2. Accreditation and Designation Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Supported by an independent educational grant from Gilead Sciences Medical Affairs.

3. Faculty: CME Course Director James E. Calvin, MD James B. Herrick Professor of Medicine Chief, Section of Cardiology Rush University Medical Center Chicago, Illinois

4. Faculty: Content Development and Training Ronald Oudiz, MD Associate Professor of Medicine David Geffen School of Medicine UCLA Medical Center Torrance, California

5. Disclosure Information It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content

6. Disclosure Information: CME Course Director James E. Calvin, MD — Grants/Research Support None — Consultant None — Speaker’s Bureau Encysive, Schering-Plough — Honoraria None — Stock Shareholder None — Other Financial or Material Support: None

7. Disclosure Information: Content Faculty Ronald Oudiz, MD — Grants/Research Support Actelion, Encysive, Gilead Sciences, Pfizer, United Therapies — Consultant Lilly/ICOS — Speaker’s Bureau None — Honoraria None — Stock Shareholder None — Other Financial or Material Support None

8. Opinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, University of South Florida College of Nursing, University of Florida College of Pharmacy, or Commission for Case Manager Certification The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose Please consult the full prescribing information before using any medication mentioned in this program

9. Program Evaluation Your feedback is essential for measuring the success of this CME/CE program A post-activity brief online survey will be e-mailed to you in 4 to 8 weeks to assess how your participation in this educational activity has affected your practice of medicine. Completion of the program evaluation, included within your materials, and submission to the onsite program Host is required CME/CE credits for this program cannot be provided without a completed evaluation

10. Learning Objectives At the completion of this educational activity, participants should be able to: — Highlight evolving data on the diagnosis, management and treatment of pulmonary arterial hypertension (PAH) as presented at the CHEST 2008 Meeting, Philadelphia, PA — Report on risk factors for PH disease progression — Discuss the evolving epidemiology and treatment strategies for PH of a variety of etiologies

11. 2008 Post Conference Update: CHEST

12. Epidemiology

13. PAH Registries: Functional Class at Diagnosis Indicates Delayed Diagnosis Frost AE. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. % Patients NYHA Functional Class III-IV at Diagnosis N=2967 N=2364N=1009N=578N=187N=674 Percent (%)

14. Survival of Geriatric Patients with IPAH Uzunpinar A. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331. N = 20, IPAH patients >65 years. Percent (%) Survival 100 90 80 70 60 50 40 30 20 10 0 Year 1 Year 2 Year 3 Time Expected Survival (NIH) Actual Survival

15. Prevalence of Resting PH in Patients Referred for Stress Echocardiography Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. N = 2,306 adults referred for stress echocardiography. RSVP >35 mmHg 11.9% RVSP <35 mmHg 88.1%

16. Diagnostic and Outcomes Markers

17. BNP Predictive Value For Adverse Outcomes Garcia-Badillo EV. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. Death Cardiogenic shock Inpatient heart failure Outpatient heart failure Ventricular dysfunction WHO Class IV WHO Class III WHO Class II WHO Class I Control N = 85

18. Biomarker Predictors of Clinical Worsening In Bosentan-treated Patients Vizza CD. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331. *P = 0.0006. † P = 0.09. Clinical worsening vs no clinical worsening. ET-1 (pg/mL) BNP (pg/mL) † *

19. Clinical and Hemodynamic Predictors of Survival in PAH Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. Concordance index (C statistic) 0.8 0.7 0.6 0.5 P<0.005 P<0.001 NS Other Clinical factors RHC Age, Sex, WHO Class ECHO & PFTs

20. Doppler Echo Overestimates PAH in Patients with Scleroderma-related Lung Disease Chan KM. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. Percent (%)

21. PAH in Obese Patients: BMI Correlates With Worsening Hemodynamics Kaw R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. N = 1600, patients undergoing right heart catheterization for suspected PH. *p < 0.05 versus comparator. 70 60 50 40 30 20 10 0 RA MeanPA SystolicPA DiastolicPA MeanPCWP Mean mmHg BMI 3030≤BMI>35BMI≥35 * * * * * * * ** * * * *

22. Clinical Pharmacology

23. No Pharmacokinetic Interactions Between Ambrisentan and Tadalafil Spence R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. C max AUC Ambrisentan+5.0%-12.5% 4-hydroxymethyl ambrisentan +5.8%-14.5% Tadalafil+0.6%+0.2% N = 26, healthy volunteers. Comparison versus single-agent/metabolite.

