Professor Emerita of Pediatrics Columbia University College of Physicians & Surgeons New York,...

Professor Emerita of PediatricsColumbia University

College of Physicians & SurgeonsNew York, New York

ROBYN BARST, MDROBYN BARST, MD

Consensus Updates in PAH Classification, Screening and Treatment

Faculty:Content Development and Training

Robyn J. Barst, MDRobyn J. Barst, MDProfessor Emerita of Pediatrics Professor Emerita of Pediatrics

Columbia University College of Physicians & SurgeonsColumbia University College of Physicians & SurgeonsNew York, New YorkNew York, New York

Vallerie McLaughlin, MDVallerie McLaughlin, MDProfessor of MedicineProfessor of Medicine

Director, Pulmonary Hypertension ProgramDirector, Pulmonary Hypertension ProgramUniversity of MichiganUniversity of MichiganAnn Arbor, MichiganAnn Arbor, Michigan

Learning Objectives (CME, CE, CPE)

At the completion of this educational activity, participants should be able to:

#̶ Describe the new classification scheme for pulmonary hypertension

#̶ Discuss important changes in the PH classification scheme and how this impacts patient management

#̶ Discuss the current diagnostic algorithms for PAH

#̶ Report on the updated guidelines regarding initial PAH therapy

Updated Clinical Classification ofPulmonary Arterial Hypertension

Updated Definition of PAH

Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294.

Increased mean pulmonary arterial pressure (mPAP)*

>25 mm Hg at rest

Normal pulmonary capillary wedge pressure (PCWP)

<15 mm Hg

Increased pulmonary vascular resistance (PVR)†

>3 Wood units

Right Heart Catheterization Confirmed

* Normal resting mPAP = 8 – 20 mm Hg. † In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR given without a value. Significance of mPAP from 21 – 24 mm Hg unclear.

Updated Hemodynamic Definitions of Pulmonary Hypertension

Adapted from: Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

Definition Characteristics Clinical groupPre-capillary PH Mean PAP ≥25 mm Hg

PWP ≤15 mm Hg

CO normal or reduced

Pulmonary arterial hypertension

PH due to lung disease CTEPH PH with unclear or

multifactorial mechanisms

Post-capillary PH Mean PAP ≥25 mm Hg

PWP >15 mm Hg

CO normal or reduced

Passive = TPG ≤12 mm Hg

Reactive = TPG >12 mm Hg

PH due to left heart disease

CO = cardiac output.

TPG = transpulmonary pressure gradient.

2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1

Idiopathic (IPAH) Heritable (PAH)

— BMPR2— ALK1— Endoglin (with or without hereditary hemorrhagic telangiectasia)— Unknown

Drugs and Toxins induced Associated with

— Connective Tissue Diseases— HIV Infection— Portal Hypertension— Congenital Heart Diseases— Schistosomiasis— Chronic hemolytic anemia

Persistent pulmonary hypertension of the newborn

Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1'

Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)

Pulmonary hypertension owing to left heart disease— Systolic dysfunction— Diastolic dysfunction— Valvular disease

Pulmonary hypertension owing to lung diseases and/or hypoxia— Chronic obstructive pulmonary disease— Interstitial lung disease— Other pulmonary diseases with mixed restrictive

and obstructive pattern— Sleep-disordered breathing— Alveolar hypoventilation disorders— Chronic exposure to high altitude— Developmental abnormalities

Chronic thromboembolic pulmonary hypertension (CTEPH)

Pulmonary hypertension with unclear multifactorial mechanisms

Hematologic disorders: myeloproliferative disorders, splenectomy

Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis

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

Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

Important Changes in Updated Clinical Classification Schema

Change from “familial” to “heritable” PAH— With or without mutations

Classifying PAH due to schistosomiasis as Group 1

PAH due to PVOD and/or PCH in separate Group 1' as a combined subcategory

Separation of CTEPH into separate, single-entity category (Group 4)

Updated Diagnostic Algorithm for Pulmonary Arterial Hypertension

Diagnostic Algorithm for PH

Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

History, Symptoms, Signs Suggestive of PH History, Symptoms, Signs Suggestive of PH

Diagnostic Algorithm for Pulmonary Hypertension: Clinical Presentation

Symptoms— Breathlessness— Fatigue— Syncope— Weakness— Angina— Abdominal distension

Signs— Accentuated pulmonary

component of second heart sound (P2) at apex

— Early systolic ejection click— Midsystolic ejection murmur— Left parasternal lift— Right ventricle S4 gallop— Prominent jugular “a” wave— Diastolic murmur of pulmonary

regurgitation— Holosystolic murmur of tricuspid

valve regurgitation— Cool extremities

Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.

