parasternal short-axis view at end-diastole) and the presence of pericardial effu-sion were assessed both at treatment initiation and follow-up. Haemodynamic variables were collected from the cardiac catheterisation at diagnosis. The main outcome param-eter was defined as lung transplantation-free survival.

data analysis

Data are presented as mean±SD, median (interquartile range (IQR)) or frequencies (percentage). In the analyses, logarithmic transformation was used to normalise the distribution of NT-proBNP. In order to ensure the reliability of the 6MWD, only those tests performed at an age ≥7 years were analyzed.37 Characteristics before and after


8

treatment initiation were compared by paired-samples t-test, McNemar test or Wilcoxon signed rank test where appropriate.

The combined end-point of transplant-free survival was estimated from time of treatment initiation until the last visit. Cox regression analysis was performed to evalu-ate the predictive value of variables before and after treatment initiation, and of the changes in-between. Follow-up measurements and treatment-induced changes were included as segmented time-dependent covariates in order to correct for potential time variability in the follow-up visits. Hazard ratios of treatment-induced changes were corrected for the initial baseline values at time of treatment initiation. Variables with p<0.100 in the univariable model were adjusted for age, sex and diagnosis.

For significant predictors at follow-up in which a treatment-induced change was also associated with survival, prognostically distinctive thresholds were estimated using survival time-dependent receiver operating characteristics (ROC) analysis.38 Kaplan-Meier curves were generated to illustrate the survival difference between high and low values. To study the prognostic implications of increases and decreases, we further estimated Kaplan-Meier curves according to four predefined risk profiles, as proposed previously in adult PAH patients.33 We defined these profiles as 1) low risk both before and after treatment initation, 2) high risk before but low risk after treatment intiation, 3) low risk before but high risk after treatment initiation, and 4) high risk both before and after treatment initiation. Survival differences were compared by log-rank testing.

Statistical analysis was performed using SPSS version 18.0 (SPSS inc., Chicago, IL, USA) and RStudio 0.98.501 (www.rstudio.com). All statistical tests were two-sided and p-values <0.05 were considered statistically significant.

results

70 consecutive treatment-naïve children were started on PAH-targeted drugs between January 2000 and April 2013. 66 of these were eligible for inclusion and 4 were excluded: 2 had LV dysfunction and in the other two cases, therapy had started >3 months before the confirmation of PAH diagnosis. In 59 cases, PAH was confirmed with cardiac cath-eterisation at a median (IQR) of 0.3 (0-6.4) months prior to treatment initiation. In the remaining seven cases, diagnosis was echocardiographically confirmed.

treatment Initiation

Patient characteristics at treatment initiation (baseline) are shown in Table 1. Median (IQR) age was 8.0 (2.9-13.7) years and 38 patients were ≥7 years old. The majority of pa-tients were diagnosed with idiopathic PAH (IPAH) or heritable PAH (HPAH), or congenital heart disease (CHD)-associated PAH (APAH). Of the 24 APAH-CHD patients, two had a

188 Chapter 8

tabl

e 1.

Pat

ient

Cha

ract

eris

tics

Stra

tified

by

Dia

gnos

is Tota

lIP

AH

/ H

PAP

APA

H-C

HD

APA

H-n

on-C

HD

N=6

6N

=34

N=2

4N

=8

Pati

ent c

hara

cter

isti

cs

Sex

mal

e n

(%)

6623

(34.

8%)

3422

(64.

7%)

2419

(79.

2%)

82

(25.

0%)

Age

at tr

eatm

ent i

nitia

tion

yrs

668.

0 (2

.9-1

3.7)

347.

9 (2

.9-1

3.7)

249.

5 (1

.4-1

5.1)

87.

6 (6

.2-1

1.5)

Hea

rt ra

te b

pm63

100

± 24

.932

99 ±

23.

623

103

± 27

.28

98 ±

25.

8

Syst

olic

blo

od p

ress

ure

mm

Hg

5510

5 ±

17.7

2810

7 ±

17.2

1997

± 1

1.6

811

5 ±

24.8

Dia

stol

ic b

lood

pre

ssur

e m

mH

g55

62 ±

12.

528

63 ±

14

1958

± 8

.18

69 ±

13.

4

WH

O fu

nctio

nal c

lass

n (%

)66

3424

8

I or I

I13

(19.

7%)

7 (2

0.6%

)1

(20.

8%)

1 (1

2.5%

)

III32

(48.

5%)

17 (5

0.0%

)11

(45.

8%)

4 (5

0.0%

)

IV21

(31.

8%)

10 (2

9.4%

)8

(33.

3%)

3 (3

7.5%

)

6MW

D m

(onl

y ch

ildre

n ≥

7 yr

s ol

d)32

350

± 91

.718

377

± 80

.613

315

± 10

0.4

132

4

Bioc

haem

ical

cha

ract

eris

tics

NT-

proB

NP

ng∙L

-148

875

(176

-309

0)24

1391

(202

-441

4)17

854

(86-

1456

)7

497

(115

-765

3)

CK U

∙L-1

3267

(33-

125)

1766

(25-

133)

1071

(39-

90)

510

6 (4

4-21

1)

CK-M

B U

∙L-1

3121

(9-3

3)16

20 (8

-32)

1024

(11-

42)

522

(14-

30)

Uric

aci

d m

mol

∙L-1

400.

3 ±

0.09

200.

3 ±

0.07

150.

3 ±

0.09

50.

4 ±

0.17

Nor

adre

nalin

e nm

ol∙L

-123

1.5

(0.9

4-2.

62)

132.

0 (1

.3-5

.9)

91.

3 (0

.8-1

.95)

11.

0

Epin

ephr

ine

nmol

∙L-1

220.

2 (0

.12-

0.54

)13

0.3

(0.2

-0.8

5)8

0.1

(0.0

5-0.

18)

10.

13

Det

ecta

ble

Trop

onin

3311

(33.

3%)

178

(47.

1%)

111

(9.1

%)

52

(40.

0%)

echo

card

iogr

aphi

c ch

arac

teri

stic

s

TAPS

E m

m49

15 (1

1.3-

17.0

)28

15 (1

1.1-

16.8

)14

15 (9

.8-1

8.0)

716

(12.

5-19

.5)

RV to

LV

ratio

481.

0 (0

.71-

1.57

)27

1.2

(0.9

-1.6

)13

0.8

(0.6

-1.2

)8

0.8

(0.6

-1.7

)

Pres

ence

of P

E50

6 (1

2.0%

)28

4 (1

4.3%

)14

0 (0

.0%

)8

2 (2

5.0%

)


8

dia

gnos

tic

card

iac

cath

eter

isat

ion

CI L

∙min

-1∙m

-253

2.8

(2.3

-4.0

)27

2.8

(2.0

-3.5

)19

2.7

(2.3

-3.8

)7

4.4

(2.4

-4.7

)

mRA

P m

mH

g59

6 (5

-8)

316

(5-9

)21

7 (5

-8)

75

(4-8

)

mPA

P m

mH

g59

50 (3

6-64

)31

54 (3

6-64

)21

49 (3

8-68

)7

47 (3

0-61

)

PVRi

WU

∙m2

5315

.3 (8

.1-2

6.8)

2718

.8 (8

.3-2

7.8)

1915

.3 (7

.1-3

2.7)

78.

5 (4

.7-1

8.5)

SvO

2 %56

63.8

(56.

0-71

.5)

2864

.9 (5

5.2-

71.4

)21

63.0

(54.

1-67

.4)

769

.8 (5

9.7-

76.2

)

Acut

e re

spon

se to

vas

odila

tor t

estin

g#47

4 (8

.5%

)24

3 (1

2.5%

)16

1 (6

.3%

)7

0 (0

.0%

)

Med

icat

ion

star

ted

at tr

eatm

ent i

niti

atio

n

Med

icat

ion

n (%

)66

3424

8

ERA

37 (5

6.1%

)18

(52.

9%)

18 (7

5%)

1 (1

2.5%

)

PDE5

i20

(30.

3%)

11 (3

2.4%

)5

(20.

8%)

4 (5

0.0%

)

Pros

tano

id16

(24.

2%)

10 (2

9.4%

)2

(8.3

%)

4 (5

0.0%

)

Ther

apy

inte

nsity

n (%

)66

3424

8

Mon

othe

rapy

60 (9

0.9%

)30

(88.

2%)

23 (9

5.8%

)7

(87.

5%)

Upf

ront

dua

l the

rapy

5 (7

.6%

)3

(8.8

%)

1 (4

.2%

)1

(12.

5%)

Upf

ront

Trip

le th

erap

y1

(1.5

%)

1 (2

.9%

)0

(0.0

%)

0 (0

.0 %

)

Dat

a ar

e pr

esen

ted

as n

(%),

mea

n±SD

or m

edia

n (in

terq

uart

ile ra

nge)

whe

re a

ppro

pria

te, u

nles

s oth

erw

ise

stat

ed. P

AH: p

ulm

onar

y ar

teria

l hyp

erte

nsio

n; IP

AH: i

diop

athi

c PAH

; H

PAH

: her

edita

ry P

AH; A

PAH

-CH

D: P

AH a

ssoc

iate

d w

ith c

onge

nita

l hea

rt d

isea

se; A

PAH

-non

-CH

D: P

AH a

ssoc

iate

d w

ith d

isea

ses

othe

r tha

n co

ngen

ital h

eart

dis

ease

; WH

O:

Wor

ld H

ealth

Org

aniz

atio

n; 6

MW

D: 6

-min

ute

wal

k di

stan

ce; N

T-pr

oBN

P: N

-ter

min

al p

ro-B

NP;

CK:

cre

atin

e ki

nase

; CK-

MB:

cre

atin

e ki

nase

-MB

fract

ion;

TAP

SE: t

ricus

pid

annu

lar

plan

e sy

stol

ic e

xcur

sion

; RV

to L

V ra

tio: r

ight

ven

tric

ular

to le

ft v

entr

icul

ar d

imen

sion

ratio

mea

sure

d at

end

-dia

stol

e; P

E: p

eric

ardi

al e

ffusi

on; C

I: ca

rdia

c in

dex;

mRA

P: m

ean

right

atr

ial p

ress

ure;

mPA

P: m

ean

pulm

onar

y ar

tery

pre

ssur

e; P

VRi;

inde

xed

pulm

onar

y va

scul

ar re

sist

ance

; SvO

2: m

ixed

ven

ous o

xyge

n sa

tura

tion;

ERA

: end

othe

lin-r

ecep

tor-

anta

goni

st; P

DE5

i: Ph

osph

odie

ster

ase-

5-in

hibi

tor.

# : Res

pons

e ac

cord

ing

to S

itbon

crit

eria

(dec

reas

e in

mPA

P of

at l

east

10

mm

Hg

to a

n ab

solu

te m

PAP

≤40

mm

Hg

with

out a

de

crea

se in

card

iac

outp

ut).

190 Chapter 8

pre-tricuspid, 17 a post-tricuspid and five a corrected shunt. All patients were treatment-naïve with respect to PAH-targeted therapy at baseline; three were already on a calcium channel blocker. Therapy consisted of monotherapy or combination therapy of endo-thelin receptor antagonists (56%), phosphodiesterase-5 inhibitors (30%) or prostanoids (24%). Patients were followed for a median (IQR) of 39 (10-75) months. In this period, 25 (38%) patients died and six (9%) underwent lung transplantation.

Univariable cox regression analysis in the full cohort revealed the baseline vari-ables diagnosis, heart rate, WHO-FC, NT-proBNP, noradrenaline, troponin, TAPSE, RV/LV-ratio and pericardial effusion as predictors of outcome (Supplementary Table 1). No association with survival was demonstrated for the variables sex, age, blood pressure, 6MWD, creatine kinase (total and MB-fraction), uric acid and adrenaline.

treatment-induced changes

Treatment effect was evaluated at a median (IQR) of 4 (3-5) months after treatment initiation. Between treatment initiation and the first follow-up, 9 (14%) patients died, leaving 57 (86%) patients available for baseline and follow-up comparison. Table 2 shows these comparisons for clinical, biochemical and echocardiographic variables and the treatment-induced changes between variables at baseline and follow-up. Systolic blood pressure, WHO-FC, NT-proBNP and RV/LV ratio had significantly decreased after treatment initiation, whereas 6MWD had increased.

The most clinically relevant candidate-predictors derived from time-dependent Cox regression analysis are shown in Figure 1 (the full time-dependent Cox regression analysis is shown in Supplementary Table 2). After adjusting for age, sex and diagnosis and taking into account both baseline and follow-up measurements, and the prognostic value of treatment-induced changes, only three predictors remained associated with survival: WHO-FC, NT-proBNP and TAPSE.

survival differences

For WHO-FC, NT-proBNP and TAPSE, Kaplan-Meier curves were estimated for high values in comparison with low values at treatment initiation and first follow-up (Figures 2-4). Patients with lower WHO-FC and NT-proBNP, and higher TAPSE had higher survival rates, either when measured at treatment initiation or at the first follow-up after treatment initiation. Optimal thresholds determined using survival time-dependent ROC analysis were NT-proBNP ≤1200 ng*L-1 and TAPSE ≥12 mm. According to the univariable baseline analysis, the threshold for WHO-FC was set to ≤III in the Kaplen-Meier analysis. Individual changes in W.

Prognostic implications of treatment-induced changes according to the four predefined risk profiles are also illustrated in Figures 2-4. Patients with low WHO-FC, low NT-proBNP and high TAPSE who remained stable after treatment initiation (profile


8

1) had the best survival rates. Patients who improved from initial high WHO-FC, high NT-proBNP and low TAPSE after treatment initiation (profile 2) had almost equally sur-vival rates compared to profile 1, whereas patients in profile 4, who did not improve and remained at high risk (WHO-FC IV, NT-proBNP >1200 ng*L-1 or TAPSE <12 mm), showed significantly worse survival (p<0.001, p<0.001 and p=0.002, respectively). The “dete-rioration after treatment initiation profile” (profile 3) was exceptional: except from one patient who deteriorated from WHO-FC ≤III to IV and died within 5 months, there were no deteriorations from low to high values for NT-proBNP or high to low values for TAPSE.

table 2. Comparison of Characteristics Before and After Treatment Initiation#

Before treatment initiation

After treatment initiation

Treatment-induced change

(N = 57) (N = 57) (N = 57) P-Value¶

Clinical diagnostics

Heart rate bpm (n = 50) 97 ± 23.3 92 ± 24.0 -5 ± 18.4 0.090

Systolic blood pressure mmHg (n = 44) 104 ± 16.4 97 ± 10.8 -7 ± 12.6 0.001

Diastolic blood pressure mmHg (n = 41) 63 ± 10.7 59 ± 7.8 -3 ± 12.2 0.104

WHO functional class n (%) (n = 55)

Class I or II 11 (20.0%) 19 (34.5%) -0.3 ± 0.66 0.003

Class III 29 (52.7%) 29 (52.7%)

Class IV 15 (27.3%) 7 (12.7%)

6MWD m (only children ≥ 7 yrs, n = 28) 349 ± 97.5 371 ± 97.1 22 ± 57 0.050

Biochaemical characteristics

NT-proBNP ng∙L-1 (n = 36) 666 (96-1543) 243 (101-686) -54 (-673-31) 0.011

CK U∙L-1 (n = 23) 67 (33-106) 83 (56-112) 13 (-13-40) 0.066

CK-MB U∙L-1 (n = 23) 21 (9-33) 19 (11-29) -2 (-10-4) 0.242

Uric acid mmol∙L-1 (n = 33) 0.3 ± 0.07 0.3 ± 0.1 0 ± 0.07 0.695

Noradrenaline nmol∙L-1 (n = 16) 1.5 (0.85-1.99) 1.9 (1.25-2.9) 0.4 (-0.62-1) 0.179

Epinephrine nmol∙L-1 (n = 16) 0.2 (0.13-0.75) 0.3 (0.2-0.39) 0.1 (-0.13-0.15) 0.698

Detectable Troponin (n = 26) 6 (23.1%) 6 (23.1%) 6 (23.1%) >0.999

echocardiographic characteristics

TAPSE mm (n=41) 15 (11.8-17.0) 16 (13.0-17.8) 1 (-1.0-2.6) 0.077

RV to LV ratio (n=40) 0.96 (0.69-1.47) 0.84 (0.67-1.20) -0.06 (-0.23-0.05) 0.029

Presence of PE (n=42) 4 (9.5%) 5 (11.9%) 1 (2.4%) >0.999

Data are presented as n (%), mean ± SD or median (interquartile range) where appropriate. WHO: World Health Organization; 6MWD: 6-minute walk distance; NT-proBNP: N-terminal pro-BNP; CK: creatine kinase; CK-MB: cre-atine kinase-MB fraction; TAPSE: tricuspid annular plane systolic excursion; RV to LV ratio: right ventricular to left ventricular dimension ratio measured at end-diastole; PE: pericardial effusion #: This table encompasses only patients who survived until first follow-up (n = 57). ¶:Comparison between before and after treatment initiation, with paired samples T-test, Wilcoxon signed rank test or McNemar test where appropriate.

192 Chapter 8

Heartrate per 10 bpm

WHO Class I or II¶

WHO Class III¶

6MWD per 50 m

NT-proBNP per log-value

TAPSE per 5 mm

RV/LV-ratio per 0.5 units

Presence of PE

Heartrate per 10 bpm

WHO Class I or II¶

WHO Class III¶

6MWD per 50 m

NT-proBNP per log-value

TAPSE per 5 mm

RV/LV-ratio per 0.5 units

Presence of PE

Δ Heartrate per 10 bpm

Δ WHO-FC per class§

Δ 6MWD per 50 m

Δ NT-proBNP per log value

Δ TAPSE per 5 mm

Δ RV/LV-ratio per 0.5 units

Δ Presence of PE

1.22 (1.03-1.44)**

0.33 (0.07-1.49)

0.25 (0.10-0.63)**

0.79 (0.55-1.15)

2.99 (1.17-7.61)**

0.52 (0.30-0.91)**

1.18 (1.01-1.38)**

3.37 (0.92-12.3)*

1.24 (1.02-1.50)**

0.10 (0.03-0.33)**

0.10 (0.04-0.27)**

0.78 (0.59-1.02)*

9.48 (2.55-35.3)**

0.51 (0.28-0.93)**

1.36 (1.08-1.71)**

4.06 (1.24-13.3)**

1.12 (0.83-1.50)

2.70 (1.27-5.82)**

0.62 (0.31-1.22)

7.16 (1.54-33.3)**

0.38 (0.14-1.01)*

1.23 (0.89-1.69)

5.40 (0.65-45.2)

1.36 (1.05-1.78)**

0.31 (0.07-1.42)

0.25 (0.10-0.63)**

-

2.34 (0.87-6.31)*

0.41 (0.18-0.94)**

1.12 (0.94-1.33)

2.28 (0.41-17.4)

1.31 (1.02-1.68)**

0.06 (0.02-0.22)**

0.06 (0.02-0.19)**

0.73 (0.54-0.97)**

5.95 (1.61-21.9)**

0.47 (0.22-0.97)**

1.39 (1.08-1.79)**

4.28 (0.80-23.0)*

-

3.64 (1.61-8.22)**

-

5.70 (1.20-27.1)**

0.39 (0.14-1.10)*

-

-

0.01 0.1 1 10 100 0.01 0.1 1 10 100

Treatment induced changes+

After treatment initiation

Time of treatment initiation

HR (CI) HR (CI)

HR (CI) HR (CI)

HR (CI) HR (CI)

Univariable analysis Adjusted for age, sex and diagnosis

HR HR

Figure 1. Univariable and multivariable Cox regression analysis#. Forest plots showing the prognostic value of the most clinically relevant candidate-predictors for death or transplantation at treatment initia-tion, after treatment initiation and of the treatment-induced changes. Data are presented as hazard ratios (95% confidence interval), derived by segmented time-dependent cox-regression. See table 2 for patient numbers. WHO-FC: WHO functional class; 6MWD: 6-minute walk distance; NT-proBNP: N-terminal pro-BNP; TAPSE: tricuspid annular plane systolic excursion; RV/LV-ratio: ratio of right- to left ventricular dimension measured at end-diastole; PE: pericardial effusion. #: This analysis encompasses only patients who survived until first follow-up (n=57); ¶: WHO-FC IV is used as reference category; +: Hazard ratios of treatment-induced changes are adjusted for baseline; §: Change in WHO-FC handled as continuous variable in the regression analysis; *: p<0.10; **: p<0.05.


8

dIsCussIon

In the perspective of the high unmet need for goal-oriented treatment strategies in paediatric PAH, the identification of treatment goals is of great clinical importance. Although predictors of survival may be important when starting treatment for PAH, this does not mean that they can be used as treatment goals. To qualify as a treatment goal it is imperative that the variable is changed by treatment and that this change is associated with a change in outcome.15,16 In the current study, baseline predictors were identified that are in line with previous reports. Of these, only WHO-FC, NT-proBNP and TAPSE showed treatment-induced changes that were associated with survival. These results indicate that improving WHO-FC, NT-proBNP and TAPSE qualify as treatment goals in children with PAH.

world health organization functional class

Our finding that WHO-FC is predictive of outcome at time of treatment initiation is consistent with previous paediatric and adult outcome studies.5–8 The enhanced prog-nostic value of WHO-FC after treatment initiation has been shown previously in adults but is now also confirmed in children. Treatment-induced changes in WHO-FC were also predictive of outcome in this paediatric cohort, which is in line with findings of Nickel et al,33 in an adult IPAH cohort, where a change in WHO-FC was an independent predictor of transplant-free survival. Our finding that improvements from WHO-FC IV to a lower class were associated with increased survival, also corresponds with recent data from REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) showing that adult PAH patients who improved in WHO-FC from III to I or II had better survival.34 The findings in the current study reinforce the clinical importance of repeated WHO-FC assessment also in children with PAH. In adults, it is recommended to achieve WHO-FC ≤II during treatment. Our study shows that WHO-FC IV should be avoided in children. Although the current study was not able to demonstrate additional value of improv-ing WHO-FC III, this may be due to lack of power. The authors do certainly not want to suggest that WHO-FC III is acceptable in paediatric PAH. On the basis of adult data and clinical grounds, it seems obvious to exert every effort to reach WHO-FC ≤II during treatment in children too.

