2. Learning Objectives Identify patients at high risk for the development of PAH. Utilize right heart catheterization to confirm the diagnosis of PAH. Evaluate right ventricular function using screening tools and imaging tests. Weigh the risks versus benefits for a given mediation, in terms of indication for use, route of administration, side effects, and long- term study data. Decide if and when combination therapy is a clinical necessity. Analyze multiple clinical endpoints to determine if treatment is successful.

3. Lecture Outline Pathology and genetics Diagnostics The right ventricle in PAH High-risk patients Evidence-based treatment Ongoing research Combination therapy Prognostication and patient monitoring

4. Epidemiology and History of PAH Prevalence in the U.S. –≈ 50,000 to 100,000 (15,000 to 25,000 diagnosed and treated) Circa 1987 –Due to rapid progression of morbidity and mortality, once patients were diagnosed with pulmonary hypertension they were described as entering “the kingdom of the near-dead” 2015 –Patient survival has dramatically improved as treatment options for PAH have increased McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.

5. Clinical Classification of Pulmonary Hypertension Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. PAH is a diagnosis of exclusion

6. Types of PAH Idiopathic BMPR2 ALK-1, ENG, SMAD9, CAV1, KCNK3 Unknown HeritableDrug- and toxin-induced Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Associated with: Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

7. PAH Associated With Connective Tissue Disease Scleroderma Most prevalent and studied type of PAH associated with CTD Rate of occurrence of PAH = 7 to 12% of patients with scleroderma; more common in limited scleroderma (CREST syndrome) Prognosis is poorer than other types of PAH PAH is the leading cause of death; 1 year mortality rate = 30% Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

8. Associated Conditions PAH Associated With: Rate of Occurrence of PAH Clinical Features HIV infection0.5% Improvement in survival since HAART; 5-year survival > 70% Portal hypertension2 – 6% Prognosis negatively impacted by cardiac dysfunction, severity of liver disease / cirrhosis Congenital heart disease10% Presence of PAH has negative impact on clinical course Schistosomiasis5%3-year survival ≈ 85% Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

9. Patient Registries for PAH RegistryTime PeriodN NIH1981 – 1985187 French2002 – 2003674 U.S. REVEAL2006 – 20093515 U.S. PHC1982 – 2006578 PAH-QuERI2005 – 2007791 Scottish-SMR1986 – 2001374 Chinese1999 – 200472 Spanish1998 – 2008866 U.K.2001 – 2009482 New Chinese Registry2008 – 2011956 Mayo1995 – 2004484 Compera2007 – 2011587 McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.

10. Observations From Patient Registries for PAH Older age at diagnosis –NIH registry: 36 (± 15 years) –REVEAL: 50 - 65 (± 15 years) Population cohorts at greater risk –Patient demographic – advanced age, male gender –Etiology – heritable PAH, PAH associated with CTD or portal hypertension McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.

11. Older Patients With PAH Older age at diagnosis –More advanced, severe disease –Greater number of comorbidities  Presence of comorbid conditions can mask symptoms of PAH and delay diagnosis, and may contribute to morbidity and mortality Treatment strategies for older patients –Exact influence of age on treatment success is unknown –Older patients are underrepresented in clinical studies Hoeper, et al. Eur Resp Rev. 2014;23(134):450-7.

12. Comorbid Conditions in Patients With PAH Poms, et al. Chest. 2013;144(1):169-76. N = 2959 Patients (%)

13. Patient 3-Year Survival Rates: REVEAL Registry Barst, et al. Chest. 2013;144(1):160-8. N = 263 N = 74N = 645 P < 0.05

14. Pathology of Pulmonary Hypertension Overview Obstructive lung panvasculopathy Prognosis is primarily determined by the functional status of the RV Most common cause of death is RV failure Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Image: www.pathhsw5m54.ucsf.edu/Image61.htmlwww.pathhsw5m54.ucsf.edu/Image61.html Plexiform lesion Thrombus Dilated vessels

15. Pathology of Pulmonary Hypertension Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Proliferative, apoptosis- resistant state Metabolic dysfunction Disordered mitochondrial structure Persistent inflammation Dysregulation of growth factors Interplay of several pathobiological and environmental factors on a “background of genetic predisposition”