Other Physical Findings:Differential Diagnosis/PH Etiology

McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S.

Finding Differential Diagnosis/PAH Etiology

Cyanosis Right-to-left shunt

Clubbing Rare in IPAHCongenital heart or pulmonary veno-occlusive disease

Rales, fine rales, abnormal breath sounds

Pulmonary congestion, parenchymal airway disease, PVOD, PCH, etc.

Obesity, kyphoscoliosis, enlarged tonsils

Hypoventilatory disorders

Sclerodermal skin changes, rashes, nail-fold capillary abnormalities

Associated connective tissue disorder

Peripheral venous insufficiency

Venous thrombosis, pulmonary thromboembolic disease

REVEAL Database: Most Frequent Symptoms at Diagnosis

Elliott EG, et al. Chest. 2007;132(suppl 4):631S.

Dyspnea at rest

Dizzy/lightheaded

Presyncope/syncope

Chest pain/discomfort

Fatigue

Dyspnea on exertion84%

0 25 50 75 100 Incidence (%)

IPAHAPAH

N=1479.

Consider Common Causes of PHConsider Common Causes of PH

Group 2: Left Heart DiseaseGroup 2: Left Heart Disease Group 3: Lung Diseases and/or Hypoxia

Group 3: Lung Diseases and/or Hypoxia

Initial Evaluation of Patients with Suspected PH

ECG Chest X-ray Transthoracic echocardiography Pulmonary function test High-resolution CT scan

Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

ECG Associated With Right Axis Deviation (RAD) and Right Ventricular Hypertrophy (RVH)

Image courtesy of Vallerie McLaughlin, MD

Electrocardiogram Associated With Right Bundle Branch Block Plus RVH

Chest X-Ray Findings Consistent with PH

Enlarged main and hilar pulmonary artery shadows

“Pruning” of peripheral pulmonary vasculature Right ventricular enlargement Patients may have normal chest x-ray Chest x-ray may reveal underlying causes

Chest X-Ray Consistent With PH

Echocardiogram:Parasternal Long Axis

Echocardiogram:Parasternal Short Axis

Echocardiogram: Apical Four Chamber

Echocardiogram: Tricuspid Regurgitation

Modified Bernoulli’s Equation:4 x (V)² + RAP = RVSP (PASP)

V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulmonary artery systolic pressure.

Accuracy of PH Diagnosis by Echocardiography in Advanced Lung Disease

Cohort study of lung transplant patients (n=374)

All patients— Doppler echo 24 to 48 hours

prior to RHC Prevalence of PH: 25% Echo frequently inaccurate

leading to over diagnosis of pulmonary hypertension in patients with advanced lung disease

Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740.

Diagnosis of PH

OverestimationAccurateUnderestimation

NoPulmonary

Hypertension

PulmonaryHypertension

Pulmonary Function Tests and Arterial Blood Gases

Findings suggestive of PAH— DLCO 40% - 80% of

expected

— Mild to moderate reduction of lung volumes

— Peripheral airway obstruction

— Arterial O2 tension normal or slightly reduced at rest

— Arterial CO2 is reduced

Findings suggestive of alternate PH diagnoses— Hypoxic PH due to COPD

• Irreversible airway obstruction + increased residual volumes + reduced DLCO + normal or increased CO2 tension

— Interstitial lung disease• Decrease in lung

volume + decreased DLCO

Galie N, et al. Eur Heart J. 2009;30(20):2493-2537.

Actual Diagnoses of Patients Referred to PH Specialty Clinic

Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923.

