american thoracic society documents...targeted pah therapy (strong recommendation, moderate-quality...

AMERICAN THORACIC SOCIETYDOCUMENTS

An Official American Thoracic Society Clinical Practice Guideline:Diagnosis, Risk Stratification, and Management of PulmonaryHypertension of Sickle Cell DiseaseElizabeth S. Klings*, Roberto F. Machado*, Robyn J. Barst†, Claudia R. Morris, Kamal K. Mubarak, Victor R. Gordeuk,Gregory J. Kato, Kenneth I. Ataga, J. Simon Gibbs, Oswaldo Castro, Erika B. Rosenzweig, Namita Sood, Lewis Hsu,Kevin C. Wilson, Marilyn J. Telen, Laura M. DeCastro, Lakshmanan Krishnamurti, Martin H. Steinberg, David B. Badesch,and Mark T. Gladwin; on behalf of the ATS Ad Hoc Committee on Pulmonary Hypertension of Sickle Cell Disease

THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY WAS APPROVED BY THE ATS BOARD OF DIRECTORS, NOVEMBER 2013. THESEGUIDELINES WERE ALSO ENDORSED BY THE AMERICAN COLLEGE OF CHEST PHYSICIANS, OCTOBER 2013, AND BY THE PULMONARY HYPERTENSION ASSOCIATION,NOVEMBER 2013

Background: In adults with sickle cell disease (SCD), an increasedtricuspid regurgitant velocity (TRV) measured by Dopplerechocardiography, an increased serum N-terminal pro–brainnatriuretic peptide (NT-pro-BNP) level, and pulmonaryhypertension (PH) diagnosed by right heart catheterization (RHC)are independent risk factors for mortality.Methods: A multidisciplinary committee was formed by clinician-investigators experienced in the management of patients with PHand/or SCD. Clinically important questions were posed, relatedevidence was appraised, and questions were answered with evidence-based recommendations. Target audiences include all clinicians whotake care of patients with SCD.Results:Mortality risk stratification guides decision making. Anincreased risk formortality is defined as a TRVequal to or greater than2.5m/second, anNT-pro-BNP level equal toor greater than160pg/ml,or RHC-confirmed PH. For patients identified as having increasedmortality risk, we make a strong recommendation for hydroxyurea as

first-line therapyandaweak recommendation for chronic transfusionsas an alternative therapy. For all patients with SCD with elevatedTRV alone or elevated NT-pro-BNP alone, and for patients with SCDwith RHC-confirmed PH with elevated pulmonary artery wedgepressure and low pulmonary vascular resistance, we make a strongrecommendation against PAH-specific therapy. However, for selectpatients with SCD with RHC-confirmed PH who have elevatedpulmonary vascular resistance andnormal pulmonary capillary wedgepressure, we make a weak recommendation for either prostacyclinagonist or endothelin receptor antagonist therapy and a strongrecommendation against phosphodiesterase-5 inhibitor therapy.

Conclusions: Evidence-based recommendations for themanagement of patients with SCD with increased mortality risk areprovided, but will require frequent reassessment and updating.

Keywords: sickle cell disease; mortality; pulmonary hypertension;dyspnea; hemolysis

ContentsOverviewIntroductionMethodsHow to Use These GuidelinesDefinition of PH in SCDDiagnosis of PH in SCD

Estimating Mortality Risk in SCDDoppler EchocardiographyN-Terminal Pro–Brain NatriureticPeptide

Rationale for Risk StratificationTreatment of Patients with SCD WhoHave Increased Mortality Risk

HydroxyureaChronic Transfusion TherapyChronic Anticoagulant TherapyAssociated ConditionsTargeted PAH Therapy

Future Directions

*E.S.K. and R.F.M. are co–first authors of this document.†Deceased.

E.S.K. receives support from NIH grant R21HL107993. M.T.G. receives research support from NIH grants R01HL098032, R01HL096973, RC1DK085852,and 1P01HL103455-01, the Institute for Transfusion Medicine, and the Hemophilia Center of Western Pennsylvania. R.F.M. receives support from NIH grantsK23HL098454 and R01HL111656-01.

This statement has an online supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org

Listen to accompanying podcast discussion at www.atsjournals.org

Am J Respir Crit Care Med Vol 189, Iss 6, pp 727–740, Mar 15, 2014

Copyright © 2014 by the American Thoracic Society

DOI: 10.1164/rccm.201401-0065ST

Internet address: www.atsjournals.org

American Thoracic Society Documents 727

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Overview

Pulmonary hypertension (PH) and right heartfailure are well-established risk factors formortality in sickle cell disease (SCD).Observational studies have consistentlyshown that increased tricuspid regurgitantjet velocity (TRV) measured by Dopplerechocardiography, an increased serumN-terminal pro–brain natriuretic peptide(NT-pro-BNP) level, and pulmonaryhypertension measured by right heartcatheterization are all independent risk factorsfor mortality in adults. To reduce thevariability and to improve the quality of carethat patients with SCD receive, we developedclinical practice guidelines to advisehematologists, pulmonologists, cardiologists,pediatricians, and internists about how toidentify and manage patients with SCD whoare at increased risk for mortality. We makethe following recommendations:

1. Risk stratification guides clinicaldecision making in SCD:a. Mortality risk can be accurately

determined by noninvasivemeasurement of the TRV viaDoppler echocardiography (see TableE1 in the online supplement). (Note:In children > 8 yr old the TRVdetermines morbidity risk, ratherthan mortality risk, and providesa baseline for future comparisons.)

b. Serum NT-pro-BNP measurement isa reasonable noninvasive alternativewhen Doppler echocardiography iseither unavailable or cannot obtainadequate images (Table E2). (Note:Measurements may be misleading inpatients with renal insufficiency.)

c. Mortality risk can also be determinedinvasively by direct hemodynamicmeasurements via right heartcatheterization (RHC).

2. An increased risk for mortality is defined asa TRV > 2.5 m/second, an NT-pro-BNPlevel > 160 pg/ml, or RHC-confirmedPH (a resting mean pulmonary arterialpressure > 25 mm Hg). Hemodynamicsin PH of SCD may be consistent with pre-or postcapillary PH or have features of both.

3. For patients with SCD who have anincreased risk for mortality, werecommend hydroxyurea (strongrecommendation, moderate-qualityevidence) (Table E3).

4. For patients with SCD who have anincreased risk for mortality and who

either are not responsive to or notcandidates for hydroxyurea, we suggestchronic transfusion therapy (weakrecommendation, low-quality evidence)(Table E4).

5. For patients with SCD who haveRHC-confirmed PH, venousthromboembolism, and no additionalrisk factors for hemorrhage, we suggestindefinite anticoagulant therapy ratherthan a limited duration of therapy(weak recommendation, low-qualityevidence) (Table E5).

6. For all patients with SCD who haveelevated TRV alone or elevated NT-pro-BNP alone, we recommend againsttargeted PAH therapy (strongrecommendation, moderate-qualityevidence). Targeted PAH therapycurrently includes prostacyclin agonist,endothelin receptor antagonist, andphosphodiesterase-5 inhibitor therapy.

7. For most patients with SCD who haveRHC-confirmed PH, we recommendagainst targeted PAH therapy (strongrecommendation, moderate-qualityevidence).

8. For select patients with SCD who haveRHC-confirmed marked elevation oftheir pulmonary vascular resistance,normal pulmonary artery wedgepressure, and related symptoms, wesuggest a trial of either a prostacyclinagonist or an endothelin receptorantagonist (weak recommendation, verylow-quality evidence).

9. For patients with SCD who have RHC-confirmed marked elevation of theirpulmonary vascular resistance, normalpulmonary artery wedge pressure, andrelated symptoms we recommendagainst phosphodiesterase-5 inhibitortherapy as a first-line agent (strongrecommendation, moderate-qualityevidence).

Introduction

Pulmonary hypertension (PH) is commonand associated with increased morbidity andmortality in sickle cell disease (SCD)(1, 2). In the past, many patients with SCDdied during childhood or early adulthoodbefore the development of PH. However,now that SCD-specific therapies exist,more patients are surviving long enough todevelop PH. Right heart catheterization(RHC) studies indicate that the prevalence

of PH in SCD is 6–11%, which is similar tothat observed in systemic sclerosis (1–3).

An elevated tricuspid regurgitant jetvelocity (TRV) detected by Dopplerechocardiography is a well-known indicatorof possible PH and predicts mortality inpatients with SCD. Studies indicate thata TRV 2 standard deviations above thenormal age-adjusted mean value occurs inapproximately 30% of hemoglobin SS(HbSS) and 10–25% of hemoglobin SC(HbSC) adults. HbSS adults with evena modest elevation in TRV have decreasedsurvival, estimated to be only 40% at 40months (4–7). In addition, 10–20% of thepediatric SCD population have an elevatedTRV, although the effects on survival areunclear (8, 9).

Despite the prevalence of PH and anelevated TRV in patients with SCD, as wellas the association of each with mortality,a standardized approach to identifying andmanaging such patients does not exist. Toreduce the variability and to improve thequality of care that patients with SCDreceive, we developed clinical practiceguidelines to advise hematologists,pulmonologists, cardiologists, pediatricians,and internists about how to identify andmanage patients with SCD who are atincreased risk for mortality. The discussionthat follows describes the definition anddiagnosis of PH in SCD, mortality riskassessment, and treatment. Epidemiology,pregnancy, and issues related to thepediatric population are reviewed in theonline supplement.

Methods

The methods used to develop this guidelineare summarized in Table 1 and described inthe online supplement.

How to Use These Guidelines

These American Thoracic Society guidelinesabout the diagnosis, risk stratification,and management of SCD-PH are notintended to impose a standard of care. Theyprovide the basis for rational decisions in themanagement of patients with SCD whohave an increased risk for death, as definedby an elevated TRV, elevated serumN-terminal pro–brain natriuretic peptide(NT-pro-BNP) level, or RHC-confirmedPH. Clinicians, patients, third-party payers,

AMERICAN THORACIC SOCIETY DOCUMENTS

728 American Journal of Respiratory and Critical Care Medicine Volume 189 Number 6 | March 15 2014

institutional review committees, otherstakeholders, or the courts should neverview these recommendations as dictates.No guidelines and recommendations cantake into account all of the often compellingunique individual clinical circumstances.Therefore, no one charged with evaluatingclinicians’ actions should attempt to applythe recommendations from these guidelinesby rote or in a blanket fashion. Statementsabout the underlying values andpreferences as well as qualifying remarksaccompanying each recommendation areits integral parts and serve to facilitate moreaccurate interpretation. They should neverbe omitted when quoting or translatingrecommendations from these guidelines.