The applicability of WHO-FC in young children has been questioned in the past; however, WHO-FC has been demonstrated to be a strong predictor of survival in several paediatric studies. The concept of WHO-FC is to describe symptoms at various levels of physical effort. Symptoms of dyspnoea at exertion in PAH are similar in children and adults, while physical efforts should be adapted appropriately in relation to the age of the child (e.g. feeding as the physical effort for an infant and holding pace with peers at

194 Chapter 8

Tim

e (m

onth

s)0

2448

7296

120

Cumulative survival

0.0

0.2

0.4

0.6

0.8

1.0

WH

O fu

nctio

nal c

lass

I, II

or I

IIW

HO

func

tiona

l cla

ss IV

Log

rank

p=0

.001

Pat

ient

s at

risk

4026

2012

72

159

73

20

Tim

e (m

onth

s)0

2448

7296

120

Cumulative survival0.

0

0.2

0.4

0.6

0.8

1.0

WH

O fu

nctio

nal c

lass

I, II

or I

IIW

HO

func

tiona

l cla

ss IV

Log

rank

p<0

.001

Pat

ient

s at

risk

4833

2615

92

72

10

00

Pat

ient

s at

risk

3926

2012

72

97

63

20

10

00

00

62

10

00

Tim

e (m

onth

s)0

2448

7296

120

Cumulative survival

0.0

0.2

0.4

0.6

0.8

1.0

WH

O-F

C I,

II or

III a

t bot

h ba

selin

e an

d af

ter t

reat

men

t ini

tiatio

nW

HO

-FC

IV a

t bas

elin

e, im

prov

ed to

I,II

or II

I afte

r tre

atm

ent i

nitia

tion

WH

O-F

C I,

II or

III a

t bas

elin

e, d

eter

iora

ted

to IV

afte

r tre

atm

ent i

nitia

tion

WH

O-F

C IV

at b

oth

base

line

and

afte

r tre

atm

ent i

nitia

tionLo

g ra

nk p

<0.0

01

A W

HO

-FC

bef

ore

trea

tmen

t ini

titat

ion

B W

HO

-FC

afte

r tre

atm

ent i

nitia

tion

C T

reat

men

t-ind

uced

cha

nges

in W

HO

-FC

Figu

re 2

. Tr

ansp

lant

-free

sur

viva

l of p

atie

nts

with

low

and

hig

h W

HO

-FC

at (A

) tre

atm

ent i

nitia

tion,

(B) a

fter

trea

tmen

t ini

tiatio

n an

d (C

) acc

ordi

ng to

risk

pro

file

cate

go-

rizat

ion

by lo

w o

r hig

h W

HO

-FC

befo

re a

nd a

fter

trea

tmen

t ini

tiatio

n. W

HO

-FC:

Wor

ld H

ealth

Org

aniz

atio

n fu

nctio

nal c

lass

.


8

Tim

e (m

onth

s)0

2448

7296

120

Cumulative survival

0.0

0.2

0.4

0.6

0.8

1.0

NT-

proB

NP

≤12

00 n

g/L

NT-

proB

NP

>12

00 n

g/L

Log

rank

p=0

.067

Pat

ient

s at

risk

2419

146

30

127

52

20

Tim

e (m

onth

s)0

2448

7296

120


0

0.2

0.4

0.6

0.8

1.0

NT-

proB

NP

≤12

00 n

g/L

NT-

proB

NP

>12

00 n

g/L

Log

rank

p<0

.001

Pat

ient

s at

risk

3125

198

50

51

00

00

Pat

ient

s at

risk

2419

146

30

76

52

20

00

00

00

51

00

00

Tim

e (m

onth

s)0

2448

7296

120

Cumulative survival

0.0

0.2

0.4

0.6

0.8

1.0

NT-

proB

NP

≤12

00 n

g/L

at b

oth

base

line

and

afte

r tre

atm

ent i

nitia

tion

NT-

proB

NP

>12

00 n

g/L

at b

asel

ine,

impr

oved

to ≤

1200

ng/

L af

ter t

reat

men

tN

T-pr

oBN

P ≤

1200

ng/

L at

bas

elin

e, d

eter

iora

ted

to >

1200

ng/

L af

ter t

reat

men

tN

T-pr

oBN

P >

1200

ng/

L at

bot

h ba

selin

e an

d af

ter t

reat

men

t ini

tiatio

n

Log

rank

p<0

.001

A N

T-pr

oBN

P be

fore

trea

tmen

t ini

tiatio

nB

NT-

proB

NP

afte

r tre

atm

ent i

nitia

tion

C T

reat

men

t-ind

uced

cha

nges

in N

T-pr

oBN

P

Figu

re 3

. Tr

ansp

lant

-free

sur

viva

l of p

atie

nts

with

low

and

hig

h N

T-pr

oBN

P at

(A) t

reat

men

t ini

tiatio

n, (B

) aft

er tr

eatm

ent i

nitia

tion

and

(C) a

ccor

ding

to ri

sk p

rofil

e ca

t-eg

oriz

atio

n by

low

or h

igh

NT-

proB

NP

befo

re a

nd a

fter

trea

tmen

t ini

tiatio

n. N

T-pr

oBN

P; N

-ter

min

al p

ro-B

NP.

196 Chapter 8

Tim

e (m

onth

s)0

2448

7296

120

Cumulative survival

0.0

0.2

0.4

0.6

0.8

1.0

TAP

SE ≥1

2 m

mTA

PS

E <1

2 m

m

Log

rank

p=0

.026

Pat

ient

s at

risk

3123

169

50

104

30

00

Tim

e (m

onth

s)0

2448

7296

120


0

0.2

0.4

0.6

0.8

1.0

TAP

SE ≥1

2 m

mTA

PSE

<12

mm

Log

rank

p<0

.001

Pat

ient

s at

risk

3625

199

50

52

10

00

Pat

ient

s at

risk

3123

169

50

52

21

00

00

00

00

52

10

00

Tim

e (m

onth

s)0

2448

7296

120

Cumulative survival

0.0

0.2

0.4

0.6

0.8

1.0

TAP

SE

≥12

mm

at b

oth

base

line

and

afte

r tre

atm

ent i

nitia

tion

TAP

SE

<12

mm

at b

asel

ine,

impr

oved

to ≥

12 m

m a

fter t

reat

men

t ini

tiatio

nTA

PS

E ≥

12 m

m a

t bas

elin

e, d

eter

iora

ted

to <

12 a

fter t

reat

men

t ini

tiatio

nTA

PS

E <

12 m

m a

t bot

h ba

selin

e an

d af

ter t

reat

men

t ini

tiatio

n

Log

rank

p=0

.002

A TA

PSE

befo

re tr

eatm

ent i

nitia

tion

B T

APS

E af

ter t

reat

men

t ini

tiatio

nC

Tre

atm

ent-i

nduc

ed c

hang

es in

TA

PSE

Figu

re 4

. Tr

ansp

lant

-free

surv

ival

of p

atie

nts w

ith lo

w a

nd h

igh

TAPS

E at

(A) t

reat

men

t ini

tiatio

n, (B

) aft

er tr

eatm

ent i

nitia

tion

and

(C) a

ccor

ding

to ri

sk p

rofil

e ca

tego

riza-

tion

by lo

w o

r hig

h TA

PSE

befo

re a

nd a

fter

trea

tmen

t ini

tiatio

n. TA

PSE:

tric

uspi

d an

nula

r pla

ne s

ysto

lic e

xcur

sion

.


8

kindergarten for a toddler). Using such an approach, assessment of WHO-FC has been shown to be reliable and reproducible in every age group.

n-terminal pro-brain natriuretic peptide

NT-proBNP is presumably related to the degree of RV dysfunction and might thereby indicate one of the pathobiological processes in PAH, which is a major strength of this biomarker.39 It is already known from several adult and paediatric studies that both BNP and NT-proBNP are baseline predictors of survival, and that baseline values and changes correlate with WHO-FC, 6MWD and haemodynamic variables.20–24 Our study adds that NT-proBNP is also a follow-up predictor, and that treatment-induced change predicts a change in survival.

It was shown previously that adults with an initial NT-proBNP level >1800 ng*L-1 that subsequently reached values below this threshold have identical outcomes to patients with low levels at baseline that remain low at follow-up.33 We found the same pattern in children with PAH when using a threshold of 1200 ng*L-1. Therefore, NT-proBNP seems suitable to incorporate in a goal-oriented treatment strategy in children. Although further research in larger paediatric cohorts may be needed to validate the current findings, we believe that it is justified to strive to achieve a NT-proBNP level of, at least, lower than 1200 ng*L-1 in the treatment of paediatric PAH.

echocardiography

Echocardiography and CMR have previously been shown to yield prognostically impor-tant measures in both adults and children.28–32 In contrast to CMR, echocardiography is a generally accessible follow-up tool and is also feasible in young children, without the need for sedation or anaesthesia.

IV

III

II

I

IV

III

II

I

Survivors Non-Survivors

Treatment induced changes in WHO-FC

Baseline Follow-up Baseline Follow-up

Figure 5. Individual treatment-induced changes in WHO-FC, stratified by survivors and non-survivors. WHO-FC: World Health Organization functional class.

198 Chapter 8

The variables TAPSE, RV/LV ratio and pericardial effusion are determinants of RV function and, at baseline, showed a significant association with survival. In the current study, a treatment-induced improvement in TAPSE tended to be related to survival as well. The poor prognosis of patients in whom TAPSE did not improve to ≥12 mm with treatment indicates that aiming for higher TAPSE in patients with values <12 mm seems a relevant treatment goal. However, since it is known that absolute values of TAPSE may vary considerably in young children, the appropriateness of such an absolute cut-off may be questioned in children <3 years of age.40 Nevertheless, additional analysis in the current cohort demonstrated that changes both in TAPSE Z-scores and in absolute values carry similar prognostic information (Supplementary Table 2).

other potential treatment goals

Both baseline and follow-up values, and changes in heart rate have been shown to have prognostic value in adults with PAH.18,19,41 In children, heart rate and heart rate variabil-ity at time of diagnosis have been shown to predict survival.17 Our study confirms the predictive value of heart rate, but a significant treatment-induced change could not be demonstrated, arguing against a role in defining treatment goals.

6MWD is a predictor of mortality in adult PAH and has been used as an end-point in clinical trials.42 However, the prognostic value of 6MWD in adult PAH patients is a topic of debate since a recent meta-analysis showed that changes in 6MWD do not reflect changes in outcome.43 Although the prognostic value of treatment-induced changes remains in question, it should be recognised that 6MWD also offers a direct measure of the patient’s functional capacity, which might be regarded as an important aspect of quality of life.44 Initiation of PAH-targeted treatment did improve 6MWD by a mean of 22 meters, which could be regarded as a clinically meaningful effect. Considering quality of life, 6MWD could play a role in goal-oriented treatment strategies in children, albeit in the knowledge that changes in 6MWD do not necessarily implicate changes in survival.

Invasively obtained haemodynamic measures have been frequently studied and are well established predictors of outcome in both adult and paediatric PAH.5–11 Cardiac catheterisation is required to confirm a diagnosis of PAH. However, serial follow-up cath-eterisations are controversial in paediatric PAH due to the frequent need for sedation or general anaesthesia and the relatively high complication rates in children.35 Therefore, the current study aimed to assess the value of noninvasive treatment goals, irrespective of the availability of haemodynamic data.

Clinical implications

This study showed substantial survival differences between children with PAH above and below the thresholds of WHO-FC ≤III, NT-proBNP ≤1200 ng*L-1 and TAPSE ≥ 12 mm. Failing to reach values below (WHO-FC and NT-proBNP) or above (TAPSE) these


8

thresholds resulted in significantly worse survival, suggesting that treatment should be escalated rapidly in these children. In the absence of previously validated treatment goals, the identification of these variables allows for the introduction of goal-oriented treatment strategies in paediatric PAH.


As paediatric pulmonary hypertension is a very rare disease, data on survival surrogates are extremely limited. The Dutch nationwide registry for pulmonary hypertension in childhood encompasses all diagnosed children with PAH in the Netherlands, represent-ing a national cohort, and the long term prospective and standardised follow-up makes this cohort uniquely qualified to identify treatment goals in paediatric PAH. Although absolute patient numbers might be relatively small, they did allow for the identification of at least three noninvasive treatment goals. We were able to perform longitudinal analyses for all clinically relevant noninvasive variables; however, number and time-points of follow-up cardiac catheterisation were not predefined in the protocol. Conse-quently, selection bias and time-variability prohibited investigation of the prognostic implications of treatment-induced changes in haemodynamic variables. Whether the type of initiated treatment affected the observed treatment effect was not studied. Profile 3 was exceptional in the studied cohort, which hampers conclusions regarding the prognostic value of worsening in the identified variables. Nevertheless, the survival difference between improvers and non-improvers is clear and underlines the usefulness of the variables as treatment goals.

ConClusIon

WHO-FC, NT-proBNP and TAPSE are not only predictors of transplant-free survival in paediatric PAH but can also be used as treatment goals, as treatment-induced improve-ments in these variables are associated with improved survival. The identification of these variables allows for the introduction of goal-oriented treatment strategies in paediatric PAH.

200 Chapter 8

reFerenCes


2. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–9.





7. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension - Prognostic factors and survival. J Am Coll Cardiol. 2002;40:780–788.





12. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery J-L, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmo-nary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493–537.

13. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 2005;26:858–863.


8

14. Haworth SG, Beghetti M. Assessment of endpoints in the pediatric population: congenital heart disease and idiopathic pulmonary arterial hypertension. Curr Opin Pulm Med. 2010;16 Suppl 1:S35–41.


16. Boissel JP, Collet JP, Moleur P, Haugh M. Surrogate End-Points - a Basis for a Rational Approach. Eur J Clin Pharmacol. 1992;43:235–244.


18. Bersohn MM, Turner MP, Traiger GL, Frost AE, Shapiro S. Systemic BP and heart rate as prognostic indicators in pulmonary arterial hypertension. Chest. 2013;144:959–65.

19. Henkens IR, Van Wolferen SA, Gan CT-J, Boonstra A, Swenne CA, Twisk JW, Kamp O, van der Wall EE, Schalij MJ, Vonk-Noordegraaf A, Vliegen HW. Relation of Resting Heart Rate to Prognosis in Patients With Idiopathic Pulmonary Arterial Hypertension. Am J Cardiol. 2009;103:1451–1456.

20. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865–870.


22. Takatsuki S, Wagner BD, Ivy DD. B-type Natriuretic Peptide and Amino-terminal Pro-B-type Na-triuretic Peptide in Pediatric Patients with Pulmonary Arterial Hypertension. Congenit Heart Dis. 2012;7:259–267.



25. Torbicki A, Kurzyna M, Kuca P, Fijałkowska A, Sikora J, Florczyk M, Pruszczyk P, Burakowski J, Wawrzyńska L. Detectable serum cardiac troponin T as a marker of poor prognosis among pa-tients with chronic precapillary pulmonary hypertension. Circulation. 2003;108:844–8.





30. van Wolferen SA, Marcus JT, Boonstra A, Marques KMJ, Bronzwaer JGF, Spreeuwenberg MD, Post-mus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J. 2007;28:1250–7.

202 Chapter 8







37. Li AM, Yin J, Au JT, So HK, Tsang T, Wong E, Fok TF, Ng PC. Standard reference for the six-minute-walk test in healthy children aged 7 to 16 years. Am J Respir Crit Care Med. 2007;176:174–180.

38. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56:337–44.

39. Nagaya N, Nishikimi T, Okano Y, Uematsu M, Satoh T, Kyotani S, Kuribayashi S, Hamada S, Kakishita M, Nakanishi N, Takamiya M, Kunieda T, Matsuo H, Kangawa K. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hyper-tension. J Am Coll Cardiol. 1998;31:202–8.

40. Koestenberger M, Ravekes W, Everett AD, Stueger HP, Heinzl B, Gamillscheg A, Cvirn G, Boysen A, Fandl A, Nagel B. Right ventricular function in infants, children and adolescents: reference values of the tricuspid annular plane systolic excursion (TAPSE) in 640 healthy patients and calculation of z score values. J Am Soc Echocardiogr. 2009;22:715–9.

41. Ciarka A, Doan V, Velez-Roa S, Naeije R, van de Borne P. Prognostic significance of sympa-thetic nervous system activation in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;181:1269–75.

42. Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of random-ized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30:394–403.

43. Savarese G, Paolillo S, Costanzo P, D’Amore C, Cecere M, Losco T, Musella F, Gargiulo P, Marciano C, Perrone-Filardi P. Do Changes of 6-Minute Walk Distance Predict Clinical Events in Patients With Pulmonary Arterial Hypertension? A Meta-Analysis of 22 Randomized Trials. J Am Coll Cardiol. 2012;60:1192–1201.

44. Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:428–33.


8

supplementary table 1. Prognostic Value of Characteristics at Time of Treatment Initiation

Univariable Adjusted for age, sex and diagnosis

HR (95% CI) P-value HR (95% CI) P-value


Diagnosis (n=66)

IPAH/HPAH compared to APAH-non-CHD 0.34 (0.12-0.96) 0.041 0.31 (0.10-0.93)# 0.037

APAH-CHD compared to APAH-non-CHD 0.29 (0.10-0.86) 0.025 0.26 (0.08-0.84)# 0.025

Sex male (n=66) 1.23 (0.59-2.57) 0.581

Age per yr (n=66) 0.95 (0.89-1.01) 0.127

Heart rate per 10 bpm (n=63) 1.23 (1.07-1.41) 0.003 1.17 (0.98-1.40) 0.090

Systolic blood pressure per 10 mmHg (n=55) 0.85 (0.67-1.08) 0.185

Diastolic blood pressure per 10 mmHg (n=55) 0.91 (0.63-1.31) 0.609

WHO functional class (n=66)

I or II compared to IV 0.17 (0.04-0.73) 0.017 0.15 (0.03-0.66) 0.012

III compared to IV 0.27 (0.12-0.57) 0.001 0.27 (0.13-0.59) 0.001

6MWD per 50 m (children ≥ 7 yrs old, n=32) 0.81 (0.58-1.12) 0.198

Biochaemical characteristics

NT-pro-BNP per 10-Log value (n=48) 3.26 (1.78-5.94) <0.001 2.53 (1.26-5.06) 0.009

CK per U∙L-1 (n=32) 1.00 (1.00-1.00) 0.876

CK-MB per U∙L-1 (n=31) 1.00 (0.97-1.04) 0.903

Uric acid per 0.1 mmol∙L-1 (n=40) 1.46 (0.73-2.91) 0.288

Norepinephrine per nmol∙L-1 (n=23) 2.42 (1.22-4.83) 0.012 2.13 (0.90-5.05) 0.085

Epinephrine per nmol∙L-1 (n=22) 2.23 (0.56-8.97) 0.257

Detectable Troponin (n=33) 6.50 (1.86-22.8) 0.003 2.84 (0.49-16.3) 0.242

echocardiographic characteristics

TAPSE per 5 mm (n=49) 0.53 (0.34-0.83) 0.006 0.41 (0.20-0.82) 0.011

TAPSE Z-score per SD (n=49) ¶ 0.90 (0.74-1.09) 0.284

RV to LV ratio per 0.5 units (n=48) 1.49 (1.09-2.03) 0.013 1.26 (0.92-1.72) 0.156

Presence of PE (n=50) 3.13 (1.14-8.58) 0.027 2.28 (0.64-8.19) 0.205

Data are presented as hazard ratios for lung-transplantation or death (95% confidence interval), derived from Cox regression analysis. HR: hazard ratio; CI: confidence interval; IPAH: idiopathic PAH; HPAH: hereditary PAH; APAH-CHD: PAH associated with congenital heart disease; APAH-non-CHD: PAH associated with diseases other than congenital heart disease; WHO: World Health Organization; 6MWD: 6-minute walk distance; NT-proBNP: N-terminal pro-BNP; CK: creatine kinase; CK-MB: creatine kinase-MB fraction; TAPSE: tricuspid annular plane sys-tolic excursion; RV to LV ratio: right ventricular to left ventricular dimension ratio measured at end-diastole; PE: pericardial effusion. #: HR of diagnosis adjusted for age and sex. ¶: Analysis of TAPSE Z-score was disturbed by an extreme outlier. This patient was a very young infant with a z-score of +5. Excluding this patient would yield an unadjusted HR (95% CI) of 0.82 (0.67-1.00), P=0.055 and an adjusted HR (95% CI) of 0.72 (0.56-0.92), P=0.009.

204 Chapter 8

supp

lem

enta

ry t

able

2.

Prog

nost

ic V

alue

of C

hara

cter

istic

s at

Tre

atm

ent I

nitia

tion

and

at F

ollo

w-U

p#

Uni

varia

ble

Tim

e D

epen

dent

Cox

Reg

ress

ion

Tim

e of

trea

tmen

t ini

tiatio

n (N

= 5

7)A

fter

trea

tmen

t ini

tiatio

n (N

= 5

7)Tr

eatm

ent-

indu

ced

chan

ge¶ (N

= 5

7)

HR

(95%

CI)

P-va

lue

HR

(95%

CI)

P-va

lue

HR

(95%

CI)

P-va

lue

Clin

ical

dia

gnos

tics

Hea

rt ra

te p

er 1

0 bp

m (n

=50)

1.22

(1.0

3-1.

44)

0.02

21.

24 (1

.02-

1.50

)0.

028

1.12

(0.8

3-1.

50)

0.45

1

Syst

olic

blo

od p

ress

ure

per 1

0 m

mH

g (n

=44)

0.81

(0.6

0-1.

10)

0.18

00.

95 (0

.74-

1.23

)0.

724

0.89

(0.4

9-1.

63)

0.71

7

Dia

stol

ic b

lood

pre

ssur

e pe

r 10

mm

Hg

(n=4

1)0.

96 (0

.61-

1.53

)0.

871

0.85

(0.5

8-1.

24)

0.40

30.

60 (0

.33-

1.08

)0.

090

WH

O fu

nctio

nal c

lass

(n=5

5)

I or I

I0.

33 (0

.07-

1.49

)0.

149

0.10

(0.0

3-0.

33)

<0.0

012.

70 (1

.27-

5.82

)0.

010

III0.

25 (0

.10-

0.63

)0.

003

0.10

(0.0

4-0.