Interstitial Lung Disease

Venous Thromboembolism

Structural Heart Disease

Obstructive Sleep Apnea

LV Dysfunction

Obstructive Lung Disease

All Alternative Diagnoses 85.0%

Algorithm for Diagnosing and Rating Severity of PH

Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294

History – Physical – CXR - ECGHistory – Physical – CXR - ECG

EchocardiographyEchocardiography

VQ Scan - ABGsVQ Scan - ABGs

Overnight OximetryOvernight Oximetry

HIV – ANA - LFTsHIV – ANA - LFTs

Functional TestingFunctional Testing

Right Heart CatheterizationRight Heart Catheterization

Index of Suspicion – Evaluate for LH & RH

disease

Index of Suspicion – Evaluate for LH & RH

disease

CTEPHCTEPH

OSAOSA

Underlying CausesUnderlying Causes

Functional SeverityFunctional Severity

Confirm DiagnosisConfirm Diagnosis

Consider Common Causes of PHConsider Common Causes of PH

Group 2: Left Heart DiseaseGroup 2: Left Heart Disease Group 3: Lung Diseases and/or Hypoxia

Group 3: Lung Diseases and/or Hypoxia

YesYes

YesYesConsider Group 2 or 3 PHConsider Group 2 or 3 PH

“Out of proportion”PH

Perform V/Q ScanPerform V/Q Scan

Segmental Perfusion DefectsSegmental Perfusion Defects

CTEPHCTEPH

PVOD/PCHPVOD/PCH

V/Q Scan for Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Normal V/Q scan makes CTEPH unlikely— Sensitivity: 90% to 100% — Specificity: 94% to 100%

>1 segmental-sized or larger mismatched perfusion defects seen with CTEPH

Spiral CT may underestimate degree of obstruction in chronic CTEPH— ~7% false negative

YesYes

YesYesConsider Group 2 or 3 PHConsider Group 2 or 3 PH

“Out of proportion”PH

Perform V/Q ScanPerform V/Q Scan

Segmental Perfusion DefectsSegmental Perfusion Defects

CTEPHCTEPH

PVOD/PCHPVOD/PCH

Perform RHCPerform RHC

Recommended Measurements during Right Heart Catheterization

Systemic artery pressure Pulmonary capillary wedge pressure (or left ventricular

end diastolic pressure if not obtainable) Pulmonary artery pressure Right ventricle pressure Right atrium pressure Left atrium (if entered via a patent foramen ovale or

atrial septal defect) pressure Mixed venous oxygen saturation

— Site dependent if congenital systematic to pulmonary shunt present; if no shunt, SVO2 = PA oxygen saturation

Systemic arterial oxygen saturation

Gibbs JSR, et al. Heart. 2008;94(suppl 1):i1-i41.

Measuring Pulmonary Capillary Wedge Pressure

Time (seconds)

BalloonOcclusion

0 2 4 6 8 10

ARDSIPAH

Time Steady State is Longer in IPAH than in ARDS

Pulmonary Artery Pressure Decay Curve

ARDS: acute respiratory distress syndrome.

Souza R, et al. Crit Care. 2005;9:R132-R138.

Inaccurate Readings of PCWP

PA and RV Recordingsin Patient with PAH

RV Pressure MistakenlyRecorded as PCWP

Oudiz RJ, et al. Advances PAH. 2005;4(3):26-30.

Misclassification of PAH Through Reliance on PCWP vs LVEDP

Halpern SD, et al. Chest. 2009;136(1):37-43.

N = 11,523, all patients undergoing LHC and RHC over 10 years at single center.

PCWP ≤15 mm Hg LVEDP >15 mm Hg

PCWP ≤15 mm Hg LVEDP ≤15 mm Hg

Diagnostic Algorithm for PAH: Results of RHC

NoNo YesYes

Perform RHCPerform RHC

mPAP ≥25 mmHg

PWP ≤15 mmHg

Increased PVR

mPAP ≥25 mmHg

PWP ≤15 mmHg

Increased PVR

Search for other causes

Specific diagnostic tests for PAH causes:Specific diagnostic tests for PAH causes:

Evaluating Causes of PAH

mPAP ≥25 mmHgPWP ≤15 mmHgIncreased PVR

CTDCTD

3-year Incidence of Pulmonary Hypertension in Systemic Sclerosis

Estimated incidence (per 100 patient years)

95% CI

All forms of pulmonary hypertension 1.37 0.74 – 2.00

Pulmonary arterial hypertension 0.61 0.26 – 1.20

PAH in limited cutaneous systemic sclerosis 0.40 0.11 – 1.03

PAH in diffuse cutaneous systemic sclerosis 1.25 0.34 – 3.20

Postcapillary pulmonary hypertension 0.61 0.26 – 1.20

PH secondary to pulmonary fibrosis 0.15 0.02 – 0.55

Hachulla E, et al. Arthritis Rheum. 2009;60(6):1831-1839.