Definition of PH in SCD

PH is defined as a resting mean pulmonaryarterial pressure (mPAP) equal to orexceeding 25 mm Hg. Although 6–11%of patients with SCD have PH by thisdefinition, the hemodynamics observedvary across patients. As a result, soon tobe published guidelines for the diagnosisand treatment of PH have placed itwithin group 5 PH (10). In some patients,there is predominantly precapillary PH.In others, hemodynamics are moreconsistent with postcapillary PH. Some

patients have hemodynamics with featuresof both.

Precapillary PH associated with SCD isdefined similarly to other types of group 1PAH: an mPAP of at least 25 mm Hgwith a mean pulmonary artery wedgepressure (PAWP) or left ventricular end-diastolic pressure less than or equal to15 mm Hg, plus increased pulmonaryvascular resistance (PVR). However, whatconstitutes increased PVR is different inSCD-related PAH compared with othertypes of group 1 PAH because patients withSCD have an anemia-induced elevation oftheir cardiac output and reduction intheir blood viscosity, which result in a lowerbaseline PVR than observed in nonanemicpatients (11).

This is illustrated by the followingobservations. In idiopathic PAH, increased PVRis defined as at least 240 dyn$ seconds$ cm25

(3 Wood units), which is 2 standarddeviations above the PVR of 80–120dyn $ seconds $ cm25 (1 Wood unit) orless observed in healthy volunteers.However, three studies (2, 3, 12) thatmeasured hemodynamic values in adultswith SCD via RHC (Table 2) found thatadults without PH had a mean cardiacoutput of 8–9 L/minute with a PVR of72–74 (625–38) dyn $ seconds $ cm25. Inthe absence of a consensus definition ofwhat constitutes an elevated PVR in SCD,most clinicians consider values that are 2–3

standard deviations above normal(i.e., approximately >160 dyn $ s $ cm25

[2 Wood units]) as indicative of a high PVR.Postcapillary PH occurs in SCD when the

left atrial pressure and, therefore, the pulmonaryvenous pressure (i.e., the mean PAWP or leftventricular end-diastolic pressure) is greaterthan 15 mm Hg (in the absence of mitral valvedisease) without an increase in PVR (13).

Patients with SCD frequently havehemodynamics with features of both pre-and postcapillary PH. This is characterizedby a mean PAP of 25 mm Hg or more,a PAWP greater than 15 mm Hg, and anincreased PVR. These patients often havean elevated transpulmonary gradient orPA diastolic pressure 2 pulmonary arterywedge pressure difference (.12 mm Hg)reflective of reactive precapillary PH (12).

Diagnosis of PH in SCD

Noninvasive tests are frequently performedto determine whether or not PH might bepresent. However, such tests are notsufficiently accurate to replace directhemodynamic measurements in patientswith SCD. Therefore, the diagnosis of PHrequires RHC.

Doppler echocardiography is one suchnoninvasive test (Figure 1). It evaluates theheart for abnormalities suggestive of PH,such as right atrial enlargement, rightventricular dilation or hypertrophy,tricuspid regurgitation, and/or a right-to-left septum shift. It also measures the TRVand uses this to estimate the pulmonaryartery systolic pressure. Although anattractive option because it is noninvasiveand readily available in most institutions,Doppler echocardiography is imperfect asa diagnostic test. This has been illustratedby a study of a population of patients withSCD with a prevalence of PH of 6%; thepositive predictive value for PH was only25% among patients with a TRV of at least2.5 m/second, although this improved to64% when a TRV greater than 2.9 m/second was used as the threshold instead.The positive predictive value of Dopplerechocardiography was also improved bycombining it with other tests. Thecombination of a TRV of at least 2.5 m/second and either an NT-pro-BNP levelgreater than 164 pg/ml or a 6-minute walkdistance less than 333 m improved thepositive predictive value to 62% (2).Because only positive results were reported,

Table 1: Overview of Methods Used for Guideline Development

Yes No

Panel assemblyd Included experts for relevant clinical and nonclinical disciplines Xd Included individual who represents the views of patients and society at large Xd Included a methodologist with appropriate expertise (documented expertisein conducting systematic reviews to identify the evidence base and thedevelopment of evidence-based recommendations)

X

Literature reviewd Performed in collaboration with librarian Xd Searched multiple electronic databases Xd Reviewed reference lists of retrieved articles X

Evidence synthesisd Applied prespecified inclusion and exclusion criteria Xd Evaluated included studies for sources of bias Xd Explicitly summarized benefits and harms Xd Used PRISMA1 to report systematic review Xd Used GRADE to describe quality of evidence X

Generation of recommendationsd Used GRADE to rate the strength of recommendations X

Definition of abbreviations: GRADE = Grading of Recommendations Assessment, Development, andEvaluation; PRISMA1 = Preferred Reporting Items for Systematic Reviews and Meta-Analyses,version 1.



it is not possible to estimate how manyresults were negative. In another study,a TRV of at least 2.5 m/second identifiedPH with a sensitivity and specificity of78 and 19%, respectively. The sensitivitydecreased but the specificity increasedto 67 and 81%, respectively, when a TRVof at least 2.88 m/second was usedinstead (14).

Serum NT-pro-BNP measurement isanother noninvasive test that is imperfectdiagnostically. It is a marker of right and leftventricular strain whose diagnosticcharacteristics have not been extensivelystudied. Most studies that evaluated thediagnostic characteristics of NT-pro-BNPwere limited because they used an elevatedTRV as the reference standard for PH,rather than direct hemodynamicmeasurements. As an example, a study of230 patients with SCD found that a serumNT-pro-BNP level of at least 160 pg/mldetected PH with a sensitivity and specificityof 57 and 91%, respectively (15). Anotherstudy of 84 patients with HbS/b-thalassemia similarly reported thata serum NT-pro-BNP level of at least153.6 pg/ml identified PH with a sensitivityand specificity of 85.7 and 94.6%,respectively (16). Limitations of thesestudies are that they did not use right heartcatheterization to define PH.

Additional details about the diagnosticperformance of Doppler echocardiographyand NT-pro-BNP are provided in theonline supplement, as are the roles of thehistory, physical examination, chestimaging, and laboratory and pulmonaryfunction testing in the evaluation ofsuspected PH. Table 3 provides samplequestions that a provider can use to elicita history of dyspnea, and Figure 2provides a suggested diagnostic algorithmfor PH of SCD.

Estimating Mortality Riskin SCD

Confirmed PH is an accepted risk factorfor mortality regardless of whether thepatient has SCD (12) or does not haveSCD. It should be noted that PH is anindependent risk factor for death ina diverse array of human diseases, fromhereditable PH, to PH secondary tosystemic sclerosis, HIV infection, portalhypertension, interstitial lung disease,and chronic obstructive pulmonarydisease (17–24). The problem with usingRHC for primary screening riskstratification is that the approach is notacceptable to many patients because it isinvasive and expensive. Noninvasive

alternatives include measurement of theestimated pulmonary artery systolicpressure (calculated from the TRV)via Doppler echocardiography andmeasurement of the serum NT-pro-BNP.These tests identify patients at higherrisk of having PH by right heartcatheterization and for increasedmortality.

Doppler EchocardiographyWe performed a systematic review to lookfor studies that evaluated how accuratelyDoppler echocardiography identifiespatients with SCD with an increasedmortality risk (Table E6). The reviewidentified three studies in adults and onein children (Figure E1 and Table E1)(4, 9, 25, 26).

The first study in adults reported thatthe mortality risk among patients witha TRV of at least 2.5 m/second was 10.1(95% confidence interval [CI], 2.2–47.0)times greater than that observed amongpatients with a TRV less than 2.5 m/second(4). A follow-up analysis demonstrated thatthe degree of TRV elevation correlatedwith mortality: among patients with a TRVof 2.5–2.9 m/second and patients witha TRV of at least 3.0 m/second, the riskratio for mortality was 4.4 (95% CI,1.6–12.2) and 10.6 (95% CI, 3.3–33.6),respectively (27). These findings weresupported by two subsequent adult studiesthat similarly found a 5.1 (95% CI,2.0–13.3) to 5.9 (95% CI, 1.7–20.8) timesincreased risk of mortality among patientswith a TRV of at least 2.5 m/second(Table E1) (25, 26). The study in childrenhad few events (i.e., deaths) and, therefore,could not detect a similar mortality riskamong children with an elevated TRV(after only 22 mo of follow-up) (9). All ofthe studies had wide confidence intervalsaround the estimates, indicatinguncertainty about the exact magnitude ofthe increased risk of death among patientswith an increased TRV.

