w.h.o gets better ? - american thoracic society · 2019-12-06 · w.h.o gets better ? phenotyping...

W.H.O gets better ?Phenotyping pulmonary hypertension:

Where are we now?

Rahul G Argula MBBS, MPHAssistant Professor,

Division of Pulmonary, Critical Care, Allergy and Sleep MedicineMedical University of South Carolina

Disclosures

• Consultant for Actelion and Gilead. • Received speaking fees from PHA for CME events. • This presentation does describe off-label use of PAH therapies in non

WHO group I patients in a research setting.

Objectives• Understand the various types and the WHO classification of

pulmonary hypertension (PH)• Review the pathophysiology of pulmonary arterial hypertension (PAH)

vs. other forms of Pulmonary hypertension (PH)• Review the treatment of pulmonary hypertension (PH) and therapies

of pulmonary arterial hypertension (PAH)• Review the current understanding of treatment of WHO groups I, II

and III pulmonary hypertension.

Age: 44 yearsHPI: Progressive dyspnea

Patient 1

Comorbidities:

• Kyphoscoliosis

• Obesity

• Obstructive Sleep Apnea

Two Women with dyspneaPatient 2

Age: 54 yearsHPI: Progressive dyspnea

Comorbidities:

• Hypertension

• Systemic sclerosis

• Mild interstitial lung disease

Patient 2

NYHA Class IV

• BP: 120/84 mm Hg

• JVP elevated

• Regular rate, rhythm

• Loud P2

• 3/6 murmur (holosystolic, left sternal border)

• 2+ leg edema

NYHA Class IV

Patient 1

• BP: 110/65 mm Hg

• JVP elevated

• Regular rate and rhythm

• Loud P2

• 2/6 murmur (holosystolic, left sternal border)

• 2+ leg edema

Two women with dyspnea

How do we manage them ?

Pulmonary hypertension: Definitions

Mean PAP ≥25 mm Hg at rest during RHCPH

Mean PAP ≥25 mm Hg plusPAWP ≤15 mm Hg plus

PVR >3 Wood units during RHCPAH

Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50.PAP: Pulmonary artery pressurePAWP: Pulmonary capillary wedge pressuePVR: Pulmonary vascular resistance

Right heart

Pulmonary hypertension

Lungs

Left heart

Brai

n

Live

r

Kidn

eys

Skin

MSK GI

Pulmonary arterial remodeling

Clots

Lung disease

mPAP ≥ 25 mm Hg

Left heart disease

Pulmonary artery

Pulmonary veins

1. Pulmonary arterial hypertension (PAH)1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK1, ENG, Smad 9, CAV1, KCNK31.2.3 Unknown

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis

1’’. Persistent PH of the newborn

2. PH due to left heart disease2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract

obstruction and congenital cardiomyopathies

3. PH due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive

and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

4. Chronic thromboembolic PH

5. PH with unclear multifactorial mechanisms5.1 Hematological disorders: chronic hemolytic anemia,

myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary

histiocytosis, lymphangioleiomyomatosis, 5.3 Metabolic disorders: glycogen storage disease,

Gaucher disease, thyroid disorders5.4 Others: tumoral obstruction, fibrosing mediastinitis,

chronic renal failure, segmental PH

5th World Symposium on PH: Classification

What is the significance of pulmonary hypertension ?

*Bonferroni-adjusted p<0.05 in pairwise comparison with lowest tertile.Lam CSP et al. Circulation. 2009;119:2663-2670.

