1. RON OUDIZ, MD Associate Professor of Medicine David Geffen School of Medicine at UCLA LA Biomedical Research Institute at Harbor-UCLA Medical Center Torrance, California Long-term Management of Patients with PAH

2. 2 Learning Objectives (CME, CE, CPE) ●At the completion of this educational activity, participants should be able to: ̶ Discuss the data regarding long-term medical therapy for PAH ̶ Describe the limitations to the long-term data of medical therapy for PAH ̶ Report on the data regarding combination medical therapy for PAH ̶ Discuss interventional and surgical approaches to PAH

3. Trends in Long-term Survival with PAH

4. 4 Updated Definition of PAH 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. Increased mean pulmonary arterial pressure (mPAP)* >25 mm Hg at rest Normal pulmonary capillary wedge pressure (PCWP) <15 mm Hg Increased pulmonary vascular resistance (PVR) † >3 Wood units Right Heart Catheterization Confirmed * Normal resting mPAP = 8 – 20 mm Hg. † In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR given without a value. Significance of mPAP from 21 – 24 mm Hg unclear.

5. 5 Survival of PAH Patients in Current Era: Comparison with NIH Historical Controls Thennapan T, et al. Chest. 2007;132(4 suppl):487S. N = 276, IPAH and FPAH patients diagnosed from 1982-2006; matched for disease variables at baseline with historical controls 67 65 32 100 91 76 43 0 10 20 30 40 50 60 70 80 90 100 Baseline1 year3 year5 year Percentage (%) Survival Observed Predicted (NIH) ^

6. 6 PAH Survival in Current Era: Insights from REVEAL Registry ●REVEAL is an ongoing registry of patients with PAH ●Participating centers include 54 major PAH referral sites in the US ●>3000 patients screened; initial data set includes 2967 patients meeting entry criteria Badesch DB et al. Chest. 2009; DOI 10.1378/chest.09-1140. E-pub ahead of print.

7. 7 REVEAL: Heritable (Familial) PAH and IPAH Comparisons Sarkar PK. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8906 ^ Two-year Survival HPAH/IPAH HPAHIPAH Age at diagnosis, years37 + 1647 + 18 mPAP at diagnosis, mm HG57 + 1453 + 14 PVRI at diagnosis, units.m 2 29 + 1323 + 12 Use of parenteral prostacyclins, %5135 IPAH 14391403134513251288124412251182113011171052961953 FPAH 919089878278777371706562 100 90 IPAH, n=1439 FPAH, n=91 0 Percentage (%) Survival 80 24 0246810121416182022 Time from Enrollment (month) Number at Risk Key HPAH/IPAH Comparisons in REVEAL 100 90 IPAH, n=1439 FPAH, n=91 0 Percentage (%) Survival 80 24 0246810121416182022 Time from Enrollment (month) Number at Risk P=0.14

8. 8 REVEAL Registry: Two-year Survival of SSc-PAH and SLE-PAH Chung L. Presented at the ACR/ACHP Scientific Meeting. Oct. 17-21, 2009. Philadelphia, PA. 1730. ^ Percentage (%) Survival SSc-APAH (n=399) SLE-APAH (n=110) log rank P value =0.0009 024681012141618202224 0 50 60 70 80 90 100 Time from Enrollment (months)

9. 9 REVEAL: Outcomes of PAH Due to Anorexigen Use Barst RJ. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8379 Females aged 19 and over at diagnosis ^ Fen/Dex Exposure 757371 68 656463 6155 IPAH/FPAH 609604595588580569561553542535513466463 Number at Risk Time from Enrollment (month) Fen/Dex Exposure, n=75 IPAH/FPAH, n=609 Percentage (%) Survival 100 90 0 80 24 0246810121416182022

10. 10 Gender Differences in PAH 5-year Mortality: REVEAL Registry Shapiro S, et al. Am J Respir Crit Care Med. 179;2009:A2648. Time from Diagnosis (Years) Percentage (%) Mortality Mortality Estimate Male (n=649) Female (n=2318) 0 1 2 3 4 5 0 5 10 15 20 25 30 35 40 45 50 ^

11. Measuring Outcomes in PAH Therapy

12. 12 Goals of Management of PAH ●Improve survival ●Prevent clinical worsening ●Improve hemodynamics (right-heart function) ●Maintain or improve functional class ●Improve exercise capacity ●Improve daily functioning and quality of life

13. 13 The Problem is… ●Clinical trial endpoints do not necessarily study endpoints that are relevant to the goals of clinical management ●Definition of “clinical worsening” and related terms can be very variable across clinical trials ●Functional class assessment is subjective ●6MWD test has inherent problems in reproducibility and correlation with disease severity ●Accurate hemodynamic measurements are invasive; improvements do not necessarily correlate with clinical status McLaughlin VV, et al. J Am Coll Cardiol. 2009; 54 (Suppl S):S97–S107.