Assuming mortality rates ofapproximately 2, 10, and 20% for adults witha TRV less than 2.5 m/second, 2.5–2.9m/second, and 3.0 m/second or more,respectively (27), and a 42% (95% CI,15–61%) relative reduction in mortality dueto hydroxyurea (Table E3), the expectedabsolute mortality reduction due tohydroxyurea therapy is 8 per 1,000 patients(95% CI, 3–12) among adults with a TRVless than 2.5 m/second, 42 per 1,000

Table 2: Hemodynamic Profiles of Patients with Sickle Cell Disease with or withoutPulmonary Hypertension: Three Cohorts*

PH No PH P Value

NIH cohort n = 56 n = 30CVP, mm Hg 10 6 5 6 6 3 ,0.001mPAP, mm Hg 36 6 9 19 6 4 ,0.001PAWP, mm Hg 16 6 5 12 6 3 ,0.001CO, L/min 8 6 3 9 6 2 0.14CI, L/min/m2 5 6 1 5 6 1 0.063PVR, dyn $ s $ cm25 229 6 149 74 6 38 ,0.001

French cohort n = 24 n = 72CVP, mm Hg 10 6 6 7 6 2 ,0.001mPAP, mm Hg 30 6 6 19 6 3 ,0.001PAWP, mm Hg 16 6 7 11 6 3 ,0.001CO, L/min 8.7 6 1.9 8.4 6 2.1 0.60PVR, dyn $ s $ cm25 138 6 58 72 6 26 ,0.001

Brazilian cohort† n = 8 n = 18mPAP, mm Hg 33.1 6 8.9 18.7 6 2.8 ,0.001PAWP, mm Hg 16.0 6 5.7 13.3 6 2 0.07CI, L/min/m2 5 6 1.36 4.9 6 1.7 0.85PVR, dyn $ s $ cm25 179 6 120 64 6 48 0.002

Definition of abbreviations: CI = cardiac index; CO = cardiac output; CVP = central venous pressure;mPAP = mean pulmonary artery pressure; NIH = National Institutes of Health; PAWP = pulmonaryartery wedge pressure; PVR = pulmonary vascular resistance.*From References 2, 3, and 12.†CVP data not provided for Brazilian cohort.



patients (95% CI, 15–61) among adultswith a TRV of 2.5–2.9 m/second, and84 per 1,000 patients (95% CI, 30–122)among adults with a TRV of at least3.0 m/second. These estimates should beinterpreted cautiously given the uncertaintyabout the exact magnitude of the increasedrisk of death among patients with anincreased TRV and the low confidencein the estimated reduction in mortalitywith hydroxyurea (Table E3). Similarcalculations could be performed for the

other benefits of hydroxyurea therapy(i.e., decreased hospitalizations, fewervaso-occlusive crises, and fewer episodesof acute chest syndrome) that aredescribed below.

The committee members routinelyperform risk stratification on their patientswith SCD by measuring the TRV viaDoppler echocardiography. This reflects thecommittee’s opinion, that the potentialfor an at least 4% absolute reduction inmortality (and the other effects of therapy)

among adults who are identified as havinga TRV of at least 2.5 m/second and arethen treated with hydroxyurea outweighsthe costs and burdens of testing, the impactof erroneous test results (i.e., unnecessarytherapy for false-positive results), andthe risks of subsequent treatment(i.e., neutropenia requiring temporarydiscontinuation of therapy followed by dosereduction). The committee also recognizesthat identification of an increased mortalityrisk affects the way a physician managesa patient in ways that cannot be measured;for example, the physician may moreaggressively manage coexisting diseasesand may also avoid some treatments ofcomorbid diseases that could be hazardousto the patient who is at higher mortalityrisk. An elevated TRV also identifiespatients at increased risk for a number ofconditions, such as venous thromboembolicdisease and sleep-disordered breathing,with effective therapies. This is particularlythe case for pulmonary thromboembolicdisease. Patients with elevated TRV are athigher risk of having a high-probabilityventilation–perfusion scan and chronicthromboembolic pulmonary hypertension(28), amenable to anticoagulation andconsideration of pulmonary endarterectomy.

The TRV should be measured byDoppler echocardiography, using the sameconditions as the studies described previously,because the TRV varies according to theclinical status of the patient (i.e., the TRVmaybe acutely and transiently increased during anacute illness such as a vaso-occlusive crisis[VOC] or acute chest syndrome [ACS]) (29).Therefore, Doppler echocardiography shouldbe performed when the patient is in a stableclinical state, defined as more than 4 weeksafter hospitalization for ACS and more than2 weeks after hospitalization for a VOCor a blood transfusion that is part of a chronictransfusion program.

The optimal frequency of Dopplerechocardiography is unknown. Longitudinalstudies of adults with SCD suggestthat 13% of those with a normalechocardiogram develop an elevated TRVafter approximately 3 years of follow-up(5). On the basis of these studies,echocardiography every 1 to 3 yearsseems reasonable.

In children, we perform a Dopplerechocardiogram to obtain a baselinefor subsequent comparisons and toidentify children who have an increasedmorbidity risk (the Pulmonary Hypertension

Figure 1. Echocardiogram of a patient with pulmonary hypertension related to sickle cell disease,and determination of tricuspid regurgitant jet velocity. (A) As demonstrated in this echocardiogramof a patient with an estimated pulmonary artery systolic pressure of 44 mm Hg, in patients withpulmonary hypertension of sickle cell disease there is dilation of the right ventricular (RV) chamber sothat it is larger than the left ventricle (LV) with shift of the interventricular septum into the LV. (B)Doppler flow of tricuspid regurgitation (demonstrated in blue) from the right ventricle (RV) into the rightatrium (RA). The velocity of this flow is measured and allows for calculation of an estimated pulmonaryartery systolic pressure. HR = heart rate; p = pressure; TR maxPG = peak gradient of tricuspidregurgitation; TR Vmax = tricuspid regurgitation peak velocity; v = velocity.



and the Hypoxic Response in Sickle CellDisease [PUSH] trial demonstrated thatchildren and adolescents with an elevatedTRV and severe hemolytic anemia were athighest risk for a decreased 6-minute walkdistance after 2 years of follow-up [9]).

N-Terminal Pro–BrainNatriuretic PeptideWe performed similar systematic reviews ofthe literature to identify evidence relevant tothe use of NT-pro-BNP levels to assessmortality risk in patients with SCD (TableE7). Two relevant studies were identified(15, 30) (Figure E2 and Table E2), one ofwhich included two separate cohorts ofconsecutive adults with SCD. In one cohort,the degree of NT-pro-BNP elevationcorrelated with mortality: among patientswith an NT-pro-BNP level not exceeding30 pg/ml, 31–159 pg/ml, and at least 160pg/ml, respectively, mortality was 6, 7, and26%. The mortality risk among adultswith an NT-pro-BNP level of at least160 pg/ml was 5.1 (95% CI, 2.1–12.5) timesgreater than that observed amongpatients with an NT-pro-BNP level lessthan 160 pg/ml. In the other cohort, thedegree of NT-pro-BNP elevation alsocorrelated with mortality: among patientswith an NT-pro-BNP level not exceeding30 pg/ml, 31–159 pg/ml, and at least160 pg/ml, respectively, mortality was 6, 17,and 49%. The risk of mortality was 2.9

(95% CI, 1.2–6.6) times greater amongpatients with an NT-pro-BNP level of atleast 160 pg/ml compared with those withlower levels of NT-pro-BNP (15). Thesefindings were confirmed by a study of 330adults recruited as part of the CooperativeStudy of Sickle Cell Disease, in which anNT-pro-BNP level of at least 160 pg/ml wasassociated with a relative risk of death of6.24 (95% CI, 2.9–13.3) compared withthose with lower levels (30).

Assuming mortality rates of 6, 7, and26% for adults with an NT-pro-BNP levelnot exceeding 30 pg/ml, 31–159 pg/ml,and at least 160 pg/ml, respectively, anda 40% relative reduction in mortality due tohydroxyurea (Table E3), the expectedabsolute mortality reduction due tohydroxyurea is 24 per 1,000 patients amongadults with an NT-pro-BNP level notgreater than 30 pg/ml, 28 per 1,000patients among adults with an NT-pro-BNP level of 31–159 pg/ml, and 104 per1,000 patients among adults with an NT-pro-BNP level of at least 160 pg/ml. Theseestimates should be interpreted cautiouslygiven the uncertainty about the magnitudeof the increased risk of death amongpatients with an increased NT-pro-BNPlevel and the low confidence in theestimated reduction in mortality withhydroxyurea. Similar calculations could beperformed for the other benefits ofhydroxyurea therapy (i.e., decreasedhospitalizations, fewer vaso-occlusivecrises, and fewer episodes of acute chestsyndrome) that are described below.

Serum NT-pro-BNP is generallymeasured in adults with SCD when Dopplerechocardiography is either unavailable orunable to obtain adequate images. In thecommittee’s opinion, the anticipated 10.4%(or more) absolute reduction in mortality(and the other effects of therapy) amongadults who are identified as having anNT-pro-BNP level of at least 160 pg/mland are then treated with hydroxyureaoutweighs the costs and burdens of testing,the impact of erroneous test results(i.e., unnecessary therapy for false-positiveresults), and the risks of subsequenttreatment (i.e., neutropenia requiringtemporary discontinuation of therapyfollowed by dose reduction). Thecommittee also recognizes thatidentification of an increased mortalityrisk affects the way a physician managesa patient in ways that cannot be measured;for example, the physician may more

aggressively manage coexisting diseasesand may also avoid some treatmentsof comorbid diseases that could behazardous to the patient who is at highermortality risk.

An important exception to ourrecommendation is patients with renaldisease. Renal dysfunction is independentlyassociated with high NT-pro-BNP levels(15, 30) and, thus, testing is more likely toprovide false-positive results in patientswith renal dysfunction than in patients withnormal renal function. In such patients, it ispossible that the undesirable consequencesof false-positive results (i.e., unnecessarytherapy and the risks associated with it)might exceed the benefits of NT-pro-BNPtesting. Until the impact of renaldysfunction on NT-pro-BNP levels isfurther studied, we suggest that NT-pro-BNP testing not be used in patients withrenal dysfunction.

Rationale for Risk StratificationIdentifying patients at increased risk formortality is important because it guidesdecision making. Specifically, it identifiespatients who may benefit from SCD-specific therapies that have been shownto improve outcomes in patients withvarious complications of SCD, asillustrated previously with hydroxyurea.Risk stratification also allows patients

Table 3: Sample Questions forEvaluation of Dyspnea

1. Do you get short of breath at rest?2. Do you get short of breath with minimal

exertion? (e.g., walking across a room,doing light housework, putting on yourshoes, talking on the telephone)

3. How far can you walk before stoppingdue to shortness of breath?

4. How far can you walk on an inclinebefore stopping?

5. How many flights of stairs can you climbbefore stopping?

6. For how long have you felt short ofbreath?

7. Do you have chest pain with exertion?8. Do you have any trouble breathing while

you sleep or lie flat in bed?9. Have you ever passed out?