86420Time (yr)

Cum

ulat

ive

surv

ival

1.00

0.95

0.90

0.85

PASP quintile1: 15-23 mm Hg2: 24-25 mm Hg3: 26-29 mm Hg4: 30-32 mm Hg*5: 34-66 mm Hg*

86420Time (yr)

Cum

ulat

ive

surv

ival

PASP tertile1: 15-24 mm Hg2: 24-28 mm Hg3: 28-43 mm Hg*

1.000

0.975

0.950

0.925

0.900

RVSP and Survival in the community

All Participants(N=1413)

Overall Log Rank p<0.001

No Cardiopulmonary Disease (N=778)

Overall Log Rank p=0.002

Epidemiology of PH by Echocardiography• Single echocardiography lab / Australian community of 165,450/ 10,314 patients/15, 633

echocardiograms • Etiology of PH noted on echocardiogram

• N=936 with echo PASP >40 mm Hg

Strange G et al. Heart. 2012;98:1805-1811.

Miscellaneous, 2.7%

Lung disease,Sleep-related

hypoventilation,9.3%

CTEPH, 2.0%

PAH, 2.7% Unknown,

15.4%

Left heartdisease, 67.9%

Idiopathic PAH, 46.20%

Other, 3.10%

Associated PAH, 50.70%

Epidemiology of PAH

Portal hypertension,

10.60%

Connective Tissue Disease, 49.90%Drugs/Toxins,

10.50%

HIV, 4%

Congenital heart disease, 19.50%

Other, 6%

Badesch DB, et al; Chest 2010;137:367-387

Data from REVEAL (US) registry for patients with pulmonary arterial hypertension

PH is common but PAH is rare

However, PAH is deadly!

Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40:780-788. D’Alonzo GE et al. Ann Intern Med.1991;115:343-349. McLaughlin VV et al. Chest. 2004;126:78S-91S.

Idiopathic PAH: Survival If Untreated

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 50

20

40

60

80

100

Years of follow-up

Per

cent

age

surv

ivin

gNIH registrySitbon historical controlACCP estimate

• Incidence: 2-6 cases per million in US

• Poor prognosis in an era lacking therapy

• Therapeutic options and research efforts now offer more hope

Chest. 2008;134(6):1271-1277. doi:10.1378/chest.08-1341

Pulmonary Arterial HypertensionHealthy Lung

Pathophysiology

Progression of PAH

RAP

PVR

PAP

CO

Pre-symptomatic / Compensated

Worsening symptoms

Decompensated/RV failure

Time

Adapted from: Taichman D, Mandel J, Clin Chest Med 34(2013) 619-637

How do we treat the PAH patients ?

Mechanisms of Action of Approved Therapies for PAH

Adapted from Humbert M et al. N Engl J Med. 2004;351:1425-1436.

cGMP

cAMP

Vasoconstriction and proliferation

Endothelinreceptor A

Endothelin-receptor

antagonists

Endothelinreceptor B

Phosphodiesterase type 5 inhibitor

Vasodilationand antiproliferation

Phosphodiesterase type 5

Vasodilationand antiproliferation

Prostacyclin derivatives

Nitric Oxide

Endothelin-1

Pre-proendothelin

L-arginine

Prostaglandin I2

L-citrulline

Nitric OxidePathway

EndothelinPathway

ProstacyclinPathway

Endothelial cells

ProendothelinEndothelial cells

Arachidonic acid

Smooth muscle cells

Prostacyclin (prostaglandin I2)

Smooth muscle cells

Exogenous nitric oxide sGCstimulator

Pharmacotherapy of Pulmonary Arterial Hypertension

Oral Inhaled Subcutaneous IntravenousPDE5 inhibitors:- Sildenafil- Tadalafil

sGC stimulators:- Riociguat

ETR-A antagonist:- Ambrisentan

ETR- A,B antagonists:- Bosentan- Macitentan

Prostacyclin analogs:- Beraprost- Treprostinil- Selexipag

Prostacyclin analogs:- Iloprost- Treprostinil

Prostacyclin analogs:- Treprostinil

Prostacyclin analogs:- Treprostinil- Epoprostenol

5th World Symposium on PH: 2013 Treatment Algorithm

Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72.

