Consensus Updates in PAH Classification, Screening and Treatment ROBYN BARST, MD Professor Emerita of Pediatrics Columbia University College of Physicians & Surgeons New York, New York Faculty: Content Development and Training Robyn J. Barst, MD Professor Emerita of Pediatrics Columbia University College of Physicians & Surgeons New York, New York Vallerie McLaughlin, MD Professor of Medicine Director, Pulmonary Hypertension Program University of Michigan Ann Arbor, Michigan 2 Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: ̶ ̶ ̶ ̶ 3 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 of Pulmonary Arterial Hypertension (PAH) Updated Definition of PAH Right Heart Catheterization Confirmed 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 * 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. Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66 Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294. 5 Updated Hemodynamic Definitions of Pulmonary Hypertension Definition Characteristics Clinical group Pre-capillary PH Mean PAP ≥25 mm Hg PWP ≤15 mm Hg CO normal or reduced 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 CO = cardiac output. TPG = transpulmonary pressure gradient. Adapted from: Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 6 Pulmonary arterial hypertension PH due to lung disease CTEPH PH with unclear or multifactorial mechanisms PH due to left heart disease 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1 Idiopathic (IPAH) Heritable (PAH) — — — — Drugs and Toxins induced Associated with — — — — — — BMPR2 ALK1 Endoglin (with or without hereditary hemorrhagic telangiectasia) Unknown 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. 7 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 1' Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 8 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 2 Pulmonary hypertension owing to left heart disease — Systolic dysfunction — Diastolic dysfunction — Valvular disease Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 9 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 3 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 Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 10 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 4 Chronic thromboembolic pulmonary hypertension (CTEPH) Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 11 2009 Updated Clinical Classification of Pulmonary Hypertension: Group 5 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 Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 12 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, singleentity category (Group 4) Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 13 Updated Diagnostic Algorithm for Pulmonary Arterial Hypertension (PAH) Diagnostic Algorithm for PH History, Symptoms, Signs Suggestive of PH Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 15 Diagnostic Algorithm for Pulmonary Hypertension: Clinical Presentation Symptoms — — — — — — Breathlessness Fatigue Syncope Weakness Angina Abdominal distension Signs — Accentuated pulmonary — — — — — — — — Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 16 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 Other Physical Findings: Differential Diagnosis/PH Etiology Finding Differential Diagnosis/PAH Etiology Cyanosis Right-to-left shunt Clubbing Rare in IPAH Congenital 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 McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 17 REVEAL Database: Most Frequent Symptoms at Diagnosis 11% 11% Dyspnea at rest IPAH APAH 13% 13% Cough 14% 16% Dizzy/lightheaded 20% 23% Presyncope/syncope 20% 21% Edema 20% 23% Chest pain/discomfort 27% 24% Other 29% 26% Fatigue 83% 84% Dyspnea on exertion N=1479. 0 25 Elliott EG, et al. Chest. 2007;132(suppl 4):631S. 18 50 Incidence (%) 75 100 Diagnostic Algorithm for PH History, Symptoms, Signs Suggestive of PH Consider Common Causes of PH Group 2: Left Heart Disease Group 3: Lung Diseases and/or Hypoxia Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 19 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. 20 ECG Associated With Right Axis Deviation (RAD) and Right Ventricular Hypertrophy (RVH) Image courtesy of Vallerie McLaughlin, MD 21 Electrocardiogram Associated With Right Bundle Branch Block Plus RVH Image courtesy of Vallerie McLaughlin, MD 22 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 of PH McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 23 Chest X-Ray Consistent With PH Image courtesy of Vallerie McLaughlin, MD 24 Echocardiogram: Parasternal Long Axis Image courtesy of Vallerie McLaughlin, MD 25 Echocardiogram: Parasternal Short Axis Image courtesy of Vallerie McLaughlin, MD 26 Echocardiogram: Apical Four Chamber Image courtesy of Vallerie McLaughlin, MD 27 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. Image courtesy of Vallerie McLaughlin, MD 28 Accuracy of PH Diagnosis by Echocardiography in Advanced Lung Disease Cohort study of lung transplant patients (n=374) All patients Diagnosis of PH 70 — 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 Studies (%) 60 Overestimation Accurate Underestimation 50 40 30 20 10 0 Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167(5):735-740. 