10. Have you ever felt you were about topass out?

11. Do you have any dizziness orlight-headedness at rest or withexertion?

12. Do you have swelling in your legs?13. Do you have swelling in your abdomen?

Conclusions from theCommittee:d Risk stratification guides decision

making.d Mortality risk can be determined

by noninvasive measurementof the TRV via Dopplerechocardiography.

d Serum NT-pro-BNP measurementis a reasonable noninvasivealternative if Dopplerechocardiography is eitherunavailable or cannot obtainadequate images. (Note:Measurements may be misleadingin patients with renal insufficiency.)

d Mortality risk can also bedetermined invasively by directhemodynamic measurements viaright heart catheterization.



to anticipate their future healthcare needs.

Treatment of Patients withSCD Who Have IncreasedMortality Risk

Patients with SCD who have beendetermined to have an increased mortalityrisk (i.e., TRV > 2.5 m/s, NT-pro-BNP >160 pg/ml, or RHC-confirmed PH) maybenefit from referral to an experiencedPH center (preferably with expertise inSCD as well) so that they can be comanagedby clinicians with experience in both PHand SCD.

HydroxyureaMild SCD genotypes (such as HbSC) havea lower prevalence of PH and mortality thansevere SCD genotypes (such as HbSS).This suggests that decreasing sickle cellformation and hemolysis (31–33) mayimprove PH and mortality in patients with

SCD. Hydroxyurea (HU) is an agent thathas been shown to reduce both sickle cellformation and hemolysis.

We performed a systematic review ofthe literature to identify studies pertinent tothe decision about whether patients withSCD with an increased risk for mortality(i.e., TRV > 2.5 m/s, NT-pro-BNP > 160pg/ml, or RHC-confirmed PH) should betreated with HU. Our search and selectioncriteria are shown in Table E8. Thesearch criteria were intentionally broadbecause we anticipated that there would beminimal direct evidence and, therefore,we wanted to capture relevant indirectevidence. The review identified threerelevant randomized trials (34–36) and twocase series (37, 38) (Figure E3).

The largest trial (the MulticenterStudy of Hydroxyurea in Sickle CellAnemia [MSH] trial) randomly assigned299 adults with SCD (HbSS genotype) andthree or more VOC per year to receive HUor placebo (35). Patients who received HUwere less likely to have an episode of ACS,

had a lower annual rate of VOC, hada longer duration until their first andsecond crises, and required fewertransfusions.

With respect to mortality, there wasno difference in mortality during the trial(2 of 152 [1.3%] vs. 5 of 147 [3.4%]).However, during a subsequent extensionstudy, there was a significant reduction inmortality at 9 years among patients whoreceived HU for at least 1 year comparedwith those who either did not receive HU orreceived HU for less than 1 year (21 vs.36.3%; relative risk [RR], 0.58; 95% CI,0.39–0.85). Similarly, at 17 years, there wasa significant decrease in mortality whenpatients who received HU for at least 5years were compared with those who eitherdid not receive HU or who received HUfor less than 5 years (30.4 vs. 51.1%; RR,0.60; 95% CI, 0.44–0.81). At both 9 and17 years, there was no significant differencein mortality when patients who receivedHU for any duration were compared withpatients who never received HU, suggesting

Figure 2. Proposed algorithm for evaluation of pulmonary hypertension related to sickle cell disease. 6MWD = 6-minute walk distance;ANA = anti-nuclear antibody; CXR = chest X-ray; EKG = electrocardiogram; LFTs = liver function tests; mPAP = mean pulmonary artery pressure;NT-pro-BNP = N-terminal pro–brain natriuretic peptide; PAWP = pulmonary artery wedge pressure; PH = pulmonary hypertension; PVR = pulmonaryvascular resistance; SCD = sickle cell disease; TRV = tricuspid regurgitant jet velocity. 1Note: The use of the term screening refers to mortality riskassessment. Echocardiography should be performed while patients are clinically stable. Patients with an mPAP between 20 and 25 mm Hg needfurther study as they may be at increased mortality risk. Note: PAH therapy is to be considered on the basis of a weak recommendation and verylow-quality evidence.



that prolonged therapy may be necessaryto achieve a clinical benefit (39, 40).

Patients who received HU during theMSH trial also had improvement in somemeasures of quality of life (i.e., socialfunction and general health perception)(37). Hydroxyurea therapy was notassociated with an increased incidence ofbirth defects (38), infection (40), stroke(40), or neoplasia (40). Bone marrowsuppression (i.e., decreased counts in oneor more cell lines) occurred in mostpatients, but resolved within 2 weeks oftemporary discontinuation of therapy(40). Therapy was later resumed ata lower dose.

Another trial enrolled 25 children andyoung adults with SCD (HbSS genotype)and a history of at least three VOC over theprevious year, stroke, or ACS (36). Thepatients were randomly assigned to receiveHU or placebo for 6 months and thencrossed over to the other arm of the trial;those who received HU were significantlyless likely to require hospitalization.Adverse effects were not reported, althoughthere was a significant decrease in theneutrophil count following the initiation ofHU therapy (from a mean of 12.47 3 109/Lto a mean of 8.90 3 109/L).

Finally, a trial that randomly assigned193 very young (,18 mo) children withSCD (HbSS genotype) to receive either HUor placebo found that HU decreasedhospitalizations, episodes of VOC, andepisodes of ACS (34). Mild to moderateneutropenia (i.e., an absolute neutrophilcount of 500–1,249/mm3) was significantlymore common among the HU group (46.9vs. 18.6%; RR, 2.53; 95% CI, 1.58–4.03)and required long-term dose reductions innine patients. Severe neutropenia(i.e., absolute neutrophil count , 500/mm3) was rare and not complicated byinfection. There were no other adverseeffects reported.

On the basis of these studies, it is widelyaccepted that HU is indicated for patientswith SCD who have the HbSS genotype andleast three VOC per year or at least oneepisode of ACS (41). Our consensus is thatthe studies are also applicable to patientswith an increased risk for mortality(i.e., TRV > 2.5 m/s, NT-pro-BNP > 160pg/ml, or RHC-confirmed PH). Thisreflects our recognition that VOC, ACS,PH, elevated TRV, and elevated NT-pro-BNP are all established independent riskfactors for death among patients with SCD.

Furthermore, there is now a well-characterized interaction between acuteepisodes of ACS and death from PH andcor pulmonale in patients with sickle celldisease (2). ACS and VOC increasepulmonary pressures acutely and canprecipitate right-sided heart failure;patients with ACS and right heart failureare at increased risk of death both duringand after that hospitalization (2, 29). Ahistory of heart failure was an independentrisk factor for mechanical ventilation inpatients with ACS in the National AcuteChest Syndrome Study Group (odds ratio,0.67; 95% CI, 2.1–22.3; P = 0.002) (42) andboth VOC and ACS increase the risk formortality in patients with SCD with PH(12). Both these study results and theexperience of the committee membersstrongly suggest that intermittentepisodes of acute chest syndrome clearlyworsen outcomes of patients withestablished PH and right heartdysfunction, and this can be prevented byHU therapy.

The committee recognizes that the useof such indirect evidence to informjudgments is controversial, with someindividuals contending that theindirectness is so minor that it should haveno impact on our confidence in theestimated effects and others arguing thatthe indirectness is so profound that theevidence should not be used. The finaljudgment of the committee was tocompromise; that is, to apply the evidencein our decision making, but to lowerthe quality of evidence to reflect theindirectness of the population. The caseseries support this extrapolation ofevidence, finding that HU treatment ofpatients with SCD with elevated TRVproduces a decline in TRV (31, 32). Thisoccurred most often in children and youngadults with a mild TRV elevation inwhom HU increased the fetal hemoglobinto more than 20%.

We recommend HU therapy for HbSSpatients who have an increased risk formortality (i.e., TRV > 2.5 m/s, NT-pro-BNP > 160 pg/ml, or RHC-confirmed PH)because the numerous desirableconsequences of HU therapy (12.3%decrease in 9-yr mortality, 23% reductionin hospitalizations, 15.4% fewer episodesof ACS, and fewer episodes of VOC)substantially outweigh the undesirableconsequences (bone marrow suppression,cost, and burden) (Table E3). The bone

marrow suppression is generally mild,resolves when the HU is held, and ismanaged by dose reduction.

The recommendation is strong becausethe committee is certain that the desirableeffects of HU outweigh the undesirableeffects in the population for which therecommendation is intended. Our certaintyderives from both the greater patient-importance of the desirable consequencesthan the undesirable consequences, as wellas our moderate confidence in the estimatedeffects. The quality of evidence ismoderate because our critical outcomeswere estimated from randomized trialsdowngraded for indirectness of thepopulation (Table E3).

Chronic Transfusion TherapyChronic scheduled transfusion of packedred blood cells is effective in reducingmost complications of SCD by decreasingboth the burden of sickle erythrocytesand the hemolytic rate (33). The HbSlevel can be reduced to less than 50%within weeks by simple transfusions orwithin hours by erythrocytapheresis, asopposed to the months usually requiredfor the gradual titration of HU to reachoptimal fetal hemoglobin levels. A goalhemoglobin concentration of 10–12 g/dlis often attainable via chronictransfusion therapy.

We performed a systematic review ofthe literature to identify studies pertinentto the decision about whether patientswho have SCD and either RHC-confirmedPH or an increased risk for mortality(i.e., TRV > 2.5 m/s or NT-pro-BNP >160 pg/ml) should be managed with

Recommendation: For patients withSCD who have an increased risk formortality, we recommend hydroxyureatherapy (strong recommendation,moderate-quality evidence).

Remarks: We define an increased riskfor mortality as a TRV of >2.5 m/second, an NT-pro-BNP level of >160pg/ml, or RHC-confirmed PH.

Values and preferences: Thisrecommendation attaches a relativelyhigh value to the potential benefitsfrom therapy and a lower value to therisks and burdens of therapy.



chronic transfusion therapy. Our searchand selection criteria are listed in Table E9.The search criteria were intentionallybroad because we anticipated that therewould be minimal direct evidence and,therefore, we wanted to capture relevantindirect evidence. The review identifiedtwo relevant randomized trials, the StrokePrevention in Sickle Cell Anemia (STOP)-1 and -2 trials (43–45); and a case series(46, 47) (Figure E4). Long-term follow-upreports of the STOP-1 trial were alsoidentified (45, 48).