16. Pathology of Pulmonary Hypertension Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Increased PVR Sustained vasoconstriction Excessive pulmonary vascular remodeling In situ thrombosis

17. Mechanisms of Pathology for PAH Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436. Nitric oxide cGMP Vasodilatation and antiproliferation Endothelial cells Nitric Oxide Pathway PreproendothelinProendothelin L-arginine NOS Arachidonic acidProstaglandin I 2 cAMP Vasodilatation and antiproliferation Vasoconstriction and proliferation Endothelin- receptor A Endothelin- receptor B Endothelin PathwayProstacyclin Pathway Endothelin-1 Endothelin- receptor antagonists Exogenous nitric oxide Prostacyclin derivates Phosphodiesterase type 5 inhibitor Phosphodiesterase type 5 GTP sGC stimulator

18. Genetic Mutations in PAH BMPR2 –Major predisposing gene –Over 300 mutations have been identified –Found in >70% of patients with H-PAH –Found in ≈ 20% of patients with IPAH ALK-1 –Major gene when PAH is associated with hereditary hemorrhagic telanglectasia (HHT) Less common mutations: –Endoglin, SMAD9, Caveolin-1, KCNK3 Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21. BMPR2

19. Group 1’ Pulmonary Hypertension Overlapping pathological features –Disordered endothelial growth or proliferation –Histologic changes in pulmonary parenchyma –Development of pulmonary arterial intimal thickening and medial hypertrophy May have similar clinical presentation Genetic predisposition –Mutations in BMPR2, EIF2AK4? Langleben. Chest. 2014;145(2):197-8. Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54.

20. Definition of Pulmonary Hypertension General definition –Mean PAP ≥ 25 mm Hg at rest, measured by right heart catheterization Hemodynamic characterization of PAH –Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, elevated PVR (> 3 Wood Units) Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50.

21. Diagnostic Algorithm for PAH: Consensus From 5 th WSPH Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. PAH is a diagnosis of exclusion

22. Clinical Presentation of PAH Symptoms Dyspnea Fatigue Syncope Weakness Angina Abdominal distension Edema Signs Loud P2 (listen at apex) RV lift (left parasternal – fingertips) RV S3, RV S4 Systolic murmur (TR; inspiratory augmentation) Early systolic click Midsystolic ejection murmur Diastolic murmur (PR) Increased jugular “a” wave McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.

23. Echocardiography for PAH Screening tool, NOT a diagnostic tool Non-invasive estimation of PAP Examine ECHO results for: –RV size and function –Left ventricular systolic and diastolic dysfunction –Left-sided chamber enlargement –Valvular heart disease Examine ECHO with contrast results for intracardiac shunt Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

24. Right Heart Catheterization for PAH  Required test for diagnostic confirmation Measures: –PAP –PAWP –CO –RAP Allows calculation of pulmonary and systemic vascular resistance Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

25. Anatomy and Physiology of the RV and LV Rich. Cardiol Clin. 2012;30:257-69. Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. Complex interplay between contractility, afterload, compliance, and heart rate Subject to significant size and shape change

26. RV Failure Syndrome Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. RV failure: High RV filling pressures, diastolic dysfunction, ↓ CO Contractile dysfunction progresses RV dilatation Progressive contractile impairment Adaptive RV hypertrophy Pulmonary hypertension ↑ PAP (pressure overload)

27. Continuum of RV Impairment and Action Towards Reversal When compensatory mechanisms in the RV are exceeded, RV dysfunction develops RV failure manifests clinically as exercise limitation and fluid retention FDA-approved therapies for PAH reverse RV remodeling –Reduction of afterload –Vasodilation Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.

28. Evaluation of RV Function Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. Echocardiography Pericardial effusion TAPSE Right atrial area LV eccentricity 2D, 3DE volumes / ejection fraction RV strain Tei index Right Heart Catheterization Right atrial pressure Cardiac index Cardiac output (CO) Cardiac MRI RV mass RV volume RV ejection fraction

29. Impact of RV Function on Therapy RV function can highlight the subtle changes in early disease and prompt rapid initiation of therapy RV function determines the patient’s functional capacity and survival Deterioration in RV function mirrors disease progression Treatment escalation can be guided by RV function correlates Badano, et al. Eur J Echocardiography. 2010;11(1):27-37.