14. 14 Prognostic Factors for Risk of PAH Disease Progression Adapted from McLaughlin VV, et al. Circulation. 2009;119:2250-2294. Lower RiskHigher Risk Evidence of RV failureNoYes Progression of symptoms GradualRapid WHO classII, IIIIV 6-minute walk distance>400 m<300 m CPET peak VO 2 >10.4 mL/kg/min<10.4 mL/kg/min Echo findingsMinimal RV dysfunction Pericardial effusion; significant RV dysfunction, RA enlargement HemodynamicsRAP 2.5 L/min/m 2 RAP >20 mm Hg, CI <2.0 L/min/m 2 Brain natriuretic peptideMinimal elevationSignificantly elevated

15. 15 Change in 6MWD Did Not Predict Survival in Long-term Epoprostenol Therapy Sitbon O, et al. J Am Coll Cardiol. 2002;40:780–788. 78 63 60 48 35 31 25 19 16 13 8 5 2 2 1 1 Subjects at risk, n ∆ 6’ WT ≥ 112 m ∆ 6’ WT < 112 m ∆ 6’ WT ≥ 112 m Survival 0 0.4 0.6 0.8 1.0 0.2 (Months) 01089684726048362412

16. 16 Long-term Management of PAH: Recommended Tests Adapted from Galie N, et al. Eur Heart J. 2009;30:2493-2537. Baseline Ea 4 – 6 months 3 – 4 months after therapy initiation or change @ clinical worsening Clinical Assessment WHO functional class ECG 6MWD CPET BNP/NT-proBNP Echo Right heart catheterization or

17. PAH Therapy

18. 18 Mechanisms of Action of Therapies for PH Humbert M, et al. N Engl J Med. 2004;351:1425-1436. Nitric oxide cGMP Vasodilation and antiproliferation Endothelial cells Nitric oxide pathway PreproendothelinProendothelin L-arginine NOS Arachidonic acidProstaglandin I 2 cAMP Vasodilation 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

19. 19 REVEAL Database: Therapy Choices at Enrollment PDE5 InhibitorERA 305 417 452 290 190 224 At-enrollment therapy of first 2438 patients in REVEAL. Excludes patients enrolled in blinded controlled trials. Prostacyclin (IV, IM and Inhaled) 295 No PAH Therapy = 266 Badesch DB, et al. Chest. 2009; DOI 10.1378/chest.09-1140. Epub ahead of print. ^

20. PAH Monotherapy

21. 21 PAH Long-term Monotherapy Trials - Caveats ●Most long-term trials were open-label extensions of placebo-controlled trials without a comparator arm ●All trials allowed add-on therapy in the setting of clinical worsening - Some trials do not define add-on therapy as a clinical endpoint ●The relative contribution of the “primary” study medication is therefore difficult to assess

22. 22 Intravenous Epoprostenol for Severe PAH: 3-Year Survival N=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from NIH historical controls. *P<0.001 at all time points. McLaughlin VV, et al. Circulation. 2002;106:1477-1482. 061218243036 Months 20 40 60 80 100 Percentage (%) Survival * * * Observed Expected

23. 23 Long-Term Outcomes With Subcutaneous Treprostinil Barst RJ, et al. Eur Respir J. 2006;28:1195-1203. Patients (%) Discontinue for Deterioration Death N=860. Patients followed for up to 4 years. Switch Therapy Add Therapy Discontinue for Adverse Events 14% 16% 11% 15% 23%

24. 24 Long-term Inhaled Iloprost In IPAH: Event-free Survival Opitz CF, et al. Eur Heart J. 2005;26:1895-1902. Event-free = freedom from death, transplantation, switch to intravenous therapy, or addition of oral therapy to inhaled iloprost monotherapy. Cumulative Event-Free Survival (%) Time (Years) 0 40 60 80 10 0 20 054321 No. at risk7639201342 No. of events033552585960

25. 25 Survival With Initial Bosentan Therapy in IPAH McLaughlin VV, et al. Eur Respir J. 2005;25:244-249. N=169. Data from 2 placebo-controlled trials and their extensions. Includes 39 patients who received additional therapy instead of or in addition to bosentan. Bosentan Predicted 100 Event-Free Patients (%) 90 80 70 60 50 40 30 20 0 10 061218243036 Months