Both randomized trials enrolledchildren with SCD and a transcranialDoppler velocity greater than 200 cm/second in the middle cerebral or internalcarotid artery, findings that place them atincreased risk for a stroke. The trialscompared mortality and stroke rates amongchildren who received either chronictransfusion therapy or standard care.Chronic transfusion therapy significantlyreduced the stroke rate (1 vs. 12%; oddsratio, 0.10; 95% CI, 0.02–0.58), but had noeffect on mortality (48). Long-term follow-up of patients from the STOP-1 trialsuggested that chronic transfusions mayimprove children’s growth (49) andreduced the frequency of ACS and VOC(50) (Table E4).

Chronic transfusion therapy iswarranted in children with SCD with anincreased risk for stroke, according tothese trials. Our consensus is that theseresults are also applicable to patients withSCD with an increased risk for mortality(i.e., RHC-confirmed PH, TRV > 2.5 m/s,or NT-pro-BNP > 160 pg/ml). This isbased on a rationale similar to thatprovided previously for HU. Specifically,we recognize that stroke risk, VOC, ACS,PH, elevated TRV, and elevated NT-pro-BNP are associated with increased risk ofmortality. Chronic transfusion therapyreduces vaso-occlusive and acute chestsyndrome events as well as hemolysis;thus, it is likely that chronic transfusiontherapy will benefit patients with any ofthese complications of SCD. A similarargument for preventing intercurrentACS and VOC events in the patient withPH and right heart failure is considered.This extrapolation of evidence issupported by a case series of patients withSCD with PH that reported thatmaintaining HbS at 30–50% via chronicred cell transfusion improved the TRV(47). One caveat to keep in mind is that

chronic transfusions may reduce theresponse to HU.

Risks of chronic transfusion therapyinclude febrile reactions, allergicreactions, hemolytic reactions, andvolume overload. Such adverse effectscollectively occur in 15% of patients. Redcell alloimmunization is anotherconsequence of chronic transfusiontherapy, occurring in 11% of patients.Alloimmunization can be reduced bymatching for the red cell antigens D, C, E,and Kell. Iron accumulates in all patientswho receive chronic transfusions, withthe magnitude of accumulationcorrelating with the volume transfused.In a series of 45 patients with SCD whoreceived chronic transfusions for SCD,most patients exhibited a serum ferritinlevel greater than 1,000 ng/ml by the timethey had been transfused with 100 ml/kg,and all patients exhibited a serumferritin level greater than 1,000 ng/ml bythe time they had been transfused with200 ml/kg. Among patients who receiveda cumulative transfusion volume greaterthan 250 ml/kg, 44% reached a serumferritin level greater than 3,000 ng/ml,whereas the remaining 56% reacheda plateau at a serum ferritin level lessthan 3,000 ng/ml (51). Iron overloadmay be minimized by the aggressiveuse of iron chelators (deferasirox,deferoxamine) or by replacingsimple transfusion therapy witherythrocytapheresis.

We suggest chronic transfusion therapyfor patients with SCD who have anincreased risk for mortality (i.e., RHC-confirmed PH, TRV > 2.5 m/s, or NT-pro-BNP > 160 pg/ml), and who are notresponsive to or are not candidates forHU therapy. This reflects our judgmentthat the desirable consequences ofchronic transfusion therapy (11% fewerstrokes, an 18.1% decrease in episodesof ACS, and an 8.3% decrease inepisodes of VOC) outweigh theundesirable consequences (cost, burden,11% incidence of alloimmunization, and15% frequency of minor adverse effects,including febrile reactions, allergicreactions, hemolytic reactions, andvolume overload) (Table E4). Therecommendation is weak, reflectingthe committee’s recognition that thedesirable and undesirable effects arefinely balanced, and that the estimatedeffects are based on low-quality

evidence (two randomized trialsdowngraded for indirectness of thepopulation and imprecision) (Table E4).

Chronic Anticoagulant TherapySCD is associated with an increased risk ofboth large and small vessel pulmonaryembolism (52–58), as well as an increasedrisk for intracerebral hemorrhage. Short-term anticoagulant therapy is widelyaccepted for most patients with acutevenous thromboembolism (VTE), but theopposing tendencies toward both VTE andhemorrhage make decisions about long-term anticoagulation challenging. Thesedecisions are even more complicated inpatients with SCD with PH because suchpatients are less likely to tolerate recurrentVTE.

We performed a systematic review ofthe literature to identify studies thatcompared indefinite anticoagulanttherapy with a shorter duration ofanticoagulant therapy in patients withSCD-related PH and VTE. Our review didnot identify any relevant studies, so webroadened our selection criteria to identifystudies that performed the samecomparison in patients with SCD (with orwithout PH) and VTE. Again, ourreview did not identify any relevantstudies. Our search and selection criteriaare listed in Tables E10 and E11.

Given the paucity of evidence regardingthe benefits versus risks of indefiniteanticoagulant therapy in patients with SCDand VTE, we sought evidence fromheterogeneous populations of patients withVTE. We did not perform our ownsystematic review; rather, we updated a well-done published systematic review (59). Fourrandomized trials were identified thatcompared long-term anticoagulant therapy

Recommendation: For patients withSCD who have an increased risk formortality and who are either are notresponsive to hydroxyurea or notcandidates for hydroxyurea, wesuggest chronic transfusion therapy(weak recommendation, low-qualityevidence).

Remarks: We define an increased riskfor mortality as a TRV of >2.5 m/second, an NT-pro-BNP level of >160pg/ml, or RHC-confirmed PH.



(i.e., uninterrupted therapy until the endof the trial) with a limited duration oftherapy (60–63). A meta-analysis foundthat patients who received indefiniteanticoagulant therapy had fewer recurrentVTE events (3.5 vs. 17.3%; RR, 0.16; 95%CI, 0.06–0.41) and a trend toward lowermortality (2.8 vs. 5.0%; RR, 0.56; 95% CI,0.31–1.01). This was partially offset by anincrease in major bleeding (3.3 vs. 0.9%;RR, 3.14; 95% CI, 1.27–7.77). After thecessation of anticoagulant therapy, the riskof recurrent VTE appears to increase,regardless of treatment duration (59).

We suggest indefinite anticoagulanttherapy for patients with RHC-confirmedPH plus VTE, and no additional riskfactors for bleeding. This reflects thecommittee’s judgment that the upsides ofindefinite anticoagulation (13.8% lessrecurrent VTE and, possibly, lowermortality) outweigh the downsides (2.4%increased bleeding risk, cost, and burdenof monitoring) in most patients withSCD-related PH and VTE. Therecommendation is weak because it isbased on low-quality evidence(randomized trials downgraded forindirectness of the population andimprecision) and we recognize that somepatients and providers may not find therisk of major bleeding to be an acceptabletrade-off for reducing the likelihood ofrecurrent VTE and, possibly, mortality(i.e., the potential benefits and risks arefinely balanced).

Associated ConditionsStandard care for patients with SCD-related PH is similar to that for patients

with other forms of PH. Hypoxemia istreated with supplemental oxygen tomaintain an arterial oxyhemoglobinsaturation of at least 90% at rest, withexertion, and during sleep (13). Proteinuriaand microalbuminuria are common inSCD-related PH (26) and may improvewith angiotensin-converting enzymeinhibitors (64). Suspected obstructive sleepapnea is evaluated via polysomnographyand treated accordingly. In a small caseseries of children with SCD, treatment ofobstructive sleep apnea, nocturnalhypoxemia, and asthma reduced theelevated TRV, suggesting that mortalityrisk can be modified by early intervention(65). Diuretics are used to treat rightventricular volume overload (13), but thismust be done carefully to minimize therisk of volume depletion–inducederythrocyte sickling. The risk of thisoccurring may be reduced by HU orchronic transfusions with concomitanttreatment for iron overload.

Targeted PAH TherapyTargeted PAH therapy refers currentlyto treatment with prostacyclin agonists (e.g.,epoprostenol, treprostinil, iloprost),endothelin receptor antagonists (e.g.,bosentan, macitentan, ambrisentan), solubleguanylate cyclase stimulators (e.g.,riociguat), or phosphodiesterase-5inhibitors (e.g., sildenafil, vardenafil,tadalafil). To identify evidence related totargeted PAH therapy in patients with SCD-related PH, a systematic review wasperformed, using the search and selectioncriteria shown in Table E12). Threerandomized trials and four case series wereidentified (Figure E5).

Two of the trials compared treatmentwith bosentan to placebo in patients withSCD with RHC-defined precapillary PH(the ASSET-1 trial) or postcapillary PH witha PVR of at least 100 dyn $ seconds $ cm25

(the ASSET-2 trial) (66). After therandomization of only 14 subjects inASSET-1 and 12 patients in ASSET-2, thetrials were prematurely terminated becauseof sponsor’s withdrawal of support for thestudy. Although few patients were enrolled,there were no apparent toxicity issues.The third trial, Walk-PHaSST (PulmonaryHypertension and Sickle Cell Disease withSildenafil Therapy) (67), compared the safetyand efficacy of sildenafil with that of placeboin patients with SCD with a TRV of at least2.7 m/second. After 74 (of a targeted 132)

subjects were enrolled, the study wasprematurely discontinued because of anincrease in serious adverse events in thesildenafil group, primarily hospitalizationfor pain.

These trials were judged by thecommittee to be insufficient to determinewhether or not patients with SCD with anRHC-confirmed marked elevation of thePVR with normal PAWP should receivetargeted PAH therapy, for two reasons.First, the trials collectively included only 14patients with an elevated PVR and normalPAWP by RHC (fewer than half ofwhom actually received targeted PAHtherapy); the remaining patients had eitherpostcapillary PH alone or elevated TRValone. Second, as a result of the smallsample size, there were few events and theestimated effects were imprecise.

