Wednesday, April 25 Screening Diagnosis and Treatment of PAH: An Overview

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1 Wednesday, April 25 Screening Diagnosis and Treatment of PAH: An Overview Kerri Akaya Smith, MD

2 Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension (PAH): An Overview New Jersey Association of Osteopathic Physicians & Surgeons Atlantic City, New Jersey April 25, 2018 K. Akaya Smith, MD Assistant Professor of Medicine Perelman School of Medicine at the University of Pennsylvania Medical Director, Pulmonary Hypertension Program Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Faculty Disclosure Dr. Smith has received research support/grants from Eiger BioPharmaceuticals, Inc, Gilead Sciences, Inc., Actelion Pharmaceuticals US, Inc, and United Therapeutics Corporation. Dr. Smith has also served on an advisory committee for United Therapeutics Corporation. 1

3 The Pulmonary Hypertension Association (PHA) is the leading non-profit organization for PH research, public awareness, and services. The organization has over 12,000 members, including patients, family members, and medical professionals. Let s get started... Vascular Pressure in Systemic and Pulmonary Circulations (mm Hg) Systemic Circulation Mean 30 Body 120/80, mean 93 25/8, mean 14 Systemic Arteries RA Mean 2-5 Pulmonary Arteries LA Mean 5 Pulmonary Circulation Mean 12 Lung Systemic Veins RV 25 / 2-5 LV 120 / 5-10 Pulmonary Veins Kovacs G et al. Eur Respir J. 2009;34:

4 5 th World Symposium on PH: Classification of PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1. PPHN 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G et al. JACC 2013;62:D th World Symposium on PH: Hemodynamic Definition of PH/PAH PH Mean PAP 25 mm Hg at rest during RHC PAH Mean PAP 25 mm Hg plus PAWP 15 mm Hg plus PVR >3 Wood units Hoeper MM et al. J Am Coll Cardiol. 2013;62:D42-D50. 5 th World Symposium on PH: Classification of PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1. PPHN 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G et al. JACC 2013;62:D

5 Heritable PAH Autosomal dominant BMPR2 (bone morphogenetic protein receptor type 2) is the major predisposing gene Mutation detection rate for known genes is 75% in familial PAH Major predisposing gene has a highly variable penetrance between families Genetic anticipation ALK1 (ACVRL1; activin A receptor type-ii-like kinase 1) is major gene when PAH is associated with hereditary hemorrhagic telangiectasia (HHT) Soubrier F et al. J Am Coll Cardiol. 2013;62:D13-D21. Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41. PAH Related to Connective Tissue Disease Connective tissue diseases limited scleroderma (most common) diffuse scleroderma mixed connective tissue disease systemic lupus erythematosus rheumatoid arthritis Sjogren s syndrome PH is one of the leading causes of death in scleroderma Similar to IPAH pathology Medical treatment same as for IPAH, but benefits less than for IPAH Hachulla E et al. Rheumatology. 2009;48: Prevalence of PAH in Scleroderma Prevalence 7.9% in large prospective study (N=599) with confirmatory catheterizations excluded severe PFT abnormalities all underwent Doppler echocardiography catheterization if VTR >3 m/sec or m/sec + unexplained dyspnea Prevalence of PAH: found in 47 of 599 scleroderma patients 29 had known PAH at study entry 18 patients were newly diagnosed with PAH Hachulla E et al. Arthritis Rheum. 2005;52:

6 Portopulmonary Hypertension Prevalence overall: 2-5% by RHC; liver transplant candidate: 4% to 17% Dependent on portal HTN, not hepatocellular dysfunction Poor prognosis: higher risk of death than IPAH pts Liver transplant may improve survival with mild to moderate PAH (28-56%, 5 yr) significant PAH (mpap >35 mm Hg) predicts unacceptably high perioperative mortality Budhiraja R et al. Chest Hadengue A et al. Gastroenterology Castro M et al. Mayo Clin Proc Kawut SM et al. Liver Transpl Ramsay MA et al. Liver Transpl Surg Krowka MJ et al. Clin Chest Med Krowka MJ et al. Liver Transpl Swanson KL et al. Hepatology th World Symposium on PH: Classification of PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1. PPHN 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G et al. JACC 2013;62:D Most Common Cause of Elevated PAPs by Echo: Left Heart Disease Symptoms paroxysmal nocturnal dyspnea orthopnea History diabetes hypertension obesity coronary artery disease metabolic syndrome ECG Echo atrial fibrillation absence of right axis deviation left atrial enlargement left ventricular hypertrophy normal RA, RV abnormal diastolic filling mitral or aortic disease 5