27)

<0.0

01

IV1.

00N

.A.

1.00

N.A

.

6MW

D p

er 5

0 m

(chi

ldre

n ≥

7 yr

s ol

d. n

=28)

0.79

(0.5

5-1.

15)

0.21

80.

78 (0

.59-

1.02

)0.

066

0.62

(0.3

1-1.

22)

0.16

3

Bioc

haem

ical

cha

ract

eris

tics

NT-

pro-

BNP

per 1

0-Lo

g va

lue

(n=3

6)2.

99 (1

.17-

7.61

)0.

022

9.48

(2.5

5-35

.3)

0.00

17.

16 (1

.54-

33.2

6)0.

012

CK p

er U

∙L-1

(n=2

3)1.

00 (0

.98-

1.02

)0.

934

1.00

(0.9

9-1.

01)

0.84

21.

00 (0

.98-

1.02

)0.

692

CK-M

B pe

r U∙L

-1 (n

=23)

1.00

(0.9

5-1.

05)

0.94

21.

00 (0

.95-

1.05

)0.

920

1.00

(0.9

5-1.

05)

0.93

3

Uric

aci

d pe

r mm

ol∙L

-1(n

=33)

0.94

(0.3

7-2.

40)

0.90

00.

91 (0

.39-

2.11

)0.

822

0.87

(0.2

8-2.

73)

0.80

8

Nor

epin

ephr

ine

per n

mol

∙L-1

(n=1

6)2.

70 (1

.06-

6.87

)0.

037

1.48

(0.8

8-2.

49)

0.13

50.

84 (0

.25-

2.77

)0.

769

Epin

ephr

ine

nmol

∙L-1

(n=1

6)2.

50 (0

.54-

11.5

)0.

239

7.62

(0.3

6-16

3)0.

194

5.01

(0.2

1-11

7)0.

316

Det

ecta

ble

Trop

onin

(n=2

6)4.

88 (0

.97-

24.5

)0.

055

3.52

(0.5

8-21

.2)

0.17

03.

20 (0

.5-2

0.6)

0.22

0


8

echo

card

iogr

aphi

c ch

arac

teri

stic

s

TAPS

E pe

r 5 m

m (n

=41)

0.52

(0.3

0-0.

91)

0.02

20.

51 (0

.28-

0.93

)0.

027

0.38

(0.1

4-1.

01)

0.05

3

TAPS

E Z-

scor

e pe

r SD

(n=4

1)0.

76 (0

.58-

1.00

)0.

047

0.66

(0.5

0-0.

88)

0.00

40.

70 (0

.49-

1.00

)0.

052

RV to

LV

ratio

per

0.5

uni

ts (n

=40)

1.18

(1.0

1-1.

38)

0.03

51.

36 (1

.08-

1.71

)0.

010

1.23

(0.8

9-1.

69)

0.20

7

Pres

ence

of P

E (n

=42)

3.37

(0.9

2-12

.27)

0.06

64.

06 (1

.24-

13.3

)0.

020

5.40

(0.6

5-45

.2)

0.11

9

Pred

icto

rs w

ith p

<0.1

00 a

djus

ted

for a

ge, s

ex a

nd d

iagn

osis

Tim

e of

trea

tmen

t ini

tiatio

n (N

= 5

7)A

fter

trea

tmen

t ini

tiatio

n (N

= 5

7)Tr

eatm

ent-

indu

ced

chan

ge¶ (N

= 5

7)

HR

(95%

CI)

P-va

lue

HR

(95%

CI)

P-va

lue

HR

(95%

CI)

P-va

lue

Hea

rt ra

te p

er 1

0 bp

m (n

=50)

*1.

36 (1

.05-

1.78

)0.

022

1.31

(1.0

2-1.

68)

0.03

3-

-

WH

O fu

nctio

nal c

lass

(n=5

5)

I or I

I0.

31 (0

.07-

1.42

)0.

131

0.06

(0.0

2-0.

22)

<0.0

013.

64 (1

.61-

8.22

)0.

002

III0.

25 (0

.10-

0.63

)0.

003

0.06

(0.0

2-0.

19)

<0.0

01

IV1.

00N

.A.

1.00

N.A

.

6MW

D (o

nly

child

ren

≥7 y

rs o

ld. n

=28)

**-

-0.

73 (0

.54-

0.97

)0.

033

--

NT-

pro-

BNP

per 1

0-Lo

g va

lue

(n=3

6)2.

34 (0

.87-

6.31

)0.

092

5.95

(1.6

1-21

.9)

0.00

75.

70 (1

.20-

27.1

)0.

029

Nor

epin

ephr

ine

per n

mol

∙L-1

(n=1

6)1.

65 (0

.62-

4.41

)0.

318

--

--

TAPS

E pe

r 5 m

m (n

=41)

0.41

(0.1

8-0.

94)

0.03

60.

47 (0

.22-

0.97

)0.

041

0.39

(0.1

4-1.

10)

0.07

6

TAPS

E Z-

scor

e pe

r SD

(n=4

1)0.

75 (0

.55-

1.02

)0.

062

0.66

(0.4

9-0.

88)

0.00

60.

70 (0

.49-

1.00

)0.

047

RV to

LV

ratio

per

0.5

uni

ts (n

=40)

1.12

(0.9

4-1.

33)

0.21

71.

39 (1

.08-

1.79

)0.

010

--

Pres

ence

of P

E (n

=42)

2.28

(0.4

1-17

.4)

0.30

34.

28 (0

.80-

23.0

)0.

090

--

Dat

a ar

e pr

esen

ted

as h

azar

d ra

tios f

or lu

ng-t

rans

plan

tatio

n or

dea

th (9

5% co

nfide

nce

inte

rval

). H

R: h

azar

d ra

tio; C

I: co

nfide

nce

inte

rval

; IPA

H: i

diop

athi

c PAH

; HPA

H: h

ered

itary

PA

H; A

PAH

-CH

D: P

AH a

ssoc

iate

d w

ith co

ngen

ital h

eart

dis

ease

; APA

H-n

on-C

HD

: PAH

ass

ocia

ted

with

dis

ease

s oth

er th

an co

ngen

ital h

eart

dis

ease

; WH

O: W

orld

Hea

lth O

rgan

i-za

tion;

6M

WD

: 6-m

inut

e w

alk

dist

ance

; NT-

proB

NP:

N-t

erm

inal

pro

-BN

P; C

K: c

reat

ine

kina

se; C

K-M

B: c

reat

ine

kina

se-M

B fra

ctio

n; T

APSE

: tric

uspi

d an

nula

r pla

ne sy

stol

ic e

xcur

-si

on; R

V to

LV ra

tio: r

ight

ven

tric

ular

to le

ft v

entr

icul

ar d

imen

sion

ratio

mea

sure

d at

end

-dia

stol

e; P

E: p

eric

ardi

al e

ffusi

on. # : T

his t

able

enc

ompa

sses

onl

y pa

tient

s who

surv

ived

un

til fi

rst f

ollo

w-u

p. H

azar

d ra

tios f

or ‘a

fter t

reat

men

t ini

tiatio

n’ a

nd ‘t

reat

men

t-in

duce

d ch

ange

’ are

cal

cula

ted

usin

g se

gmen

ted

time-

depe

nden

t cox

regr

essi

on. ¶ : C

hang

e in

W

HO

func

tiona

l cla

ss h

andl

ed a

s con

tinuo

us v

aria

ble

in th

e Co

x re

gres

sion

mod

el.

1

2

3

4

5

6

7

8

9

10

Chapter 9Clinical worsening as composite study endpoint in pediatric pulmonary arterial hypertension

Mark-Jan Ploegstra*

Sanne Arjaans*

Willemijn M.H. ZijlstraJohannes M. DouwesTheresia R. Vissia-KazemierMarcus T.R. RoofthooftHans L. HillegeRolf M.F. Berger*Contributed equally

Chest 2015: 148: 655-66

208 Chapter 9

ABstrACt

Background

Clinical worsening (CW), an increasingly used composite end point in adult pulmonary arterial hypertension (PAH), has not yet been evaluated in pediatric PAH. This study aims to evaluate the usefulness of CW in pediatric PAH by assessing the event incidence and prognostic value of each separate component of CW and of the composite CW end point.

Methods

Seventy pediatric patients with PAH from the Dutch National Network for Pediatric Pulmonary Hypertension, who started PAH-targeted therapy between January 2000 and January 2014, were included and underwent standardized follow-up. The follow-ing CW-components were prospectively registered: death, lung-transplantation (LTx), PAH-related hospitalizations, initiation of IV prostanoids and functional deterioration (World Health Organization functional-class deterioration, ≥15% decrease in 6-min walk distance, or both). The longitudinal event incidence and prognostic value were assessed for each separate component and their combination.

results

The end-point components of death, LTx, hospitalizations, initiation of IV prostanoids, and functional deterioration occurred with a longitudinal event rate of 10.1, 2.5, 21.4, 9.4 and 48.1 events per 100 person-years, respectively. The composite CW end point occurred 91.5 times per 100 person-years. The occurrences of either hospitalization, initiation of IV prostanoids or functional deterioration were predictive of death or LTx (p<0.001 for each component). In this cohort, 1-, 3- and 5-year transplant-free survival was 76%, 64% and 56%, respectively. Freedom from CW at 1, 3 and 5 years was 43%, 22% and 17%, respectively.

Conclusions

CW occurred with a high event incidence and each of the soft end point components was predictive of death or LTx. This supports the usefulness of CW as a study end point in clinical trials in pediatric PAH.

Clinical worsening in pediatric PAH 209

9

IntroduCtIon

Pediatric pulmonary arterial hypertension (PAH) is a severe, progressive disease of the pulmonary vasculature and has an unsatisfactory prognosis despite the introduction of PAH-targeted therapies.1–3 Most drugs currently used in the treatment of PAH have not been evaluated in pediatric clinical trials.4,5 This is largely explained by the rarity and heterogeneity of pediatric PAH, leading to small study cohorts, but is also due to the lack of appropriate outcome parameters to evaluate drug efficacy.6–8

Time to death would seem the most robust trial end point, as improving survival is the first priority in treating pediatric PAH.3 However, death as an end point would require long-duration clinical trials in a very vulnerable group of pediatric patients unable to give consent, thereby challenging study ethics and leading to high costs.7,8 Short-duration clinical trials with lower number of patients required are preferable but need an alternative end point to obtain sufficient statistical power. Such an end point should be either a direct or surrogate measure of how a patient feels, functions or survives9 and would ideally be able to be measured earlier and more frequently than the final end point of interest.10 Such an end point would lead to increased statistical power, reduction of required study participants, shorter study periods, and lower costs.11

The 6-min walk distance (6MWD) has been the most commonly used primary end point in the pivotal trials in adult PAH.12,13 The absolute value of 6MWD is regarded as a clinically meaningful end point, measuring how a patient functions. Moreover, 6MWD has been demonstrated to be an independent predictor of mortality in adults and in children >7 years old.14,15 However, in the current era with accumulating treatment modalities, more ambitious treatment effects such as improved morbidity and mortality are desired. Evidence suggests that changes in 6MWD are not accurate surrogates for disease progression or survival, neither in adults or children.13,16,17 This challenges the usefulness of 6MWD as an end point and has led to a call for alternative, more clinically meaningful end points.

Clinical worsening (CW) has been suggested as an alternative end point in PAH.18–21 CW consists of a combination of hard unambiguous events such as death and lung-transplantation (LTx), and softer events, including hospitalizations, need for addi-tional therapy and worsening of function. CW has been used for some time as primary or secondary end point in adult trials,22–39 and its validity has been evaluated in adults.40 Us-ing 2-year outcome data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), it was shown that the soft CW end point components were highly predictive of subsequent mortality.

As 6MWD is not reliable in young children, this end point is not feasible for the pediatric age group. Although not yet evaluated, CW might be an appealing clinical end point in pediatric PAH, since it provides a patient-centered composite end point that

210 Chapter 9

decreases the required study participants and it would be applicable in different age groups. Moreover, it would account for the risk of rapid clinical deterioration in children.8 However, before CW can be used in clinical trials, essential evaluation steps are required that would include a description of how frequent the end point components of CW oc-cur, how the soft end point components relate to mortality and what the timing of CW is compared with mortality.10 Therefore, the primary aim of this study was to evaluate the usefulness of CW in pediatric PAH by assessing event incidence and prognostic value of each separate component end point and the composite CW end point. The secondary aim was to describe the timing of CW compared with death or LTx in pediatric PAH.

MAterIAls And Methods


This study is a retrospective analysis of data from a prospective clinical registry. In the Netherlands, all children with PAH are referred to the University Medical Center Gron-ingen, which serves as the national referral center of the Dutch National Network for Pediatric Pulmonary Hypertension.41 Children are followed and registered prospectively according to a standardized protocol. Ethical approval for this ongoing registry was obtained from the institutional review board (medical ethics review board of the Uni-versity Medical Center Groningen, approval number M11.097816) and the subjects and/or their guardians provided written informed consent at enrollment. All treatment-naive patients in whom PAH-targeted therapy was initiated between January 1, 2000, and January 1, 2014, were included in this study.

end point definition and data collection

The definition of CW included the following end point components: (1) death; (2) LTx; (3) nonelective PAH-related hospitalizations, including hospitalizations for atrial septosto-mies; (4) initiation of IV prostanoids; and (5) functional deterioration, defined as either worsening of World Health Organization functional class (WHO-FC), ≥15% decrease in 6MWD, or both. This CW definition is in-line with various CW end points used in adult PAH trials and as proposed in consensus statements.42,43 As the change in 6MWD as an end point has been challenged, a sensitivity analysis was performed with defining functional deterioration as worsening of WHO-FC only. The CW components were longitudinally registered from initiation of PAH-targeted therapy until the last follow-up visit before January 1, 2014.


9

data analysis

Data are presented as mean±SD, median (interquartile range[IQR]) or frequencies (per-centage). Statistical analysis was performed using IBM SPSS version 22.0 (IBM Corpora-tion). All statistical tests were two-sided and P values <0.05 were considered statistically significant.

For the first functional deterioration event, follow-up WHO-FC and 6MWD were compared to the best achieved WHO-FC or 6MWD in the first year after treatment ini-tiation. For consecutive events, WHO-FC and 6MWD were compared to the preceding follow-up visit. As WHO-FC IV indicates a functional status where further deterioration is not possible due to a ceiling effect, WHO-FC IV was always regarded as a functional deterioration event, also when it had been present at baseline.

To describe the longitudinal event incidence of the end points, the longitudinal event rate per 100 person-years was calculated for each component and for the compos-ite of these using the following formula: event rate per 100 person-years = total number events/(total observation time/100). In this analysis, patients could experience multiple events and were censored at death or end of follow-up. A separate event rate analysis was performed involving first events only, with censoring at time of the event or end of follow-up. Cumulative event incidence curves were depicted for the separate end point components. To assess the relationship between the soft and hard end point compo-nents, the prognostic value of the first occurring soft CW components 3, 4 and 5 were assessed using time-dependent Cox regression analysis with the hard end point death or LTx as the dependent analysis outcome (component 1+2). To describe the timing of CW in relation to death or LTx, both survival and event-free survival were reported and compared using Kaplan-Meier analysis.

To align the study sample with the specific setting of a clinical trial, all analyses were repeated for a subgroup of what we called “trial-eligible patients”. These patients were defined as not hospitalized, not in WHO-FC IV and/or not immediately started on IV prostanoids at baseline. The results from these analyses were presented as Supple-mentary Material.

results


In total, 70 patients were included in this study. The expected nationwide representa-tion is confirmed by the fact that the current sample size over a 14-year period is in-line with several reports on annual PAH incidence (reports ranging from one to three cases per million; the Dutch pediatric population approximately 3 million).2,44,45 Patient characteristics at treatment initiation (baseline) are shown in Table 1. Median age was

212 Chapter 9

tabl

e 1.

Bas

elin

e Ch

arac

teris

tics

Stra

tified

by

Dia

gnos

is

Tota

lIP

AH

/HPA

HA

PAH

-CH

DA

PAH

-non

-CH

D

nN

=70

nN

=37

nN

=25

nN

=8P

Age,

y70

8.0

(2.7

-13.

7)37

8.0

(2.7

-13.

2)25

8.5

(1.3

-15.

0)8

7.6

(6.2

-11.

5)0.

967

Mal

e70

24 (3

4)37

13 (3

5)25

5 (2

0)8

6 (7

5)0.

018a

WH

O-F

C70

3725

80.

458a

I4

(6)

4 (1

1)0

(0)

0 (0

)

II25

(36)

12 (3

2)10

(40)

3 (3

8)

III28

(40)

16 (4

3)10

(40)

2 (2

5)

IV13

(19)

5 (1

4)5

(20)

3 (3

8)

6MW

D, m

4438

4±10

124

413±

6015

347±

115

535

8±17

90.

112

NT-

proB

NP,

ng/L

5839

9 (1

13-1

612)

3054

9 (1

90-3

164)

2031

7 (9

3-75

2)8

145

(67-

6800

)0.

287

Hem

odyn

amic

sb

mRA

P, m

mH

g61

7.3±

4.5

348.

1±5.

420

6.2±

2.8

76.

4±3.

10.

271

mPA

P, m

mH

g61

54±1

834

54±1

820

56±1

87

45±1

60.

376

PVRi

, WU

*m2

5920

±12

3220

±12

2022

±13

712

±80.

157

CI, L

/min

/m2

593.

3±2.

332

2.8±

1.0

204.

0±3.

67

3.7±

1.1

0.17

7

Trea

tmen

t70

3725

8>0

.999

a

Upf

ront

mon

othe

rapy

66 (9

4)34

(92)

24 (9

6)8

(100

)

Upf

ront

dua

l the

rapy

3 (4

)2

(5)

1 (4

)0

(0)

Upf

ront

trip

le th

erap

y1

(1)

1 (3

)0

(0)

0 (0

)

Base

line

IV p

rost

anoi

ds70

13 (1

9)37

8 (2

2)25

2 (8

)8

3 (3

8)0.

108a

Hos

pita

lized

at b

asel

inec

7010

(14)

376

(16)

251

(4)

83

(38)

0.05

2a

Obs

erva

tion

time,

py

7027

6.4

3714

5.0

2511

9.6

811

.8N

.A.

Dat

a ar

e pr

esen

ted

as n

(%) o

r med

ian

(inte

rqua

rtile

rang

e) o

r mea

n±SD

, unl

ess o

ther

wis

e in

dica

ted.

IPAH

=idi

opat

hic

pulm

onar

y ar

teria

l hyp

erte

nsio

n; H

PAH

=her

edita

ry p

ul-

mon

ary

arte

rial h

yper

tens

ion;

APA

H-C

HD

=pul

mon

ary

arte

rial h

yper

tens

ion

asso

ciat

ed w

ith c

onge

nita

l hea

rt d

isea

se; A

PAH

-non

-CH

D=p

ulm

onar

y ar

teria

l hyp

erte

nsio

n as

-so

ciat

ed w

ith co

nditi

ons o

ther

than

cong

enita

l hea

rt d

isea

se; W

HO

-FC=

Wor

ld H

ealth

Org

aniz

atio

n fu

nctio

nal c

lass

; 6M

WD

=6-m

inut

e-w

alk-

dist

ance

; mRA

P=m

ean

right

atr

ial

pres

sure

; mPA

P=m

ean

pulm

onar

y ar

teria

l pre

ssur

e; P

VRi=

inde

xed

pulm

onar

y va

scul

ar re

sist

ance

; CI=

card

iac

inde

x; N

.A.=

not a

pplic

able

; NT-

proB

NP=

N-t

erm

inal

B-t

ype

natr

i-ur

etic

pep

tide;

py=

pers

on-y

ears

. a Fish

er’s

exac

t tes

t use

d to

calc

ulat

e P-

valu

e. b Ri

ght h

eart

cath

eter

izat

ion

prio

r to

trea

tmen

t ini

tiatio

n (th

e m

edia

n tim

e fro

m ca

thet

eriz

atio

n to

tr

eatm

ent i

nitia

tion

was

1 m

onth

).c Non

-ele

ctiv

e PA

H re

late

d ho

spita

lizat

ion.


9

8.0 years (IQR, 2.7-13.7 years). In total, 37 patients were diagnosed with idiopathic PAH (IPAH) or heritable PAH (HPAH), 25 with PAH associated with congenital heart disease (APAH-CHD), and eight with PAH associated with conditions other than congenital heart disease (APAH-non-CHD). Of the 25 patients with APAH-CHD, 16 (64%) had Eisenmenger physiology. Patients were followed for a median of 39 months (IQR, 12-76 months), for a total observation time of 276.4 person-years.

event incidence

During the observation time, 28 patients (40%) died and seven (10%) underwent LTx (Table 2). The soft end point components - hospitalizations, initiation of IV prostanoids and functional deterioration - occurred in 38 (54%), 26 (37%) and 50 (71%) patients, respectively. The longitudinal event rates of the separate components were as follows: 10.1 deaths, 2.5 times LTx, 21.4 hospitalizations, 9.4 initiations of IV prostanoids and 48.1 functional deteriorations per 100 person-years (Table 2). The corresponding cumulative event-incidence curves are depicted in Figure 1 and show that a substantial propor-tion of the patients experienced components 3 and 5 more than once. The composite CW end point occurred in 59 of 70 patients, with an event rate of 91.5 events per 100 person-years (Table 2). Defining the functional deterioration component alternatively as worsening WHO-FC only, yielded a composite event rate of 77.4. Stratification by diag-nostic groups showed a lower event rate of the composite CW end point in APAH-CHD and a higher event rate in APAH-non-CHD. Table 3 shows the event rates when only each first event of an individual is taken into account. This yielded an event rate of 55.5 CW events per 100 person-years.

The event incidence analyses were repeated in the trial-eligible subgroup, consist-ing of 49 patients who were not hospitalized, not in WHO-FC IV and/or not immediately started on IV prostanoids at baseline. The results are presented as Supplementary Mate-rial (event rates in Supplementary Tables 1 and 2, cumulative event incidence curves in Supplementary Figure 1) and show that the event incidence of the separate components and the end point combinations were slightly lower in this subgroup.

