An Industry-Organized Symposium at the ATS 2018 International Conference .

1. Pulmonary Hypertension at the Crossroads of Current Clinical Challenges and Novel Therapeutic Strategies An Industry-Organized Symposium at the ATS 2018 International Conference . A non-CME educational program sponsored by PVI, PeerView Institute for Medical Education, open to all ATS 2018 International Conference attendees.

2. Differential Diagnosis of Pulmonary Hypertension: Is It PAH, CTEPH, or Something Else? Nick H. Kim, MDProfessor of Medicine University of California San Diego La Jolla, California Go online to access full [Certification Type] information, including faculty disclosures.

3. Clinical Classification of PH1 • PAH • Idiopathic PAH • Heritable PAH • BMPR2 • Other mutations • Drug- and toxin-induced • Associated with • CTD • HIV infection • Portal hypertension • Congenital heart disease • Schistosomiasis • 1’. PVOD and/or PCH • 1”. Persistent PH of the newborn • PH due to left heart disease • Left ventricular systolic dysfunction • Left ventricular diastolic dysfunction • Valvular disease • Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies • PH due to lung diseases and/or hypoxia • COPD • Interstitial lung disease • Other pulmonary diseases with mixed restrictive and obstructive pattern • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitude • Developmental lung diseases • CTEPH and other pulmonary artery obstructions • PH with unclear multifactorial mechanisms • Hematologic disorders • Systemic disorders • Metabolic disorders • Others 1. Galiè N et al; ESC Scientific Document Group. Eur Heart J. 2015;37:67-119.

4. Hemodynamic Definitions of Pulmonary Hypertension1 1. Galiè N et al; ESC Scientific Document Group. Eur Heart J. 2015;37:67-119.

5. Diana, a 37-Year-Old Woman

6. Diana’s Physical Exam • HR: 90 bpm • BP: 110/68 mmHg • Wt: 190 lb • Ht: 5'4“ • JVP: ≈15 cm, reduced carotid upstrokes • Clear lungs • Palpable RV heave, RRR, loud P2, 3/6 TR, intermittent right sided S3 • 2+ LE edema

7. Diana’s ECG • Normal sinus rhythm; incomplete right bundle branch block; prolonged QT

8. Diana’s Laboratory Results

9. 2015 ESC/ERS Guidelines for PH Diagnosis1 Symptoms, signs, hx suggestive of PH Echocardiographic probability of PH? High or intermediate Low Consider LH disease, lung disease by sympotoms, signs, risk factors, ECG, PFT + DLCO, chest x-ray and HRCT, ABG Consider other causes and/or follow-up Dx of heart or lung disease confirmed? No V/Q scintigraphyUnmatched perfusion defects? 1. Galiè N et al; ESC Scientific Document Group. Eur Heart J. 2015;37:67-119.

10. Why Is V/Q Imaging Necessary? • V/Q scan is the imaging modality of choice for CTEPH screening • CT pulmonary angiogram may miss evidence of chronic thromboembolic disease • Patients with PH and clot in their pulmonary arteries do not necessarily have CTEPH V/Q scan of normal lungs V/Q scan showing CTEPH

11. PAH-QuERI: Adherence to Guideline-Recommended Screening1 1. McLaughlin VV et al. Chest. 2013;1438:324-332.

12. Diana’s V/Q Scan

13. 2015 ESC/ERS Guidelines for PH Diagnosis1 Symptoms, signs, hx suggestive of PH Echocardiographic probability of PH? High or intermediate Low Consider LH disease, lung disease by sympotoms, signs, risk factors, ECG, PFT + DLCO, chest x-ray and HRCT, ABG Consider other causes and/or follow-up Dx of heart or lung disease confirmed? No V/Q scintigraphyUnmatched perfusion defects? No CTEPH not likely, RHC 1. Galiè N et al; ESC Scientific Document Group. Eur Heart J. 2015;37:67-119.

14. Right Heart Catheterization1 • Rigorous diagnosis of PAH requires RHC prior to initiation of therapy • RHC remains the gold standard assessment of hemodynamics in PAH Image courtesy of Curt Daniels, MD. 1. McLaughlin VV et al. J Am CollCardiol. 2009;53:1573-1619.

15. Right Heart Catheterization (Cont’d)1 Measure Pressure RA Image courtesy of Curt Daniels, MD. 1. McLaughlin VV et al. J Am CollCardiol. 2009;53:1573-1619.

16. Right Heart Catheterization (Cont’d)1 Measure Pressure RA Image courtesy of Curt Daniels, MD. 1. McLaughlin VV et al. J Am CollCardiol. 2009;53:1573-1619.

17. Right Heart Catheterization (Cont’d)1 Measure Pressure PA RV Image courtesy of Curt Daniels, MD. 1. McLaughlin VV et al. J Am CollCardiol. 2009;53:1573-1619.

18. Right Heart Catheterization (Cont’d)1 Measure Pressure PCWP Measure PVR Measure cardiac output Image courtesy of Curt Daniels, MD. 1. McLaughlin VV et al. J Am CollCardiol. 2009;53:1573-1619.