26. 26 Long-term Outcome with Initial Bosentan Therapy Provencher S, et al. Eur Heart J. 2006;27:589-595. Event-free = survival without lung transplantation, initiation of prostanoid therapy, or hospitalization for right-heart failure. Survival Event-free 103 76 49 48 26 20 11 12 6 0 0 Subjects at risk, n of mortality of event Percentage Survival and Event-Free Status 0 40 60 80 100 20 (Months) 06048362412

27. 27 ARIES-E: Survival With Long-Term Ambrisentan Therapy Oudiz RJ, et al. J Am Coll Cardiol. 2009;54:1975-1981. 0 20 40 60 80 100 0.00.51.01.5 2.0 Years Survival (%) 2 Year = 88%1 Year = 94% Combined doses 2.5 mg 5 mg 10 mg At Risk: n=383 n=334 n=315 n=298 n=255 ^

28. 28 ARIES-E: Long-term Ambrisentan Survival by Etiology 2009 ATS Abstract. Pulido T. Am J Respir Crit Care Med. 179;2009:A3356. 0 Event Free (%) 100 60 0 20 80 40 0.51.01.5 1 Year 94% (90% to 97%) 2.0 91% (82% to 95%) 2 Year 89% (83% to 93%) 87% (77% to 92%) Years At Riskn=178n=161n=151n=145n=122 At Riskn=94n=81n=71n=69n=57 IPAH PAH-CTD ^

29. 29 SUPER-2: Sildenafil Open-label Extension Clinical Outcomes at 3 Years Improved 6MWD Worsened 6MWD Discontinued/ Lost Died Percentage (%) N=259. Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. ^

30. 30 Long-term Tadalafil: 6MWD by Initial Treatment Assignment 2009 ATS Abstract. Oudiz RJ, et al. Am J Respir Crit Care Med. 179;2009:A1042. Open-label extension of 16 week blinded study. Most patients titrated to 40 mg qd in open-label phase. 420 400 380 360 340 320 0 4 8 1013 16 Months Extension Study 16-Week Study Abbreviation: 6MWD = 6-minute walk distance Mean 6MWD (m) Placebo:40mg 20mg:20mg 2.5-20mg:40mg 40mg:40mg ^

31. PAH Combination Therapy

32. 32 Combination Therapy Trials Caveats ●No trial to date has studied the question of monotherapy versus de novo combination therapy ●All currently reported trials featured “add-on” protocols ●Relative contribution of individual agents to treatment success difficult to assess ●Combination therapy trials often have only a short-term component, with no long-term follow-up

33. 33 Combination Therapy: Sildenafil Added to Failing Inhaled Iloprost Monotherapy Ghofrani HA, et al. J Am Coll Cardiol. 2003;42:158-164. N = 14. Patients with inadequate response to inhaled iloprost. 6 Minute Walk Distance (m) 400 380 360 340 320 300 280 260 240 220 200 180 Inhaled iloprost + oral sildenafil p=0.002 p=0.014 + + + Treatment interval 18+/-4 months Baseline Ilo 3 mo. Pre-Sil Sil-Ilo 3 mo. Sil-Ilo 6 mo. Sil-Ilo 9-12 mo.

34. 34 PACES: Sildenafil Add-On to Stable Epoprostenol Therapy ●16-week study (N=267) - Patients on stable epoprostenol for >3 months - 80% of patients provided with sildenafil 80 mg tid ●Deaths at 16 weeks - Placebo (n=7) - Sildenafil (n=0) Any Clinical Worsening Event at 16 Weeks Patients (%) PlaceboSildenafil Simonneau G, et al. Ann Intern Med. 2008;149:521-530.