30. Diagnostic Issues Misdiagnosis 1 –Most patients see three or more physicians over a three- year period before an accurate diagnosis is made Diagnostic delay 1 –Time to reach diagnosis has not improved in 20 years Advanced disease at diagnosis 2 –Approximately 75% of patients have advanced disease at diagnosis (functional class III and IV) 1) Deano, et al. JAMA Intern Med. 2013;173(10):887-93. 2) Thenappan, et al. Eur Respir J. 2007;30(6):1103-10.

31. Patient Screening “Systematic testing of asymptomatic individuals to search for preclinical disease and mildly symptomatic patients to prevent progression and / or development of the disease” Appropriate for PAH since symptoms are nonspecific and condition is uncommon and progressive; however, presentation is confounded by diversity of PAH Determine which screening populations to preselect Schwaiger, et al. Eur Resp Rev. 2013;22(130):515-25. Proper screening Earlier diagnosis Rapid intervention Improved outcomes

32. Patients at High Risk for PAH Patients with a family history of PAH Heritable PAH Patients with a history of high-risk drug / toxin use Drug- and toxin-induced PAH Patients with an associated condition: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Associated conditions Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

33. Guidelines for Screening High-Risk Patients Schwaiger, et al. Eur Resp Rev. 2013;22(130):515-25. Heritable PAH –Yearly echocardiography in asymptomatic carriers of BMPR2 mutation and RHC if the echocardiograph is abnormal Associated conditions –Scleroderma – yearly echocardiography in symptomatic patients, optional in asymptomatic patients –HIV infection – echocardiography recommended if unexplained dyspnea

34. Treatment of PAH Strategy: –Evaluation of disease severity –Adoption of general measures and supportive therapy –Assessment of vasoreactivity –Estimation of drug efficacy –Combination of different drugs and interventions Goals of therapy: –Improve symptoms, hemodynamics, exercise capacity, functional class, quality of life –Prevent clinical decline –Reduce hospitalizations –Extend survival Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33.

35. General Measures and Supportive Therapy General Measures Rehabilitation / exercise Psychosocial support Family planning Vaccinations Supportive Therapy Anticoagulants Diuretics Oxygen Digoxin Referral to a PAH Clinic Multidisciplinary care Continuous monitoring Patient and family education Psychosocial support Access to clinical trials Disease advocacy Society participation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

36. General Measures and Supportive Therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Agarwal, et al. Am Heart J. 2011;162:201-13 Cardiac catheterization / acute vasoreactivity testing –Mandatory if IPAH (optional if associated condition) –Identifies patients who are responders –Inhaled nitric oxide (10 – 20 parts per million) or inhaled epoprostenol (50 ng/kg/min) are the preferred testing agents Chronic CCB therapy –Appropriate for patients with a positive response = reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO –Therapeutics – amlodipine, nifedipine, or diltiazem

37. Mechanisms of Pathology for PAH Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436. Nitric oxide cGMP Vasodilatation and antiproliferation Endothelial cells Nitric Oxide Pathway PreproendothelinProendothelin L-arginine NOS Arachidonic acidProstaglandin I 2 cAMP Vasodilatation and antiproliferation Vasoconstriction and proliferation Endothelin- receptor A Endothelin- receptor B Endothelin PathwayProstacyclin Pathway Endothelin-1 Endothelin- receptor antagonists Exogenous nitric oxide Prostacyclin derivates Phosphodiesterase type 5 inhibitor Phosphodiesterase type 5 GTP sGC stimulator

38. Prostacyclin Pathway Prostacyclin –Produced primarily by endothelial cells –Induces potent vasodilation of vascular beds –Inhibits platelet aggregation –Cytoprotective and antiproliferative properties Prostacyclin analogs Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. EpoprostenolContinuous IV infusion, inhalation TreprostinilSubcutaneous, IV, inhalation, oral IloprostInhalation