CTDCTD Drugs/ToxinsDrugs/Toxins

PAH Due to Drugs and Toxins

Definite RiskAminorexFenfluramineDexfenfluramineToxic rapeseed oil

Possible RiskCocainePhenylpropanolamineSt. John’s wortChemotherapeutic agentsSSRI

Likely RiskAmphetaminesL-tryptophanMethamphetamines

Unlikely RiskOral contraceptivesEstrogenCigarette smoking

SSRIs in Late Pregnancy and Risk of Persistent Pulmonary Hypertension in the Newborn

Chambers CD, et al. N Engl J Med. 2006;354(6):579–587.

Maternal use of SSRIs

PPHN(N=377)

Matched Controls(N=836)

Adjusted Odds Ratio(95% CI)

P value

Never during pregnancy (%) 361 (95.8) 812 (97.1) 1 NS

Before wk 20 (%) 2 (0.5) 18 (2.2) 0.3 (0.1 - 1.2) 0.08

After wk 20 (%) 14 (3.7) 6 (0.7) 6.1 (2.2 - 16.8) 0.001

CTDCTD

HIVHIV

Drugs/ToxinsDrugs/Toxins

PAH and HIV Disease

Seen in approximately 0.5% of HIV-infected patients

Etiology appears related to HIV itself— No evidence for direct infection of HIV of vascular

endothelium— Higher prevalence among injection drug users

PAH incidence and course unaffected by HIV disease (stage or use of antiretrovirals)— ~66% of mortality related to PAH

Limsukon A, et al. Mt Sinai J Med. 2006;73(7):1037-1044.

Prevalence of Methamphetamine Use in HIV-PAH

Lewis JE et al. Am J Respir Crit Care Med. 2008;177:A444.

N = 17 patients with HIV-PAH

Methamphetamine

Methamphetamine + cocaine

Cocaine

Denied stimulant use

CTDCTD

HIVHIV

Congenital heart disease

Congenital Heart Disease and PAH

Systemic to pulmonary shunts — Prevalence of PAH associated with shunts

estimated at 1.6 to 12.5 cases per million adults— May result in PAH if not repaired early in life— Eisenmenger Syndrome – severe PAH with reversal

of shunt direction

Post switch repair transposition of the great vessels

CTDCTD

HIVHIV

PortopulmonaryPortopulmonary

Portopulmonary Hypertension (PoPH)

Portal hypertension is main risk— Prevalence is 2% to 6% in this population

Pathologic changes in small arteries appears identical to IPAH

Right heart catheterization mandatory for diagnosing PoPH

Survival in Portopulmonary Hypertension Related to Cirrhosis

Le Pavec J, et al. Am J Respir Crit Care Med. 2008;178(6):637-643.

N = 154.

PoPH without cirrhosis

p = 0.003

PoPH with cirrhosis

0 12 24 36 48 60 72 84 96 108 120

Months

CTDCTD

HIVHIV

SchistosomiasisSchistosomiasis

Schistosomiasis-associated PAH

PH associated with schistosomiasis can have a similar clinical presentation to IPAH— Similar histologic findings

• Development of plexiform lesions

May include PoPH— 200 million people are infected with any of the 3

species of Schistosoma • 4% to 8% of patients will develop hepatosplenic disease

Invasive hemodynamics required for diagnosis— Post-capillary PH also prominent in this population

CTDCTD

HIVHIV

PVOD/PCHPVOD/PCH

Pulmonary Venous Occlusive Disease / Pulmonary Capillary Hemangiomatosis

Shares characteristics of IPAH— Histology— Clinical features— Genetic alterations– familial forms for PVOD/PCH

(with or without identified mutations)