7 Percentage of PAH and PVH Patients With All 4 Metabolic Syndrome Factors * * PAH PVH Percent of patients * ** 20 0 OR 95% CI HTN 13.7 ( ) Obesity 7.1 ( ) DM 5.7 ( ) HL 4.2 ( ) *p 0.005; **p= Robbins IM et al. Chest. 2009;136: th World Symposium on PH: Classification of PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1. PPHN 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G et al. JACC 2013;62:D Chronic Obstructive Pulmonary Disease (COPD) and PH Retrospective study of 215 COPD patients 13.5% had a PA mean >35 mm Hg Correlated best (inversely) with PaO2 A small number had only moderate obstruction: treatable sub-group? mpap (mm Hg) Thabut G et al. Chest. 2005;127: FEV 1 (% pred.) 1 4 6

8 Cumulative incidence of CTEPH 5 th World Symposium on PH: Classification of PH 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH BMPR ALK1, ENG, SMAD9, CAV1, KCNK Unknown 1.3 Drug- and toxin-induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart disease Schistosomiasis 1. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis 1. PPHN 2. PH due to LHD 2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction 3. PH due to lung diseases and/or hypoxia 3.1 COPD 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH Simonneau G et al. JACC 2013;62:D Incidence of CTEPH Approximately 3% to 4% 1-2 yr after acute PE USA: 600,000 cases of acute PE each year Only 40% to 50% of CTEPH patients have a history of previous episodes of acute PE VQ scan identifies old PE better than CTA McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Pengo V et al. N Engl J Med. 2004;350: Tapson VF, Humbert M. Proc Am Thorac Soc. 2006;3: Years Pathology of PAH WHO Group I: Characterized by progressive growth and vasoconstriction of small pulmonary arteries Gaine S. JAMA. 2000;284:

9 PAH: Hemodynamic and Clinical Course Adventitia Media Intima NORMAL CO PAP PVR NYHA I Adapted from Gaine S. JAMA. 2000;284: Time PAH: Hemodynamic and Clinical Course Adventitia Media Intima Smooth Muscle Hypertrophy Early Intimal Thickening NORMAL REVERSIBLE DISEASE CO PAP PVR NYHA I II III Adapted from Gaine S. JAMA. 2000;284: Time PAH: Hemodynamic and Clinical Course Adventitia Media Intima Smooth Muscle Hypertrophy Early Intimal Thickening Smooth Muscle Hypertrophy Adventitial, Intimal Proliferation Thrombosis Plexiform Lesions NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE CO PAP PVR NYHA I II III IV Time Adapted from Gaine S. JAMA. 2000;284:

10 Percentage surviving Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Survival in PAH Percent survival Portopulmonary CTD HIV Congenital heart disease Years IPAH McLaughlin VV et al. Chest. 2004;126:78S-92S. Idiopathic PAH: Survival If Untreated NIH registry Sitbon historical control ACCP 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 Years of follow-up Adapted from: Sitbon O et al. J Am Coll Cardiol. 2002;40: D Alonzo GE et al. Ann Intern Med. 1991;115: McLaughlin VV et al. Chest. 2004;126:78S-91S. French Registry: Kaplan-Meier Survival Estimates in Combined PAH Population vs NIH-predicted Observed Survival (%) Predicted (NIH Registry) No. at risk: Time (mo) All patients Humbert M et al. Circulation. 2010;122:

11 REVEAL: Observed 1-year Survival From Time of Enrollment According to Predicted Risk Strata 100 Survival (%) No. at risk: Low Average Mod. high High Very high 80 Risk strata Low 60 Average Moderately high 40 High Very high Months from enrollment Benza RL et al. Circulation. 2010;122: Key Pathways Implicated in PAH Pathogenesis Endothelin Pathway Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin-1 Endothelin receptor A Endothelin receptor B Vasoconstriction and proliferation L-arginine L-citrulline Nitric Oxide cgmp Phosphodiesterase type 5 Vasodilation and antiproliferation Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Smooth muscle cells Humbert M et al. N Engl J Med. 2004;351: Case: Jane 37-yr-old woman, previously healthy Delivered second child 14 mo previously Limited exercise tolerance since delivery, attributed to weight gain Dyspnea while playing with older child; syncope while walking up an incline 10

12 Jane: Initial Symptoms Currently has dyspnea with mild exertion, walks slowly in store Exertional light-headedness Atypical chest pain Occasional palpitations Lower extremity edema Multiple Guidelines, Consistent Message: Comprehensive Diagnostic Evaluation/ Robust PH Specialty Center Collaboration Are Necessary Follow Basic Steps of American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Consensus Algorithm, With Some Updates To identify: the presence of PH which group of PH (WHO I-V) McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society, Inc; and the Pulmonary Hypertension Association 11