24. Sitaxsentan and Acencoumarol Interactions Pulido T, et al. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. N = 50. Dose adjustments of 1.6 – 2.0 mg required to reach INR target. 3.0 2.5 2.0 1.5 1.0 0.5 2 Duration (weeks) INR 6 10 14 18 22 2630 34 384246 5054 58 62667074 7882 86 90 94 98 102 106 110

25. Short-term Clinical Trials

26. Tadalafil for PAH: Change in 6MWD at 16 Weeks Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. N = 405 *p = 0.05; † p = 0.03; ‡ p = 0.0004 vs. placebo. † * ‡ 70 60 50 40 30 20 10 0 048 1216 placebo 2.5 mg 10 mg 20 mg 40 mg Weeks Change in 6-Minute Walking Distance (m)

27. Tadalafil for PAH: Change in WHO Functional Class at 16 Weeks Barst RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. P = NS for all comparisons. Percent (%) n = 82 n = 80n = 79 20.7 25.6 23.8 36.6 22.8 63.4 52.4 62.5 45.1 67.1 15.9 22 13.8 18.3 10.1 0% 20% 40% 60% 80% 100% Placebo2.5 mg10 mg20 mg40 mg ImprovedNo ChangeWorsened

28. Long-term Clinical Trials

29. ARIES-E: Survival With Long-term Ambrisentan Therapy Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. 0 20 40 60 80 100 0.00.51.01.5 2.0 Years Survival (%) ABS 2.5 mg 5 mg 10 mg At Risk: n=383 n=334 n=315 n=298 n=255 2 Year = 88%1 Year = 94%

30. ARIES-E: Change in 6MWD Over 2 Years With Ambrisentan Oudiz RJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. Change in 6MWD (m) Years -20 -10 0 10 20 30 40 50 60 0.00.250.51.0 1.5 2.0 70 2.5 mg, n = 93 5 mg, n = 186 10 mg, n = 96

31. TRIUMPH-1: Long-term Inhaled Treprostinil Plus Oral Therapy 6MWD Improvements Over Time Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. Baseline Month 6Month 12Month 18 Month 24 349 377 380 383 399 N = 206 Subjects received either bosentan (n = 143) or sildenafil ( n = 63) in addition to inhaled treprostinil up to 72 µg four times daily Total 6-Minute Walk Distance (meters)

32. Long-term Inhaled Treprostinil Plus Oral Therapy: Change in NHYA Functional Class Over Time Benza R. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. *p < 0.05 NYHA Unchanged (%)NYHA Worsened (%)NYHA Improved (%) Month 12 N=93 Month 9 N=121 Month 6 N=160 Month 3 N=197 Change from Baseline 80 70 60 50 40 30 20 10 0 * * * *

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

34. SUPER-2: Long-term Sildenafil Change in Functional Class at 3 Years Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. N = 259 Improved 2 Classes Improved 1 Class Worsened 1 Class UnchangedDC/LostDied Percent (%)

35. Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. NNYA Functional Class Pre- and Post-Transition (6 months of therapy) N = 30 60 50 40 30 10 20 0 Percentage of Patients (%) NYHA CLASS I II III IV Pre-transition Post-transition

36. Long-term Outcomes in Patients Transitioned From Epoprostenol to SC Treprostinil Yan C. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. Discontinuation of Treprostinil Over Time (Excluding Death) N = 30 1.0 0.8 0.6 0.4 0.2 0 01224364860 Time (Months) Proportion of Patients Remaining on SC TRE

37. Adverse Effects of PAH Therapies

38. Epoprostenol-related Thrombocytopenia Jacob S. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. Platelet count drop >50,000 noted in red Platelet count at Baseline Platelet count at 2-4 months Platelet count at 8-12 months 450 400 350 300 250 200 150 100 50 0

39. ARIES- 3: Long-term Ambrisentan Following Bosentan or Sitaxsentan Failure for LFT Abnormalities Feldman JP. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2206. N = 226, Subset analysis among 26 patients forced to discontinue alternative ERA therapy for LFT abnormalities. 25 20 15 10 0 No LFT Abnormalities ALT/AST >3X AND  5xULN 1 (4%) 5 Number of Patients 25 (96%)

40. ARIES-1 & 2: 6MWD of Patients Experiencing Edema Versus No Edema Shapiro SL. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244. PlaceboAmbrisentan AllNoYes -120 -100 -80 -60 -40 -20 0 20 40 60 Change in 6MWD (m) p = 0.032 AllYes -9 -55 +34 +39 +19 Edema

41. Expanding Populations

42. PH Inhibits Stress Echo Exercise Duration Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2331. Exercise duration, mins 6 1014 182 100 80 60 40 20 0 No PH (8.6±3 mins) Ex - PH (7.4±3 mins) P<0.0001 Percentage (%) Patients

43. PAH in Sickle Cell Disease 10% of sickle cell patients will have PAH/PH Pathophysiology not necessarily related to occlusion — Soluble factors have been identified Mixed PH (PAH combined with diastolic dysfunction) associated with 11-fold relative risk of mortality Clinical trials of PAH medications in sickle cell have been slow to recruit Barst RJ, Machado RF, Mubarak KK. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session 15983.

44. Summary: CHEST 2008 Evidence suggests PAH treatment can be effective in wide range of patient types and ages Tadalafil may provide a new choice in PDE-5 inhibitor class Inhaled treprostinil in combination with oral therapy may provide an additional choice in prostacyclin class Long-term data for ambrisentan, sildenafil show 2+ years of benefit in survival and time to clinical worsening