Distinct features— Crackles and clubbing, ground glass opacities,

septal thickening, mediastinal adenopathy, hemosiderin-laden macrophages, lower DLCO and PaO2

— Response to therapy also different• Risk for pulmonary edema with PAH-specific medications

CTDCTD

HIVHIV

PVOD/PCHPVOD/PCH

Chronic hemolysis

New Group 1 Classification Category: PAH Due to Chronic Hemolytic Anemia

Chronic hemolytic anemias associated with PAH— Sickle cell disease — Thalassemia— Hereditary spherocytosis — Stomatocytosis— Microangiopathic hemolytic anemia

Prevalence not established Mechanism of PAH in this population still not well

understood PH also occurs with hemolytic anemias due to LVDD

with pulmonary venous hypertension PH may also be “mixed” pulmonary vasculopathy with

increased PCWP and increased PVRSimonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54.

No known cause

CTDCTD

HIVHIV

PVOD/PCHPVOD/PCH

Chronic hemolysis

Idiopathic or heritable PAHIdiopathic or heritable PAH

Assessment of PAH

Prognostic Factors for Risk of PAH Disease Progression

McLaughlin VV, et al. Circulation. 2006;114(13):1417-1431.

Lower Risk Higher Risk

Evidence of RV failure No Yes

Progression Gradual Rapid

WHO Class II, III IV

6-minute walk distance >380 m <325 m

Brain natriuretic peptide <180 pg/mL >180 pg/mL

Echo findings Minimal RV dysfunction

Pericardial effusion; significant RV dysfunction

Hemodynamics Normal/near normal RAP and CI

High RAP, Low CI

Assessment of PH Severity: WHO Functional Classification (NYHA Modification for PH)

WHO Class Description

I No limitation of usual activities

II Mild limitation of usual activitiesNo discomfort at restNormal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope

III Marked limitation of physical activityNo discomfort at restLess than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope

IV Patient unable to perform any physical activity at rest and may have signs of right ventricular failureDyspnea and/or fatigue and/or syncope/near-syncope may be present at rest, and symptoms are increased by almost any physical activity

Rich S. World Health Organization. 1998.

6-Minute Walk Distance Correlates With IPAH Disease Severity

Miyamoto S, et al. Am J Respir Crit Care Med. 2000;161:487-492.

Control NYHA II

*P<0.05 versus control.†P<0.05 versus NYHA Class II.‡P<0.05 vs NYHA Class III.

NYHA III NYHA IV

*†‡

Impact of Baseline 6-Minute Walk Distance on Survival in IPAH/HPAH

Barst RJ, et al. N Engl J Med. 1996;334(5):296-302.

6-minute walk distance at baseline was the only independent predictor of survival (P<0.003)

6-MinuteWalk Distance

Survivors(n=73)

305 + 14

Deaths (n=8)

195 + 63

Epoprostenol (n=41)Conventional Therapy (n=40)

00 2 4 6 8 10 12

Epoprostenol Versus Placebo

NT-proBNP Elevations Correlate With Right Ventricular Systolic Dysfunction (RVSD) in PH

Blyth KG, et al. Eur Respir J. 2007;29(4):737-744.

With RVSD

Without RVSD

Threshold value RVD detection: 1,685 ng/L-1.Sensitivity for RVD 100%; specificity 94%.

Composite Scoring System Predicts Disease Progression in PAH

Anderson D, et al. Am J Respir Crit Care Med. 2008;177:A915.

Time (years)

Composite Score 3-year Survival

%) 100

0 1 2 3

Walk (m) 340 260-340 190-260 <190

FC 1 2 3 4

NT-proBNP <2000 >2000

QOL (CAMPHOR) <12 >12

Activity <11 >11

Symptoms <16 >16

Heritable PAH: Frequency of BMPR2 and ALK1 Mutations

Nakanishi N, et al. Am J Respir Crit Care Med. 2008;177:A256.

N = 222.