13 ACCF/AHA Diagnostic Algorithm Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG RVE, RAE, RVSP, RV TEE Function Echocardiogram Exercise Echo Left Heart Disease VHD, CHD Pulmonary Angiography Chest CT Angiogram Chronic PE V/Q Scan Coagulopathy Profile PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response History and Physical Exam Findings Are Insensitive Unless Advanced Disease/RV Failure Present History Exam (PH) Exam (RV Failure) Dyspnea (86%) Fatigue (27%) Chest pain (22%) Edema (22%) Syncope (17%) Dizziness (15%) Cough (14%) Palpitations (13%) Loud P2 (listen at apex) RV lift (left parasternal fingertips) RV S3, S4 Systolic murmur (TR; inspiratory augmentation) Early systolic click Midsystolic ejection murmur Diastolic murmur (PR) JVD; increased A wave, V wave; hepatojugular reflex Pulsatile liver Hepatomegaly Edema Ascites Low BP, low PP, cool extremities REVEAL. Brown LM et al. Chest. 2011;140: Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Jane: Physical Exam HR 90 bpm; BP 130/68 mm Hg; Wt 190 lb; Ht 5'4" JVP ~15 cm, reduced carotid upstrokes Clear lungs Palpable RV heave, RRR, normal S, loud P2, III/VI, TR m 2+ LE edema 12

14 Jane: Additional History PMH: 2 children, 4 yr and 14 mo IBS: diet-controlled Meds: none Allergies: contrast dye FH: PPH in a paternal aunt, CAD, DM, Htn SH: rare ETOH, o/w unremarkable Chest Radiograph May Show Right Heart and Vascular Abnormalities in Advanced Disease Peripheral hypovascularity (pruning) Healthy PH Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Prominent central pulmonary artery Chest Radiograph May Show Right Heart and Vascular Abnormalities in Advanced Disease RV enlargement into retrosternal clear space Healthy PH Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

15 ACCF/AHA Diagnostic Algorithm Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Electrocardiogram May Show Right Heart Abnormalities in Advanced Disease Right Axis Deviation Right Ventricular Hypertrophy Right Atrial Enlargement Right Ventricular Strain Image courtesy Christopher F. Barnett, MD, MPH Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG RVE, RAE, RVSP, RV TEE Function Echocardiogram Exercise Echo Left Heart Disease VHD, CHD Pulmonary Angiography Chronic Chest CT Angiogram V/Q Scan Thromboembolic PH Coagulopathy Profile PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response Checklist for Echocardiographic Assessments When PH Is Suspected Estimate pulmonary artery systolic pressure Evaluate severity of TR Evaluate right heart size and function Exclude left heart valvular disease and systolic dysfunction Exclude congenital heart disease Differentiate PAH from PH due LHD Estimate RA pressure Evaluate for pericardial effusion Adapted from McLaughlin VV et al. J Am Coll Cardiol. 2015;65:

16 PASP Is Estimated Using Tricuspid Regurgitant Jet Velocity PASP=RVSP in the absence of pulmonic outflow obstruction Modified Bernoulli Equation RVSP= 4(V TR ) 2 + RAP Barnett C et al. JAMA. 2008;299: TR Jet Signal Quality Affects Reliability of Estimated PASP B Poor signal quality Good signal quality Images courtesy Christopher F. Barnett, MD, MPH Structural Echocardiographic Findings in Patients With PH RV enlargement RA enlargement Septal flattening Pericardial effusion McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

17 ACCF/AHA Diagnostic Algorithm Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG RVE, RAE, RVSP, RV TEE Function Echocardiogram Exercise Echo Left Heart Disease VHD, CHD Pulmonary Angiography Chronic Chest CT Angiogram V/Q Scan Thromboembolic PH Coagulopathy Profile PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response Ventilation Perfusion Scan (V/Q): Best Screening Test to Exclude CTEPH Should never be missed Is potentially curable with pulmonary endarterectomy (PEA) 3% to 4% of acute PE will develop CTEPH Half of those with CTEPH do not have an apparent history of thromboembolism Normal V/Q scan excludes CTEPH CTEPH may be diagnosed on CT pulmonary angiogram, however, reported sensitivity varies from 50-98% McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Fedullo PF et al. N Engl J Med. 2001; 345: Reichelt A et al. Eur J Radiol. 2009;71: Tunariu N et al. J Nucl Med. 2007;48: Ventilation Perfusion Scan (V/Q) to Exclude CTEPH Image courtesy Kelly Chin, MD 16

18 ACCF/AHA Diagnostic Algorithm Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension High-Quality Conventional Pulmonary Angiography: Gold Standard Test for CTEPH Diagnosis PA Lateral Reproduced with permission from Barnett, CF, in: Yuan JX-J et al, eds, Textbook of Pulmonary Vascular Disease. Springer, CTEPH: A Surgical Disease Survival Without Surgery Is Poor Image courtesy Christopher F. Barnett, MD, MPH Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG RVE, RAE, RVSP, RV TEE Function Echocardiogram Exercise Echo Left Heart Disease VHD, CHD Pulmonary Angiography Chronic Chest CT Angiogram V/Q Scan Thromboembolic PH Coagulopathy Profile PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response 17