Sequential CombinationTherapy (I-A)

Referral for LungTransplantation (I-C)

Consider Eligibility for Lung Transplantation

Inadequate ClinicalResponse

on Maximal Therapy

INITIAL THERAPY WITH PAH-APPROVED DRUGS

PDE-5 I orsGCs

ERAs

Prostanoids

++

+

Balloon AtrialSeptostomy (IIa-C)

Inadequate ClinicalResponse

Phenotype Vs. Genotype

Phenotype: The observable attributes of an Individual

Genotype: The inherited material transmitted by gametes

Why Phenotype pulmonary hypertension?

1. Identify patients appropriate for therapy (PAH vs. PH)

2.Identify patients at risk for morbidity and mortality

3.Understand disease progression and trajectory

1965 : The origins of PH phenotyping & The Aminorex epidemic

THE W.H.O classification

First WHO classification: Geneva, 1973

Second WHO classification: Evian, 1998

Third World Symposium on PH : Venice, 2003

Fourth World Symposium on PH : Dana Point, 2008

Fifth World Symposium on PH : Nice, 2013

The first W.H.O classification of PH: 1973

1) Primary Pulmonary Hypertension (PPH): Any patient with a pulmonary artery pressure > 25mm Hg without elevation of PCWP (pulmonary capillary wedge pressure

- Pathologic Classification of PPH1. Plexogenic pulmonary arteriopathy2. Recurrent pulmonary thromboembolic disease3. Pulmonary veno-occlusive disease (PVOD)

2) Secondary Pulmonary hypertension

1. Pulmonary arterial hypertension (PAH)1.1 Idiopathic PAH1.2 Heritable PAH

1.2.1 BMPR21.2.2 ALK1, ENG, Smad 9, CAV1, KCNK31.2.3 Unknown

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

1’. Pulmonary veno-occlusive disease and/orpulmonary capillary hemangiomatosis

1’’. Persistent PH of the newborn

2. PH due to left heart disease2.1 LV systolic dysfunction2.2 LV diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract

obstruction and congenital cardiomyopathies

3. PH due to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive

and obstructive pattern3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung diseases

4. Chronic thromboembolic PH

5. PH with unclear multifactorial mechanisms5.1 Hematological disorders: chronic hemolytic anemia,

myeloproliferative disorders, splenectomy5.2 Systemic disorders: sarcoidosis, pulmonary

histiocytosis, lymphangioleiomyomatosis, 5.3 Metabolic disorders: glycogen storage disease,

Gaucher disease, thyroid disorders5.4 Others: tumoral obstruction, fibrosing mediastinitis,

chronic renal failure, segmental PH

5th World Symposium on PH: Classification

How do we manage the non WHO group I patients ?

WHO group II pulmonary hypertension

WHO group II pulmonary hypertension: Pathophysiology

Vachiery JL et al, JACC 2013;62( Suppl D): D100 – 108

Post-capillary PH

RA RV PA PVPC

LA LV Ao

mPAP ≥ 25 mm HgPCWP >15 mm HgDPG < 7 mm Hg

PVR <3 Wood units

Spectrum of PH in left heart disease

Mixed PHmPAP ≥ 25 mm HgPCWP >15 mm Hg

DPG ≥ 7 mm HgPVR ≥3 Wood units DPG: PA diastolic – PCWP gradient

Heart failure with preserved ejection fraction (HFpEF)

Heart failure with reuced ejection fraction (HFrEF)

Management of PH in left heart disease: HFpEF and HFrEF

1. Manage left heart disease

2.No currently approved therapies for HFpEF or HFrEF associated PH

3.Unique phenotypes ?

NO Pathway ERA Prostacyclin pathwayPDE5-inhibitors sGC stimulators

‘HFpEF without PH’ RELAX trial –– no benefit1

SOCRATES-PRESERVED – Vericiguatin HfPEF. No change in LA size and BNP but improved quality of life.

Most ERA studies have been in patients with heart failure alone.

The impact of ERAs on WHO II PH is unknown

IV epoprostenol in ‘HFrEF + PH’ – ‘FIRST’ trial – terminated due to increased mortality in the epoprostenol arm.