Given the serious limitations of therandomized trials, the committee decidedthat its judgments regarding whethertargeted PAH therapy is indicated inpatients with SCD with an elevated PVRand normal PAWP should be informed byindirect evidence from group 1 PAHpopulations and our own clinicalexperience. In group 1 patients with PAH,it has been well established by meta-analyses of randomized trials that targetedPAH therapy consistently improvesexercise capacity, functional status,symptoms, cardiopulmonaryhemodynamics, and outcome (68–70).This indirect evidence is supported by fourcase series in which patients with SCDwith RHC-confirmed precapillary PHreceived targeted PAH therapy withbosentan, sildenafil, and/or epoprostenol.Targeted PAH therapy was associated withimprovement in exercise capacity, withthe 6-minute walk distance increasing 41to 144 m beyond baseline (71–74). Therewere also improvements in the mean PAP,PVR, and cardiac index, although theseparameters were measured in only a fewpatients (74). The magnitude of thebenefits was greatest among symptomaticpatients. The most common adverseeffects were headache (15%) andperipheral edema (21%); transaminaseelevation was reported in 14% of patientsduring endothelin receptor antagonisttherapy (71–74).

Although sildenafil has been shownto produce clinical and hemodynamicimprovement compared with placebo ina small number of non-SCD patients with

Recommendation: For patients withSCD who have RHC-confirmed PH,venous thromboembolism, and noadditional risk factors for bleeding, wesuggest indefinite anticoagulanttherapy rather than a limited durationof therapy (weak recommendation,low-quality evidence).

Values and preferences: Thisrecommendation attaches a relativelyhigh value to the prevention ofrecurrent venous thromboembolicevents and a lower value to the risksand burdens of anticoagulant therapy.



PVH due to diastolic dysfunction, thisneeds to be studied in a larger populationbefore this becomes widely accepted (75).Targeted PAH therapy has never beenshown to benefit patients with elevatedTRV alone or elevated NT-pro-BNPalone.

After taking the evidence and thecommittee’s collective clinical experienceinto consideration, we recommend againsttargeted PAH therapy for all patients withSCD who have elevated TRV alone, or anelevated NT-pro-BNP level alone, and formost patients with SCD and RHC-confirmed PH, because targeted PAHtherapy has not been shown to be beneficialin such patients. Therefore, the risks, costs,and burdens may exceed the benefits. Therecommendation is strong, to emphasizethe importance of avoiding costly andpotentially harmful therapies in the absenceof evidence of a benefit.

In carefully selected symptomaticpatients with RHC-confirmedhemodynamics demonstrating elevatedPVR and normal PAWP, however, wesuggest targeted PAH therapy with eithera prostacyclin agonist or an endothelinreceptor antagonist. This reflects ourjudgment that the benefits of such therapies(i.e., improved exercise capacity and

hemodynamic measures) likely outweighthe cost, burdens, and risks (i.e., headacheand peripheral edema) in most patients. Therecommendation is weak because the lowquality of evidence (randomized trialsdowngraded for indirectness of thepopulation and imprecision of the estimatedeffects, as well as case series) allows littleconfidence in the estimated effects oftargeted PAH therapy and, therefore, in thebalance of benefits versus harms in thispopulation.

In contrast, we recommend againstphosphodiestase-5 inhibitor therapy in lightof the harmful effects of sildenafil in theWalk-PHaSST trial described previously.The recommendation is strong to emphasizethe importance of avoiding harmfultherapies, especially when alternative agentsare available. As the soluble guanylatecyclase stimulators have never beenstudied in SCD, we cannot comment on

their use in this patient group, buthave similar concerns related to theobservations with phosphodiesterase-5inhibitor therapy.

Future Directions

These guidelines reflect thecomplexity and caveats of pulmonaryhypertension in sickle cell disease and arereflective of the current state of theliterature as of 2014. We anticipate thatchanges to this document will needto be made in the future as ourunderstanding of this disease grows. Inthe future, the management of patientswith SCD with an increased risk formortality and PH is certain to includecollaboration across the disciplines ofadult and pediatric pulmonarymedicine, cardiology, and hematology.Controlled clinical trials for thetreatment of such patients areneeded, particularly trials thatevaluate combination therapy targetingthe hemoglobinopathy and pulmonaryvasculopathy of these patients.Continued research is expected to lead toearlier disease detection and enhancedtreatment strategies to improve theprognosis and quality of life for thesepatients. n

Recommendation: For all patientswith SCD who have elevated TRValone, or elevated NT-pro-BNP alone,and for most patients with SCD whohave RHC-confirmed PH, werecommend against targeted PAHtherapy (strong recommendation,moderate-quality evidence).

Remarks: Targeted PAH therapyrefers to prostacyclin agonist,endothelin receptor antagonist, solubleguanylate cyclase stimulator, andphosphodiesterase-5 inhibitor therapy.

Values and preferences: Thisrecommendation places a greater valueon avoiding expensive and potentiallyharmful agents in patients who may notbenefit and a lower value on avoidingthe complications of invasivehemodynamic testing by usingnoninvasive results for decisionmaking.

Recommendation: For select patientswith SCD who have an RHC-confirmed marked elevation of theirpulmonary vascular resistance, normalpulmonary artery wedge pressure, andrelated symptoms, we suggest a trialwith either a prostacyclin agonist or anendothelin receptor antagonist (weakrecommendation, low-qualityevidence).

Remarks: This group of patients withSCD is characterized by a meanpulmonary arterial pressure (mPAP)of >25 mm Hg with a pulmonaryartery wedge pressure , 15 mm Hg,plus increased pulmonary vascularresistance (PVR) of >160 dyn $seconds $ cm25 (2 Wood units).Patients with SCD who haveconfirmed PH are now categorized asbeing within WHO group 5, instead ofWHO group 1. As a result, use oftargeted PAH therapy in such patientsis considered off-label.

Values and preferences: Thisrecommendation places a greater valueon improving symptoms andhemodynamic measures and a lowervalue on the costs, burdens, and risksof therapy.

Recommendation: For patients withSCD who have an RHC-confirmedmarked elevation of their pulmonaryvascular resistance, a normalpulmonary artery wedge pressure, andrelated symptoms, we recommendagainst phosphodiesterase-5 inhibitortherapy as a first-line treatment(strong recommendation, moderate-quality evidence).

Remarks: The recommendation isbased on the observation thatphosphodiesterase-5 inhibitor therapymay increase the risk ofhospitalization for vaso-occlusivecrisis.

Values and preferences: Thisrecommendation places a higher valueon avoiding serious complications anda lower value on symptomatic andhemodynamic improvement.



This guideline was prepared by an ad hoc subcommittee of the ATS Assembly on Pulmonary Circulation.

Writing Committee

ELIZABETH S. KLINGS, M.D. (Chair)*ROBERTO F. MACHADO, M.D. (Co-Chair)*ROBYN J. BARST, M.D.CLAUDIA R. MORRIS, M.D.KAMAL K. MUBARAK, M.D.VICTOR R. GORDEUK, M.D.GREGORY J. KATO, M.D.KENNETH I. ATAGA, M.D.J. SIMON GIBBS, M.D.OSWALDO CASTRO, M.D.ERIKA B. ROSENZWEIG, M.D.NAMITA SOOD, M.D.LEWIS HSU, M.D., Ph.D.KEVIN C. WILSON, M.D.MARILYN J. TELEN, M.D.LAURA M. DECASTRO, M.D.LAKSHMANAN KRISHNAMURTI, M.D.MARTIN H. STEINBERG, M.D.DAVID B. BADESCH, M.D.MARK T. GLADWIN, M.D. (Co-Chair)

*Drs. Klings and Machado are co–first authors ofthis document.

Committee members were as follows(in alphabetical order):

Committee ChairELIZABETH S. KLINGS, M.D.

Committee Co-ChairsMARK T. GLADWIN, M.D.ROBERTO F. MACHADO, M.D.

Pulmonary—AdultDAVID B. BADESCH, M.D.KAMAL K. MUBARAK, M.D.NAMITA SOOD, M.D.

Pulmonary—PediatricROBERT STRUNK, M.D.

Pulmonary and Evidence-Based ApproachesKEVIN C. WILSON, M.D.

Cardiology—AdultHUNTER C. CHAMPION, M.D.J. SIMON GIBBS, M.D.

Cardiology—PediatricROBYN J. BARST, M.D.ERIKA B. ROSENZWEIG, M.D.

Hematology—AdultKENNETH ATAGA, M.D.OSWALDO CASTRO, M.D.LAURA M. DECASTRO, M.D.VICTOR R. GORDEUK, M.D.MARTIN H. STEINBERG, M.D.MARILYN J. TELEN, M.D.

Hematology—PediatricLEWIS HSU, M.D., Ph.D.GREGORY J. KATO, M.D.LAKSHMANAN KRISHNAMURTI, M.D.ELLIOTT VICHINSKY, M.D.

Emergency Medicine—PediatricCLAUDIA R. MORRIS, M.D.

Author Disclosures: R.J.B. was a consultantto Actelion ($50,000–99,999), Gilead ($1,000–9,999), Ikaria ($10,000–49,999), Novartis($10,000–49,999), and Pfizer ($100,000–249,999); she was a speaker for Actelion($1,000–9,999). K.K.M. was a consultant toActelion ($1,000–9,999) and Gilead ($1,000–9,999) and served on advisory committees ofActelion ($1,000–9,999) and Gilead ($1,000–9,999); he was a speaker for Actelion ($1,000–9,999) and Gilead ($1,000–9,999), andreceived research support from Actelion($25,000–49,999), Fibrogen ($25,000–49,999),Gilead ($25,000–49,999), Novartis ($25,000–49,999), and Pfizer ($25,000–49,999). G.J.K.received research support from Ikaria($100,000–249,999). K.I.A. received researchsupport from BioMarin ($25,000–49,999),HemaQuest ($100,000–249,999), Eli Lilly($25,000–49,999), and TRF Pharma ($50,000–99,999). J.S.G. served on advisory committeesof Actelion ($1,000–4,999), Bayer Schering($1,000–4,999), GlaxoSmithKline ($1,000–4,999), Pfizer ($1,000–4,999), and UnitedTherapeutics ($1,000–4,999); he wasa speaker for Actelion ($1,000–4,999),GlaxoSmithKline ($1,000–4,999), Lilly ($1,000–4,999), Pfizer ($1,000–4,999), and Schering($1,000–4,999); he received research supportfrom BioMarin ($10,000–49,999) and Lung Rx($1,000–9,999). O.C. was a consultant toActelion ($1–4,999), Icagen ($1–4,999), andCellerant ($1–4,999). E.B.R. was on advisorycommittees of Actelion ($5,000–24,999) andUnited Therapeutics ($5,000–24,999), anda speaker for Actelion ($5,000–24,999), Gilead($5,000–24,999), and United Therapeutics($5,000–24,999); she received researchsupport from Actelion ($50,000–99,999),Gilead ($50,000–99,999), Lilly ICOS ($25,000–49,999), and United Therapeutics ($50,000–99,999). L.H. was a consultant to BioMarin($1–4,999) and Eli Lilly ($1–4,999), andreceived research support from BioMarin($50,000–99,999), Ikaria/INO Therapeutics($50,000–99,999), and GlycoMimetics($25,000–49,999). K.C.W.’s spouse previouslyheld stocks or options of Moody Lynn and Co.