39. Endothelin Pathway Endothelin –Plasma levels are elevated in patients with PAH –Increases vasoconstriction –Mitogenic properties Endothelin receptor antagonists Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. BosentanOral AmbrisentanOral MacitentanOral

40. Nitric Oxide Pathway Nitric oxide –Impairment of nitric oxide (NO) synthesis and signaling in patients with PAH –Mediated through the NO-sGC-cGMP pathway NOSNOsGCcGMP Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. L-ArginineL-Citrulline GMP PDE-5 Vasodilation

41. Nitric Oxide Pathway Phosphodiesterase-5 inhibitors –Inhibit the cGMP degrading enzyme, PDE-5 –Enhance the pathway, slowing cGMP degradation –Vasodilation and antiproliferative effects Soluble guanylate cyclase stimulators –Increase cGMP production –Antiproliferative and antiremodeling properties Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. SildenafilOral, IV TadalafilOral RiociguatOral

42. WHO Functional Classification for PAH Class I No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope. Class II Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class III Marked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class IV Inability to perform any physical activity without symptoms; signs of right ventricular failure or syncope; dyspnea and / or fatigue may be present at rest; discomfort is increased by any physical activity. Taichman, et al. Clin Chest Med. 2007;28:1-22.

43. Evidence-Based Treatment Algorithm: Consensus From 5 th WSPH FC IIFC IIIFC IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Treprostinil sc, inhalation Iloprost inhalation Epoprostenol IV Treprostinil IVBosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Treprostinil sc, inhalation, IV Iloprost inhalation Initial combination therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Sequential Combination Therapy Interventional Procedure IA/B IIbC IIaC BAS Lung Transplantation Inadequate clinical response Inadequate clinical response on maximal therapy ERA PAPDE-5i sGCS + + +

44. Initial Therapy for PAH: Consensus From 5 th WSPH FC IIFC IIIFC IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Treprostinil sc, inhalation Iloprost inhalation Epoprostenol IV Treprostinil IVBosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Treprostinil sc, inhalation, IV Iloprost inhalation Initial combination therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. IA/B IIbC IIaC Strength of recommendation and clinical evidence Strength of recommendation and clinical evidence

45. Prostacyclin Analogs EpoprostenolTreprostinilIloprost Indication / FC III, IVII, III, IVIII, IV Administration Continuous IV Inhalation SC IV Inhalation Oral Inhalation Dosage 20-40 ng/kg/minInitial = 1.25 ng/kg/min Usual = 30-100 ng/kg/min Usual = 2.5-5 µg, 6-9 times per day Other 2 branded versions available Only PAH clinical study to demonstrate survival benefit Administer in well- ventilated areas Max dosage = 45 µg

46. Treprostinil for PAH Clinical Study Route of Administration N Study Duration Study Results Simonneau 1 SC47012 weeksSS improvement in 6-MWD Tapson 2 IV1412 weeks SS improvements in 6-MWD, FC McLaughlin 3 Benza 4 Inhalation + Bosentan or sildenafil RCT = 212 OL = 206 12 weeks 24 months SS improvements in 6-MWD, QOL with combination therapy, which were sustained for OL extension 1) Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4. 2) Tapson, et al. Chest. 2006;129:683-8. 3) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18):1915-22. 4) Benza, et al. J Heart Lung Transplant. 2011;30(12):1327-33.

47. Treprostinil Oral for PAH: FREEDOM-C Clinical Trial Study design –RCT –N = 350 patients with background ERA or PDE-5 inhibitor –Study duration = 16 weeks Study results –High discontinuation rate: 22% of treprostinil-treated patients and 14% of placebo-treated patients –Improvement in 6-MWD did not reach statistical significance –Reduced efficacy may be due to the low dose of treprostinil or presence of background therapy Tapson, et al. Chest. 2012;142(6):1383-90.