Prognostic value of soft components

The occurrences of either PAH-related hospitalization, initiation of IV prostanoids, or functional deterioration were significantly associated with death or LTx, also after adjusting for diagnosis (P<0.001 for all models) (Table 4). A merge of these three soft components into a soft composite end point, in which the first occurrence of one of the three components was regarded as the event of interest, was also significantly associ-ated with death or LTx (hazard ratio, 19.1; P<0.001). Analysis of alternative combinations of these soft end points, such as a combination without functional deterioration, yielded significant associations as well (P<0.001 for all analyzed combinations). An interaction

214 Chapter 9

tabl

e 2.

Eve

nt R

ate

of S

epar

ate

and

Com

bine

d En

d po

int-

Com

pone

nts

Stra

tified

by

Dia

gnos

is: A

ll Ev

ents

Tota

lN

=70

IPA

H/H

PAH

N=3

7A

PAH

-CH

DN

=25

APA

H-n

on-C

HD

N=8

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

n (%

)n/

100

pyn

(%)

n/10

0 py

n (%

)n/

100

pyn

(%)

n/10

0 py

(1) D

eath

28 (4

0)10

.114

(38)

9.7

9 (3

6)7.

55

(63)

42.5

(2) L

ung-

tran

spla

ntat

ion

7 (1

0)2.

54

(11)

2.8

3 (1

2)2.

50

(0)

0.0

(3) H

ospi

taliz

atio

na38

(54)

21.4

21 (5

7)22

.811

(44)

14.2

6 (7

5)76

.5

(4) I

nitia

tion

of IV

pro

stan

oids

26 (3

7)9.

418

(49)

12.4

4 (1

6)3.

34

(50)

34.0

(5) F

unct

iona

l det

erio

ratio

n

(5A

) ↑W

HO

-FCb

44 (6

3)34

.027

(73)

39.3

11 (4

4)23

.46

(75)

76.5

(5A

B) ↑

WH

O-F

Cb or ↓

6MW

Dc

50 (7

1)48

.130

(81)

54.5

14 (5

6)35

.96

(75)

93.5

End

poin

t com

bina

tions

(1)(2

)(3)(4

)51

(73)

43.4

29 (7

8)47

.615

(60)

27.6

7 (8

8)15

2.9

(1)(2

)(3)(4

)(5A

)56

(80)

77.4

33 (8

9)86

.916

(64)

51.0

7 (8

8)22

9.4

(1)(2

)(3)(4

)(5A

B) (C

W-c

ompo

site

)59

(84)

91.5

35 (9

5)10

2.1

17 (6

8)63

.57

(88)

246.

4

Dat

a ar

e pr

esen

ted

as n

(%) o

r num

ber o

f eve

nts p

er 1

00 p

erso

n-ye

ars.

IPAH

=idi

opat

hic

pulm

onar

y ar

teria

l hyp

erte

nsio

n; H

PAH

=her

edita

ry p

ulm

onar

y ar

teria

l hyp

erte

nsio

n;

APAH

-CH

D=p

ulm

onar

y ar

teria

l hyp

erte

nsio

n as

soci

ated

with

con

geni

tal h

eart

dis

ease

; APA

H-n

on-C

HD

=pul

mon

ary

arte

rial h

yper

tens

ion

asso

ciat

ed w

ith c

ondi

tions

oth

er

than

con

geni

tal h

eart

dis

ease

; IV=

intr

aven

ous;

WH

O-F

C=W

orld

Hea

lth O

rgan

izat

ion

func

tiona

l cla

ss; 6

MW

D=6

-min

ute-

wal

k-di

stan

ce; p

y=pe

rson

-yea

rs; C

W=c

linic

al w

orse

n-in

g. a N

on-e

lect

ive

PAH

rela

ted

hosp

italiz

atio

n. b W

orse

ning

of W

HO

func

tiona

l cla

ss. W

HO

func

tiona

l cla

ss IV

was

alw

ays

rega

rded

as

a fu

nctio

nal d

eter

iora

tion

even

t.c ≥15%

de

crea

se in

6-m

inut

e-w

alk-

dist

ance

.


9

No. at risk70 44 31 21 10 3

Time since treatment initiation (months)0 24 48 72 96 120

Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0A

No. at risk70 44 28 19 10 3


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0B

No. at risk70 34 22 13 7 270 41 28 19 8 370 43 30 21 8 3


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0 1st event2nd event3rd event

C

No. at risk70 38 24 17 7 1


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0D

No. at risk70 26 17 13 8 370 39 26 16 8 370 44 28 19 9 370 44 29 20 10 3


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0 1st event2nd event3rd event4th event

E

No. at risk70 23 13 9 4 270 32 17 11 6 270 39 25 17 8 270 42 28 18 8 370 44 29 20 8 3


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0 1st event2nd event3rd event4th event5th event

F

Figure 1. Cumulative event incidence of separate end point-components. A: Component 1, death. B: Com-ponent 2, lung-transplantation. C: Component 3, non-elective PAH related hospitalization. D: Component 4, initiation of IV prostanoids. E: Component 5A, functional deterioration (defined as worsening of WHO func-tional class only). F: Component 5AB, functional deterioration (defined as worsening of WHO functional class and/or ≥15% decrease in 6-minute-walk-distance). Since the end point-components 3 (panel C) and 5 (panel E/F) could occur repetitive, the occurrence of every second, third, fourth and fifth are also depicted.

216 Chapter 9

tabl

e 3.

Eve

nt R

ate

of S

epar

ate

and

Com

bine

d En

d po

int-

Com

pone

nts

Stra

tified

by

Dia

gnos

is: F

irst E

vent

s

Tota

lN

=70

IPA

H/H

PAH

N=3

7A

PAH

-CH

DN

=25

APA

H-n

on-C

HD

N=8

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

n (%

)n/

100

pyn

(%)

n/10

0 py

n (%

)n/

100

pyn

(%)

n/10

0 py

(1) D

eath

28 (4

0)10

.114

(38)

9.7

9 (3

6)7.

55

(63)

42.5

(2) L

ung-

tran

spla

ntat

ion

7 (1

0)2.

74

(11)

2.9

3 (1

2)2.

60

(0)

0.0

(3) H

ospi

taliz

atio

na38

(54)

18.6

21 (5

7)20

.011

(44)

12.2

6 (7

5)74

.0

(4) I

nitia

tion

of IV

pro

stan

oids

26 (3

7)11

.918

(49)

17.8

4 (1

6)3.

84

(50)

38.0

(5) F

unct

iona

l det

erio

ratio

n

(5A

) ↑W

HO

-FCb

44 (6

3)24

.027

(73)

29.1

11 (4

4)13

.36

(75)

77.7

(5A

B) ↑

WH

O-F

Cb or ↓

6MW

Dc

50 (7

1)33

.930

(81)

42.0

14 (5

6)20

.56

(75)

77.7

End

poin

t com

bina

tions

(1)(2

)(3)(4

)51

(73)

31.2

29 (7

8)40

.115

(60)

17.8

7 (8

8)10

0.4

(1)(2

)(3)(4

)(5A

)56

(80)

43.7

33 (8

9)66

.416

(64)

22.2

7 (8

8)10

6.3

(1)(2

)(3)(4

)(5A

B) (C

W-c

ompo

site

)59

(84)

55.5

35 (9

5)92

.817

(68)

27.4

7 (8

8)10

6.3

Dat

a ar

e pr

esen

ted

as n

(%) o

r num

ber o

f eve

nts p

er 1

00 p

erso

n-ye

ars.

IPAH

=idi

opat

hic

pulm

onar

y ar

teria

l hyp

erte

nsio

n; H

PAH

=her

edita

ry p

ulm

onar

y ar

teria

l hyp

erte

nsio

n;

APAH

-CH

D=p

ulm

onar

y ar

teria

l hyp

erte

nsio

n as

soci

ated

with

con

geni

tal h

eart

dis

ease

; APA

H-n

on-C

HD

=pul

mon

ary

arte

rial h

yper

tens

ion

asso

ciat

ed w

ith c

ondi

tions

oth

er

than

con

geni

tal h

eart

dis

ease

; IV=

intr

aven

ous;

WH

O-F

C=W

orld

Hea

lth O

rgan

izat

ion

func

tiona

l cla

ss; 6

MW

D=6

-min

ute-

wal

k-di

stan

ce; p

y=pe

rson

-yea

rs; C

W=c

linic

al w

orse

n-in

g.a N

on-e

lect

ive

PAH

rela

ted

hosp

italiz

atio

n. b W

orse

ning

of W

HO

func

tiona

l cla

ss. W

HO

func

tiona

l cla

ss IV

was

alw

ays

rega

rded

as

a fu

nctio

nal d

eter

iora

tion

even

t.c ≥15%

de

crea

se in

6-m

inut

e-w

alk-

dist

ance

.


9

tabl

e 4.

Ass

ocia

tion

of S

oft E

nd p

oint

-Com

pone

nts W

ith D

eath

or L

ung-

Tran

spla

ntat

ion

Tim

e-de

pend

ent M

odel

1U

niva

riabl

e an

alys

isTi

me-

depe

nden

t Mod

el 2

Adju

sted

for d

iagn

osis

Inte

ract

ion

Ana

lysi

sd

Com

paris

on w

ith IP

AH

/HPA

H

HR

(95%

CI)

PH

R (9

5% C

I)P

APA

H-C

HD

PA

PAH

-non

-CH

DP

Dea

th (1

) and

Lun

g-tr

ansp

lant

atio

n (2

) use

d as

com

bine

d an

alys

is e

nd p

oint

(3) H

ospi

taliz

atio

na9.

4 (4

.5-1

9.8)

<0.0

018.

9 (4

.2-1

8.8)

<0.0

010.

892

0.68

6

(4) I

nitia

tion

of IV

pro

stan

oids

6.2

(3.1

-12.

5)<0

.001

6.4

(3.1

-13.

4)<0

.001

0.83

80.

507

(5) F

unct

iona

l det

erio

ratio

n

(5A

) ↑W

HO

-FCb

14.3

(5.8

-35.

3)<0

.001

13.5

(5.5

-33.

6)<0

.001

0.30

40.

332

(5A

B) ↑

WH

O-F

Cb or ↓

6MW

Dc

14.4

(5.4

-38.

6)<0

.001

13.4

(5.0

-36.

3)<0

.001

0.66

40.

437

Soft

end

poi

nt c

ombi

natio

ns

(3)(4

)12

.3 (4

.7-3

2.1)

<0.0

0112

.1 (4

.6-3

1.8)

<0.0

010.

720

0.93

6

(3)(4

)(5A

)14

.1 (4

.3-4

6.8)

<0.0

0113

.8 (4

.2-4

6.0)

<0.0

010.

626

0.94

5

(3)(4

)(5A

B)19

.1 (4

.5-8

1.2)

<0.0

0118

.6 (4

.4-7

9.1)

<0.0

010.

950

0.94

6

Dat

a ar

e pr

esen

ted

as h

azar

d ra

tio (9

5% co

nfide

nce

inte

rval

) or P

-val

ues.

IPAH

=idi

opat

hic p

ulm

onar

y ar

teria

l hyp

erte

nsio

n; H

PAH

=her

edita

ry p

ulm

onar

y ar

teria

l hyp

erte

nsio

n;

APAH

-CH

D=p

ulm

onar

y ar

teria

l hyp

erte

nsio

n as

soci

ated

with

con

geni

tal h

eart

dis

ease

; APA

H-n

on-C

HD

=pul

mon

ary

arte

rial h

yper

tens

ion

asso

ciat

ed w

ith c

ondi

tions

oth

er

than

con

geni

tal h

eart

dis

ease

; WH

O-F

C=W

orld

Hea

lth O

rgan

izat

ion

func

tiona

l cla

ss; 6

MW

D=6

-min

ute-

wal

k-di

stan

ce; I

V=Iin

trav

enou

s; py

=per

son-

year

s. a N

on-e

lect

ive

PAH

re

late

d ho

spita

lizat

ions

.b Wor

seni

ng o

f WH

O fu

nctio

nal c

lass

. WH

O fu

nctio

nal c

lass

IV w

as a

lway

s re

gard

ed a

s a

func

tiona

l det

erio

ratio

n ev

ent.c ≥1

5% d

ecre

ase

in 6

-min

ute-

wal

k-di

stan

ce.d P-

valu

es <

0.05

indi

cate

sign

ifica

nt d

iffer

ence

s in

the

asso

ciat

ions

acr

oss t

he d

iagn

ostic

gro

ups.

218 Chapter 9

analysis revealed that the effect size of the found associations did not significantly differ between the diagnostic groups. Similar associations with death or LTx were found in the trial-eligible subgroup (Supplementary Table 3).

Cw compared to death/ltx

Figure 2 shows event-free survival curves for six end point-combinations. The composite CW end point occurred early and in a higher proportion of patients, compared to the other end point combinations. The event-free survival curves were similar in the trial-eligible subgroup (Supplementary Figure 2).

No. at risk70 44 31 21 10 370 44 28 19 10 370 34 21 13 7 270 30 17 11 5 070 20 11 9 5 070 18 9 6 2 0


Cum

ulat

ive

surv

ival

0.0

0.2

0.4

0.6

0.8

1.0 component 1component 1 + 2component 1 + 2 + 3component 1 + 2 + 3 + 4component 1 + 2 + 3 + 4 + 5A component 1 + 2 + 3 + 4 + 5AB (CW-endpoint)

Freedom from:

Figure 2. Event-free survival of 6 end point combinations. Only the first occurrence of end point-compo-nents are incorporated as events. Component 1 = death; Component 2 = lung-transplantation; Component 3 = non-elective PAH-related hospitalization; Component 4 = initiation of IV prostanoids; Component 5A = functional deterioration (defined as worsening of WHO functional class only); Component 5AB = functional deterioration (defined as worsening of WHO functional class and/or ≥15% decrease in 6-minute-walk-dis-tance); CW-end point = Full composite clinical worsening end point consisting of death, lung-transplan-tation, non-elective PAH related hospitalization, initiation of IV prostanoids and functional deterioration.


9

dIsCussIon

In this study, a proposed definition of CW was evaluated as a potential end point in pediatric PAH, which consisted of the following end point components: death, LTx, nonelective PAH-related hospitalization, initiation of IV prostanoids, and functional deterioration. The results show that CW occurs with a high event incidence and that all soft end point components are highly predictive of death or LTx. The first CW events occurred early in the disease course, supporting the usefulness of CW as a study end point and also as an early clinical warning sign.

A study end point should be a clinically meaningful outcome, defined as a direct or surrogate measure of how a patient feels, functions or survives.9 To date, no validated surrogates for survival are available in PAH and multiple well-established predictors of survival in adults have recently been shown to fail to comply with criteria for sur-rogacy.13,16,46–48 CW consists of components that are all clinically meaningful outcomes in themselves. LTx, hospitalization, initiation of IV prostanoids, and functional deteriora-tion are all undesirable events associated with major impairment in daily life (i.e., how a patient “functions”), thereby making CW a valid and useful composite end point.

An important criticism of CW is that the definitions used in clinical trials have not been completely consistent.18,49 Death and LTx have been included in most definitions. The same holds true for hospitalizations, although definitions may vary. For example, in the recent REVEAL Registry substudy40 in which CW was evaluated in adults, all-cause hospitalizations were included, whereas, in many trials, nonelective PAH-related hospi-talizations have been used. It might be debated whether the REVEAL Registry definition is best for future trial designs, as hospitalizations due to comorbidities or social reasons should not be regarded as CW events.49 The need for additional PAH therapy has been a common CW component throughout the trials, but has not always exclusively been defined as initiation of IV prostanoids. In this respect, it is important to realize that dose increments and addition of oral drugs might be part of currently changing, more aggressive, and goal-oriented treatment strategies, and are not necessarily induced by actual worsening of the disease. Moreover, in contrast to the initiation of continuous IV therapy, the addition of an oral therapy not necessarily affects a patient’s ability to function in daily life. Therefore, inclusion of these events may distort the validity of CW as a clinically meaningful end point. Various definitions of functional deterioration have been used, including decrease in 6MWD only, worsening of WHO-FC only, either worsen-ing of WHO-FC or decrease in 6MWD, and decrease in 6MWD with concurrent worsening of WHO-FC. The latter definition was proposed by the (adult) task forces on end points and clinical trial design that met at the fourth and fifth World Symposium on Pulmonary Hypertension.42,43 However, as 6MWD is not feasible in the youngest children,7 the “ei-ther/or” definition seems most preferable in pediatric PAH. Last, symptomatic progres-

220 Chapter 9

sion has been proposed and occasionally used as a separate CW component,43 but we argue that this is likely to be captured in WHO-FC.

Recently, time to clinical failure has been introduced as primary end point in a clinical trial evaluating combination therapy in adult PAH.50 An important difference with the CW end point is the inclusion of the component “unsatisfactory clinical response”. As evidence from adults and children suggest that there are prognostic implications as-sociated with failure to achieve predefined treatment goals, this might be an interesting concept for future end point definitions.17,51,52

CW as defined and evaluated in this study seems to provide a feasible and valid alternative end point for future pediatric studies. Notwithstanding, the authors feel the following remarks should be taken into account with regard to the design of future stud-ies. To allow comparison of pediatric studies using CW as an end point, definitions of CW should be consistent in different studies. The currently evaluated definition appears suitable. A prerequisite for a consistent implementation is a broad consensus within the pediatric field regarding the exact definition of CW.18,42 Each of the components might need to be defined as objectively and unequivocally as possible.19 Accuracy and consistency of reporting CW events are of utmost importance. Therefore, to guarantee the integrity of studies using CW as an end point, the use of blinded independent ad-judication committees is recommended.19,43,49 For example, it should be ensured that hospitalizations and functional deteriorations are indeed caused by worsening PAH and not by comorbidities or other causes.

Patients with unstable disease can usually not be included in clinical trials, which might lead to discrepancies in included patients and event rates between registries and trials. This is illustrated by a comparison of the REVEAL Registry and the event-driven Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial that used CW as a primary end point.37,40 In REVEAL, 64% of the patients experienced an event within 2 years, whereas in the SERAPHIN trial, only 39% had an event over a median period of 115 weeks. However, the results from the current study show only minor differences between the full cohort and the trial-eligible subgroup: 84% of the full cohort experienced CW (Table 2), compared to 78% of the trial-eligible subgroup (Supplementary Table 1). This confirms that PAH can progress more quickly in children compared with adults,8 and suggests that the use of CW allows for pediatric study designs with an achievable number of children.

study limitations

Evaluation of alternative end points is important though hampered by the extremely limited data on pediatric PAH. The Dutch National Network for Pediatric Pulmonary Hypertension is a national prospective registry with complete follow-up that encom-passes all diagnosed children with PAH in the Netherlands.53 Despite the relatively small


9

number of patients in our study, limiting our analyses, we found strong associations between the soft end point components and death or LTx. The highly standardized and complete longitudinal follow-up allowed for time-dependent Cox regression, which is an appropriate method for evaluating the prognostic value of time-varying variables such as the CW end point components.54 Inherent to the analytical approach, censoring of deceased patients was taken into account rather than the competing risk of death. Although all subsequent CW events were captured in the cumulative event-incidence curves and longitudinal event rates, only the soft CW-events that occurred first could be analyzed in time-dependent Cox regression analysis. The sample size and analytic approach did not allow for an identification of which CW component carried the most prognostic value.

ConClusIon

CW occurs early and frequently in the follow-up of children with PAH. Each of the soft end point components was highly predictive of death or LTx, as was the CW composite. This strongly supports the usefulness of CW as a patient-centered, composite study end point and allows for pediatric study designs with an achievable number of required children. Regarding its prognostic value, CW could also serve as an early clinical warning sign.

222 Chapter 9

reFerenCes




4. Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BKS, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125:324–34.

5. Barst RJ, Beghetti M, Pulido T, Layton G, Konourina I, Zhang M, Ivy DD, STARTS-2 Investigators. STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment- Naive Pediatric Pulmonary Arterial Hypertension. Circulation. 2014;129:1914–1923.

6. Berger RMF. Pulmonary hypertension: smaller kids, smaller steps. Lancet Respir Med. 2014;2:348–50.


8. Haworth SG, Beghetti M. Assessment of endpoints in the pediatric population: congenital heart disease and idiopathic pulmonary arterial hypertension. Curr Opin Pulm Med. 2010;16 Suppl 1:S35–41.


10. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605–613.


12. Gaine S, Simonneau G. The need to move from 6-minute walk distance to outcome trials in pulmonary arterial hypertension. Eur Respir Rev. 2013;22:487–94.

13. Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM, Halpern SD. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circu-lation. 2012;126:349–356.


15. Douwes JM, Hegeman AK, van der Krieke-van der Horst M, Roofthooft MTR, Hillege HL, Berger RMF. Six-minute walk-test in childhood pulmonary arterial hypertension: Walking distance and decrease in oxygen saturation provide additional prognostic information. Eur Heart J. 2014;35:174–175.


9

16. Savarese G, Paolillo S, Costanzo P, D’Amore C, Cecere M, Losco T, Musella F, Gargiulo P, Marciano C, Perrone-Filardi P. Do Changes of 6-Minute Walk Distance Predict Clinical Events in Patients With Pulmonary Arterial Hypertension? A Meta-Analysis of 22 Randomized Trials. J Am Coll Cardiol. 2012;60:1192–1201.


18. Peacock A, Keogh A, Humbert M. Endpoints in pulmonary arterial hypertension: the role of clini-cal worsening. Curr Opin Pulm Med. 2010;16 Suppl 1:S1–9.

19. Galiè N, Simonneau G, Barst RJ, Badesch D, Rubin L. Clinical worsening in trials of pulmonary arterial hypertension: results and implications. Curr Opin Pulm Med. 2010;16 Suppl 1:S11–9.

20. Hoeper MM, Oudiz RJ, Peacock A, Tapson VF, Haworth SG, Frost AE, Torbicki A. End points and clinical trial designs in pulmonary arterial hypertension: clinical and regulatory perspectives. J Am Coll Cardiol. 2004;43:48S–55S.

21. Kawut SM, Palevsky HI. Surrogate end points for pulmonary arterial hypertension. Am Heart J. 2004;148:559–565.

22. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903.

23. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR, Group S-1 S. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441–447.

24. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G, Sildenafil Use in Pulmonary Arterial Hyperten-sion (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–57.

25. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, Naeije R, Galie N; STRIDE-2 Study Group. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006;47:2049–2056.

26. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–1263.

27. Galiè N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi E, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093–100.

28. Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE, Engel PJ, Kramer MR, Burgess G, Collings L, Cossons N, Sitbon O, Badesch DB; PACES Study Group. Addition of Sildenafil to Long-Term Intravenous Epoprostenol Therapy in Patients with Pulmonary Arterial Hypertension A Randomized Trial. Ann Intern Med. 2008;149:521–W102.

29. Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil Therapy for Pulmonary Arterial Hypertension. Circulation. 2009;119:2894–U65.

30. Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaugh-lin V V, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ. Ambrisentan for the treatment of pulmonary arterial hypertension - Results of the Ambrisentan in Pulmonary Arterial Hyperten-

224 Chapter 9

sion, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES) Study 1 and 2. Circulation. 2008;117:3010–3019.

31. Benza RL, Seeger W, McLaughlin V V, Channick RN, Voswinckel R, Tapson VF, Robbins IM, Olschewski H, Rubin LJ. Long-term effects of inhaled treprostinil in patients with pulmonary arterial hy-pertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension. J Heart Lung Transplant. 2011;30:1327–33.

32. Sandoval J, Torbicki A, Souza R, Ramírez A, Kurzyna M, Jardim C, Jerjes-Sánchez Díaz C, Teal SA, Hwang L-J, Pulido T, STRIDE-4 investigators. Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension. Pulm Pharmacol Ther. 2012;25:33–9.

33. Oudiz RJ, Brundage BH, Galie N, Ghofrani HA, Simonneau G, Botros FT, Chan M, Beardsworth A, Barst RJ; PHIRST Study Group. Tadalafil for the Treatment of Pulmonary Arterial Hypertension A Double-Blind 52-Week Uncontrolled Extension Study. J Am Coll Cardiol. 2012;60:768–774.

34. Tapson VE, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, Badesch DB, Frost AE, Shapiro SM, Laliberte K, Sigman J, Arneson C, Galie N. Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodies-terase Type 5 Inhibitor Therapy (The FREEDOM-C Study) A Randomized Controlled Trial. Chest. 2012;142:1383–1390.

35. Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, Angel Gomez-Sanchez M, Grim-minger F, Gruenig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA. Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension Results of the Randomized IMPRES Study. Circulation. 2013;127:1128–38.

36. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing Z-C, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ, PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–40.

37. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani H-A, Jansa P, Jing Z-C, Le Brun F-O, Mehta S, Mittelholzer CM, Perchenet L, Sastry BKS, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G, Investigators S. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013;369:809–818.

38. Tapson VF, Jing Z-C, Xu K-F, Pan L, Feldman J, Kiely DG, Kotlyar E, McSwain CS, Laliberte K, Arneson C, Rubin LJ, Team F-CS. Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients Receiving Background Endothelin Receptor Antagonist and Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C2 Study) A Randomized Controlled Trial. Chest. 2013;144:952–958.

39. Jing Z-C, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, Torbicki A, Xu K-F, Yehle D, Laliberte K, Arneson C, Rubin LJ. Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension A Randomized, Controlled Trial. Circulation. 2013;127:624–633.

40. Frost AE, Badesch DB, Miller DP, Benza RL, Meltzer LA, McGoon MD. Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL Registry analysis. Chest. 2013;144:1521–1529.


42. McLaughlin VV, Badesch DB, Delcroix M, Fleming TR, Gaine SP, Galiè N, Gibbs JSR, Kim NH, Oudiz RJ, Peacock A, Provencher S, Sitbon O, Tapson VF, Seeger W. End points and clinical trial design in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S97–107.


9

43. Gomberg-Maitland M, Bull TM, Saggar R, Barst RJ, Elgazayerly A, Fleming TR, Grimminger F, Rainisio M, Stewart DJ, Stockbridge N, Ventura C, Ghofrani AH, Rubin LJ. New trial designs and potential therapies for pulmonary artery hypertension. J Am Coll Cardiol. 2013;62:D82–91.

44. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216–23.

45. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier J-F, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simon-neau G. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–30.

46. Savarese G, Musella F, D’Amore C, Losco T, Marciano C, Gargiulo P, Rengo G, Dellegrottaglie S, Bossone E, Leosco D, Perrone-Filardi P. Haemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension. Eur Respir J. 2013;42:414–24.


48. Freedman LS, Graubard BI, Schatzkin A. Statistical validation of intermediate endpoints for chronic diseases. Stat Med. 1992;11:167–78.

49. McGlinchey N, Peacock AJ. Endpoints in PAH clinical trials in the era of combination therapy: How do we decide whether something is working without going bankrupt? Drug Discov Today. 2014;19:1236–1240.

50. Galie N. The AMBITION study: design and results [abstract]. In: European Respiratory Society. Amsterdam, The Netherlands: European Respiratory Society; 2014.




54. Beyersmann J, Schumacher M. Time-dependent covariates in the proportional subdistribution hazards model for competing risks. Biostatistics. 2008;9:765–76.

226 Chapter 9

No. at risk49 39 26 18 8 1


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0A

No. at risk49 39 24 17 8 1


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0B

No. at risk49 29 17 11 5 049 36 23 16 6 149 38 25 18 6 1


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0 1st event2nd event3rd event

C

No. at risk49 36 23 17 7 1


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0D

No. at risk49 24 15 11 6 149 34 22 13 6 149 39 24 16 7 149 39 24 17 8 1


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0 1st event2nd event3rd event4th event

E

No. at risk49 21 11 7 3 149 28 15 9 4 149 35 22 15 6 149 38 24 16 6 149 39 24 17 6 1


Cum

ulat

ive

even

t inc

iden

ce

0.0

0.2

0.4

0.6

0.8

1.0 1st event2nd event3rd event4th event5th event

F

supplementary Figure 1. Cumulative event incidence of separate end point components in trial-eligible subgroup (n=49). A: Component 1, death. B: Component 2, lung-transplantation. C: Component 3, non-elective PAH related hospitalization. D: Component 4, initiation of intravenous prostanoids. E: Component 5A, functional deterioration (defined as worsening of WHO functional class only). F: Component 5AB, func-tional deterioration (defined as worsening of WHO functional class and/or ≥15% decrease in 6-minute-walk-distance). Since the endpoint-components 3 (panel C) and 5 (panel E/F) could occur repetitive, the occurrence of every second, third, fourth and fifth are also depicted.


9

No. at risk49 39 26 18 8 149 39 24 17 8 149 29 17 11 5 049 28 17 11 5 049 20 11 9 5 049 18 9 6 2 0


Cum

ulat

ive

surv

ival

0.0

0.2

0.4

0.6

0.8

1.0

component 1component 1 + 2component 1 + 2 + 3component 1 + 2 + 3 + 4component 1 + 2 + 3 + 4 + 5A component 1 + 2 + 3 + 4 + 5AB (CW-endpoint)

Freedom from:

supplementary Figure 2. Event-free survival of 6 endpoint combinations in trial-eligible subgroup (n=49). Only the first occurrence of endpoint-components are incorporated as events. Component 1 = death; Com-ponent 2 = lung-transplantation; Component 3 = non-elective PAH-related hospitalization; Component 4 = initiation of intravenous prostanoids; Component 5A = functional deterioration (defined as worsen-ing of WHO functional class deterioration only); Component 5AB = functional deterioration (defined as worsening of WHO functional class and/or ≥15% decrease in 6-minute-walk-distance); CW-endpoint = Full composite clinical worsening endpoint consisting of death, lung-transplantation, non-elective PAH related hospitalization, initiation of intravenous prostanoids and functional deterioration.

228 Chapter 9

supp

lem

enta

ry t

able

1.

Even

t Rat

e of

Sep

arat

e an

d Co

mbi

ned

End

Poin

t Com

pone

nts

Stra

tified

by

Dia

gnos

is: A

ll Ev

ents

in T

rial-E

ligib

le S

ubgr

oup

Tota

lN

=49

IPA

H/H

PAH

N=2

6A

PAH

-CH

DN

=19

APA

H-n

on-C

HD

N=4

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

n (%

)n/

100

pyn

(%)

n/10

0 py

n (%

)n/

100

pyn

(%)

n/10

0 py

(1) D

eath

12 (2

5)5.

27

(27)

6.2

4 (2

1)3.

81

(25)

9.5

(2) L

ung-

tran

spla

ntat

ion

5 (1

0)2.

23

(12)

2.7

2 (1

1)1.

90

(0)

0.0

(3) H

ospi

taliz

atio

na24

(49)

18.8

14 (5

4)21

.37

(37)

12.2

3 (7

5)57

.0

(4) I

nitia

tion

of IV

pro

stan

oids

10 (2

0)4.

49

(35)

8.0

1 (5

)0.

90

(0)

0.0

(5) F

unct

iona

l det

erio

ratio

n

(5A

) ↑W

HO

-FCb

27 (5

5)30

.519

(73)

39.1

5 (2

6)18

.83

(75)

57.0

(5A

B) ↑

WH

O-F

Cb or ↓

6MW

Dc

32 (6

5)43

.221

(81)

53.3

8 (4

2)30

.13

(75)

66.5

End

poin

t com

bina

tions

(1)(2

)(3)(4

)30

(61)

30.5

18 (6

9)38

.29

(47)

18.8

3 (7

5)66

.5

(1)(2

)(3)(4

)(5A

)35

(71)

61.0

22 (8

5)77

.310

(53)

37.6

3 (7

5)12

3.5

(1)(2

)(3)(4

)(5A

B) (C

W-c

ompo

site

)38

(78)

73.7

24 (9

2)91

.511

(58)

48.9

3 (7

5)13

3.0

Dat

a ar

e pr

esen

ted

as n

(%) o

r num

ber o

f eve

nts p

er 1

00 p

erso

n-ye

ars.

The

resu

lts a

re fr

om a

n an

alys

is w

ithin

the

tria

l-elig

ible

subg

roup

(n=4

9), t

hat c

onsi

sts o

f pat

ient

s who

w

ere

not h

ospi

taliz

ed, n

ot in

WH

O fu

nctio

nal c

lass

IV a

nd/o

r not

imm

edia

tely

sta

rted

on

intr

aven

ous

pros

tano

ids

at b

asel

ine.

IPAH

=idi

opat

hic

pulm

onar

y ar

teria

l hyp

erte

n-si

on; H

PAH

=her

edita

ry p

ulm

onar

y ar

teria

l hyp

erte

nsio

n; A

PAH

-CH

D=p

ulm

onar

y ar

teria

l hyp

erte

nsio

n as

soci

ated

with

con

geni

tal h

eart

dis

ease

; APA

H-n

on-C

HD

=pul

mon

ary

arte

rial h

yper

tens

ion

asso

ciat

ed w

ith co

nditi

ons o

ther

than

cong

enita

l hea

rt d

isea

se; I

V=in

trav

enou

s; W

HO

-FC=

Wor

ld H

ealth

Org

aniz

atio

n fu

nctio

nal c

lass

; 6M

WD

=6-m

inut

e-w

alk-

dist

ance

; py=

pers

on-y

ears

; CW

=clin

ical

wor

seni

ng. a N

on-e

lect

ive

PAH

rela

ted

hosp

italiz

atio

n. b W

orse

ning

of W

HO

func

tiona

l cla

ss. W

HO

func

tiona

l cla

ss IV

was

alw

ays

rega

rded

as a

func

tiona

l det

erio

ratio

n ev

ent.c ≥1

5% d

ecre

ase

in 6

-min

ute-

wal

k-di

stan

ce.


9

supp

lem

enta

ry t

able

2.

Even

t Rat

e of

Sep

arat

e an

d Co

mbi

ned

End

poin

t-Co

mpo

nent

s St

ratifi

ed b

y D

iagn

osis

: Firs

t Eve

nts

in T

rial-E

ligib

le S

ubgr

oup

Tota

lN

=49

IPA

H/H

PAH

N=2

6A

PAH

-CH

DN

=19

APA

H-n

on-C

HD

N=4

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

Patie

nts

Even

t rat

ePa

tient

sEv

ent r

ate

n (%

)n/

100

pyn

(%)

n/10

0 py

n (%

)n/

100

pyn

(%)

n/10

0 py

(1) D

eath

12 (2

5)5.

27

(27)

6.2

4 (2

1)3.

81

(25)

9.5

(2) L

ung-

tran

spla

ntat

ion

5 (1

0)2.

33

(12)

2.8

2 (1

1)1.

90

(0)

0.0

(3) H

ospi

taliz

atio

na24

(49)

14.9

14 (5

4)18

.97

(37)

8.8

3 (7

5)43

.0

(4) I

nitia

tion

of IV

pro

stan

oids

10 (2

0)4.

89

(35)

9.5

1 (5

)1.

00

(0)

0.0

(5) F

unct

iona

l det

erio

ratio

n

(5A

) ↑W

HO

-FCb

27 (5

5)17

.319

(73)

28.2

5 (2

6)6.

23

(75)

38.9

(5A

B) ↑

WH

O-F

Cb or ↓

6MW

Dc

32 (6

5)25

.121

(81)

39.9

8 (4

2)11

.93

(75)

38.9

End

poin

t com

bina

tions

(1)(2

)(3)(4

)30

(61)

19.2

18 (6

9)25

.89

(47)

11.3

3 (7

5)43

.0

(1)(2

)(3)(4

)(5A

)35

(71)

27.3

22 (8

5)44

.310

(53)

13.9

3 (7

5)45

.5

(1)(2

)(3)(4

)(5A

B) (C

W-c

ompo

site

)38

(78)

35.7

24 (9

2)63

.611

(58)

17.7

3 (7

5)45

.5

Dat

a ar

e pr

esen

ted

as n

(%) o

r num

ber o

f eve

nts p

er 1

00 p

erso

n-ye

ars.

The

resu

lts a

re fr

om a

n an

alys

is w

ithin

the

tria

l-elig

ible

subg

roup

(n=4

9), t

hat c

onsi

sts o

f pat

ient

s who

w

ere

not h

ospi

taliz

ed, n

ot in

WH

O fu

nctio

nal c

lass

IV a

nd/o

r not

imm

edia

tely

sta

rted

on

intr

aven

ous

pros

tano

ids

at b

asel

ine.

IPAH

=idi

opat

hic

pulm

onar

y ar

teria

l hyp

erte

n-si

on; H

PAH

=her

edita

ry p

ulm

onar

y ar

teria

l hyp

erte

nsio

n; A

PAH

-CH

D=p

ulm

onar

y ar

teria

l hyp

erte

nsio

n as

soci

ated

with

con

geni

tal h

eart

dis

ease

; APA

H-n

on-C

HD

=pul

mon

ary

arte

rial h

yper

tens

ion

asso

ciat

ed w

ith co

nditi

ons o

ther

than

cong

enita

l hea

rt d

isea

se; I

V=in

trav

enou

s; W

HO

-FC=

Wor

ld H

ealth

Org

aniz

atio

n fu

nctio

nal c

lass

; 6M

WD

=6-m

inut

e-w

alk-

dist

ance

; py=

pers

on-y

ears

; CW

=clin

ical

wor

seni

ng.a N

on-e

lect

ive

PAH

rela

ted

hosp

italiz

atio

n. b W

orse

ning

of W

HO

func

tiona

l cla

ss. W

HO

func

tiona

l cla

ss IV

was

alw

ays

rega

rded

as a

func

tiona

l det

erio

ratio

n ev

ent.c ≥1

5% d

ecre

ase

in 6

-min

ute-

wal

k-di

stan

ce.

230 Chapter 9

supp

lem

enta

ry t

able

3.

Ass

ocia

tion

of S

oft E

nd p

oint

-Com

pone

nts W

ith D

eath

or L

ung-

Tran

spla

ntat

ion:

Tria

l-Elig

ible

Sub

grou

p A

naly

sis

Tim

e-de

pend

ent M

odel

1U

niva

riabl

e an

alys

isTi

me-

depe

nden

t Mod

el 2

Adju

sted

for d

iagn

osis

Inte

ract

ion

Ana

lysi

sd

Com

paris

on w

ith IP

AH

/HPA

H

HR

(95%

CI)

PH

R (9

5% C

I)P

APA

H-C

HD

PA

PAH

-non

-CH

DP

Dea

th (1

) and

Lun

g-tr

ansp

lant

atio

n (2

) use

d as

com

bine

d an

alys

is e

nd p

oint

(3) H

ospi

taliz

atio

na6.

3 (2

.0-1

9.3)

0.00

16.

0 (2

.0-1

8.8)

0.00

20.

910

0.96

6

(4) I

nitia

tion

of IV

pro

stan

oids

8.2

(2.8

-24.

0)<0

.001

8.6

(2.6

-28.

2)<0

.001

0.97

4(n

ot a

vaila

ble)

e

(5) F

unct

iona

l det

erio

ratio

n

(5A

) ↑W

HO

-FCb

7.9

(2.3

-27.

3)0.

001

7.4

(2.1

-25.

8)0.

002

0.13

40.

973

(5A

B) ↑

WH

O-F

Cb or ↓

6MW

Dc

7.7

(1.8

-32.

9)0.

006

7.0

(1.6

-30.

4)0.

009

0.40

50.

968

Soft

end

poi

nt c

ombi

natio

ns

(3)(4

)10

.8 (2

.9-3

9.4)

<0.0

0110

.3 (2

.8-3

8.1)

<0.0

010.

367

0.97

1

(3)(4

)(5A

)6.

4 (1

.7-2

3.8)

0.00

66.

0 (1

.6-2

2.7)

0.00

80.

499

0.96

5

(3)(4

)(5A

B)7.

7 (1

.6-3

7.8)

0.01

27.

2 (1

.5-3

5.8)

0.01

60.

965

0.96

2

Dat

a ar

e pr

esen

ted

as h

azar

d ra

tio (9

5% co

nfide

nce

inte

rval

) or P

-val

ues.

The

resu

lts a

re fr

om a

n an

alys

is w

ithin

the

tria

l-elig

ible

subg

roup

(n=4

9), t

hat c

onsi

sts o

f pat

ient

s who

w

ere

not h

ospi

taliz

ed, n

ot in

WH

O fu

nctio

nal c

lass

IV a

nd/o

r not

imm

edia

tely

sta

rted

on

intr

aven

ous

pros

tano

ids

at b

asel

ine.

IPAH

=idi

opat

hic

pulm

onar

y ar

teria

l hyp

erte

n-si

on; H

PAH

=her

edita

ry p

ulm

onar

y ar

teria

l hyp

erte

nsio

n; A

PAH

-CH

D=p

ulm

onar

y ar

teria

l hyp

erte

nsio

n as

soci

ated

with

con

geni

tal h

eart

dis

ease

; APA

H-n

on-C

HD

=pul

mon

ary

arte

rial h

yper

tens

ion

asso

ciat

ed w

ith c

ondi

tions

oth

er th

an c

onge

nita

l hea

rt d

isea

se; W

HO

-FC=

Wor

ld H

ealth

Org

aniz

atio

n fu

nctio

nal c

lass

; 6M

WD

=6-m

inut

e-w

alk-

dist

ance

; IV

=int

rave

nous

; py=

pers

on-y

ears

. a Non

-ele

ctiv

e PA

H re

late

d ho

spita

lizat

ions

.b Wor

seni

ng o

f WH

O fu

nctio

nal c

lass

. WH

O fu

nctio

nal c

lass

IV w

as a

lway

s reg

arde

d as

a fu

nctio

nal

dete

riora

tion

even

t.c ≥15%

dec

reas

e in

6-m

inut

e-w

alk-

dist

ance

.d P-va

lues

<0.

05 in

dica

te si

gnifi

cant

diff

eren

ces i

n th

e as

soci

atio

ns a

cros

s the

dia

gnos

tic g

roup

s. e Ev

ent 4

did

not

oc

cur i

n AP

AH-n

on-C

HD

gro

up.

1

2

3

4

5

6

7

8

9

10

Chapter 10General discussion and future prospects

General discussion and future prospects 235

10

generAl dIsCussIon

During the past decades, more clinical data on pulmonary arterial hypertension (PAH) have emerged than ever before. Important breakthroughs in adults have furthered the understanding of the pathophysiology, improved diagnosis and led to the availability of targeted treatments for this devastating disease. However, children with PAH have less benefited from these breakthroughs compared to adults, evidenced by unsatisfactory high mortality rates. The field of pediatric PAH suffers from a lack of clinical data on how to tailor and monitor the treatment in the individual child, how to evaluate treatment success during follow-up and how to guide subsequent treatment decisions. The avail-able drugs are barely tested in children as pediatric clinical trial design is hampered by the lack of appropriate clinical endpoints.

In order to improve risk stratification, treatment strategies and clinical trial design for children with PAH, the aims of this thesis were to identify (1) prognostic factors, (2) treatment goals and (3) clinical endpoints in pediatric PAH. In this chapter, the clinical implications of the results of this thesis are discussed, together with directions for future research.

PrognostIC FACtors

Prognostic factors are clinical or biological characteristics that are objectively measur-able and that provide information on the outcome of the disease, e.g. in terms of disease severity and mortality.1 Prognostic factors are essential for risk stratification and to enable adequate treatment tailoring. First, we systematically reviewed the literature. Chapter 3 identified clinical measurements that were reported to be consistently and significantly associated with mortality in children with PAH: WHO functional class (WHO-FC), serum levels of (N-terminal pro-)B-type natriuretic peptide ([NT-pro]BNP), and four hemody-namic variables obtained by cardiac catheterization. This recapitulation of available data in pediatric PAH did not preclude the potential of the many other variables that have incidentally been shown to correlate with mortality, but rather provided directions for further research to address gaps in evidence. Subsequently, the studies presented in Chapters 4 to 6 have added to the available data that additional clinical measurements, namely echocardiographic variables, a child’s growth, and serum levels of uric acid are also associated with disease severity and/or mortality in pediatric PAH.