19 ACCF/AHA Diagnostic Algorithm Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Presence and Severity of Lung Disease Must Be Assessed Abnormalities on PFTs may suggest cause of PAH or reveal PH from lung disease (Group III) CT scanning useful in identifying parenchymal lung disease IPAH and CTEPH 20% have isolated reduction in DLCO DLCO mildly reduced (60%-80% predicted NIH registry) PVR correlates with reduction in DLCO Systemic Sclerosis 20% have isolated reduction in DLCO Severity predicts future PAH DLCO correlates inversely with PASP DLCO=diffusing capacity of the lungs for carbon monoxide Overnight Pulse Oximetry Is a Useful Screening Test for Sleep Disordered Breathing Hypoxia may signal underlying sleep apnea In patients with obstructive sleep apnea (OSA), PAPs reported to decrease in response to CPAP therapy Untreated response to other treatment likely to be less effective Somers VK et al. J Am Coll Cardiol. 2008;52: Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG RVE, RAE, RVSP, RV TEE Function Echocardiogram Exercise Echo Left Heart Disease VHD, CHD Pulmonary Angiography Chronic Chest CT Angiogram V/Q Scan Thromboembolic PH Coagulopathy Profile PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response 18

20 ACCF/AHA Diagnostic Algorithm Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Functional Assessment: WHO Functional Class Modified From NYHA Classification Class I II III IV Description No limitation of physical activity; ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope Slight limitation of physical activity; no discomfort at rest; ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope Marked limitation of physical activity; no discomfort at rest; less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope Unable to carry out any physical activity without symptoms; signs of right-heart failure; dyspnea and/or fatigue may be present at rest; discomfort is increased by any physical activity Rubin LJ. Chest. 2004;126:7S-10S. Jane: Laboratory Studies ANA: negative Echo: normal LV function, RAE, RVE, RVSP 60 mm Hg, TEE no shunt found after agitated saline injection VQ: normal PFTs: normal volumes and flows, DLCO 81% 6MWD: 222 m, 99-96% Pivotal Tests Contingent Tests Contribute to Assessment of: History Exam Index of Suspicion of PH CXR ECG RVE, RAE, RVSP, RV TEE Function Echocardiogram Exercise Echo Left Heart Disease VHD, CHD Pulmonary Angiography Chronic Chest CT Angiogram V/Q Scan Thromboembolic PH Coagulopathy Profile PFT s ABG s Ventilatory Function Gas Exchange Overnight Oximetry Polysomnography Sleep Disorder HIV ANA LFT s Other CTD Serologies HIV Infection Scleroderma, SLE, RA Portopulmonary Htn Functional Test (6MWT, CPET) RH Cath McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Vasodilator Test Exercise RH Cath Volume Loading Left Heart Cath Establish Baseline Prognosis Confirmation of PH Hemodynamic Profile Vasodilator Response 19

21 Cardiac Catheterization Required when PAH is suspected Confirm echo findings Survey for left heart disease measure wedge pressure or LVEDP Measure CO; calculate PVR Exclude systemic to pulmonary shunts Establish severity and prognosis Acute vasodilator challenge Assessment of Pressures as the Catheter Passes Through the Heart Reproduced with permission from Barnett Cf. In: Murray & Nadel s Textbook of Respiratory Medicine, 6 th ed, Elsevier PH: The Importance of Hemodynamics Pulmonary venous hypertension Elevated PCWP, normal PVR VC RA RV PA PV PC LA LV Ao PAH PH with respiratory disease CTEPH Normal PCWP, elevated PVR Other: high CO 20

22 Cumulative survival Vasodilator Testing Identifies Patients Who Respond Well Long Term to Treatment With Calcium Channel Blockers Vasodilator testing Nitric Oxide Inh or epoprostenol IV Positive test defined by: Drop in mpap 10 mm Hg to a mpap 40 mmhg + normal CO Long-term CCB responders* Long-term CCB failure p= Years Subjects at risk, n *~50% of acute responders or 7% of IPAH patients Responders Failure Sitbon O et al. Circulation. 2005;111: Jane: Right Heart Cath 1/29/07 Baseline Nitric Oxide 20 ppm RAP (mm Hg) PAP (mm Hg) 93/40, mean 63 93/46, mean 64 LVEDP (mm Hg) 10 Oxygen saturation (%) Pulmonary artery Femoral artery Cardiac output / Cardiac index (L/min) Fick / /1.52 PVR (Wood units) Fick Screening and Diagnosis Summary High index of suspicion Thorough diagnostic evaluation Exclude thromboembolic disease Evaluate potential causes/contributing issues RHC required prior to initiating PAH therapy Baseline functional evaluation 21