48. Treprostinil Oral for PAH: FREEDOM-M Clinical Trial Study design –RCT –N = 228 treatment-naïve patients, no background therapy permitted –Study duration = 12 weeks Jing, et al. Circulation. 2013;127:624-33. Weeks Change in 6-MWD Change from Baseline (meters) * P < 0.05 * *

49. Endothelin Receptor Antagonists BosentanAmbrisentanMacitentan Indication / FCII, III, IV AdministrationOral Dosage 62.5 mg twice daily for 4 weeks then 125 mg twice daily 5 mg and 10 mg daily 10 mg daily Other Sustained receptor binding and enhanced tissue penetration

50. 62.5 mg twice daily 125 or 250 mg twice daily -40 -20 0 20 40 60 80 Bosentan (N = 144) Placebo (N = 69) 48 16 Weeks P = 0.0002 Change from Baseline (meters) Rubin, et al. N Engl J Med. 2002;346:896-903. Bosentan for PAH: BREATHE Clinical Trial Change in 6-MWD (From Baseline to Week 16)

51. Bosentan for PAH: EARLY Clinical Trial Time to Clinical Worsening (From Baseline to Week 32) 100 80 60 40 20 0 048121620282432 Event-Free Patients (%) Placebo Bosentan P < 0.02 Weeks Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.

52. Ambrisentan for PAH: ARIES Clinical Trials Time to Clinical Worsening (From Baseline to Week 12) --- Placebo --- 2.5 mg (P = 0.03) --- 5 mg (P = 0.005) --- 10 mg (P = 0.03) 70 80 90 100 04812 Weeks Event-Free Patients (%) Ambrisentan → 71% relative risk reduction Galie, et al. Circulation. 2008;117:3010-9.

53. Ambrisentan for PAH: ARIES-3 Clinical Trial Study results 6-MWD –Increased by 21 meters (P < 0.05) BNP levels –Decreased by 26% (NSS) Badesch, et al. Cardiovasc Ther. 2012;30(2):93-9. Patient population (N = 224)

54. Ambrisentan for PAH: ARIES-E Clinical Trial Change in 6-MWD (From Baseline to 24 Months) Change from Baseline (meters) 2.5 mg (N = 93) 5 mg (N = 186) 10 mg (N = 96) Years -20 -10 0 10 20 30 40 50 60 0.0 0.25 0.5 1.01.52.0 70 7 23 28 Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.

55. Macitentan for PAH: SERAPHIN Clinical Trial 1) Pulido, et al. NEJM. 2013;369(9):809-18. 2) Channick, et al. JACC Heart Fail. 2015;3(1):1-8. Macitentan 10 mg (N = 242) Average duration of treatment (event driven) 1 103.9 weeks Risk reduction in the occurrence of morbidity and mortality events versus placebo 1 45%* All-cause hospitalizations 2 Risk reduced by 32%* and rate reduced by 33%* PAH-related hospitalizations 2 Risk reduced by 52%* and rate reduced by 50%* *P < 0.05

56. Nitric Oxide Pathway Agents SildenafilTadalafilRiociguat TypePDE-5 inhibitor Soluble guanylate cyclase stimulator Indication / FCII, III, IV Administration Oral IV Oral Dosage 20 mg oral three times daily 10 mg IV three times daily 40 mg daily1 mg – 2.5 mg three times daily

57. Sildenafil for PAH Clinical Study Study Design AgentsN Study Duration Study Results SUPER-1 1 RCT Sildenafil 20 - 80 mg three times daily 27812 weeksSS improvements in 6- MWD, FC SUPER-2 2 OL Sildenafil 80 mg three times daily 2 nd agent added in 18% of patients 1703 years46% maintained or improved 6-MWD 60% maintained or improved FC Patient survival = 79% PACES 3 RCT Epoprostenol Epoprostenol + sildenafil 80 mg three times daily 53 214 16 weeksPatients on combination therapy had SS improvement in 6-MWD, fewer clinical worsening events, and delayed TTCW 1) Galie, et al. N Engl J Med. 2005;353:2148-57. 2) Rubin, et al. Chest. 2011:140(5):1274-83. 3) Simonneau, et al. Ann Intern Med. 2008;149(8):521-30.