‘HFrEF + PH’ – Sildenafil improved hemodynamics and exercise performance

HFpEF + PH’ – DILATE study -Riociguat did not have significant impact on PAP but increased CI and lowered PVR.

‘HFpEF + PH’ – ‘MELODY’ trial –Macitentan in ‘HFpEF + PH’ –currently ongoing

‘HFpEF + PH’ – ‘SOUTHPAW’ trial – Oral Treprostinil in ‘HFpEF + PH’ – currently ongoing

A meta-analysis of 6 RCTs (HFrEF+ PH) - PDE5-I improved hemodynamics and exercise performance

‘HFrEF + PH’ – LEPHT study -Riociguat did not lower PAP (1o

end point), but increased CI and lowered PVR.5

Comment: From small studies, we know that ERA use in ‘HFpEF + PH’ causes significant peripheral edema7

SUMMARY: Routine use of Prostacyclin pathway analogs in WHO II PH is not approved.

PARAGON HF– results pending

‘HFpEF + PH’ – Sildenafil improved hemodynamics and exercise performance3

Comment: Riociguat could be having a systemic vasocilatory vs. cardiac effect instead of pulmonary vasodilation. SUMMARY: Routine use of ERAs in

WHO II PH is not approved. SUMMARY: Routine use of PDE5-i in WHO II PH is not approved, but may benefit a specific RV phenotpye.

SUMMARY: Routine use of sGCstimulators in WHO II PH is discouraged. May cause systemic hypotension and cardiac specific effects. Vachiery JL et al, JACC 2013;62( Suppl D): D100 – 108

WHO group II PH – clinical studies

WHO group II PH therapy : Summary

• None of the therapies for WHO group I PH (PAH) are approved for the treatment of WHO group II PH

• The NO pathway has been well studied and holds some promise in specific WHO group II phenotypes

• ERAs and Prostacyclin pathway analogs – no benefit in WHO II PH1,2

• IV Prostacyclins increase mortality in HfREF (‘FIRST’ trial)• HFpEF & PH - ERA Clincal trials underway (MELODY –macitentan)• HFpEF & PH – Prostacyclin – Clinical trial underway ( SOUTHPAW -

treprostinil)

1. Vachiery JL et al, JACC 2013;62( Suppl D): D100 – 1082. Rosenkranz S et al Int J Cardiol 2011; 154:S34-S44

WHO group III pulmonary hypertension

WHO group III pulmonary hypertension

• Second commonest cause of pulmonary hypertension (25% of all PH cases)• COPD, ILD and OSA are the commonest lung diseases associated with

pulmonary hypertension• No therapies have yet been proven to improve quality of life or survival in

patients with WHO group III pulmonary hypertension• A small subset of patients might have pulmonary hypertension that is out of

“proportion to their lung disease”• Could there be a unique “endo-phenotype” inside the WHO III population,

that could benefit from targeted therapies?

Pulmonary vasoconstriction

+ Increase in PVR

+Pulmonary vascular

remodeling

Hyperinflation

Hypercarbia

Alveolar hypoxia +

Pulmonary arterial hypoxemia

Loss of pulmonaryvascular surface

area

WHO group III pulmonary hypertension: Pathophysiology

Impact of PH in Lung disease: survivalCOPD and ILD1 COPD2

1. Leuchte HH et al, AJRCCM 2006; 173(7): 7482. Calverley P et al, COPD, 2nd Ed; 2003 (p.239)

COPD and pulmonary hypertension. Treatment with PDE5 inhibitors

Study Disease phenotype

Study design & Duration

Number of participants

(n)Outcome Results/Conclusions

Alp S, et al, 2006

COPD with moderate PH

Single arm,prospective.3-months

Sildenafil: 6 1) 6MWTD2) Hemodynamics

1) 6MWTD increased significantly2) mPAP, PVR decreased significantly

with sildenafil

Madden et al, 2006


Single arm,prospective.8 weeks Sildenafil: 4

1) Hemodynamics (RHC & Echo)