23 PAH Treatment Goals Fewer/less severe symptoms Improved exercise capacity Improved hemodynamics Prevention of clinical worsening Improved quality of life Improved survival 5 th World Symposium on PH Goals of Therapy: Setting the Bar Higher Functional Class Hemodynamics Echocardiography/ MRI BNP level 6MWD CPET I or II Normalization of RV function (RAP <8 mm Hg and CI > L/min/m 2 ) Normal/near normal RV size and function Normal m, may not be aggressive enough Peak VO 2 >15 ml/kg/min VE/VCO AT <45 McLaughlin VV et al. J Am Coll Cardiol 2013.:62:D What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Oral CCB Positive Acute Vasoreactivity Testing Negative Sustained Response Yes Continue CCB No LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>400 m) 6MWD Shorter (<300 m) Peak VO 2 >10.4 ml/kg/min CPET Peak VO 2 <10.4 ml/kg/min Minimal RV dysfunction McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Echocardiography Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP <10 mm Hg; CI >2.5 L/min/m 2 Hemodynamics RAP >20 mm Hg; CI <2.0 L/min/m 2 Minimally elevated BNP Significantly elevated 22

24 Chronic Adjuvant Therapies in PAH Digoxin Variable inotropic effect and use No long-term data; need to balance unproven benefits with known risks Oxygen Use to prevent hypoxic vasoconstriction Consider exercise, sleep, altitude Aim for target saturation >90% May not correct hypoxia with shunt Diuretics Most need; hypotension not a contraindication (may need BP support) Renal function and electrolytes must be monitored closely Anticoagulation Recommended in IPAH Observational studies only (2 retrospective, 1 prospective); need to balance unproven benefits with known risks INR Adapted from: Badesch DB et al. Chest. 2004;126:35S-62S. Badesch DB et al. Chest. 2007;131: McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Other Management Issues Encourage exercise and activity within the limits of disease and ability to maintain O 2 levels Consider enrollment in a pulmonary rehabilitation program Immunizations Contraception What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Oral CCB Positive Acute Vasoreactivity Testing Negative Sustained Response Yes Continue CCB No LOWER RISK DETERMINANTS OF RISK HIGHER RISK McLaughlin VV et al. J Am Coll Cardiol. 2009;53: No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>400 m) 6MWD Shorter (<300 m) Peak VO 2 >10.4 ml/kg/min CPET Peak VO 2 <10.4 ml/kg/min Minimal RV dysfunction Echocardiography Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP <10 mm Hg; CI >2.5 L/min/m 2 Hemodynamics RAP >20 mm Hg; CI <2.0 L/min/m 2 Minimally elevated BNP Significantly elevated 23

25 Cumulative survival Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Survival in IPAH: Long-term CCB Responders Long-term CCB responders (~50% of acute responders or 7% of IPAH patients) Long-term CCB failure p= Subjects at risk, n Years Sitbon O et al. Circulation. 2005;111: Long-term CCB responders Long-term CCB failure Revised Definition of Vasodilator Responder Vasodilator Response Fall in mpap 10 mm Hg + mpap (absolute) 40 mm Hg + Normal CO Only acute vasodilator responders should be tried on CCB therapy to treat PAH McLaughlin VV et al. J Am Coll Cardiol. 2009;53: PAH Determinants of Risk LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>400 m) 6MWD Shorter (<300 m) Peak VO 2 >10.4 ml/kg/min CPET Peak VO 2 <10.4 ml/kg/min Minimal RV dysfunction RAP <10 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >20 mm Hg; CI <2.0 L/min/m 2 Minimally elevated BNP Significantly elevated McLaughlin VV et al. J Am Coll Cardiol. 2009;53:

26 What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Positive Acute Vasoreactivity Testing Oral CCB Negative Sustained Response Yes Continue CCB No LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>400 m) 6MWD Shorter (<300 m) Peak VO 2 >10.4 ml/kg/min CPET Peak VO 2 <10.4 ml/kg/min Minimal RV dysfunction RAP <10 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >20 mm Hg; CI <2.0 L/min/m 2 Minimally elevated BNP Significantly elevated McLaughlin VV et al. J Am Coll Cardiol. 2009;53: Approved Therapeutic Targets Endothelin Pathway Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin-1 Endothelin receptor A Endothelin receptor B Endothelinreceptor antagonists Smooth muscle cells Vasoconstriction and proliferation L-arginine L-citrulline Nitric Oxide Exogenous nitric oxide cgmp sgc Phosphodiesterase stimulator type 5 Vasodilation and antiproliferation Phosphodiesterase type 5 inhibitor Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;351: Approved Therapeutic Targets Endothelin Pathway Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin-1 Endothelin receptor A Endothelin receptor B Endothelinreceptor antagonists Smooth muscle cells Vasoconstriction and proliferation L-arginine L-citrulline Nitric Oxide Exogenous nitric oxide cgmp sgc Phosphodiesterase stimulator type 5 Vasodilation and antiproliferation Phosphodiesterase type 5 inhibitor Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 2004;351:

27 Survival (%) Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension Prostacyclin Analogues: Intravenous, Subcutaneous, Inhaled, or Oral Epoprostenol (Flolan or Veletri ) Treprostinil (Remodulin ) WG Treprostinil (Remodulin ) Treprostinil (Orenitram ) Selexipag (Uptravi ) Iloprost (Ventavis ) Treprostinil (Tyvaso ) Epoprostenol IV: FC III-IV, 2 ng/kg/min titrated to desired clinical response in 1-2 ng/kg/min increments. Treprostinil IV / SC: FC II-IV, ng/kg/min/wk. IV=diluted. Inhaled: FC III, to 54 mcg, 4 inh/d. Oral: FC II-III, starting at 0.25 mg bid and titrated in 0.25 mg increments as tolerated. Selexipag: FC II-III, starting at 200 mcg bid, and titrated as tolerated up to 1600 mcg bid. Iloprost Inhaled: FC III-IV, mcg, 6-9 inh/d. Prostacyclin Analogues: Pivotal Trials for IV and SC Formulations Study Name / Drug IV epoprostenol vs conventional Rx IV epoprostenol vs conventional Rx TRUST IV treprostinil vs placebo SC treprostinil vs SC placebo N / Etiol / Class 81 IPAH/FPAH III,IV 111 APAH SSc III,IV 44 PAH III 470 PAH II-IV Design Open-label 12-week Open-label 12-week Double-blind, placebocontrolled 12-week Double-blind 12-week Positive Results 6MWD Symptoms Hemodynamics Survival 6MWD Hemodynamics Symptoms 6MWD Symptoms 6MWD Symptoms Hemodynamics Barst RJ et al. N Engl J Med. 1996;334: Badesch D et al. Ann Intern Med 2000;132: Hiremath J et al. J Heart Lung Transplant. 2010;29: Simonneau G et al. Am J Respir Crit Care Med. 2002;165: Survival Among Patients With IPAH: Epoprostenol vs Conventional Therapy Epoprostenol (n=41) p=0.003* Conventional therapy (n=40) Week *Two-sided, by log-rank test. Barst RJ et al for the PPH Study Group. N Engl J Med. 1996;334:

28 Prostacyclin Analogues: Pivotal Trials for Inhaled and Oral Formulations Study Name / Drug AIR Inhaled iloprost vs placebo TRIUMPH 1 Inhaled treprostinil vs placebo FREEDOM-M Oral treprostinil vs placebo GRIPHON Oral selexipag vs placebo N / Etiol / Class Design Positive Results 203 PH III-IV 235 PAH III-IV* 228 PAH II-III 1156 PAH II-III Double-blind 12-week Double-blind 6MWD 12-week on background oral Rx Double-blind, placebo-controlled 12-week Double-blind, naïve or on background ERA and/or PDE5I, event-driven morbidity/mortality Composite end point 6MWD Symptoms Hemodynamics 6MWD Time to first morbid or mortality event * Approved for class III only. Included background therapy with ERA or PDE5-I. Olschewski H et al. N Engl J Med. 2002;347: McLaughlin VV et al. J Am Coll Cardiol. 2010;55: Hiremath J et al. J Heart Lung Transplant. 2010;29: Jing Z-C et al. Circulation. 2013;127: Sitbon O et al. NEJM. 2015;373: Prostanoid Side Effects Flushing Headache Diarrhea, nausea, vomiting Jaw pain Leg pain Hypotension Dizziness Syncope Rebound PH if interruption of epoprostenol delivery (due to short half-life) Delivery site complications (pain, infection, cough, thrombosis, infusion) Vary according to drug and route of delivery Approved Therapeutic Targets Endothelin Pathway Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin-1 Endothelin receptor A Endothelin receptor B Endothelinreceptor antagonists Smooth muscle cells Vasoconstriction and proliferation L-arginine L-citrulline Nitric Oxide Exogenous nitric oxide cgmp sgc Phosphodiesterase stimulator type 5 Vasodilation and antiproliferation Phosphodiesterase type 5 inhibitor Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Adapted from Humbert M et al. N Engl J Med. 2004;351:

29 Endothelin Receptor Antagonists: Pivotal Trials Study Name Drug BREATHE-1 Oral bosentan* vs placebo N Etiology Class 213 PAH III, IV Design Double-blind 16-week Positive Results 6MWD Delay clinical worsening Symptoms EARLY Oral bosentan vs placebo 185 PAH II Double-blind 6-month Delay clinical worsening Hemodynamics ARIES-1&2 Oral ambrisentan vs placebo 394 PAH II, III Double-blind 12-week 6MWD Delay clinical worsening SERAPHIN Oral macitentan vs placebo 742 PAH II,III Double-blind Event-driven morbidity/mortality Delay disease progression 6MWD Symptoms *Bosentan = Tracleer. Approved for FC II-IV mg po bid. Ambrisentan = Letairis. Approved for FC II-III mg po qd Macitentan = Opsumit. Approved for FC II-III. 10 mg po qd. Rubin L et al. N Engl J Med. 2002;346: Channick RN et al. Lancet. 2001;358: Galiè N et al. Lancet. 2008;371: Galiè N et al. Circulation. 2008;117: Pulido T et al. N Engl J Med. 2013;369: Endothelin Receptor Antagonists: Side Effects Nasal congestion Abnormal hepatic function* monthly LFTs required for bosentan Anemia monitor CBC quarterly Edema lower extremity edema may require diuretic adjustment Teratogenic use requires dual contraceptive methods (hormonal plus barrier) *PHA Scientific Leadership Council recommends LFT testing at onset of all treatments for PAH and periodically thereafter, at prescriber s discretion. Approved Therapeutic Targets Endothelin Pathway Pre-proendothelin Proendothelin Endothelial cells Nitric Oxide Pathway Endothelial cells Prostacyclin Pathway Arachidonic acid Prostaglandin I 2 Endothelin-1 Endothelin receptor A Endothelin receptor B Endothelinreceptor antagonists Vasoconstriction and proliferation L-arginine Nitric Oxide L-citrulline Exogenous cgmp nitric oxide Phosphodiesterase sgc stimulator type 5 Vasodilation and antiproliferation Phosphodiesterase type 5 inhibitor Prostacyclin (prostaglandin I 2 ) camp Vasodilation and antiproliferation Smooth muscle cells Prostacyclin derivatives Smooth muscle cells Humbert M et al. N Engl J Med. 2004;351:

30 PDE-5 Inhibitor Pivotal Trials Study Name Drug N Etiol Class Design Positive Results SUPER-1 Oral sildenafil* vs placebo 278 PAH I-IV Double-blind 12-week 6MWD Symptoms Hemodynamics PHIRST-1 Oral tadalafil vs placebo 405 PAH I-IV Double-blind 16-week 6MWD Delay clinical worsening Hemodynamics HRQoL *Sildenafil = Revatio. Approved for FC II-III. 20 mg po tid. Tadalafil = Adcirca. Approved for FC I-IV. 40 mg po qd. Galiè N et al. N Engl J Med. 2005:353: Galiè N et al. Circulation. 2009;119; PDE-5 Side Effects Nose bleed Headache Dyspepsia Flushing Diarrhea Visual changes Contraindicated with use of nitrate sgc Stimulator Pivotal Trials Study Name Drug N Etiol Class Design Positive Results PATENT-1 Oral riociguat* vs placebo 443 PAH I-IV Double-blind 12-week 6MWD Symptoms Hemodynamics Delay clinical worsening CHEST-1 Oral riociguat vs placebo 261 CTEPH I-IV Double-blind 16-week 6MWD Symptoms Hemodynamics *Riociguat = Adempas. Approved for WHO Group 1; persistent CTEPH (WHO Group 4) after surgical treatment, or inoperable CTEPH; titrated to maximum 2.5 mg po tid. Ghofrani HA et al. N Engl J Med. 2013;369: Ghofrani HA et al. N Engl J Med. 2013;369:

31 sgc Stimulator Side Effects Headache Dizziness Dyspepsia/gastritis Nausea Diarrhea Hypotension Vomiting Anemia Gastroesophageal reflux Constipation Contraindicated in pregnancy, with use of nitrates or NO donors in any form, or with use of PDE inhibitors 5 th World Symposium on PH: 2013 PAH Treatment Algorithm Supervised exercise training (I-A) Psycho-social support (I-C) Avoid strenuous physical activity (I-C) Avoid pregnancy (I-C) Influenza and pneumococcal immunization (I-C) General measures and supportive therapy Expert Referral (I-C) Acute vasoreactivity test (I-C for IPAH) (IIb-C for APAH) Oral anticoagulants: IPAH, heritable PAH, and PAH due to anorexigens (IIa-C) APAH (Ilb-C) Diuretics (I-C) Oxygen (I-C) Digoxin (IIb-C) VASOREACTIVE NON-VASOREACTIVE WHO FC I-III CCB (I-C) Sustained response (WHO FC I-II) YES Continue CCB NO INITIAL THERAPY WITH PAH-APPROVED DRUGS Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. 5 th World Symposium on PH: 2013 Treatment Algorithm INITIAL THERAPY WITH PAH-APPROVED DRUGS Inadequate Clinical Response Consider Eligibility for Lung Transplantation Sequential Combination Therapy (I-A) Prostanoids + ERAs + + PDE-5 I or sgcs Inadequate Clinical Response on Maximal Therapy Balloon Atrial Septostomy (IIa-C) Referral for Lung Transplantation (I-C) Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. 30