29 No Pulmonary Hypertension Pulmonary Hypertension 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 Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 30 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 Actual Diagnoses of Patients Referred to PH Specialty Clinic Interstitial Lung Disease 5.0% Venous Thromboembolism 5.0% Other Structural Heart Disease Obstructive Sleep Apnea LV Dysfunction Obstructive Lung Disease 12.0% 13.0% 19% 22.0% 24.0% All Alternative Diagnoses Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923. 31 85.0% Algorithm for Diagnosing and Rating Severity of PH History – Physical – CXR - ECG Echocardiography VQ Scan - ABGs CTEPH Overnight Oximetry OSA HIV – ANA - LFTs Underlying Causes Functional Testing Functional Severity Right Heart Catheterization Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294 32 Index of Suspicion – Evaluate for LH & RH disease Confirm Diagnosis Diagnostic Algorithm for PH History, Symptoms, Signs Suggestive of PH Consider Common Causes of PH Group 3: Lung Diseases and/or Hypoxia Group 2: Left Heart Disease No Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 33 Diagnostic Algorithm for PH Consider Group 2 or 3 PH Yes No “Out of proportion” PH Perform V/Q Scan CTEPH Yes Segmental Perfusion Defects PVOD/PCH Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 34 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 McGoon M, et al. Chest. 2004;126(suppl 1):14S-34S. 35 Diagnostic Algorithm for PH Consider Group 2 or 3 PH Yes No “Out of proportion” PH Perform V/Q Scan CTEPH Yes PVOD/PCH Segmental Perfusion Defects No Perform RHC Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 36 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. 37 Measuring Pulmonary Capillary Wedge Pressure Pulmonary Artery Pressure Decay Curve 160 Balloon Occlusion Pressure (mm Hg) 140 120 ARDS IPAH 100 80 60 40 20 0 0 2 4 6 Time (seconds) 8 10 Time Steady State is Longer in IPAH than in ARDS ARDS: acute respiratory distress syndrome. Souza R, et al. Crit Care. 2005;9:R132-R138. 38 12 Inaccurate Readings of PCWP PA and RV Recordings in Patient with PAH Oudiz RJ, et al. Advances PAH. 2005;4(3):26-30. 39 RV Pressure Mistakenly Recorded as PCWP Misclassification of PAH Through Reliance on PCWP vs LVEDP 100 90 Percent (%) 80 70 53.5 60 46.5 50 40 30 20 10 0 PCWP ≤15 mm Hg LVEDP >15 mm Hg PCWP ≤15 mm Hg LVEDP ≤15 mm Hg N = 11,523, all patients undergoing LHC and RHC over 10 years at single center. Halpern SD, et al. Chest. 2009;136(1):37-43. 40 Diagnostic Algorithm for PAH: Results of RHC mPAP ≥25 mmHg PWP ≤15 mmHg Perform RHC Increased PVR No Yes Search for other causes Specific diagnostic tests for PAH causes: Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 41 Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 42 3-year Incidence of Pulmonary Hypertension in Systemic Sclerosis Estimated incidence (per 100 patient years) 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. 43 95% CI Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 44 Drugs/Toxins PAH Due to Drugs and Toxins Definite Risk Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Possible Risk Cocaine Phenylpropanolamine St. John’s wort Chemotherapeutic agents SSRI Likely Risk Amphetamines L-tryptophan Methamphetamines Unlikely Risk Oral contraceptives Estrogen Cigarette smoking Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 45 SSRIs in Late Pregnancy and Risk of Persistent Pulmonary Hypertension in the Newborn Maternal use of SSRIs PPHN (N=377) Matched Controls (N=836) 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 Chambers CD, et al. N Engl J Med. 2006;354(6):579–587. 46 Adjusted Odds Ratio P (95% CI) value Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD HIV Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 47 Drugs/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. 48 Prevalence of Methamphetamine Use in HIV-PAH 12% 29% Methamphetamine 18% Methamphetamine + cocaine Cocaine Denied stimulant use 41% N = 17 patients with HIV-PAH Lewis JE et al. Am J Respir Crit Care Med. 2008;177:A444. 49 Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 50 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 Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 51 Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Portopulmonary Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 52 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 Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 53 Survival in Portopulmonary Hypertension Related to Cirrhosis PoPH without cirrhosis Cumulative Survival 1.0 0.8 p = 0.003 0.6 PoPH with cirrhosis 0.4 0.2 0 0 12 24 36 48 60 72 84 96 Months N = 154. Le Pavec J, et al. Am J Respir Crit Care Med. 2008;178(6):637-643. 54 108 120 Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Portopulmonary Schistosomiasis Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 55 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 Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 56 Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Portopulmonary Schistosomiasis PVOD/PCH Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 57 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 Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 58 Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease Portopulmonary Schistosomiasis PVOD/PCH Chronic hemolysis Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 59 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 PVR Simonneau G, et al. J Am Coll Cardiol. 2009;54(suppl 1):S43-S54. 