As these prognostic factors allow for risk stratification, it is reasonable to utilize them for tailoring the initial treatment in an individual child with PAH. A treatment algorithm has been proposed by the Pediatric Task Force of the 5th World Symposium on Pulmonary Hypertension (WSPH) in Nice in 2013, in which more aggressive treat-

236 Chapter 10

ment regimens are recommended for children at higher risk as assessed according to a suggested list of clinical measurements.2 Monotherapy with oral endothelin receptor antagonists, oral posphodiesterase-5-inhibitors or inhaled prostanoids is recommended for lower risk children and combination therapy or parental prostanoids are recom-mended for higher risk children (see Chapter 2 for more extensive discussion). Given the lack of data on prognostic factors at the time when these clinical measurements were first proposed in 2013, the pediatric task force had to rely on small cohort studies and expert consensus. Which new insights do the findings of this thesis provide with respect to this important topic of risk stratification?


Clinical characteristics that have been suggested for risk stratification at the 5th WSPH include clinical evidence of right ventricular (RV) failure, progression of symptoms, syncope, growth and WHO functional class. The findings of Chapter 3 demonstrate that there is a paucity of data regarding associations with mortality for the first three of these. However, either RV failure, symptoms and syncope are of direct clinical value regarding disease severity, which justifies their use for risk stratification. WHO-FC is a direct disease severity measure also, and the meta-analysis results have shown its association with mortality to be strong and consistent.The prognostic value of 6-minute walk distance (6MWD) in pediatric PAH has been questioned in the past, as infants cannot walk and young children might be easily distracted during the test. However, recent data demon-strate that 6MWD does carry prognostic value in children of 7 years and older,3 and is therefore of importance for risk stratification and tailoring treatment.

Growth has rightly been proposed for risk stratification, if only in view of the fact that failure to thrive is an alarming sign associated with serious pediatric illness. However, the clinical interpretation of growth measurements is almost impossible without an evidence-based perspective. This especially holds true for pediatric PAH, as concomitant conditions that concurrently affect growth are very common. Assess-ment of the degree of growth impairment, longitudinal descriptions over time, and the identification of subgroups at risk and associated determinants are all prerequisites for enabling clinicians to make use of growth in the management of children with PAH. The findings of Chapter 5 do not only confirm previous suggestions that growth is a prognos-tic factor, but also allow for its actual use in clinical practice. Children with Trisomy-21, ex-prematurity and growth-affecting concomitant diseases including congenital heart disease (CHD) are more likely to have growth deficits, but significant growth impairment was also observed in children with idiopathic PAH without any comorbidities. Clinicians observing growth impairment can now use this new information to place growth of an individual child with PAH in context, and assess risk accordingly.


10

Biological serum markers

Ventricular (and also atrial) wall stress due to volume or pressure overload results in synthesis of the precursor proBNP that is cleaved in the biologically active BNP and the inactive amino-terminal fragment NTproBNP.4 Serum levels of both BNP and NT-proBNP are closely linked to RV function, which is the main determinant of the clinical course in PAH. Monitoring serum levels of (NT-pro)BNP provides valuable information on the degree to which the RV is capable of coping with the increased afterload due to PAH. Important to consider when interpreting single absolute values of (NT-pro)BNP is the fact that normal serum levels vary by age. In newborns, serum levels are extremely high, with a dramatic decrease in infancy, a mild gradual further decline during childhood and a gradual increase during adulthood.5 Furthermore, although less relevant in the pediatric setting, levels may increase with renal dysfunction and decrease with obesity.6 (NT-pro)BNP fluctuations have been demonstrated to accurately track hemodynamic and echocardiographic changes over time in PAH.7 In Chapter 8 we demonstrate that such fluctuations also carry prognostic value regarding outcome, strongly underlining the usefulness of (NT-pro)BNP as a prognostic biomarker in pediatric PAH.

Uric acid qualifies for risk stratification as well. As a degradation product of purine metabolism, uric acid is increased in oxidative stress conditions such as vascular and car-diac dysfunction. Hyperuricemia is frequently observed in PAH, and has previously been shown to be associated with disease severity and outcome in cross-sectional studies in both children and adults.8–12 The extensive longitudinal evaluation of uric acid in pediat-ric PAH described in Chapter 6, demonstrates that these associations remain consistent during the course of the disease and that a gradual incline in uric acid is an ominous sign associated with poor outcome. In view of their suggested role in vascular remodeling and inflammation, which are important parts of the PAH disease process, purine me-tabolism and its degradation products have been recognized as interesting candidate biomarkers in PAH for a long time.13 However, as purine metabolism is involved in many other mechanisms also, hyperuricemia can occur in many circumstances unrelated to PAH.14,15 For example, uric acid levels increase in cases of gout, renal dysfunction, treat-ment with diuretics and insulin resistance. The lack of specificity of uric acid in these settings has depreciated its clinical value in adults with PAH. However, this should not be the case in pediatric PAH as the occurrence of such comorbidities is rare in children.

(NT-pro)BNP and uric acid are not interchangeable as biomarkers, since they rep-resent different aspects of the disease and appear to behave very differently over time. To illustrate this, Figure 1 shows long-term trajectories of uric acid and NT-proBNP of two individual children with PAH from the Dutch Network for Pediatric PH, from time of diag-nosis until time of death (patient A: female, diagnosed at age 11 years; patient B: male, diagnosed at age 9 years). In both patients, there is a gradual linear incline of serum uric acid levels over time, already from early stages of the disease, whereas NT-proBNP levels

238 Chapter 10

remain relatively low during the earlier stages and increase more abruptly to its highest levels late in the disease course. These different trends over time are presumably due to the fact that these biomarkers represent different disease aspects: uric acid as a global marker of a child’s gradually declining condition during the full disease course, and NT-proBNP as a more specific marker of RV function with high sensitivity to detect RV decompensation in the advanced disease stage. The importance of monitoring trends of these biomarkers over time rather than interpreting single absolute values is illustrated by a comparison of patient A and B in Figure 1. Especially for uric acid, it appears that changes over time carry much more important information than the absolute uric acid level at any specific time point. Monitoring over time allows a patient to be its own refer-ence, and also allows accounting for natural variability in these markers.

Cardiovascular imaging

The findings of Chapter 4 allow for specific recommendations regarding the role of echocardiography in risk stratification. Based on our results and also confirmed by findings of Jone et al,16 right-to-left ventricular (RV/LV) diameter ratio is a reliable and easily obtainable echocardiographic prognostic factor in pediatric PAH, that incorpo-rates both pathologic septal shift and RV enlargement. RV ejection time and tricuspid annular plane systolic excursion (TAPSE) are indicators of RV function and are now both also demonstrated as prognostic factors. Another important new insight from Chapter 4, is the fact that reduced left ventricular (LV) dimensions have prognostic value as well. An interesting unanswered question is whether the smaller LV in advanced PAH is a result of an imbalanced RV/LV ratio due to compression by a dilated high-pressure RV and prolonged systolic RV contraction, or whether this is explained by ventricular interdependence-related failure of the LV structure and function.

Chapter 3 shows that cardiac magnetic resonance imaging (CMR) has not yet been sufficiently studied to allow recommendations for its use in risk stratification in

Time since diagnosis (years)

NT-

proB

NP

(ng/

L)

Uric acid (m

mol/L)

0 5 100

2000

4000

6000

8000

0.0

0.2

0.4

0.6

0.8

NT-proBNP

Uric acid

Time since diagnosis (years)

NT-

proB

NP

(ng/

L)

Uric acid (m

mol/L)

0 5 100

2000

4000

6000

8000

0.0

0.2

0.4

0.6

0.8

Uric acid

NT-proBNP

Patient A (female, diagnosed at age 11) Patient B (male, diagnosed at age 9)

† †

Figure 1. Longitudinal uric acid and NT-proBNP trajectories in two deceased patients.

Dotted lines represent major therapy adaptations.


10

children with PAH. Even in adult PAH, only few studies have assessed CMR in predicting outcome. The quality of obtainable images is superior to echocardiography and allows for an extensive assessment of RV structure and function. Drawbacks are the reduced feasibility in young children without sedation or general anesthesia, and the limited ac-cessibility to required infrastructure and expertise on a global scale. Nevertheless, CMR is a promising modality in pediatric PAH and studies are currently ongoing to evaluate its value as indicator of disease severity and prognosis.

Cardiac catheterization

Chapter 3 convincingly demonstrates the prognostic importance of the conventional hemodynamic variables pulmonary vascular resistance (PVR), mean right atrial pressure, cardiac index and acute response to vasodilator testing. This strongly supports the role of hemodynamics for risk stratification at time of diagnosis.

In addition to their role as prognostic factors for risk stratification in advanced PAH, hemodynamics are also used in specific settings where a patient is at risk for future devel-opment of advanced PAH. This is the case in children with CHD in whom early pulmonary vascular disease (PVD) has developed due to increased pulmonary blood flow. In these circumstances, clinical decision making regarding operability is a particular challenge. Conventionally, PVR and sometimes also mean pulmonary arterial pressure (mPAP) are used to guide therapy decisions such as whether and when a cardiac defect should be repaired or when PAH-targeted therapy should be initiated. The 20-year follow-up study presented in Chapter 7 confirms previous findings that conventional hemodynamics are very useful but lack accuracy in predicting disease progression, re-emphasizing the need for complementary measurements that provide additional insight in the state and dynamics of the pulmonary vasculature. Main findings of the study were that indices of pulmonary arterial (PA) stiffness, measured by intravascular ultrasound during cardiac catheterization, provide information on vascular wall dynamics that carry prognostic value regarding disease progression and outcome in children with PVD, also in settings of a favorable hemodynamic profile (i.e. relatively low PVR and/or mPAP).

Watching the actual disease development more closely rather than relying on the hemodynamic effects of PVD, probably allows for better prognostication of disease progression. Conventional measurements obtained during cardiac catheterization show the hemodynamic consequences of PVD, rather than the disease itself. However, increased PA stiffness is at least partly explained by the hemodynamic consequences of PAH as well, since increases in PAP mechanically increase PA wall stiffness by mov-ing the artery wall to a higher point on the volume/pressure curve.17 Nevertheless, PA wall stiffening is also inherently part of the disease process of PAH.18 Hence, PA stiffness indices incorporate valuable information on both hemodynamic consequences and the pathological process, which may explain the prognostic value that we found in settings

240 Chapter 10

of still favorable hemodynamics. Therefore, Chapter 7 suggests assessment of PA stiff-ness as a complement to conventional hemodynamics, to improve prediction of disease progression in such settings.

In the studied cohort, patients who underwent shunt closure all showed sub-sequent reversal of PVD. Therefore, the results of Chapter 7 could not inform whether PA-stiffness indices can predict adverse effects of shunt closure. There is a great clinical need of data on how to assess operability, as there is a substantial population of patients with PAH after shunt closure that have a dismal prognosis when compared to other forms of CHD-associated PAH.19 On the other hand, there is also a population of CHD-associated PAH whose shunt should have been closed to prevent progression of PVD. Already for many years, pediatric and congenital cardiologists debate on how to assess operability based on cardiac catheterization, in the absence of randomized controlled data.20,21 Patients with an indexed PVR (PVRi) < 6 WU*m2 are considered safe for surgery by some clinicians.20,22,23 A PVRi between 6 and 9 is considered borderline, and although controversial, acute vasodilator testing is encouraged to help decide whether a patient is operable in those cases.23 More recently, a PVRi of 4 WU*m2 was proposed as the limit for operability, and a PVRi of 4-8 WU*m2 as the borderline range.2 Empirical data sup-porting any of the proposed cut-offs are extremely limited.24 Therefore, clinicians agree that assessment of operability is a matter of discussion on an individual basis, in which not only hemodynamic cut-off values but the whole diagnostic scenario of a patient has to be taken into account, e.g. including the type of cardiac defect, clinical history and functional status.20

treAtMent goAls And ClInICAl endPoInts

The prognostic factors as put forth in Chapters 3 to 6 are useful in risk stratification in PAH. An important additional question, which was a particular focus in Chapters 8 and 9, is whether and how such clinical measurements may be used to evaluate treatment efficacy throughout the disease course, either in clinical practice or clinical trial design. Among both clinicians and regulators, there is consensus that an outcome measure-ment to evaluate treatment efficacy should be clinically meaningful, directly measuring how a patient feels, functions or survives.25,26 Alternatively, indirect surrogates of such clinically meaningful outcomes may qualify.

Treatment goals may be regarded as the treatment efficacy measurements for clinical practice, and clinical endpoints are the treatment efficacy measurements for the specific setting of a clinical trial. The concept of a treatment goal, which is becoming widespread in the field of PAH, has been introduced in Chapters 1 and 2 as a predefined improvement of a measurement that is the direct equivalent of a clinically meaningful


10

outcome (e.g. relieve of symptoms), or a predefined improvement of a measurement that serves as an indirect surrogate for a clinically meaningful outcome (e.g. represent-ing a decrease in the chance of mortality). Prior to reviewing the yield and implications of this thesis regarding treatment goals and clinical endpoints, direct and indirect (sur-rogates for) clinically meaningful outcomes are discussed.

direct clinically meaningful outcomes

Multiple aspects of routine clinical history taking and physical examination of children with PAH are directly clinically meaningful. For example, PAH symptoms like dyspnea, chest pain or syncope are direct indicators of how a patient feels and hence are clini-cally meaningful. This also holds true for WHO-FC, growth status, physical activity level (e.g. measured with accelerometer) and 6MWD, being indicators of patients’ ability to function in daily life. For each of these clinical measurements, reliability needs to be carefully considered for each individual patient as some of these may be susceptible to subjectivity, clinical judgment and motivational issues. Obviously, the disease course of a patient (i.e. “how a patient survives”) is also clinically meaningful, including the rate of disease progression, need for additional therapies (intravenous prostanoids, atrial septostomy, Potts shunt, (heart-)lung transplantation), and mortality. Although event rates of such occurrences may qualify as study outcomes, the irreversible nature of these events hampers their usefulness for clinical decision making.

Most of the diagnostic variables commonly used in the follow-up of children with PAH do not provide directly clinically meaningful outcomes. For example, echocardiog-raphy and cardiac magnetic resonance imaging can yield important measurements regarding the severity of the disease and prognosis, but none of these measurements does directly represent how a patients feels, functions or survives. Similarly, highly prog-nostic hemodynamic variables obtained during cardiac catheterization or laboratory biomarkers are not directly clinically meaningful for a patient.

surrogates for clinically meaningful outcomes

Diagnostic variables that are not directly clinically meaningful might still qualify for the evaluation of treatment efficacy, provided that they are valid surrogates for a true clini-cally meaningful outcome measure. The results of this thesis have revealed that echo-cardiographic and hemodynamic measurements and laboratory values prognosticate disease severity and survival, which are outcomes that are both clinically meaningful. However, a correlation with outcome does not always indicate surrogacy.25 In addition to a strong correlation with outcome, there are two additional basic characteristics of a surrogate: (1) the measurement is modifiable by treatment and (2) treatment-induced changes in the measurement correlate with changes in outcome as well. A “true” sur-rogate is part of the causal pathway of the disease, which in theory can be validated

242 Chapter 10

by testing whether influences on the final clinically meaningful endpoint are causally explained by influences on the surrogate,27 requiring extensive modeling in very large prospective cohorts that are not available in the field of (pediatric) PAH. Nevertheless, this should not distract from the vital first step in surrogacy validation, which is the evaluation of changes of prognostic factors over time. Which of the prognostic factors can be improved by treatment, and do such improvements predict improved outcome?

The study in Chapter 8 aimed to answer this specific question by investigating the prognostic value of treatment-induced changes in a set of noninvasive prognostic factors. The results revealed that WHO-FC, NT-proBNP and TAPSE were modifiable prog-nostic factors of which changes over time were associated with survival. This suggests that these three clinical measurements are not only simple predictors of outcome, but also hold promise as surrogates for survival. As improvements of WHO-FC, NT-proBNP and TAPSE appear to lead to better outcomes, it seems reasonable to consider the striv-ing for these improvements as prognostically relevant.

In this same line of reasoning, it deserves speculation that growth and uric acid qualify as surrogates as well. An important finding of Chapter 5 was that Z-scores for height could improve throughout the disease and that catch-up growth was indepen-dently associated with a favorable disease course (a clinically meaningful outcome). In addition to demonstrating the prognostic value of serum levels of uric acid (both at baseline and throughout the disease), Chapter 6 showed that deteriorations and a gradual incline in uric acid are associated with worse outcome. As changes of both height-for-age Z-score and uric acid over time appear to lead to changes in outcomes, it seems of added value to monitor these clinical variables and strive for their improve-ment.

treatment goals

The identification of treatment goals allows for the development of goal oriented treatment strategies for pediatric PAH. In adult PAH-patients, a goal-oriented treatment strategy is recommended, in which validated clinical and laboratory variables are used to guide the clinician in the timing of therapy escalations or lung transplantation. A goal oriented treatment strategy appears the most appropriate in a progressive incurable disease like PAH, since the conventional “waiting for clinical deterioration” leads to lag-ging behind events. During the 5th WSPH, potential treatment goals for a pediatric goal oriented treatment strategy have been suggested, based on expert opinion (introduced in Chapter 2).2

When improvement of quality of life (directly clinically meaningful for a patient) is the overall objective of such a goal-oriented treatment strategy in pediatric PAH, then all direct indicators of how a patient feels or functions directly qualify for its use as treatment goals. For example, these include PAH symptoms, WHO-FC, growth status,


10

and 6MWD. Cut-offs in these variables can be predefined according to a desired target level of symptom relieve or functional abilities, allowing for its clinical applicability as treatment goals.

However, when improvement of outcome is the overall objective (or part of the objective), then the data regarding surrogacy validation becomes highly essential. This thesis provides clues regarding the surrogacy of WHO-FC, NT-proBNP, TAPSE, growth and uric acid. For the first three of these, prognostically relevant cut-offs were determined as part of Chapter 8, to allow definition of clinically applicable treatment goals. It was demonstrated that reaching values below the identified cut-offs for WHO-FC (≤III) and NT-proBNP (≤1200 ng/L) and above the cut-off for TAPSE (≥12 mm) during follow-up, indeed correlated with better survival rates. Failing to reach values below (WHO-FC and NT-proBNP) or above (TAPSE) these thresholds resulted in significantly worse survival, suggesting that treatment should be escalated rapidly in these children.

With respect to the identification of treatment goals, an understudied area is car-diac catheterization. Data regarding the prognostic values of changes in hemodynamics are absent in children.

Clinical endpoints

In both adult and pediatric PAH, there is ongoing debate regarding the optimal selec-tion of endpoints for clinical trials. In adults, the 6MWD and hemodynamics have been the most frequently used endpoints in clinical trials.28 Although children as young as three or four years of age may be able to do a 6-minute walk test, a reliable performance cannot be expected under the age of seven or eight years.3,29 Invasively mPAP and PVR are objective and robust measurements, but obtaining hemodynamic data carries a risk in children.30 Besides, hemodynamics are not directly clinically meaningful for a patient, and its surrogacy for survival has been questioned in adults.31

Do the non-invasive treatment goals identified in Chapter 8, WHO-FC, NT-proBNP or TAPSE, also qualify as potential trial endpoints for children? WHO-FC is both clinically meaningful and a powerful prognostic factor, but its reliability depends on what the pa-tients or parents tell the treating physician. Another drawback is the categorical nature of the variable, which hampers the detection of subtle changes, especially for patients who are in WHO FC II or III. Also, WHO-FC is susceptible to ceiling and flooring effects, as patients in WHO-FC IV cannot deteriorate and in WHO-FC I cannot improve. NT-proBNP and TAPSE or not directly clinically meaningful for a child, but the demonstrated prog-nostic value of changes over time provides important clues for surrogacy. Both are at-tractive as potential endpoints, as both measurements are easily obtainable and can be repeated as many times as needed. Prior to installment as an endpoint, further research is desired on sensitivity and specificity, and on how to deal with variations in age.

244 Chapter 10

The clinical worsening (CW) endpoint as presented in Chapter 9 of this thesis, has gained increasing interest. The most important advantage is that it is patient-centered, and consists of clinically meaningful components only. The results of the validation study show high event rates and a strong correlation of the soft components with outcome, which support its potential as a composite clinical endpoint. Important prerequisites to guarantee its reliability and comparability throughout trials, are the installment of independent adjudication committees and the agreement on a uniform endpoint definition. A general caveat of composite endpoints is reduced interpretability compared to single endpoints, especially when the incorporated components have dif-ferent clinical meaning.25 In frequently used and well-established clinical trial endpoints in cardiovascular disease, such as the Major Cardiovascular Event composite endpoint, all components represent irreversible morbidity and mortality (cardiovascular death, stroke or myocardial infarction). For the CW endpoint, some of the components indicate irreversible morbidity / mortality, but not all. For example, deteriorations in WHO-FC and 6MWT indicate clinical worsening, but this might be reversible. Also, hospitalizations for PAH do not necessarily indicate irreversible morbidity. When CW is considered as an endpoint for trials in PAH, it is important that these drawbacks will be taken into account.

Other potential clinical endpoints for pediatric PAH that have not been studied in this thesis but are interesting include CMR and ambulant physical activity monitoring. In pediatric PAH, the available data on the prognostic value of CMR variables is limited.32,33 In adults with PAH, changes in RV functional CMR measurements have been shown to correlate with outcome, pointing in the direction that such measurements might have potential as survival surrogates.34 Longitudinal studies in children are needed to evaluate whether CMR variables might qualify as surrogates for clinically meaningful outcomes. Ambulant physical activity monitoring using accelerometer recordings seems suited ideally to children to measure changes in physical activity in response to therapy.29 The data from the recordings are directly clinically meaningful, as they are expected to represent a child’s functional capacity. Studies are currently ongoing to evaluate its value as indicator of disease severity and prognosis in pediatric PAH, and its usefulness as clinical trial endpoint.

ConsIderAtIons And Future ProsPeCts

PAH is a heterogeneous disease, which poses challenges for any study to be conducted in this field. A “one-size-fits-all approach” is outdated in medicine, with personalized precision medicine becoming the new standard. This especially seems the way to go in the field of PAH with multiple heterogeneous phenotypes. One must remind, however, that the goal of individualized medicine can only be achieved by large patient-based


10

studies.35 International registries such as Tracking Outcomes and Practice in Pediatric PH (TOPP) are ideally suited to characterize patients and detect subgroup differences in therapy response and clinical disease course. In a rare disease like PAH, it is of impor-tance that treatment strategies and collection of clinical parameters are standardized, to allow reliable conclusions from such observational data. As registries are labor-intensive and costly, they should be designed adaptive. For example, when there are new insights regarding potential biomarkers or when there are clues that a certain treatment strategy is superior to the conventional one, case report forms of the registry can be adjusted to allow timely capture of such potential important information.