and State Street Bank ($50,000–99,999).M.J.T. was a consultant to GlycoMimetics($25,000–49,999) and received researchsupport from Dilafor ($25,000–49,999). L.M.D.received research support from AntheraPharmaceuticals ($1,000–4,999) andGlycoMimetics ($1,000–4,999). L.K. receivedresearch support from INO Therapeutics/Ikaria ($50,000–99,999). M.H.S. wasa consultant to Ikaria ($1–4,999) andserved on an advisory committee ofTRF Pharma ($1–4,999). D.B.B. wasa consultant to Actelion ($25,000–49,999),Arena ($1–4,999), Bayer ($5,000–24,999),Gilead ($5,000–24,999), Ikaria ($1–4,999),Lung Rx ($1–4,999), Pfizer ($5,000–24,999), and United Therapeutics ($1–4,999); he was on an advisory committeeof MondoGen ($1–4,999), and receivedresearch support from Actelion ($25,000–49,999), Bayer ($100,000–249,999),Gilead ($100,000–249,999), Ikaria($1–4,999), Novartis ($50,000–99,999),and United Therapeutics ($100,000–249,999). M.T.G. received research supportfrom Bayer (USA) ($10,000–49,999) andGilead ($100,000–249,999); he receivedroyalties from a patent for the use of nitritesalts for cardiovascular indications ($1,000–4,999). E.S.K., R.F.M., C.R.M., V.R.G., andN.S. reported no relevant commercialinterests.

Acknowledgment: The members of thecommittee dedicate this document to thememory of Dr. Robyn J. Barst, who was anintegral part of our group until her passing inApril 2013. Dr. Barst was a passionateadvocate for the importance of pulmonaryhypertension as a devastating complication forpatients with sickle cell disease. She broughther wealth of experience as an internationalleader in the care of patients with pulmonaryhypertension to her committee, and all of uslearned a tremendous amount from workingwith her. The committee acknowledges theAmerican Thoracic Society (ATS) for support ofthis project. The committee acknowledgesMr. Lance Lucas, Ms. Jessica Wisk, Ms.Miriam Rodriguez, and the ATS staff foradministrative assistance with conferencecalls and face-to-face meetings; and theclinicians and patients with sickle celldisease who have participated in thestudies that have made this documentpossible.

References

1. Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adultswith sickle cell disease and pulmonary hypertension. JAMA 2012;307:1254–1256.

2. Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, Habibi A, BennaniS, Savale L, Adnot S, et al. A hemodynamic study of pulmonaryhypertension in sickle cell disease. N Engl J Med 2011;365:44–53.

3. Fonseca GH, Souza R, Salemi VC, Jardim CV, Gualandro SF. Pulmonaryhypertension diagnosed by right heart catheterization in sickle celldisease. Eur Respir J 2011.

4. GladwinMT, Sachdev V, JisonML, Shizukuda Y, Plehn JF, Minter K, Brown B,Coles WA, Nichols JS, Ernst I, et al. Pulmonary hypertension as a risk factorfor death in patients with sickle cell disease.NEngl JMed 2004;350:886–895.

5. Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A,Orringer EP. Pulmonary hypertension in patients with sickle



cell disease: a longitudinal study. Br J Haematol 2006;134:109–115.

6. Castro O, Hoque M, Brown BD. Pulmonary hypertension in sickle celldisease: cardiac catheterization results and survival. Blood 2003;101:1257–1261.

7. Klings ES, Anton BD, Rosenman D, Princeton S, Odhiambo A, Li G,Bernard SA, Steinberg MH, Farber HW. Pulmonary arterial hypertensionand left-sided heart disease in sickle cell disease: clinical characteristicsand association with soluble adhesion molecule expression. Am JHematol 2008;83:547–553.

8. Kato GJ, Onyekwere OC, Gladwin MT. Pulmonary hypertension in sicklecell disease: relevance to children. Pediatr Hematol Oncol 2007;24:159–170.

9. Gordeuk V, Minniti CP, Nouraie M, Campbell AD, Rana S,Luchtman-Jones L, Sable C, Dham N, Ensing G, Prchal JT, et al.Elevated tricuspid regurgitation velocity and decline inexercise capacity over 22 months of follow-up in childrenand adolescents with sickle cell anemia. Haematologica 2011;96:33–40.

10. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C,Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, LandzbergM, Machado RF, et al. Updated clinical classification ofpulmonary hypertension. J Amer Coll Cardiol 2013;62(25 Suppl):D34–D41.

11. Gladwin MT, Machado RF. Pulmonary hypertension in sickle celldisease. N Engl J Med 2011;365:1646–1647.

12. Mehari A, Alam S, Tian X, Cuttica MJ, Barnett CF, Miles G, Xu D,Seamon C, Adams-Graves P, Castro OL, et al. Hemodynamicpredictors of mortality in adults with sickle cell disease. Am J RespirCrit Care Med 2013;187:840–847.

13. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW,Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS,et al. ACCF/AHA 2009 expert consensus document on pulmonaryhypertension: a report of the American College of CardiologyFoundation Task Force on Expert Consensus Documents and theAmerican Heart Association. Circulation 2009.

14. Fitzgerald M, Fagan K, Herbert DE, Al Ali M, Mugal M, Haynes J Jr.Misclassification of pulmonary hypertension in adults with sicklehemoglobinopathies using Doppler echocardiography. South Med J2012;105:300–305.

15. Machado RF, Anthi A, Steinberg MH, Bonds D, Sachdev V, Kato GJ,Taveira-DaSilva AM, Ballas SK, Blackwelder W, Xu X, et al. N-terminal pro–brain natriuretic peptide levels and risk of death in sicklecell disease. JAMA 2006;296:310–318.

16. Voskaridou E, Tsetsos G, Tsoutsias A, Spyropoulou E, Christoulas D,Terpos E. Pulmonary hypertension in patients with sickle cell/bthalassemia: incidence and correlation with serum N-terminalpro–brain natriuretic peptide concentrations. Haematologica2007;92:738–743.

17. Barbera JA, Peinado VI, Santos S. Pulmonary hypertension in chronicobstructive pulmonary disease. Eur Respir J 2003;21:892–905.

18. Barnett CF, Hsue PY, Machado RF. Pulmonary hypertension: anincreasingly recognized complication of hereditary hemolyticanemias and HIV infection. JAMA 2008;299:324–331.

19. Burger CD. Pulmonary hypertension in COPD: a review andconsideration of the role of arterial vasodilators. COPD 2009;6:137–144.

20. Han MK, McLaughlin VV, Criner GJ, Martinez FJ. Pulmonary diseasesand the heart. Circulation 2007;116:2992–3005.

21. Le Pavec J, Souza R, Herve P, Lebrec D, Savale L, Tcherakian C, JaisX, Yaici A, Humbert M, Simonneau G, et al. Portopulmonaryhypertension: survival and prognostic factors. Am J Respir Crit CareMed 2008;178:637–643.

22. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, DetreKM, Fishman AP, Goldring RM, Groves BM, Kernis JT. Survival inpatients with primary pulmonary hypertension: results from a nationalprospective registry. Ann Intern Med 1991;115:343–349.

23. Hassoun PM. Pulmonary arterial hypertension complicating connectivetissue diseases. Semin Respir Crit Care Med 2009;30:429–439.

24. Patel NM, Lederer DJ, Borczuk AC, Kawut SM. Pulmonaryhypertension in idiopathic pulmonary fibrosis. Chest 2007;132:998–1006.

25. Sachdev V, Kato GJ, Gibbs JS, Barst RJ, Machado RF, Nouraie M,Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, et al.Echocardiographic markers of elevated pulmonary pressure and leftventricular diastolic dysfunction are associated with exerciseintolerance in adults and adolescents with homozygous sickle cellanemia in the United States and UK. Circulation 2011;124:1452–1460.

26. De Castro LM, Jonassaint JC, Graham FL, Ashley-Koch A, Telen MJ.Pulmonary hypertension associated with sickle cell disease: clinicaland laboratory endpoints and disease outcomes. Am J Hematol2008;83:19–25.

27. Gladwin MT, Vichinsky E. Pulmonary complications of sickle celldisease. N Engl J Med 2008;359:2254–2265.

28. Anthi A, Machado RF, Jison ML, Taveira-DaSilva AM, Rubin LJ, HunterL, Hunter CJ, Coles W, Nichols J, Avila NA, et al. Hemodynamic andfunctional assessment of patients with sickle cell disease andpulmonary hypertension. Am J Respir Crit Care Med 2007;175:1272–1279.

29. Machado RF, Kyle MA, Martyr S, Barnett C, Macarthur P, Sachdev V,Ernst I, Hunter LA, Coles WA, Nichols JP, et al. Severity ofpulmonary hypertension during vaso-occlusive pain crisis andexercise in patients with sickle cell disease. Br J Haematol 2007;136:319–325.

30. Machado RF, Hildesheim M, Mendelsohn L, Remaley AT, Kato GJ,Gladwin MT. NT-pro brain natriuretic peptide levels and the risk ofdeath in the Cooperative Study of Sickle Cell Disease. Br J Haematol2011;154:512–520.

31. Pashankar FD, Carbonella J, Bazzy-Asaad A, Friedman A. Longitudinalfollow up of elevated pulmonary artery pressures in children withsickle cell disease. Br J Haematol 2009;144:736–741.