1.37.7 5.4

BMPR2 ALK1

HPAH IPAH APAH

Updated Treatment Algorithm For PAH

Supportive Therapy and General Measures in PAH

Oral anticoagulants (IPAH/HPAH)— Favorable data primarily from retrospective trials

Diuretics— Standard of care for right-heart failure— Clinician preference on choice of agents

Oxygen— Low-flow supplemental O2 improved outcome in clinical case

series; maintain SaO2 >92%• Not evaluated in randomized controlled trial

Digoxin— Modest increase in cardiac output— No data available on long-term management

Supervised exercise program rehabilitationBarst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

Additional General and Supportive Measures in PAH

Avoid excessive exertion Avoid pregnancy Avoid constipation Appropriately refer to ensure psychological

and social support Provide appropriate training and counseling on

infection prevention— Including, but not limited to, infections related to

infusion/injection-based PAH therapy— Pneumococcal and flu vaccines

Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

When to Initiate PAH-specific Therapy

No data support “wait-and-see” approach to diagnosed PAH

Data suggests that patients assigned to placebo in randomized controlled trials may fail to “catch-up” when enrolled into long-term observational arms

In FC II patients, bosentan improved outcomes consistent with usefulness of early intervention

Bosentan (n=86)

Placebo (n=91)

3Months

6Months

EARLY: 6MWD Results With Bosentan for NYHA Class II PAH

Galie N, et al Lancet. 2008;371(9630):2093–2100.

Note: 15% of both groups also received open-label sildenafil.

Role of Calcium Channel Blockers (CCBs) in PAH

Acute vasodilator challenge should be performed during right heart catheterization— Use inhaled NO or IV epoprostenol for acute challenge

Favorable responders to vasodilator challenge may be treated with CCBs— Decrease in mPAP of at least 10 mm Hg to <40 mm Hg— Increased or unchanged cardiac output— Amlodipine, diltiazem, nifedipine recommended agents

• Avoid verapamil

Patients who fail acute vasodilator challenge should NOT be treated with CCBs

Patients should NOT be treated empirically with CCBs

Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.Badesch DB, et al. Chest. 2004;126(suppl 1):35S-62S.

French Registry:Response to Acute Vasodilator Challenge

Idiopathic

N=649.Challenge with vasodilator at time of right heart catheterization.

Humbert M, et al. Am J Respir Crit Care Med. 2006;173(9):1023-1030.

Familial ConnectiveTissue

CongenitalHeart

PortalHypertension

Anorexigens HIV >2 Factors

Survival in IPAH on Oral Calcium Channel Blocker Therapy

Sitbon O, et al. Circulation. 2005;111(23):3105-3111.

Survival endpoint included those who received transplants or were lost to follow-up.

0 2 4 6 8 10 12 14 16 18

38 33 30 22 13 8 3 3 2 1

Failures

ival Responders

19 12 7 4 0Subjectsat Risk (n)

RespondersFailures

Long-term Calcium Channel Blocker Therapy

PAH-specific Therapies Approved for Use in the US

Endothelin Receptor Antagonists

Phosphodiesterase-type 5 Inhibitors

Prostanoids – Prostacyclin Analogs

Ambrisentan (PO) Sildenafil (PO) Epoprostenol (IV)

Bosentan (PO) Tadalafil (PO) Iloprost (inhaled)

Treprostinil (IV, SC, and inhaled)

FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed November 1, 2009.

Updated Guidelines: PAH-Specific Therapies Available in the US

Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84.

Strength of Recommendation

WHO Class II WHO Class III WHO Class IV

A Ambrisentan, bosentan, sildenafil

Ambrisentan, bosentan, epoprostenol IV, iloprost inh, sildenafil

Epoprostenol IV

B Tadalafil Tadalafil, treprostinil SC

Iloprost inh

C Treprostinil SC

E/B Treprostinil IV Treprostinil IV, initial combo tx

E/C Ambrisentan, bosentan, sildenafil, tadalafil

Recently approved Treprostinil inh Treprostinil inh

Choice of Initial PAH-specific Therapy

Dependent on many factors— Disease severity— Approval status— Route of administration— Side-effect profile— Patient preference— Physician experience and clinical judgment

Updated Guidelines: Inadequate Clinical Response to Initial PAH Therapy

Atrial septostomy and/or

Lung transplantation

Failure to show improvement or deterioration with monotherapy

Sequential Combination Therapy

Prostanoids

EndothelinReceptor

Antagonists

PDE5Inhibitors

Professor Emerita of Pediatrics Columbia University College of Physicians & Surgeons New York,...

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