We have proposed prognostic factors that seem suitable for risk stratification in children with PAH. When considering the proposed prognostic factors, it of great future interest which of the clinical measurements carry independent predictive value above the other ones. This could be evaluated in larger datasets, which may be achieved by international collaboration. It was not studied whether the actual use of these prognostic factors in clinical practice leads to better management outcomes. Similarly, the treatment goals have been identified based on solid data, but whether its incorporation in goal oriented treatment strategies translates into better outcomes remains to be demonstrated. Prospective, preferably randomized, studies are desired to evaluate the comparative effectiveness of conventional treatment strategies and newly proposed ones. As an example, many clinical trials have been conducted in patients with heart failure, to show that NT-proBNP guided treatment leads to better outcomes than conventional treatment strategies, independent of the received heart failure medica-tion.36 Such studies may be challenging in PAH due to small patient numbers, but well-designed prospective observational studies can already provide valuable information on this topic.

The data that support valid clinical endpoints now allow for the design of clinical trials in pediatric PAH. To achieve the number of required children, international col-laborations will be necessary. In view of the drawbacks of CW as an endpoint, the quest for suitable pediatric endpoints must continue.

ConCludIng reMArks

The studies described in this thesis provide prognostic factors, treatment goals and potential clinical endpoints for the field of pediatric PAH. The presented data constitute a substantial and highly needed step towards better risk stratification, treatment strat-egies and clinical trial design for this delicate patient population. The limitations and newly arisen questions of this thesis underline the huge amount of work that remains to be done, but increasing international collaborations among PH experts and promising

246 Chapter 10

diagnostic and therapeutic developments do bring hope for the children and families that have to cope with this devastating disease.


10

reFerenCes

1. Italiano A. Prognostic or Predictive? It’s Time to Get Back to Definitions! J Clin Oncol. 2011;29:4718–4718.


3. Douwes JM, Hegeman AK, Van Der Krieke MB, Roofthooft MTR, Hillege HL, Berger RMF. Six-minute walking distance and decrease in oxygen saturation during the six-minute walk test in pediatric pulmonary arterial hypertension. Int J Cardiol. 2016;202:34–39.

4. King L, Wilkins MR. Natriuretic peptide receptors and the heart. Heart. 2002;87:314–5. 5. Nir A, Lindinger A, Rauh M, Bar-Oz B, Laer S, Schwachtgen L, Koch A, Falkenberg J, Mir TS. NT-

pro-B-type natriuretic peptide in infants and children: Reference values based on combined data from four studies. Pediatr Cardiol. 2009;30:3–8.

6. Kim HN, Januzzi JL. Natriuretic peptide testing in heart failure. Circulation. 2011;123:2015–2019. 7. Bernus A, Wagner BD, Accurso F, Doran A, Kaess H, Ivy DD. Brain natriuretic peptide levels in

managing pediatric patients with pulmonary arterial hypertension. Chest. 2009;135:745–51. 8. Van Albada ME, Loot FG, Fokkema R, Roofthooft MTR, Berger RMF. Biological serum markers in the

management of pediatric pulmonary arterial hypertension. Pediatr Res. 2008;63:321–7. 9. Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, Yamagishi M, Kunieda T,

Miyatake K. Serum uric acid levels correlate with the severity and the mortality of primary pulmo-nary hypertension. Am J Respir Crit Care Med. 1999;160:487–92.

10. Oya H, Nagaya N, Satoh T, Sakamaki F. Haemodynamic correlates and prognostic significance of serum uric acid in adult patients with Eisenmenger syndrome. Heart. 2000;53–58.

11. Voelkel MA, Wynne KM, Badesch DB, Groves BM, Voelkel NF. Hyperuricemia in severe pulmonary hypertension. Chest. 2000;117:19–24.



14. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J. 1997;18:858–865.



17. Arnett DK, Evans GW, Riley WA. Arterial stiffness: a new cardiovascular risk factor? Am J Epidemiol. 1994;140:669–82.

18. Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ. Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am J Respir Crit Care Med. 1994;149:1317–26.

248 Chapter 10

19. van Albada ME, Berger RMF. Pulmonary arterial hypertension in congenital cardiac disease – the need for refinement of the Evian-Venice classification. Cardiol Young. 2008;18:10–7.

20. Lopes AA, Barst RJ, Haworth SG, Rabinovitch M, Al Dabbagh M, Del Cerro MJ, et al. Repair of con-genital heart disease with associated pulmonary hypertension in children: what are the minimal investigative procedures? Consensus statement from the Congenital Heart Disease and Pediatric Task Forces, Pulmonary Vascular Research Institute (PVRI). Pulm Circ. 2014;4:330–41.

21. Berger RM. Possibilities and impossibilities in the evaluation of pulmonary vascular disease in congenital heart defects. Eur Heart J. 2000;21:17–27.

22. Lopes AA, O’Leary PW. Measurement, interpretation and use of haemodynamic parameters in pul-monary hypertension associated with congenital cardiac disease. Cardiol Young. 2009;19:431–5.

23. Beghetti M, Galiè N, Bonnet D. Can “inoperable” congenital heart defects become operable in pa-tients with pulmonary arterial hypertension? Dream or reality? Congenit Heart Dis. 2012;7:3–11.

24. Myers PO, Tissot C, Beghetti M. Assessment of operability of patients with pulmonary arterial hypertension associated with congenital heart disease. Circ J. 2014;78:4–11.



27. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431–40.

28. Parikh KS, Rajagopal S, Arges K, Ahmad T, Sivak J, Kaul P, Shah SH, Tapson V, Velazquez EJ, Douglas PS, Samad Z. Use of outcome measures in pulmonary hypertension clinical trials. Am Heart J. 2015;170:419–429.


30. Beghetti M, Schulze-Neick I, Berger RMF, Ivy DD, Bonnet D, Weintraub RG, Saji T, Yung D, Mallory GB, Geiger R, Berger JT, Barst RJ, Humpl T. Haemodynamic characterisation and heart catheteri-sation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension). Int J Cardiol. 2016;203:325–330.



33. Pandya B, Quail MA, Steeden JA, McKee A, Odille F, Taylor AM, Schulze-Neick I, Derrick G, Moledina S, Muthurangu V. Real-time magnetic resonance assessment of septal curvature accurately tracks acute hemodynamic changes in pediatric pulmonary hypertension. Circ Cardiovasc Imaging. 2014;7:706–13.

34. van de Veerdonk MC, Kind T, Marcus JT, Mauritz G-J, Heymans MW, Bogaard H-J, Boonstra A, Marques KMJ, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol. 2011;58:2511–9.


10

35. Austin ED, Loyd JE. Toward Precision Medicine in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2015;192:1272–4.

36. Troughton RW, Frampton CM, Brunner-La Rocca H-P, Pfisterer M, Eurlings LWM, Erntell H, Persson H, O’Connor CM, Moertl D, Karlström P, Dahlström U, Gaggin HK, Januzzi JL, Berger R, Richards AM, Pinto YM, Nicholls MG. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35:1559–67

1

2

3

4

5

6

7

8

9

10

AppendicesEnglish summary

Nederlandse samenvatting

Dankwoord

About the author

List of publications

253English summary

englIsh suMMAry

Pediatric pulmonary arterial hypertension (PAH) is a progressive life-threatening disease of the pulmonary arteries, and is introduced in Chapter 1. In PAH, the increased pressure in the pulmonary vasculature causes an afterload burden on the right ventricle (RV), which leads to RV failure and death. Despite major advances in the past decades in the treatment of adults with PAH, it remains a devastating disease without a cure. Especially in children, mortality rates are unsatisfactory and need improvement.

Clinicians taking care of children with PAH face several challenges. It is difficult to tailor optimal treatment regimens for the individual patient, as risk stratification is hampered by a lack of prognostic factors. Clinical measurements that provide informa-tion on the prognosis of the disease are essential for clinical decision-making, both at time of treatment initiation and during the course of the disease. Important additional challenges are the evaluation of treatment success, the appropriate timing of therapy escalation during follow-up, and adequate timing of surgical interventions such as Potts shunts or (heart-)lung transplantation. A standardized treatment strategy is much desired, but requires the identification of clinically and prognostically relevant treatment goals. Moreover, most of the drugs that are currently being used in the treatment of pediatric PAH have not yet been tested in pediatric randomized clinical trials. A crucial problem is the lack of appropriate clinical endpoints to evaluate treatment efficacy in children with PAH, hampering the design of pediatric clinical trials. In view of these chal-lenges, the overall aims of this thesis were to identify (1) prognostic factors, (2) treatment goals and (3) clinical endpoints in pediatric PAH.

As an extension to the introduction of this thesis, we review the available treat-ments of PAH and the limited efficacy and safety data in children with PAH in Chapter 2. This overview demonstrates the importance of designing clinical trials specifically for the pediatric age group, and underlines the great need for appropriate clinical endpoints for children with PAH. Potential treatment goals for a pediatric goal-oriented treatment strategy are discussed, and we point out that defining clinically relevant treatment goals that correlate with long-term outcome has emerged as one of the most critical tasks in the field pediatric PAH.

As a starting point with regards to the identification of prognostic factors in pediatric PAH, the results of an extensive literature study are presented in Chapter 3. A systematic review was conducted, and the prognostic value of reported prognostic fac-tors in children with PAH was combined and summarized using meta-analysis. Clinical measurements that were reported to be consistently and significantly associated with mortality included WHO functional class, serum levels of (N-terminal pro-)B-type natri-uretic peptide and four hemodynamic variables obtained by cardiac catheterization. This recapitulation of available data in pediatric PAH did not preclude the potential of

254 Appendices

the many other variables that have incidentally been shown to correlate with mortality, but rather provided directions for further research to address gaps in evidence.

The value of echocardiography in assessing disease severity and predicting out-come in pediatric PAH is insufficiently defined. Therefore, the study in Chapter 4 aimed to describe correlations between echocardiography and disease severity and outcome in pediatric PAH. This descriptive study was conducted as part of the Dutch National Network for Pediatric Pulmonary Hypertension and showed that echocardiographic characteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The data from this study support the potential value of echocardiography as an easily accessible bedside tool in guiding management in children with PAH.

An interesting topic that exclusively applies to PAH in children, is the influence of the disease on growth. Impaired growth is an indicator of disease severity and out-come in several severe pediatric diseases. To enable adequate interpretation of growth measurements in the management of children with PAH, growth and its associated determinants in children with PAH was evaluated in Chapter 5. A retrospective longi-tudinal study of height and body mass index in reference to WHO growth standards was conducted by pooling four contemporary prospective registries of pediatric PAH representing 601 children from 53 centers in 19 countries. The results demonstrated that PAH is associated with impaired growth, especially in younger children and those with PAH associated with congenital heart disease. The degree of impairment was shown to be independently associated with the cause of PAH and comorbidities, but also with disease severity and duration. As a favorable clinical course was found to be associated with catch-up growth, we suggest height for age as an additional and globally available clinical parameter to assess and monitor the clinical condition of children with PAH.

Previous observations have suggested that serum uric acid, a degradation product of purine metabolism, has potential as a non-invasive, inexpensive and easily obtainable biomarker in PAH. Single measurements of uric acid have been shown to correlate with outcome in earlier studies, but the prognostic value of serially measured levels required evaluation, including the clinical value of an incline over time. In the study presented in Chapter 6, we aimed to evaluate the association of serum uric acid with disease severity and outcome during the full disease course of pediatric PAH. The results of this longitu-dinal study demonstrate that higher serum uric acid levels are associated with disease severity and mortality in children with PAH, throughout the full disease course. Closely monitoring uric acid levels and especially their course over time provides important information on the state of the disease and may aid in clinical decision-making in the management of children with PAH.

In children with abnormal pulmonary hemodynamics due to uncorrected con-genital heart defects, information is needed regarding pulmonary vascular disease

255English summary

(PVD) reversibility. Early PVD can progress rapidly to advanced PAH, and shunt closure becomes harmful in the later disease stages. To guide clinical-decision making in these early stages, clinical measurements are needed that can predict whether the disease will reverse or progress to advanced PAH in the future. In Chapter 7, a 20-year outcome study is reported that focused not only on advanced PAH, but also on the earlier stages of PVD. In this chapter, the value of PA stiffness assessed by intravascular ultrasound was evaluated, with regards to prediction of future disease progression to advanced PAH and long-term mortality. PA-stiffness was shown to predict long-term disease progres-sion and mortality in children with PVD. Based on this data, we have suggested that assessment of PA stiffness may complement to conventional hemodynamic evaluation, with particular added value in the early stages of pediatric PVD.

A goal-oriented treatment strategy has been shown to be effective in adults with PAH. However, to allow for such a strategy in children, clinically and prognosti-cally relevant treatment goals need to be defined. Potential treatment goals in children with PAH were identified and evaluated in Chapter 8, as a step towards the design of a pediatric goal oriented treatment strategy. The prognostic value of treatment-induced changes were assessed, and optimal prognostic thresholds were estimated. The results revealed that WHO functional class, serum levels of N-terminal pro-B-type natriuretic peptide and the echocardiographic measurement tricuspid annular plane systolic excursion were modifiable prognostic factors of which changes over time were associ-ated with changes in outcome. As improvements of WHO functional class, N-terminal pro-B-type natriuretic peptide and tricuspid annular plane systolic excursion appeared to lead to better outcomes in this study, it seems reasonable to consider the striving for these improvements as prognostically relevant treatment goals in the management of pediatric PAH.

Most of the drugs currently used in the treatment of PAH have not been tested in pediatric randomized clinical trials. A crucial problem is the lack of clinical endpoints that are applicable in children with PAH, hampering the design of pediatric clinical trials. In Chapter 9, the combined morbidity/mortality endpoint “clinical worsening” (CW) was studied as a candidate composite study endpoint for future clinical trials in pediatric PAH. The usefulness of CW was evaluated by assessing the event incidence and prognos-tic value of each separate endpoint component and of the composite clinical worsen-ing endpoint in children with PAH who participate in the Dutch Network for Pediatric Pulmonary Hypertension. The results showed CW to occur with a high event incidence and that each of the soft endpoint components of CW was predictive of death or (heart-)lung transplantation. The findings reported in this chapter support the usefulness of CW as a study endpoint in clinical trials in pediatric PAH.

In Chapter 10, the clinical implications of the results of this thesis were discussed, together with directions for future research.

257Nederlandse samenvatting

nederlAndse sAMenvAt tIng

Pulmonale arteriële hypertensie (PAH) is een progressieve levensbedreigende ziekte van de longslagaders en wordt geïntroduceerd in hoofdstuk 1 van dit proefschrift. Bij PAH zorgt de toegenomen bloeddruk in het longvaatbed voor een overbelasting van de rechter hartkamer, wat leidt tot hartfalen van de rechter hartkamer en uiteindelijk tot de dood. Ondanks grote stappen die de afgelopen decennia zijn gemaakt in de behandelmogelijkheden voor volwassenen, is PAH op de kinderleeftijd nog steeds een verwoestende ongeneeslijke ziekte. De sterftecijfers zijn vooral bij kinderen onbevredi-gend, en dienen te worden verbeterd.

Behandelaars van kinderen met PAH worden geconfronteerd met meerdere uitdagingen. Het is moeilijk om een behandeling op maat in te stellen voor de indivi-duele patiënt, omdat risicostratificatie gehinderd wordt door een gebrek aan klinische metingen die kunnen dienen als prognostische factoren. Klinische metingen die infor-matie geven over de prognose van de ziekte zijn essentieel voor het maken van goede behandelbeslissingen, en zijn zowel nodig op het moment dat therapie wordt gestart, als gedurende het verdere beloop van de ziekte. Belangrijke bijkomende uitdagingen zijn de evaluatie van therapiesucces tijdens follow-up, de juiste timing van therapie-escalatie, en adequate timing van chirurgische ingrepen zoals een Potts shunts of (hart-) longtransplantatie. Een gestandaardiseerde doelgeoriënteerde behandelingsstrategie zou zeer gewenst zijn, maar hiervoor is het nodig om klinisch en prognostisch relevante behandeldoelstellingen te definiëren. Verder zijn de meeste geneesmiddelen die op dit moment worden gebruik in de behandeling van PAH nog niet getest in gerandomi-seerde klinische trials met kinderen. Een cruciaal probleem is het gebrek aan klinische eindpunten, wat het ontwerp van klinische trials in kinderen met PAH bemoeilijkt. Met het oog op deze uitdagingen waren de algemene doelen van dit proefschrift het iden-tificeren van (1) prognostische factoren, (2) behandelingsdoelstellingen en (3) klinische eindpunten in PAH op de kinderleeftijd.

Als een voortzetting van de introductie van dit proefschrift, geven we in hoofd-stuk 2 een overzicht van de beschikbare behandelingen van PAH en de beperkte data over werkzaamheid en veiligheid bij kinderen. Dit overzicht toont het belang aan van het ontwerp van klinische trials specifiek gericht op de kinderleeftijd en onderstreept de grote behoefte aan geschikte klinische eindpunten voor kinderen met PAH. Potentiële behandelingsdoelstellingen om op te nemen in een doelgeoriënteerde behandelings-strategie worden besproken, en we wijzen erop dat het definiëren van klinisch relevante behandelingsdoelstellingen die correleren met langetermijnuitkomsten een prioriteit is geworden in dit veld.

hoofdstuk 3 beschrijft de resultaten van een uitgebreide literatuurstudie naar prognostische factoren in kinderen met PAH. In deze studie hebben we een systemati-

258 Appendices

sche review gecombineerd met data-extracties en datasamenvoegingen middels meta-analyses. Klinische metingen die op grond van deze studie consistent en significant geassocieerd bleken met mortaliteit betreffen WHO functionele klasse, serumbepalin-gen van (N-terminal) B-type natriuretisch peptide en vier hemodynamische variabelen verkregen middels hartkatheterisatie. Deze samenvoeging van beschikbare gegevens in het veld van PAH op de kinderleeftijd staat het potentieel van de vele andere variabelen die ook incidenteel aan sterfte zijn gecorreleerd niet in de weg, maar geeft richting aan verder onderzoek om lacunes in het momenteel beschikbare wetenschappelijk bewijs aan te pakken.

De waarde van echocardiografie voor het bepalen van ziekte-ernst en prog-nose in pediatrische PAH is onvoldoende vastgesteld. Daarom was de doelstelling van hoofdstuk 4 om correlaties te beschrijven tussen echocardiografische metingen en ziekte-ernst en langetermijnuitkomsten. Deze studie werd uitgevoerd als onderdeel van het Landelijk Netwerk voor Pulmonale Hypertensie op de Kinderleeftijd en toonde aan dat echocardiografische kenmerken van zowel de rechter als de linker hartkamer correleren met de ziekte-ernst en prognose in kinderen met PAH. Dit geldt zowel op het moment van presentatie als gedurende het beloop van de ziekte. De bevindingen van deze studie demonstreren de potentiële waarde van echocardiografie als een gemak-kelijk toegankelijke “bedside tool” voor het monitoren en sturen van de behandeling in kinderen met PAH.

Een interessant onderwerp dat uitsluitend van toepassing is op de kinderleeftijd, is de invloed van PAH op groei. In meerdere ernstige ziektes op de kinderleeftijd is groeivertraging een belangrijke voorspeller gebleken van ziekte-ernst en langetermijn-uitkomsten. Om adequate interpretatie van groeimetingen mogelijk te maken voor het volgen van kinderen met PAH, hebben we groeivertraging en voorspellers van groei in kinderen met PAH geëvalueerd in hoofdstuk 5. Een retrospectieve longitudinale studie van lengte en body mass index in referentie tot WHO groeistandaarden werd uitgevoerd door vier hedendaagse prospectieve registraties van pediatrische PAH samen te voe-gen. Deze registraties representeren tezamen 601 kinderen met PAH uit 53 centra in 19 landen. De resultaten laten zien dat PAH geassocieerd is met verminderde groei, met name bij jongere kinderen en in PAH geassocieerd met een aangeboren hartafwijking. De mate van groeivertraging bleek onafhankelijk geassocieerd te zijn met de onderlig-gende oorzaak, comorbiditeiten, en de ernst en duur van de ziekte. Een interessante bevinding was dat een gunstig ziektebeloop geassocieerd bleek te zijn met inhaalgroei. Dit suggereert dat lengte voor leeftijd - een gemakkelijke en wereldwijd beschikbare maat - bruikbaar is om de klinische conditie van een kind met PAH te bepalen en te vervolgen gedurende de ziekte.

De resultaten van eerdere observationele studies suggereren dat serumbepalin-gen van urinezuur (een afbraakproduct van purine metabolisme) potentie heeft als een

259Nederlandse samenvatting

non-invasieve, goedkope en gemakkelijk te gebruiken biomarker in PAH. Enkelvoudige metingen van serum urinezuur bleken gerelateerd te zijn aan langetermijnuitkomsten in eerdere studies, maar de prognostische waarde van serieel gemeten bepalingen en het beloop in de tijd is nog niet geëvalueerd. hoofdstuk 6 beschrijft een studie waarin we hebben gekeken naar de correlatie van urinezuur met ziekte-ernst en mortaliteit ge-durende het volledige ziektebeloop. De resultaten van deze longitudinale studie laten zien dat hogere urinezuurwaarden geassocieerd zijn met de ernst van de ziekte en een hogere kans op mortaliteit, en deze correlatie bleef bestaan tijdens het volledige ziek-tebeloop. In dit hoofdstuk concluderen we dat het nauwlettend vervolgen van serum urinezuur belangrijke informatie oplevert over de klinische conditie van een kind met PAH en dat dit kan helpen in de klinische besluitvorming gedurende de behandeling.