35. 35 BREATHE-2: Bosentan Add-On to Stable Epoprostenol Therapy ●Placebo-controlled prospective 16-week study (N=33) ●Patients initiated on epoprostenol, then assigned 2:1 to bosentan or placebo ●No statistical improvements in hemodynamics or WHO functional class Mean Improvement in 6MWD 6MWD (m) Bosentan Humbert M, et al. Eur Respir J. 2004;24:353-359. Placebo 68 74

36. 36 STEP: Add-On Inhaled Iloprost to Stable Bosentan Monotherapy Patients (%) Improved 1 Class 34.4% Clinical Deterioration 6.0% 62.5% N=67. Inhaled iloprost added to stable bosentan monotherapy for a mean of 17.6 to 18.8 months. 94% of patients were NYHA class III at baseline. Iloprost Placebo McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174:1257-1263. 0% 15.2% No Change Change From Baseline in NYHA Class 91.0% Worsened 1 Class 3% 0%

37. 37 Goal-Directed Combination Therapy: Suggested Treatment Algorithm Baseline and 2- to 6-Month Evaluation for Treatment Goals 6-Minute Walk Distance >380 meters; Peak VO 2 >10.4 mL/min/kg Peak systolic BP >120 mm Hg during exercise Oral Monotherapy Dual-Class Oral Combination Therapy Addition of Inhaled Prostanoid Transition to Intravenous Prostanoid Refer for Lung Transplantation Hoeper MM, et al. Eur Respir J. 2005;26:858-863.

38. 38 Transplantation and Intravenous Prostaglandin-Free Treatment Goal-Directed Therapy: Transplantation- and IV Prostanoid-Free Survival Hoeper MM, et al. Eur Respir J. 2005;26:858-863. *P=0.002 versus historical controls. Dual therapy (43.2%), triple therapy (16.1%), and IV prostanoid (4.2%). 1.0 0.8 0.6 0.4 0.2 0 061218 24 30 36 Subjects at Risk (n) Patient Population Historical Control Group 1231138770 57 53 38 84705442 34 27 18 Months Historical Controls Goal-Directed Treatment*

39. Interventional and Surgical Modalities in PAH

40. 40 Surgical Interventions for PAH: When to Refer for Transplantation ●Although drug therapy may delay transplantation, a class IV patient who fulfills criteria should be referred for consideration for transplantation ●Patients who improve to WHO class II with therapy may be removed from the waiting list ●Patients remaining in or progressing to WHO class III after combination therapy should be assessed for transplantation ●Patients with PVOD/PCH should be referred immediately at time of diagnosis Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

41. 41 Type of Transplantation in PAH ●Heart-lung or bilateral lung transplants are preferred - Single-lung transplantation has been abandoned as ineffective in IPAH ●Choice of surgery dependent on several variables - Etiology of PAH - Donor organ availability - Center experience Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

42. 42 IPAH Long-term Transplant Survival at University of Pittsburgh Transplant Center Toyoda Y, et al. Ann Throac Surg. 2008;86:1116-1122. Percentage (%) Survival 1 year5 year10 year N = 30. Transplanted between 1994 to 2006 with a diagnosis of IPAH.

43. 43 Transplant Survival – IPAH, PAH-SSc and IPF Schachna L, et al. Arthritis Rheum. 2006;54:3954-3961. Survival No. at risk:SSc2920171615 IPF7056413326 IPAH3830282422 Months after Transplantation 1.0 0.9 0.8 0.7 0.6 0.5 0 6121824 SSc IPF IPAH Johns Hopkins and University of Pittsburgh transplant centers.

44. 44 Atrial Septostomy ●Indications - Failure of maximal medical therapy with persisting RV failure and/or recurrent syncope - Bridge to transplantation - When no other therapeutic options exist ●Right-to-left shunting increases systemic output, decompresses failing RV and LV ●Increases O 2 transport ●Stepwise balloon dilatation is procedure of choice Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

45. 45 Recommendations to Reduce Procedure- related Morality in Atrial Septostomy ●Only perform in a PAH center ●Contraindications - Severe RV failure or cardiorespiratory support - mRAP >20 mm Hg - PVRI >55 U/m 2 - Resting O 2 saturation <90% on room air - LVEDP >18 mm Hg Adapted from Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

46. 46 Recommendations to Reduce Procedure- related Morality in Atrial Septostomy ● Pre-procedure - Optimize cardiac function with adequate RH filling pressure and inotropic support ●During procedure - Supplemental O 2 - Appropriate sedation - Monitoring LAP SaO 2 %, and mPAP - Tailor defect to <10% decrease in O 2 saturation ●Postprocedure - Optimize O 2 delivery with transfusion or packed red blood cells or darbepoetin before and after Adapted from Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.

47. 47 Summary: Long-term Management of Patients with PAH ●Patients with PAH appear to be surviving longer on medical therapy ●Long-term data on choice of initial medical therapy, de novo combination therapy, or therapy sequencing are still incomplete ●Considerations for initial therapy selection should include decisions on long-term efficacy, safety, and second-line choices ●In patients with severe disease or failing under medical therapy, early referral for possible surgical interventions is important