60 Evaluating Causes of PAH mPAP ≥25 mmHg PWP ≤15 mmHg Increased PVR Specific diagnostic tests for PAH causes: CTD Drugs/Toxins HIV Congenital heart disease No known cause Portopulmonary Schistosomiasis PVOD/PCH Chronic hemolysis Idiopathic or heritable PAH Adapted from Galie N, et al. Eur Heart J. 2009;30(20):2493-2537. 61 Assessment of PAH Prognostic Factors for Risk of PAH Disease Progression Lower Risk Higher Risk No Yes Progression Gradual Rapid WHO Class II, III IV >380 m <325 m Brain natriuretic peptide <180 pg/mL >180 pg/mL Echo findings Minimal RV dysfunction Pericardial effusion; significant RV dysfunction Normal/near normal RAP and CI High RAP, Low CI Evidence of RV failure 6-minute walk distance Hemodynamics McLaughlin VV, et al. Circulation. 2006;114(13):1417-1431. 63 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 activities No discomfort at rest Normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope III Marked limitation of physical activity No discomfort at rest Less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope Patient unable to perform any physical activity at rest and may have signs of right ventricular failure Dyspnea and/or fatigue and/or syncope/near-syncope may be present at rest, and symptoms are increased by almost any physical activity IV Rich S. World Health Organization. 1998. 64 Distance Walked in 6 Minutes (m) 6-Minute Walk Distance Correlates With IPAH Disease Severity 800 700 600 * 500 *† 400 300 *†‡ 200 100 0 Control NYHA II NYHA III *P<0.05 versus control. †P<0.05 versus NYHA Class II. ‡P<0.05 vs NYHA Class III. Miyamoto S, et al. Am J Respir Crit Care Med. 2000;161:487-492. 65 NYHA IV Impact of Baseline 6-Minute Walk Distance on Survival in IPAH/HPAH Epoprostenol Versus Placebo Percent Survival 100 80 Survivors (n=73) 60 Deaths (n=8) 195 + 63 40 Epoprostenol (n=41) Conventional Therapy (n=40) 20 0 0 2 4 6 8 10 Week Barst RJ, et al. N Engl J Med. 1996;334(5):296-302. 66 6-Minute Walk Distance 305 + 14 12 6-minute walk distance at baseline was the only independent predictor of survival (P<0.003) NT-proBNP Elevations Correlate With Right Ventricular Systolic Dysfunction (RVSD) in PH 5000 4127 NT-proBNP (ng/L) 4000 3000 2000 1000 354 0 With RVSD Threshold value RVD detection: 1,685 ng/L-1. Sensitivity for RVD 100%; specificity 94%. Blyth KG, et al. Eur Respir J. 2007;29(4):737-744. 67 Without RVSD Composite Scoring System Predicts ^ Disease Progression in PAH Survival (%) Composite Score 3-year Survival 100 0-6 75 50 6-9 25 9-12 0 0 Walk (m) FC NT-proBNP 1 Time (years) 0 1 2 3 340 260-340 190-260 <190 1 2 3 4 <2000 >2000 QOL (CAMPHOR) <12 >12 Activity <11 >11 Symptoms <16 >16 Anderson D, et al. Am J Respir Crit Care Med. 2008;177:A915. 68 3 2 Heritable PAH: Frequency of BMPR2 ^ and ALK1 Mutations BMPR2 100 ALK1 92.3 Percent (%) 80 60 40 23.8 20 7.7 5.4 1.3 1.3 0 HPAH IPAH N = 222. Nakanishi N, et al. Am J Respir Crit Care Med. 2008;177:A256. 69 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 rehabilitation Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 71 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. 72 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 Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 73 Mean Change in 6-Minute Walking Distance (m) EARLY: 6MWD Results With Bosentan for NYHA Class II PAH 30 Bosentan (n=86) 25 20 Placebo (n=91) 15 10 5 0 -5 -10 -15 -20 -25 3 Months Note: 15% of both groups also received open-label sildenafil. Galie N, et al Lancet. 2008;371(9630):2093–2100. 74 6 Months 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. 75 French Registry: Response to Acute Vasodilator Challenge 12 10.3% Response (%) 10 8 6.8% 6 4 3.3% 2.6% 1.6% 2 0 0% Idiopathic Portal Anorexigens Familial Connective Congenital Tissue Heart Hypertension 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. 76 0% 0% HIV >2 Factors Survival in IPAH on Oral Calcium Channel Blocker Therapy Long-term Calcium Channel Blocker Therapy Cumulative Survival 1.0 Responders 0.8 0.6 Failures 0.4 0.2 0 0 2 4 6 8 10 12 14 16 18 Years Subjects at Risk (n) 38 19 33 12 30 7 22 4 13 0 8 3 3 2 Survival endpoint included those who received transplants or were lost to follow-up. Sitbon O, et al. Circulation. 2005;111(23):3105-3111. 77 1 Responders Failures PAH-specific Therapies Approved for Use in the US Endothelin Receptor Antagonists Phosphodiesterasetype 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. 78 Updated Guidelines: PAH-Specific Therapies Available in the US Strength of Recommendation A B WHO Class II Ambrisentan, bosentan, sildenafil Tadalafil WHO Class III Ambrisentan, bosentan, epoprostenol IV, iloprost inh, sildenafil Tadalafil, treprostinil SC C E/B Treprostinil IV Treprostinil inh Adapted from Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 79 Epoprostenol IV Iloprost inh Treprostinil SC E/C Recently approved WHO Class IV Treprostinil IV, initial combo tx Ambrisentan, bosentan, sildenafil, tadalafil 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 Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 80 Updated Guidelines: Inadequate Clinical Response to Initial PAH Therapy Failure to show improvement or deterioration with monotherapy Sequential Combination Therapy Prostanoids Endothelin Receptor Antagonists PDE5 Inhibitors Barst RJ, et al. J Am Coll Cardiol. 2009;54(suppl 1):S78-S84. 81 Atrial septostomy and/or Lung transplantation