32 Recommendation Participants with no event (%) Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension 5 th World Symposium on PH: 2013 PAH Treatment Algorithm INITIAL THERAPY WITH PAH-APPROVED DRUGS YELLOW: Morbidity and mortality as primary end point in randomized controlled study or reduction in all-cause mortality (prospectively defined) Level of evidence based on WHO-FC of majority of patients of studies I Evidence WHO FC II WHO FC III WHO FC IV A or B Ambrisentan, Bosentan Macitentan Riociguat Sildenafil Tadalafil Ambrisentan, Bosentan, Epoprostenol IV Iloprost inh Macitentan Riociguat Sildenafil Tadalafil Treprostinil SC, inh Epoprostenol IV IIa C Iloprost IV*, Treprostinil IV Ambrisentan, Bosentan, Iloprost inh and IV* Macitentan Riociguat Sildenafil, Tadalafil Treprostinil SC, IV, Inh* B Beraprost* IIb C Initial Combination Therapy Initial Combination Therapy Galiè N et al. J Am Coll Cardiol. 2013;62:D60-D72. *Not approved in US. Combination Therapy sgc Stimulators PATENT-1*? Prostanoids PATENT-1*? TRIUMPH STEP SERAPHIN GRIPHON γ?? TRIUMPH PACES GRIPHON Endothelin Receptor Antagonists? PHIRST* SERAPHIN AMBITION Phosphodiesterase Inhibitors *53% on background ERA for PHIRST, 50% on background ERA or prostanoid for PATENT-1 64% on background PDE-5I or prostanoid in SERAPHIN. γ 84% on background ERA and/or PDE-5I in GRIPHON AMBITION: Effect of Ambrisentan Plus Tadalafil Versus Monotherapy on Clinical Worsening* Combination therapy Pooled monotherapy No. at risk: Combination therapy Pooled monotherapy 20 Hazard ratio, 0.50 (95% Cl, ) P< Weeks * Death, hospitalization for worsening PAH, disease progression, unsatisfactory long-term clinical response. Galiè N et al. N Engl J Med. 2015;373:

33 Patients without an event (%) Patients without an event related to PAH or death from from any cause* (%) Patients without an event (%) Screening, Diagnosis, and Treatment of Pulmonary Arterial Hypertension GRIPHON: Effect of Selexipag on Time to First Morbidity or Mortality Event % on background therapy: - 47% on ERA or PDE5I - 33% on ERA+PDE5I Selexipag Placebo 20 Selexipag vs placebo: RR 40%; HR=0.60; p< No. at Risk Months Placebo Selexipag Sitbon O et al. N Engl J Med. 2015;373: SERAPHIN: Effect of Macitentan on Disease Progression % on background therapy: - 62% PDE5I - 5% Prostanoid 60 No. at risk: Placebo Macitentan 3 mg Macitentan 10 mg Months Macitentan 10 mg qd Macitentan 3 mg qd Placebo * Worsening of PAH, initiation of treatment with IV or SC prostanoids, lung transplantation or atrial septostomy Pulido T et al. N Engl J Med. 2013;369: COMPASS-2: Effect of Sildenafil + Bosentan Versus Sildenafil + Placebo on Time to First Morbidity/Mortality Event* Sildenafil + Bosentan Sildenafil + Placebo Months Patients at risk (n) Placebo Bosentan * All-cause death, hospitalization for worsening PAH or IV prostanoid, atrial septostomy, lung transplant, or PAH worsening. McLaughlin VV et al. Eur Respir J. 2015;46: DOI: /

34 Combination Therapy Caveats Experience evolving Most data from add-on -? De novo? Order? More drugs available more options more ways to get it wrong More questions than answers Costs/expenditures; third-party hurdles Taichman DB. Ann Intern Med. 2008;149: Jane: Initial Management Admitted to hospital following cath IV diuresis IV epoprostenol initiation On-therapy Prognostic Indicators Functional class I or II 6MWD >380 m limiting supporting data; do not use in isolation Hemodynamics normal cardiac index (>2.2 L/min/m 2 ) normal RA pressure Positive response to CCB BNP <180 pg/ml Sitbon O et al. J Am Coll Cardiol. 2002;40: McLaughlin VV et al. Circulation. 2002;106: Wensel R et al. Circulation. 2002;106:

35 Important Prognostic Variables French Registry Functional class 6-minute walk RAP CO Age Gender Etiology Humbert M et al. Circulation. 2010;122: Benza RL et al. Circulation. 2010;122: REVEAL Registry Functional class 6-minute walk PVR, RAP Vitals BNP Pericardial effusion DLCO Age Gender Etiology Jane: Return Visits in May & September Significantly improved No limitations Functional class I Meds epoprostenol 30 ng/kg/min warfarin furosemide 20 mg KCl 10 meq qd Jane: Follow-up Physical Exam HR 80 bpm; BP 103/59 mm Hg; Wt lb JVP 6, carotid upstrokes normal Clear lungs Palpable RV heave, normal S, loud P2, II/VI TR murmur No LE edema 34

36 Jane: 6MWD 222 m: 99-96% in January 486 m: 99-97% in May 556 m: 99-97% in September Collaborative Care With PH Centers: Local Care Diagnostic dilemmas Diagnostic cath/ vasodilator trial Fluid management Acute issues PAH-specific therapies Side effects Hospitalizations Transplant Clinical trials PH Center Thank you for your participation! For more information on upcoming PHA Medical Education Programs, please visit: 35