Bij kinderen met abnormale pulmonale hemodynamiek ten gevolge van een ongecorrigeerde aangeboren hartafwijking, is het van belang om te weten of de pul-monale vaatziekte nog reversibel is. De ziekte wordt al snel in het beloop onomkeerbaar met de ontwikkeling van irreversibele PAH tot gevolg, en in de latere stadia is sluiting van een shunt gecontraïndiceerd. Om adequate behandelbeslissingen te kunnen ma-ken bij deze kinderen, zijn er klinische metingen nodig die kunnen voorspellen of de ziekte nog reversibel is, of dat er juist verdere progressie zal optreden in de toekomst. In hoofdstuk 7 beschrijven we de resultaten van een studie waarin 20-jarige follow-up uitkomsten worden bekeken van kinderen bij wie in de jaren ’90 de pulmonaal arteriële (PA) stijfheid is bepaald door middel van intravasculaire echografie. In deze studie bleek de PA stijfheid een significante voorspeller van zowel toekomstige ziekteprogressie als mortaliteit. Daarom stellen we in dit hoofdstuk dat PA stijfheid gebruikt kan worden als aanvullende maat in de hemodynamische evaluatie van deze patiënten, waarbij we met name toegevoegde waarde benadrukken in de evaluatie van de vroege stadia van pulmonale vaatziekte.

Ervaringen uit de behandeling van volwassenen met PAH hebben geleerd dat er veel gezondheidswinst valt te behalen, wanneer er gebruik wordt gemaakt van een gestandaardiseerde doelgeoriënteerde behandelingsstrategie. Om een dergelijke be-handelingsstrategie mogelijk te maken in kinderen met PAH, is het nodig om klinisch en prognostisch relevante behandeldoelstellingen te definiëren. Het doel van de studie in hoofdstuk 8 was daarom het identificeren van zulke behandeldoelstellingen in kinde-ren met PAH. We hebben de prognostische waarde van therapiegeïnduceerde verande-ringen in een set van veelgebruikte klinische parameters bepaald, en vastgesteld welke afkappunten in de parameters het sterkst prognostisch onderscheidend waren. Uit de resultaten bleek dat WHO functionele klasse, serumbepalingen van N-terminal B-type natriuretisch peptide en de echocardiografische maat “tricuspid annular plane systolic excursion” prognostische factoren waren waarvan ook veranderingen in de tijd geas-socieerd bleken met veranderingen in langetermijnuitkomsten. Verbeteringen van deze

260 Appendices

parameters door therapie bleek in deze studie te leiden tot verbeteringen in longtrans-plantatievrije overleving. Daarom concluderen we in dit hoofdstuk dat het streven naar verbetering van deze parameters geschikte behandeldoelstellingen lijken te zijn tijdens de behandeling van kinderen met PAH, en we bevelen deze behandeldoelstellingen dan ook aan voor een gestandaardiseerde doel-georiënteerde behandelingsstrategie in PAH op de kinderleeftijd.

De meeste geneesmiddelen die op dit moment worden gebruik in de behande-ling van PAH zijn nog niet getest in gerandomiseerde klinische trials met kinderen. Een cruciaal probleem is het gebrek aan klinische eindpunten die toepasbaar zijn op de kinderleeftijd, wat het ontwerp van klinische trials in kinderen met PAH bemoeilijkt. In hoofdstuk 9 hebben we het samengestelde morbiditeits- en mortaliteitseindpunt geëvalueerd dat bij het ontwerp van trials voor volwassenen met PAH toenemend in de belangstelling staat: het zogenoemde “clinical worsening” (CW) eindpunt. De bruikbaar-heid van CW als potentieel eindpunt voor PAH op de kinderleeftijd werd geëvalueerd door de incidentie en prognostische waarde van zowel elk afzonderlijk eindpuntcom-ponent als het samengestelde CW-eindpunt te bepalen in de kinderen met PAH die participeren in het Landelijk Netwerk voor Pulmonale Hypertensie op de Kinderleeftijd. De resultaten lieten zien dat CW gedurende het ziektebeloop optreedt met een hoge incidentie, en dat elk afzonderlijk eindpuntcomponent significant geassocieerd is met de kans op overlijden of (hart-)longtransplantatie. Deze bevindingen ondersteunen de potentie van CW als een eindpunt in klinische studies in kinderen met PAH.

hoofdstuk 10 bestaat uit een discussie van de resultaten van de studies in dit proefschrift, en bespreekt suggesties voor toekomstig vervolgonderzoek.

263Dankwoord

dAnkwoord

Promoveren doe je niet alleen, gelukkig. Het plezier dat ik aan dit promotietraject heb beleefd, is dankzij de mensen met wie ik heb samengewerkt, de mensen uit mijn om-geving die me hebben gesteund en dankzij de kinderen met pulmonale hypertensie die uiteindelijk de achterliggende reden en inspiratiebron zijn van dit onderzoek. Een aantal personen wil ik in het bijzonder noemen.

Prof. dr. R.M.F. Berger. Beste Rolf, dankzij jou kan ik terugkijken op een succesvol promotietraject. Jouw visionaire blik heeft in 2002 geleid tot een landelijke registry, die nu een goudmijn aan unieke longitudinale data heeft opgeleverd. Vanwege je leidersrol binnen het veld waren er gemakkelijk internationale samenwerkingen mogelijk, waar-van onder andere hoofdstuk 5 het resultaat is. Bedankt de je mij zo laagdrempelig in jouw netwerk hebt toegelaten; dit heeft mij naast de leuke herinneringen aan de vele transatlantische en Europese tripjes ook waardevolle connecties in het veld opgeleverd. Naast al het inhoudelijke (inclusief de fysiologielesjes tijdens hartcatheterisaties) heb ik veel geleerd van jou als persoon. Je zorgvuldige, doortastende en optimistische houd-ing en het feit dat je me altijd vertrouwen gaf, hebben dit traject voor mij glans gegeven.

Prof. dr. H.L. Hillege. Beste Hans, mijn eerste kennismaking met jou was tijdens de voorbereiding van hoofdstuk 8. In mijn naïviteit veronderstelde ik dat het stuk zo’n beetje klaar zou zijn om voor het eerst in te sturen bij een journal, maar van jou moesten alle analyses anders... De ideeën waar je toen mee kwam fascineerden me enorm en hebben er toe geleid dat we sinds die dag veel meer uit de data van onze landelijke reg-istry kunnen halen. Jouw inbreng heeft dit proefschrift naar een hoger niveau gebracht. Bedankt voor je toegankelijkheid, behulpzaamheid en je persoonlijke belangstelling.

I would like to thank the members of the reading committee, prof. dr. S.H. Abman, prof. dr. R. Naeije and prof. mr. dr. A.A.E. Verhagen, for their evaluation of this thesis.

Het Centrum voor Congenitale Hartafwijkingen. Marc en Theresia, jullie rol bin-nen het PH expertisecentrum is onmisbaar, en uiteindelijk zijn jullie degenen die alle data verzamelen. Nynke en Gideon, bedankt voor jullie TEE-lesjes en jullie geduld met het buiten dit proefschrift vallende project over pulmonale vaatwanddynamiek. Beatrijs en Eryn, bedankt voor de gezellige borrels en jullie scherpe suggesties bij de diverse projecten. Elke, bedankt voor de gezelligheid op de HC en de samenwerking buiten dit proefschrift: onze OCT pogingen. De medewerkers van het echolab en de hartcatheter-isatie-afdeling wil ik bedanken voor de fijne leerzame samenwerking en de goede hulp. Ook het personeel van de zorgaminstratie en het stafsecretariaat kindercardiologie, voor de uitstekende ondersteuning, het helpen zoeken naar statussen en de praatjes in de wandelgangen. Monique, jij in het bijzonder bedankt voor het op je nemen van het meest uitdagende onderdeel van dit promotietraject: elke keer weer een gaatje vinden

264 Appendices

in Rolf’s agenda. Marlies, ik ben heel blij met jou als opvolger en ik kijk er naar uit om samen te werken.

Diverse publicaties zijn het resultaat geweest van verschillende samenwerkings-verbanden. De contactpersonen van het Landelijk Netwerk voor PH op de Kinderleeftijd; met een zeldzaam ziektebeeld als PAH moet je krachten bundelen. Dit proefschrift was er niet geweest zonder de waardevolle data uit ons gezamenlijke netwerk. Daarnaast de co-auteurs van het Erasmus MC, voor hun bijdrage aan hoofdstuk 7 (Jolien Roos-Hesselink, Annemien van den Bosch, Maarten Witsenburg, Lennie van Osch-Gevers). Chapter 5 is the result of a fruitful cooperation with our international colleagues: the board of the Association for Pediatric Pulmonary Hypertension (Dunbar Ivy, Damien Bonnet, Maurice Beghetti and Tilman Humpl), the French registry for pediatric PAH (Damien Bonnet, Xavier Iriart), the American REVEAL registry (Erika Rosenzweig, Dunbar Ivy), Actelion (Monika Brand, Erwan Muros-Le Rouzic) and Quanticate (Jeremy Wheeler, thanks for your statistical support). Usha en Erika, thanks for welcoming me in New York and for helping me scrutinize your Eisenmenger charts for our collaborative CHD project outside the current thesis. Dunbar, a special thanks to you, for being such a nice American. No matter where I went during this trajectory, I always kept running into you: TOPP-meetings in Barcelona and Chicago, ATS conferences in Philadelphia and San Diego, AEPC in Rome, even a PVRI-meeting in Bad Nauheim (of all places) and of course our home conferences in Groningen. Thanks for all our amusing lunches and dinners together!

Medebewoners van het triadegebouw, wat was ik blij dat ik daar niet in m’n eentje zat! Mijn naaste collega’s in het KZ00.22 keldertje: Menno en Willemijn, jullie zijn twee indrukwekkende dokters. Menno, bedankt voor je enthousiasme en gedrevenheid waarme je het stokje aan mij hebt overgedragen. Willemijn, je bent de meest punctuele en zorgvuldige persoon die ik ken. Floris-Jan en Djoeke, dank voor de gezelligheid! Vrienden Van de Rechter Kamer, Diederik, Guido, Quint, Lysanne, Annemarie, natuurlijk niet in de kelder maar op de eerste verdieping van de voormalige AZG directievleugel, met nieuw tapijt, wekelijkse schoonmaak en zelfs centrale verwarming! Bedankt dat de deur altijd openstond en dat wij mochten delen in jullie luxe, met liters koffie en kilo’s bitterballen. Guido, ik heb met jou de meest fantastische synergistische research samen-werking gehad, en hoop dat we die voortzetten! Ganggenoten, jullie waren samen met ons veroordeeld tot de allerdonkerste krochten van het triade: Marrit, Annemiek, Jozien, Michelle, Janyte, Karen, Rianne, Danique, Mirthe, Sara, Nicole, bedankt voor de praatjes op de gang en de huiselijkheid op jullie kelderkamertjes. De studenten / aanstaande colega’s die de afdaling naar de Triade-kelder aandurfden wil ik hartelijk danken voor de inzet en hulp bij de verschillende projecten: Jody, Lynn, Karel, Sanne, Sylvia, Jens, Elvira, Rakan en Fatema. Ook collega’s uit the early days van de kindercardiologie re-search groep (Michael, Reinout, Jan Renier), en collega’s van nog eerder bij de afdeling

265Dankwoord

cardiologie, zowel van de ischemiegroep (Iwan, Marthe, Youlan, Wouter W, Karim, Chris), als daarbuiten (Bart, Wouter te R, Jozine, Lennaert, Ruben, Vincent, Licette), veel dank! Vincent, dank voor de goede adviezen en je vernieuwende kijk op het leven.

De kinderartsen en collega arts-assistenten in het Medisch Centrum Leeuwarden. Het is een groot plezier om met jullie te werken. Dank voor het geduld en de toewijding waarmee jullie mij dit mooie vak proberen te leren!

Vrienden van dispuut FURORE en N.S.G. Anne en Sjoerd-Pieter, weldra wederom speciaalbiertjes als vanouds. Imhof en Hogeveen, de hoogste tijd voor een goed gesprek in een Utrechtse of Groningse kroeg. Jan-Paul, Tjeerd, Anne en Ronald, stelletje burg-ers, bedankt voor de inspirerende vrijdagavonden en nu allemaal opdonder’n met die mountainbikes ;). Jan Veninga, het is een behoorlijke geruststelling om naast mijn zus als kinderarts jou als advocaat aan mijn zijde te hebben bij de verdediging! Bedankt dat je me al sinds ons bestuursjaar jouw prachtige conservatieve versie van work hard / play hard probeert aan te leren.

Ruud en Serge, jullie hebben een rol gespeeld in mijn persoonlijke ontwikkeling gedurende dit promotietraject. Dank! Harmen, jonge, wat binne we moai fuort west net!? Bedankt voor de mooie uitstapjes, en dat ik voor alles bij jou terecht kan.

Mijn familie en schoonfamilie. Papa en mem, zonder jullie was ik niet geweest waar ik nu ben, in vele opzichten. Bedankt voor de vrijheid en het vertrouwen, ook als wij soms keuzes maken die jullie anders zouden maken. Andries, Rombout & Wieteke, Pake, bedankt voor jullie aanhoudende belangstelling voor mijn bezigheden. Andries, jouw wiskundeconsultaties heb ik in hoofdstuk 7 verwerkt! De avondjes in de pintelier waren te weinig hoor.. Wieteke, heel fijn om jou als kinderarts aan mijn zijde te hebben bij de verdediging. Uit een soort laat-puberale rebellie heb ik jarenlang geprobeerd niet al te veel in jouw voetsporen te treden en keuzes net iets anders te maken dan jij destijds gedaan hebt. Echter, het bloed kruipt waar het niet gaan kan, wij lijken nu eenmaal erg veel op elkaar! Je hebt een prachtig vak gekozen, en ik heb heel veel respect voor hoe jij de afgelopen jaren hebt doorlopen. Je bent een voorbeeld voor me en het is logisch dat je mijn paranimf primus bent. Pake, de libbensles “as it net kin sa’t it moat, dan moat it mar sa’t it kin” learde ik as lyts jonkje by pake yn ‘e skuorre. Tidens it promovearjen eltse dei ta te passen! Schoonfamilie, bedankt voor jullie aanhoudende geduld met een drukbezette schoonzoon / zwager. Bedankt dat jullie altijd voor ons klaar staan, of het nu gaat om trouwen of verbouwen. Conny, jij bedankt voor het vele oppassen op Hanna en Floor.

Sagha, Hanna en Floor, bij jullie is mijn thuis. We gaan op naar het volgende avontuur! Lieve Sagha, jij hebt mijn leven mooi gemaakt en ik ben er trots op dat je mijn vrouw bent.

267About the author

ABout the Author

Mark-Jan Ploegstra was born on May 12th 1987 in Dokkum, the Netherlands. He grew up in Zwagerbosch and attended primary school in Twijzelerheide. After finishing his secondary education at the Gymnasium of the Lauwers College in Buitenpost in 2005, Mark-Jan started Medical School at the University of Groningen.

Upon completion of his bachelor, he served a year as a board member of the Navigators Studentenvereniging Groningen. After this, he proceeded with his master’s research project at the department of cardiology of the University Medical Center Gron-ingen (UMCG). Here his interest in clinical research started while working on a project investigating the quality of secondary prevention after acute myocardial infarction. After clinical rotations at the UMCG and Medisch Centrum Leeuwarden, he completed his final clinical rotations at the department of cardiology of the UMCG and graduated from medical school in 2012. During his clinical training, he developed a particular inter-est in pediatric and congenital cardiology. Professor Rolf M.F. Berger offered him the opportunity to start a PhD project at the Center for Congenital Heart Diseases of the Beatrix Children’s Hospital, UMCG. As part of this 4-year project, Mark-Jan managed the Dutch National Network for Pediatric Pulmonary Hypertension. The research projects have resulted in the current thesis entitled “Prognostic factors, treatment goals and clini-cal endpoints in pediatric pulmonary arterial hypertension” which he plans to defend on March 1st 2017. He has presented his research at several international conferences. He participated in the organization committee of the 2nd European Conference on Neonatal and Pediatric Pulmonary Vascular Disease and he is a junior member of the Association for European Pediatric and Congenital Cardiology (AEPC).

Mark-Jan is currently working as a resident at the department of pediatrics of the Medisch Centrum Leeuwarden. It is his wish and ambition to become an academic pediatrician. He is married to Sagha Ploegstra-Jongsma and together they live in Haren with their two daughters Hanna and Floor.

269List of publications

lIst oF PuBlICAtIons

1. Bossers GPL, Hagdorn QAJ, Ploegstra MJ, Borgdorff MAJ, Silljé HHW, Berger RMF, Bartelds B. Systematic review of volume load-induced right ventricular dysfunction in animal models: a translational gap in congenital heart disease. Submitted.

2. Ploegstra MJ, Brokelman J, Roos-Hesselink JW, Douwes JM, Van Osch-Gevers LM, Hoendermis ES, Van den Bosch AE, Witsenburg M, Bartelds B, Hillege HL, Berger RMF. Pulmonary arterial stiffness indices assessed by intravascular ultrasound in children with early pulmonary vascular disease: prediction of advanced disease and mortal-ity during 20-year follow-up. European Heart Journal - Cardiovascular Imaging. 2017.

3. Zijlstra WM, Ploegstra MJ, Vissia-Kazemier T, Roofthooft MTR, du Marchie Sarvaas GJ, Bartelds B, Rackowitz A, Hillege HL, Plasqui G, Berger RMF. Physical activity in pediatric pulmonary arterial hypertension measured by accelerometry: a candidate clinical endpoint. American Journal of Respiratory and Critical Care Medicine. 2017;195.

4. Leberküne LJ, Ploegstra MJ, Douwes JM, Bartelds B, Roofthooft MT, Hillege HL, Berger RM. Serially measured uric acid levels predict disease severity and outcome in pediatric pulmonary arterial hypetension. American Journal of Respiratory and Critical Care Medicine. 2017;195.

5. Ploegstra MJ, Ivy DD, Wheeler JG, Brand M, Beghetti M, Rosenzweig EB, Humpl T, Iri-art X, Muros-Le Rouzic EM, Bonnet D, Berger RM. Growth in children with pulmonary arterial hypertension: a longitudinal retrospective multiregistry study. The Lancet Respiratory Medicine. 2016;4:281-90

6. Zijlstra WM, Douwes JM, Ploegstra MJ, Krishnan U, Roofthooft MT, Hillege HL, Ivy DD, Rosenzweig EB, Berger RM. Clinical classification in pediatric pulmonary arte-rial hypertension associated with congenital heart disease. Pulmonary Circulation. 2016;6:302-12.

7. Ploegstra MJ, Ivy DD, Wheeler JG, Brand M, Beghetti M, Rosenzweig EB, Humpl T, Iri-art X, Muros-Le Rouzic EM, Bonnet D, Berger RM. Growth in children with pulmonary arterial hypertension: a longitudinal multi-registry study. Cardiology in the Young. 2016;26:O6-1 (AEPC Conference 2016, Rome, Italy)

8. Ploegstra MJ, Zijlstra WM, Douwes JM, Hillege HL, Berger RM. Outcome in paediatric pulmonary arterial hypertension: a systematic review and meta-analysis. Cardiology in the Young. 2015;25:O1-1 (AEPC Conference 2015, Prague, Czech Republic)

9. Ploegstra MJ, Arjaans S, Zijlstra WM, Douwes JM, Vissia-Kazemier TR, Roofthooft MT, Hillege HL, Berger RM. Clinical worsening as composite study endpoint in pediatric pulmonary arterial hypertension. Chest. 2015;148:655-66

10. Ploegstra MJ, Berger RM. What’s the (end) point? European Respiratory Journal. 2015;45:854-5

270 Appendices

11. Ploegstra MJ, Zijlstra WM, Douwes JM, Hillege HL, Berger RM. Prognostic factors in pediatric pulmonary arterial hypertension: a systematic review and meta-analysis. International Journal of Cardiology. 2015;184:198-207

12. Ploegstra MJ, Roofthooft MT, Douwes JM, Bartelds B, Elzenga NJ, van der Weerd D, Hillege HL, Berger RM. Echocardiography in pediatric pulmonary arterial hyperten-sion: early study on assessing disease severity and predicting outcome. Circulation Cardiovascular Imaging. 2014;8:e000878

13. Zijlstra WM, Ploegstra MJ, Berger RM. Current and advancing treatments for pulmonary arterial hypertension in childhood. Expert Review of Respir Medicine. 2014;8(5):615-28

14. Ploegstra MJ, Douwes JM, Roofthooft MTR, Zijlstra WM, Hillege HL, Berger RM. Iden-tification of treatment goals in paediatric pulmonary arterial hypertension. European Respiratory Journal. 2014;44:1616-26

15. Ploegstra MJ, Arjaans S, Douwes JM, Zijlstra WM, Roofthooft MT, Berger RM. Definition and validation of clinical worsening as a composite endpoint in pediatric pulmonary arterial hypertension. European Heart Journal. 2014;35:Suppl264 (ESC Conference 2014, Barcelona, Spain)

16. Ploegstra MJ, Roofthooft MTR, Douwes JM, Bartelds B, Elzenga NJ, Van de Weerd D, Hillege HL, Berger RM. The value of echocardiography in pediatric pulmonary arterial hypertension: assessing disease severity and outcome. American Journal of Respira-tory and Critical Care Medicine. 2014;189:A3256(ATS Conference 2014, San Diego, US)

17. Ploegstra MJ, Douwes JM, Roofthooft MTR, Zijlstra WM, Hillege HL, Berger RM. Identification of treatment targets in pediatric pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine. 2014;189:A3255 (ATS Conference 2014, San Diego, US)

18. Douwes JM, Roofthooft MTR, Van Loon RLE, Ploegstra MJ, Bartelds B, Hillege HL, Berger RMF. Sildenafil add-on therapy in paediatric pulmonary arterial hypertension: experiences of a national referral centre. Heart. 2014;100:224-30.

19. Gerds-Ploeger HZ, Koster G, Hiemstra B, Ploegstra MJ, Kampinga MA, Lipsic E, Keus E, Van Gelder IC, Van der Harst P, Van der Horst IC. The effect of protocolized nurse-based care on guideline adherence in patients after acute myocardial infarction. Submitted.

20. Ploegstra MJ, Kampinga MA, Croon DH, Zijlstra F, Van der Horst IC. Secundaire preventie na myocardinfarct kan beter: medicatiegebruik conform de richtlijn op de lange termijn. Nederlands Tijdschrift voor Geneeskunde. 2010;154:2260-6.

Prognostic factors, treatment goals and clinical endpoints in pediatric pulm

onary arterial hypertension

· prognostic factors, treatment goals and clinical endpoints in pediatric pulmonary arterial...

Documents