58. Tadalafil for PAH Clinical Study Study Design AgentsN Study Duration Study Results PHIRST-1 1 RCT Tadalafil 20 or 40 mg daily Tadalafil + bosentan 189 216 16 weeksSS improvements in 6-MWD, QOL, clinical worsening events, TTCW, especially in treatment-naïve patients PHIRST-2 2 OL Tadalafil 20 or 40 mg daily Tadalafil + bosentan 135 158 52 weeksImprovements in 6-MWD, clinical worsening events were sustained 1) Galie, et al. Circulation. 2009;119(22):2894-903. Barst, et al. J Heart Lung Transplant. 2011;30(6):632-43. 2) Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74.

59. Riociguat for PAH Ghofrani, et al. NEJM. 2013;369(4):330-40. Clinical Study Study Design AgentsN Study Duration Study Results PATENTRCT Riociguat 1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily 44312 weeksSS improvements in 6-MWD, PVR, NT-proBNP, FC, Borg Dyspnea Scale score, QOL measures, TTCW

60. Ongoing Clinical Research in PAH PAH is a chronic, debilitating disease with significant associated morbidity and mortality A cure for PAH has yet to be discovered Standard treatment eventually becomes inadequate Enrollment in clinical trials posits patients for cutting-edge therapies and progressive treatment protocols

61. Selexipag for PAH Investigational agent Mechanism of action –Prostacyclin IP receptor agonist –Targets the prostacyclin pathway Administration – oral Image: www.chemspider.com/Chemical-Structure.8089417.htmlwww.chemspider.com/Chemical-Structure.8089417.html

62. Combination Therapy for PAH Rationale – to target multiple disease pathways REVEAL: 34% of patients on 2 or more treatments Background Starting in one drug class and adding an agent from another class Used when therapy needs to be augmented because response to initial therapy is inadequate Sequential Therapy Used in early PAH disease May improve patient outcomes, slow disease progression, and reduce costs associated with managing clinical worsening Upfront Therapy Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Badesch, et al. Chest. 2010;137(2):376-87.

63. Combination Therapy for PAH: Published Studies Clinical StudyAgentsN Study DurationStudy Endpoints Statistical Significance BREATHE-2 1 Epoprostenol Bosentan 3316 weeks Hemodynamics, 6-MWD, FC No STEP-1 2 Iloprost Bosentan 6712 weeks Hemodynamics, 6-MWD, FC, TTCW Yes COMBI 3 Iloprost Bosentan 4012 weeks 6-MWD, FC, TTCW No Zhuang 4 Ambrisentan Tadalafil 12416 weeks 6-MWD, clinical worsening events Yes 1) Humbert, et al. Eur Respir J. 2004;24:353-9. 2) McLaughlin, et al. Am J Respir Crit Care Med. 2006;174:1257-63. 3) Hoeper, et al. Eur Respir J. 2006;28:691-4. 4) Zhuang, et al. Hypertens Res. 2014;37(6):507-12.

64. Combination Therapy for PAH: COMPASS Clinical Trials COMPASS-2 1 RCT N = 334 Sildenafil +/- bosentan Study duration = event driven Study endpoint = TTCW Study results = NSS COMPASS-3 2 Open-label extension N = 100 Bosentan +/- sildenafil Study duration = 28 weeks Study endpoint = 6-MWD Study results = 31% reached 6-MWD goal, 34% improved FC 1) McLaughlin, et al. Chest. 2014;146(4):ABSTRACT (NCT00303459) 2) Benza, et al. Chest. 2010;138(4):ABSTRACT (NCT00433329)

65. Upfront Combination Therapy Kemp, et al. J Heart Lung Transplant. 2012;31(2):150-8. P = 0.07 Patient Survival (%) Months

66. Upfront Combination Therapy: AMBITION Clinical Trial Study design RCT N = 500 treatment-naïve patients Study groups –Ambrisentan –Tadalafil –Ambrisentan + tadalafil Study duration = event driven Primary endpoint = TTCW Galie, et al. Eur Respir J. 2014;44(58):ABSTRACT. Study results Combination therapy reduced the risk of clinical failure events by 50%* SS* improvements in: –6-MWD –NT-proBNP –% Patients with a satisfactory clinical response *P < 0.05