2) 6MWTD

1) Cardiac output increased, PVR decreased in all patients with sildenafil

2) 3 of 4 COPD patients improved 6MWTD on sildenafil

Lederer D, et al 2008

COPD without PH

Double blind randomizedcrossover trial. 4 weeks

Sildenafil:10Placebo:10

1) 6MWTD2) O2 consumption

at peak exercise

1) No change in 6MWTD2) Gas exchange worsened in sildenafil

arm3) Quality of life worsened in sildenafil

arm

Blanco I, et al, 2013


Double blind randomizedtrial during pulm rehab. 3 months


1) Cycle endurance time

2) 6MWTD3) Quality of life

1) Cycle endurance time increased in the sildenafil arm

2) No difference in 6MWTD change between groups

3) No difference in quality of life between groups

COPD and pulmonary hypertension. Treatment with sGC stimlators and Nitric

Oxide





Ghofrani HA,et al 2015

COPD withPH (mPAP>23 and PVR>270 dynes.sec.cm-

5.

Single arm prospectivestudy

Oral Riociguat: 22 1) Hemodynamics

1) Mean PA pressure decreased2) PVRI decreased3) Cardiac output increased4) Oxygenation remained stable.5) Lung function remained stable

Vonbank K, et al, 2003


Double blind, placebo controlled, Randomized trial, 3-months

O2+ pulsed NO inhaled:20O2 alone: 20

1) Hemodynamics

1) Mean PA pressure decreased2) PVRI decreased3) Cardiac output increased4) Oxygenation remained stable.

COPD and pulmonary hypertension. Treatment with Endothelin Receptor

Antagonists (ERA)





Stolz D, et al 2008

Severe or very severe COPD

Double blind placebo controlled trial. 12 weeks

Bosentan:20Placebo:10

1) 6MWTD2) Quality of life3) Lung function4) Hemodynamics5) Max Oxygen

uptake

1) No change in 6MWTD2) Gas exchange worsened in Bosentan

arm3) No change in Quality of life,

hemodynamics, lung function between groups.

Valerio G, et al, 2009


Prospectivecohort + controls, 18 months

Bosentan: 16Controls: 16

1) Hemodynamics2) Lung function3) Dyspnea4) 6MWTD5) Quality of life

1) mPAP, PVR decreased significantly with sildenafil (more pronounced in GOLD III and IV)

2) 6MWTD improved with Bosentan3) GOLD IV patients did not improve4) GOLD II, III with severe PH showed

more improvement

Badesch D,et al, 2006

COPD with PH ARIES III, prospective.8 weeks

Ambrisentan: 24

1) 6MWTD2) BNP

1) No improvement in 6MWTD2) Significant reduction in BNP levels

from baseline.

COPD and pulmonary hypertension. Treatment with Prostacyclin pathway

agonists (PPA)





Dernaika TA,et al 2010

COPD with PH (Echo)

Single arm,prospective.Before vs. 30 min vs. 2h after iloprost (2 doses)

Iloprost : 10

1) Lung function2) Blood gases3) 6MWTD4) Hemodynamics5) Max Oxygen

uptake

1) No change in lung function2) Peak O2 consumption and CO2

production increased with iloprost3) Increase in 6MWTD with iloprost4) No changes in gas exchange, dead

space fraction and ABG.