32. Olnes M, Chi A, Haney C, May R, Minniti C, Taylor J, Kato GJ.Improvement in hemolysis and pulmonary arterial systolic pressure inadult patients with sickle cell disease during treatment withhydroxyurea. Am J Hematol 2009;84:530–532.

33. Lezcano NE, Odo N, Kutlar A, Brambilla D, Adams RJ. Regulartransfusion lowers plasma free hemoglobin in children with sickle-cell disease at risk for stroke. Stroke 2006;37:1424–1426.

34. Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Rana S,Thornburg CD, Rogers ZR, Kalpatthi RV, et al. Hydroxycarbamide invery young children with sickle-cell anaemia: a multicentre, randomised,controlled trial (BABY HUG). Lancet 2011;377:1663–1672.

35. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV,McMahon RP, Bonds DR; Investigators of the Multicenter Study ofHydroxyurea in Sickle Cell Anemia. Effect of hydroxyurea on thefrequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317–1322.

36. Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, FonduP, Toppet M, Sariban E. Hydroxyurea for treatment of severe sickle cellanemia: a pediatric clinical trial. Blood 1996;88:1960–1964.

37. Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR,Pegelow CH, Koshy M, Barton BA, Bonds DR. Hydroxyurea andsickle cell anemia: effect on quality of life. Health Qual Life Outcomes2006;4:59.

38. Ballas SK, McCarthy WF, Guo N, DeCastro L, Bellevue R, Barton BA,Waclawiw MA. Exposure to hydroxyurea and pregnancy outcomes inpatients with sickle cell anemia. J Natl Med Assoc 2009;101:1046–1051.

39. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A,Orringer E, Bellevue R, Olivieri N, Eckman J, et al. Effect ofhydroxyurea on mortality and morbidity in adult sickle cell anemia:risks and benefits up to 9 years of treatment. JAMA 2003;289:1645–1651.

40. Steinberg MH, McCarthy WF, Castro O, Ballas SK, Armstrong FD,Smith W, Ataga K, Swerdlow P, Kutlar A, DeCastro L, et al. The risksand benefits of long-term use of hydroxyurea in sickle cell anemia:a 17.5 year follow-up. Am J Hematol 2010;85:403–408.

41. Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, InturrisiC, James AH, Laraque D, Mendez M, Montoya CJ, et al. NationalInstitutes of Health consensus development conference statement:hydroxyurea treatment for sickle cell disease. Ann Intern Med 2008;148:932–938.



42. Vichinsky EP, Neumayr LD, Earles AN, Williams R, Lennette ET, DeanD, Nickerson B, Orringer E, McKie V, Bellevue R, et al.; NationalAcute Chest Syndrome Study Group. Causes and outcomes of theacute chest syndrome in sickle cell disease. N Engl J Med 2000;342:1855–1865.

43. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, AbboudM, Gallagher D, Kutlar A, Nichols FT, et al. Prevention of a first strokeby transfusions in children with sickle cell anemia and abnormalresults on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11.

44. Adams RJ, Brambilla D. Discontinuing prophylactic transfusions usedto prevent stroke in sickle cell disease. N Engl J Med 2005;353:2769–2778.

45. Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, BrambillaDJ, Adams RJ. Stroke Prevention Trial in Sickle Cell Anemia(STOP): extended follow-up and final results. Blood 2006;108:847–852.

46. Collins FS, Orringer EP. Pulmonary hypertension and cor pulmonale inthe sickle hemoglobinopathies. Am J Med 1982;73:814–821.

47. Claster S, Hammer M, Hagar W, Ataga K, Orringer E, Vichinsky E.Treatment of pulmonary hypertension in sickle cell disease withtransfusion [abstract]. Blood 1999;94:420A.

48. Riddington C, Wang W. Blood transfusion for preventing stroke inpeople with sickle cell disease. Cochrane Database Syst Rev 2002;1:CD003146.

49. Wang WC, Morales KH, Scher CD, Styles L, Olivieri N, Adams R,Brambilla D. Effect of long-term transfusion on growth in childrenwith sickle cell anemia: results of the STOP trial. J Pediatr 2005;147:244–247.

50. Miller ST, Wright E, Abboud M, Berman B, Files B, Scher CD, Styles L,Adams RJ. Impact of chronic transfusion on incidence of pain andacute chest syndrome during the Stroke Prevention Trial (STOP) insickle-cell anemia. J Pediatr 2001;139:785–789.

51. Files B, Brambilla D, Kutlar A, Miller S, Vichinsky E, Wang W, Granger S,Adams RJ. Longitudinal changes in ferritin during chronictransfusion: a report from the Stroke Prevention Trial in Sickle CellAnemia (STOP). J Pediatr Hematol Oncol 2002;24:284–290.

52. Stein PD, Beemath A, Meyers FA, Skaf E, Olson RE. Deep venousthrombosis and pulmonary embolism in hospitalized patients withsickle cell disease. Am J Med 2006;119:897.e7–e11.

53. Ataga KI, Moore CG, Hillery CA, Jones S, Whinna HC, Strayhorn D,Sohier C, Hinderliter A, Parise LV, Orringer EP. Coagulationactivation and inflammation in sickle cell disease–associatedpulmonary hypertension. Haematologica 2008;93:20–26.

54. van Beers EJ, Spronk HM, Ten Cate H, Duits AJ, Brandjes DP, vanEsser JW, Biemond BJ, Schnog JB. No association of thehypercoagulable state with sickle cell disease related pulmonaryhypertension. Haematologica 2008;93:e42–e44.

55. Minter KR, Gladwin MT. Pulmonary complications of sickle cell anemia:a need for increased recognition, treatment, and research. Am JRespir Crit Care Med 2001;164:2016–2019.

56. Thomas AN, Pattison C, Serjeant GR. Causes of death in sickle-cell disease in Jamaica. Br Med J (Clin Res Ed) 1982;285:633–635.

57. Lisbona R, Derbekyan V, Novales-Diaz JA. Scintigraphic evidence ofpulmonary vascular occlusion in sickle cell disease. J Nucl Med1997;38:1151–1153.

58. Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, NickersonB; Cooperative Study of Sickle Cell Disease. Acute chest syndromein sickle cell disease: clinical presentation and course. Blood1997;89:1787–1792.

59. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ.Antithrombotic therapy for venous thromboembolic disease:American College of Chest Physicians Evidence-Based ClinicalPractice Guidelines (8th edition). Chest 2008;133:454S–545S.[Published erratum appears in Chest 134:892.]

60. Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P,Nicol P, Eklund SG, Nordlander S, Larfars G, Leijd B, et al.; Durationof Anticoagulation Trial Study Group. The duration of oralanticoagulant therapy after a second episode of venousthromboembolism. N Engl J Med 1997;336:393–398.

61. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, TurpieAG, Green D, Ginsberg JS, Wells P, et al. A comparison of threemonths of anticoagulation with extended anticoagulation for a firstepisode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901–907.

62. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, Pengo V,Ghirarduzzi A, Pattacini C, Testa S, et al. D-dimer testing todetermine the duration of anticoagulation therapy. N Engl J Med2006;355:1780–1789.

63. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, DeitcherSR, Cushman M, Moll S, Kessler CM, Elliott CG, et al. Long-term,low-intensity warfarin therapy for the prevention of recurrent venousthromboembolism. N Engl J Med 2003;348:1425–1434.

64. Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC.Prevalence and pathologic features of sickle cell nephropathyand response to inhibition of angiotensin-converting enzyme.N Engl J Med 1992;326:910–915.

65. Ambrusko SJ, Gunawardena S, Sakara A, Windsor B, Lanford L,Michelson P, Krishnamurti L. Elevation of tricuspid regurgitant jetvelocity, a marker for pulmonary hypertension in children with sicklecell disease. Pediatr Blood Cancer 2006;47:907–913.

66. Barst RJ, Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O,Naeije R, Sood N, Swerdlow PS, Hildesheim M, et al. Exercisecapacity and haemodynamics in patients with sickle cell disease withpulmonary hypertension treated with bosentan: results of theASSET studies. Br J Haematol 2010;149:426–435.

67. Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR,Gibbs JS, Little JA, Schraufnagel DE, Krishnamurti L, et al.Hospitalization for pain in patients with sickle cell disease treated withsildenafil for elevated TRV and low exercise capacity. Blood 2011.

68. Liu C, Chen J, Gao Y, Deng B, Liu K. Endothelin receptor antagonistsfor pulmonary arterial hypertension. Cochrane Database Syst Rev[serial on the Internet]. 2009 [accessed January 2014];3:CD004434.Available from: http://summaries.cochrane.org/

69. Paramothayan NS, Lasserson TJ, Wells AU, Walters EH. Prostacyclinfor pulmonary hypertension in adults. Cochrane Database Syst Rev[serial on the Internet]. 2005 [accessed January 2014];2:CD002994.Available from: http://summaries.cochrane.org/

70. Kanthapillai P, Lasserson T, Walters E. Sildenafil for pulmonaryhypertension. Cochrane Database Syst Rev [serial on the Internet].2004 [accessed January 2014];4:CD003562. Available from: http://summaries.cochrane.org/

71. Machado RF, Martyr S, Kato GJ, Barst RJ, Anthi A, Robinson MR,Hunter L, Coles W, Nichols J, Hunter C, et al. Sildenafil therapyin patients with sickle cell disease and pulmonary hypertension.Br J Haematol 2005;130:445–453.

72. Derchi G, Forni GL, Formisano F, Cappellini MD, Galanello R, D’AscolaG, Bina P, Magnano C, Lamagna M. Efficacy and safety of sildenafilin the treatment of severe pulmonary hypertension in patientswith hemoglobinopathies. Haematologica 2005;90:452–458.

73. Morris CR. New strategies for the treatment of pulmonary hypertensionin sickle cell disease: the rationale for arginine therapy. Treat RespirMed 2006;5:31–45.

74. Minniti CP, Machado RF, Coles WA, Sachdev V, Gladwin MT, Kato GJ.Endothelin receptor antagonists for pulmonary hypertension in adultpatients with sickle cell disease. Br J Haematol 2009;147:737–743.

75. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heartfailure with preserved ejection fraction: a target of phosphodiesterase-5inhibition in a 1-year study. Circulation 2011;124:164–174.



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