67. Upfront Triple Combination Therapy Study design Retrospective review N = 18 treatment-naïve patients in FC III or IV Epoprostenol + bosentan + sildenafil First assessment of endpoints at 4 months Sitbon, et al. Eur Respir J. 2014;43(6):1691-7. Study results SS* improvements in –6-MWD –Hemodynamics Functional class –Improvement to FC I or II for 17 patients Overall patient survival –100% at 1, 2, and 3 years *P < 0.05

68. Interventional Procedures: Balloon Atrial Septostomy Creation of an interatrial right-to-left shunt In order to: ›Decompress right heart chambers ›Increase LV preload ›Increase CO ›Improve systemic oxygen transport ›Decrease sympathetic hyperactivity Considered a palliative or bridging procedure –Patients refractory to medical therapy –Patients awaiting lung transplantation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

69. Interventional Procedures: Lung Transplantation Surgical procedures –Single lung transplant – rare –Bilateral (sequential) lung transplant – most common –Heart-lung transplant – increasingly less common; only 70 – 90 performed per year* Lung transplantation remains the standard of care for select patients who fail aggressive medical therapy, with specific eligibility criteria determined by the transplant center *Long, et al. Pulm Circ. 2011;1(3):327-33. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

70. Diagnosis of PAH Vasoreactivity test: negative Baseline exam and 3 - 6 monthly re-evaluation to assess treatment goals: Clinically stable, FC II, 6-MWD > 400 meters, RAP / CI normal Baseline exam and 3 - 6 monthly re-evaluation to assess treatment goals: Clinically stable, FC II, 6-MWD > 400 meters, RAP / CI normal Treatment goals NOT met Treatment goals met Start ERA or PDE-5i Add ERA or PDE-5i Parenteral PA and / or enrollment in clinical trials Urgent lung transplantation Continue treatment Goal-Directed Therapy Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63.

71. Low RiskDeterminants of RiskHigh Risk NoClinical evidence of RV failureYes GradualDisease progressionRapid II, IIIFunctional classIV Longer (> 400 meters)6-MWDShorter (< 300 meters) Peak VO 2 > 10.4 mL/kg/minCPETPeak VO 2 < 10.4 mL/kg/min Minimally elevated and stableBNP / NT-proBNPSignificantly elevated PaCO 2 > 34 mm HgBlood gassesPaCO 2 < 32 mm Hg Minimal RV dysfunctionECHO cardiography Pericardial effusion, RV dysfunction, RA enlargement RAP < 10 mm Hg; CI > 2.5 L/min/m 2 Pulmonary hemodynamics RAP > 20 mm Hg; CI < 2 L/min/m 2 McLaughlin, et al. Circulation. 2006;114:1417-31. McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. Prognostication: Determinants of Patient Risk

72. Clinical Endpoints Exercise Capacity 6-MWD CPET Treadmill Functional Class Biomarkers BNP / NT-proBNP Hemodynamics (PVR, PAP, CO) Imaging Cardiac MRI 2D 3DE Clinical Variables Quality of life TTCW Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91.

73. Longitudinal Patient Monitoring: ACCF / AHA Recommendations Patient Evaluation 6-MWDFCBNPECHORHC Stable patient Every 3-6 months Every visit Center dependent Every 12 months If clinical deterioration Unstable patient Every 1-3 months Every visit Center dependent Every 6-12 months Every 6-12 months or if deterioration McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5.

74. Treatment Goals: Consensus From 5 th WSPH 6-MWDCPETFCBNPECHOHemodynamics > 380 – 440 meters Peak VO 2 > 15 mL/min/kg EqCO 2 < 45 L/min I or II Normal levels Normal or near normal RV size and function RAP < 8 mm Hg CI > 2.5 - 3 L/min/m 2 McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81.

75. Summary Expedient diagnosis sets in motion timely and focused patient care. The continuum of RV impairment in PAH must be met with aggressive action towards reversal. The evidence-based treatment algorithm provides a foundation for disease management. Upfront combination therapy may become the standard of care for patients. In order to capture and address any subtle change in a patient’s clinical condition, comprehensive patient monitoring is essential.