19. Diana’s Right Heart Catheterization Results

20. Distinguishing Heart Failure With Preserved Ejection Fraction From Pulmonary Hypertension1 PH-HFpEF may often be misclassified as WHO class I PAH 1. Thenappan T et al. Circ Heart Fail. 2011;4:257-265.

21. Delay in Recognition of PAH: REVEAL Registry1 • REVEAL registry: enrolled 2,967 adult patients with PAH from Mar 2006 to Sep 2007 • In 21.1 percent of patients, symptoms were experienced for >2 years before PAH was recognized 1. Brown LM et al. Chest. 2011;140:19-26.

22. Alison, a 55-Year-Old Female: Presents for Second Opinion • Abrupt onset dyspnea two years ago • Diagnosed and treated for pneumonia by urgent care • Dyspnea improved, but never returned to normal • Six months later, she developed worsening dyspnea and new LE edema following a trans-Atlantic flight • She was evaluated by a physician who obtained an echo that demonstrated RV enlargement and pulmonary hypertension • The physician who ordered echo diagnosed our patient with PAH and started her on bosentanand diuretics

23. Alison, a 55-Year-Old Female

24. Alison, 55-Year-Old Female (Cont’d)

25. CTEPH Diagnosis and Surgical Consideration: SCAR Concept1 • Suspecta • Echocardiogramb • V/Q scanc Evaluate for PH/PAH No Yes Refer to expert center a Based on symptoms, signs, and history suggestive of CTEPH. b Used to assess the probability of PH; if high or intermediate, then continue with V/Q scan. c Remains the preferred and recommended test for CTEPH screening. 1. Kim N et al. J Am Coll Cardiol. 2013;62:D92-99.

26. 2015 ESC/ERS Guidelines for PH Diagnosis1 Symptoms, signs, hx suggestive of PH Echocardiographic probability of PH? High or intermediate Low Consider LH disease, lung disease by sympotoms, signs, risk factors, ECG, PFT + DLCO, chest x-ray and HRCT, ABG Consider other causes and/or follow-up Dx of heart or lung disease confirmed? No V/Q scintigraphyUnmatched perfusion defects? 1. Galiè N et al; ESC Scientific Document Group. Eur Heart J. 2015;37:67-119.

27. Comparing V/Q and CTPA:Which Is the Preferred Strategy in Clinical Practice? Performance Indicators for V/Q Scintigraphy and CTPAa The sensitivity of the V/Q scan is almost 50 percent greater than that of CTPA (>96 vs ~51 percent, respectively) • Other indicators favoring V/Q over CTPA: • Lower radiation exposure • Fewer IV contrast complications • Less training for data interpretation • Low costd a A retrospective analysis of 227 patients. b Intermediate with high-probability scans as indicative of CTEPH. c Only high-probability scans as indicative of CTEPH. d When perfusion is omitted. 1. Tunariu N et al. J Nucl Med. 2007;48:680-684.

28. Alison’s V/Q Scan V/Q scan demonstrates bilateral segmental and subsegmental defects

29. CTEPH Diagnosis and Surgical Consideration: SCAR Concept1 • Suspecta • Echocardiogramb • V/Q scanc Evaluate for PH/PAH No Yes Refer to expert center • Confirm • RHCd • High-quality pulmonary angiograme (or CTPA, MRA) • Assess Risk • Hemodynamics • Comorbidities • Surgeon/CTEPH team experience Determine suitability for PEA a Based on symptoms, signs, and history suggestive of CTEPH. b Used to assess the probability of PH; if high or intermediate, then continue with V/Q scan. c Remains the preferred and recommended test for CTEPH screening. d Used for hemodynamic evaluation to confirm the PAH and CTEPH and assess the severity of hemodynamic impairment. e Remains the gold standard for confirmation of chronic thromboembolic disease and evaluation of operability. 1. Kim N et al. J Am Coll Cardiol. 2013;62:D92-99.

30. Alison’s Angiogram and Surgical Specimen Right Left Pulmonary endarterectomy resulted in normalization of pulmonary artery pressures; patient able to discontinue bosentan

31. Bill, a 40-Year-Old Male With Insidious Onset of Dyspnea on Exertion Over Past Year

32. Bill, 40-Year-Old Male With Insidious Onset of Dyspnea on Exertion Over Past Year (Cont’d)

33. Bill’s HRCT Scan • CT scan indicates CTEPH • Patient referred for PEA

34. Bill’s V/Q Scan • V/Q scan is normal, indicating PAH, not CTEPH • Clots seen on CT scan due to in situ thrombosis, not obstructive • If patient had undergone pulmonary endarterectomy, PH would not have improved and the patient may not have survived surgery

35. Conclusions • Exclude non-PAH causes of PH • V/Q scan is the imaging modality of choice for CTEPH screening • CT pulmonary angiogram may miss evidence of chronic thromboembolic disease • RHC remains the gold standard assessment of hemodynamics in PAH

36. Tailoring PAH Therapy to the Individual: What Have We Learned From Post-Approval Analyses? Vallerie V. McLaughlin, MDKim A. Eagle, M.D. Endowed Professor of Cardiovascular Medicine Associate Chief, Cardiovascular Medicine Director, Inpatient Cardiology Services Director, Pulmonary Hypertension Program Director, Disease Management ACU Director, Heart Vessel Blood CTSU University of Michigan Ann Arbor, Michigan Go online to access full [Certification Type] information, including faculty disclosures.