PH in COPD: ‘Proportion’ vs ‘Out of Proportion’ to disease

1. Mild Obstructive disease and Mild PH

2. Severe Obstructive disease and Mild PH

3. Severe Obstructive disease and Severe PH

4. Mild Obstructive disease and Severe PH

Thabut G et al, Chest 2005;127(5):1535

ILD and pulmonary hypertension. Treatment with PDE5 inhibitors





Zimmerman GS, et al, 2014

ILD with PH Observational study. 6.9 + 5.8 months

Sildenafil or Tadalafil : 10 (IPF:6, HP:4)

1) Hemodynamics2) 6MWTD3) BNP

1) Hemodynamics improved (CO improved and PVR decreased from baseline)

2) No change in 6MWTD from baseline 3) No difference in BNP from baseline

Zisman DA,et al 2010(STEP IPF)

Advanced IPF

Double blind randomizedtrial. 12 weeks + 12 wks open labeled ext


1) 6MWTD2) Oxygenation3) Dyspnea severity4) Quality of life

1) No between group difference in 6MWTD

2) Gas exchange stable in sildenafil arm and worsened in placebo arm

3) Quality of life and dyspnea were better in the sildenafil arm

Han MK et al, 2013

IPF patients with RV dysfunction and RV hypertrophy

Sub group analysis of STEP IPF population


1) 6MWTD2) Quality of life

IPF + RV dysfunction patients had greater improvement in 6MWTD and Quality of

life (SGRQ) with sildenafil when compared to placebo.

Jackson RM, et al, 2010 Advanced IPF

Double blind randomizedtrial. 24 weeks

Sildenafil: 14Placebo: 15

1) 6MWTD2) BORG dyspnea

score

1) No between group difference in 6MWTD

2) No between group difference in BORG dyspnea score change

ILD and pulmonary hypertension. Treatment with sGC stimlators and Nitric

Oxide





Hoeper MM et al, 2013

ILD – PH (IPF, Sarcoidosis,NSIP)

Single arm prospectivestudy

Oral Riociguat: 22

1) Hemodynamics2) 6MWTD3) Arterial

oxygenation4) Mixed venous

oxygenation

1) Mean PA pressure remained same2) PVRI decreased3) Cardiac output increased4) Arterial oxygenation decreased5) Mixed venous oxygenation improved

BellerophonPPH-PF

Idiopathic ILD with & without PH

Double blind, placebo controlled, Randomized trial,

Pulsed inhaled NO

1) 6MWTD2) BNP3) Hemodynamics4) Lung function5) Dyspnea6) Quality of life

ONGOING.AWAITING IRB APPROVAL AT MUSC

ILD and pulmonary hypertension. Treatment with Endothelin Receptor

Antagonists (ERA)





Corte TJ, et al 2014BPHIT study

Fibrotic IIP patients (RHC confirmed PH)

Double blind placebo controlled (2:1) trial. 16 weeks.

Bosentan: 40Placebo: 20

1) Decrease in PVRi2) Pulmonary

hemodynamics3) Quality of life4) Lung function5) Disease

progression

1) No between group differences in PVRi

2) No between group differences in pulmonary hemodynamics, quality of life, disease progression.

Badesch D,et al, 2006ARIES III study

ILD with PH ARIES III, prospective.8 weeks

Ambrisentan: 21

1) 6MWTD2) BNP

1) No improvement in 6MWTD2) Significant reduction in BNP levels

from baseline.

ILD and pulmonary hypertension. Treatment with Prostacyclin pathway

agonists (PPA)





Saggar R et al, 2009

Advanced IPF with pulmonary hypertension

case report 1 IPF + pulmonary hypertension

1. Patient had pulmonary vascular resistance severely elevated –suggesting PH out of proportion to lung disease.

2. Patient was successfully bridged to lung transplant with IV treprostinil

INCREASE

ILD (CTD associated or idiopathic) or CPFE, with PH

Double blind, placebo controlled, Randomized trial,

Inhaledtreprostinil: vs PlaceboTotal: 314

1) 6MWTD2) BNP3) Lung function4) Dyspnea5) Quality of life

ONGOING.CURRENTLY RECRUITING AT MUSC

PH in ILD and COPD: Treatment summary

• Treat hypoxemia, hyperinflation and avoid hypercapnia. • None of the WHO group I therapies are approved for treatment of

PH associated with ILD or COPD. • PDE5 inhibitors are the best studied PA vasodilator therapies in

COPD and ILD related PH• PDE5 inhibitors have not been shown to improve quality of life or

survival in patients with ILD/COPD related pulmonary hypertension• A small subset of patients with pulmonary hypertension that is out

of “proportion to their lung disease” might be the most favorable targets for therapies in the future.