37. Long-Term Outcomes in PAH1 • Despite improvement in overall survival with available therapy, annual mortality rate remains high at ~15 percent • Right ventricular failure is the main cause of mortality Survival, percent Long-term studies evaluating the impact of PAH therapies on mortality are needed 1. Sitbon O et al. Annual Congress 2007 of the European Respiratory Society (ERS 2007).

38. Sue, a 34-Year-Old Woman With Newly Diagnosed PAH

39. 2015 ESC/ERS Guidelines: Risk Assessment in PAH1 1. Galiè N et al; ESC Scientific Document Group. Eur Heart J. 2015;37:67-119.

40. PAH Management Pathway PAH therapy targets multiple pathways Nitric oxide pathway Endothelin pathway Prostacyclin pathway Risk assessment Initiate monotherapy Sequentially adding in a new drug Upfront combination therapy Consideration of switching therapies?

41. Efficacy of Approved Therapies in PAH1-8 1. Galiè N et al. N Engl J Med. 2005;353:2148-2157. 2. Galiè N et al. Circulation. 2008;117:3010-3019. 3. Galiè N et al. Circulation. 2009;119:2894-2903. 4. Ghofrani HA et al. N Engl J Med. 2013;369:319-329. 5. Oudiz RJ et al. J Am Coll Cardiol. 2012;60:768-774. 6. Pulido T et al. N Engl J Med. 2013;369:809-818. 7. Rubin JN et al. N Engl J Med. 2002;346:896-903. 8. Rubin LJ et al. Chest. 2011;140:1274-1283.

42. Efficacy of Approved Therapies in PAH (Cont’d)1-7 1. Barst RJ et al. N Engl J Med. 1996;334:296-302. 2. Galiè N et al. N Engl Med. 2015;373:834-844. 3. McLaughlin VV et al. J Am Coll Cardiol. 2010;55:1915-1922. 4. Olschedwiski H et al. N Engl J Med. 2002;347:322-329. 5. Rubin LJ et al. Ann Intern Med. 1990;112:485-491. 6. Simonneau G et al. Am J Respir Crit Care Med. 2002;165:800-804. 7. Sitbon O. et al. N Engl J Med. 2015;373:2522-2533..

43. AMBITION: Ambrisentan and Tadalafil in Patients With PAH1 Participants With No Event, percent HR = 0.50 (95 percent CI, 0.35-0.72) P < .001 1. Galiè N et al. N Engl J Med. 2015; 373:834-844.

44. Upfront Combination Therapy: an Evolving Paradigm Risk assessment Initiate monotherapy Sequentially adding in a new drug Upfront combination therapy Consideration of switching therapies?

45. ESC/ERS Consensus PAH Treatment Algorithm1 Acute vasoreactivity testing Anticoagulant ± diuretics ± oxygen ± digoxin Vasoreactive Non-vasoreactive Oral CCB Low or intermediate risk (WHO FC II-III) High risk (WHO FC IV) Initial monotherapy Initial oral combination therapy Initial combination therapy including IV PCA 1. Galiè N et al; ESC Scientific Document Group. Eur Heart J. 2015;37:67-119.

46. PAH Registry Data Reinforce Importance of Achieving Low-Risk Status1-3 Survival, percent Survival, percent Transplant-Free Survival, percent 1. Kylhammar D et al. Eur Heart J. 2017 June 1 [Epub ahead of print]. 2. Boucly A et al. Eur Respir J. 2017;50(2). 3. Hoeper MM et al. Eur Respir J. 2017;50(2)

47. REVEAL Registry: Updated PAH Risk Score1 • New variables added (hospitalization in the past year, eGFR) • New cut-off points for BNP, APAH-PoPH, HR, DLCO, NYHA FC, and PVR • Change in score from 12 to 24 months adds predictive ability • A consistently high score over time has a worse prognosis than having a higher score at 24 months than at 12 months 1. Benza RL et al. American Thoracic Society Conference 2017 (ATS 2017). Poster 5447.

48. Longitudinal Evaluation of the PAH Patient1 1. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

49. Longitudinal Evaluation of the PAH Patient (Cont’d)1 1. McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

50. Sue, 36-Year-Old Woman With PAH: Inadequate Response With ERA and PDE5i • Diagnosed with PAH two years ago • ERA + PDE5i; furosemide • Sue responded to therapy with an improvement in FC symptoms and 6MWD until the past three months. Then her symptoms worsened and she experienced worsening dyspnea. She presented back with the following • 6MWD: 325 m • mRAP: 12 mmHg • mPAP: 55 mmHg • Cardiac output/cardiac index: 4.1/2.3, L/min Fick • PVR: 8.3