PH in Obstructive sleep apnea : Treatment• Treat OSA with CPAP or BiPAP

therapy• Pulmonary hemodynamics

usually improve with OSA therapy

• No indication for PA vasodilator therapies

• Consider treatment in : Patients with persistent pulmonary hypertension and symptoms despite OSA therapy

Sajkov D et al, AJRCCM 2002 165 (2):154

Patient 2

Labs

• ABG: PH:7.42/40/86 mm Hg (FiO2:21%)

• HcO3- = 26

• BMP:134/3.8/98/26/19/0.9

• CBC, Renal function: WNL

• CXR: Cardiomegaly, mild ILD in bases

Two Women with dyspnea

Labs

Patient 1

• ABG: pH: 7.3/78/68mm Hg (FiO2:30%)

• HCO3- = 45

• BMP:136/4.8/98/45/16/0.8

• CBC, Renal function: WNL

• CXR: Kyphoscoliosis

Patient 2

Echo

• LV: EF 58%

• Grade 1 diastolic dysfunction

• RV: ↑↑↑ size

• 3+ RV dysfunction

• PASP: 76 mm Hg

• RA: 10 mm Hg

• 2+ TR

Echo

Patient 1

• LV: EF 65%

• No diastolic dysfunction

• RV: ↑ size

• 1+ RV dysfunction

• PASP: 60 mm Hg

• RA: 10 mm Hg

• 1+ TR


Patient 2

Invasive Hemodynamics• RA: 12 mm Hg

• mPAP: 41 mm Hg

• PCWP: 10 mm Hg

• CO: 2.6 L/min

• PVR: 11.9 Wood units

• BP: 93/69 mm Hg• Vasodilator challenge with iNO: non-responder

Invasive Hemodynamics

Patient 1

• RA: 8 mm Hg

• mPAP: 39 mm Hg

• PCWP: 11 mm Hg

• CO: 5.6 L/min

• PVR: 5 Wood units

• BP: 148/80 mm Hg• Vasodilator challenge with iNO: non responder


Patient 2

Final Diagnosis• WHO Group I—pulmonary

arterial hypertension (PAH)

• PAH due to connective tissue disease

Final Diagnosis

Patient 1

• WHO Group III—pulmonary hypertension due to chronic alveolar hypoventilation

• Severe Obstructive sleep apnea and chest wall restriction (FVC :64% predicted)

Sleep study: Severe Sleep apnea with multiple apneic events during sleep

Sleep study: Not performed as patient had no risk factors for sleep apnea


Patient 2: WHO group I PH or PAH

Clinical Course

• Patient was already on two agents for PAH

• Swan ganz catheter placed and titrated on IV epoprostenol

• Now on IV epoprostenol via portable pump with improved symptoms

• NYHA II

Clinical Course

Patient 1: WHO group III PH

• Started on CPAP therapy

• Added Furosemide + Spironolactone

• Improved symptoms

• BNP reduced from 3400 to 40

• NYHA I


Summary: PH Lessons1. PH is common, but most often due to LHD or chronic lung disease:

selective pulmonary vasodilators are not proven in these patients2. PAH is rare but deadly:3. Learn to differentiate Group I PAH from other forms of PH: when in

doubt, refer to a PH center. 4. No currently approved therapies for WHO group II or left heart

disease related PH. There might be a unique RV phenotype suitable for therapy with PDE5 inhibitors.

5. No currently approved therapies for WHO group III or lung disease related PH. Among IPF patients, there might be a unique RV phenotype suitable for therapy with PDE5 inhibitors.

6. No indication for PA vasodilator use in patients with OSA associated PH.

w.h.o gets better ? - american thoracic society · 2019-12-06 · w.h.o gets better ? phenotyping...

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