1. Treatment Strategies for Pulmonary Hypertension Sarfraz Saleemi MRCP, FCCP, FACP Section of pulmonary medicine Department of medicine King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia

4. Without treatment: survival correlates with functional class McLaughlin VV, et al. Chest 2004;126:78S-92S

6. PH treatment algorithm Badesch D. B. et.al. Chest 2007;131:1917-1928

10. Targets for Current or Emerging Therapies Humbert M et al. N Engl J Med. 2004;351:1425-1436. Pathophysiology of PAH Big Endothelin Endothelin- converting Enzyme Endothelin Receptor A Endothelin Receptor B Vasoconstriction and Proliferation Endothelin Receptor Antagonists Endothelin-1 Endothelin Pathway Arginine Nitric Oxide Synthase Vasodilatation and Antiproliferation Nitric Oxide cGMP Exogenous Nitric Oxide Phosphodiesterase Type-5 Phosphodiesterase Type-5 Inhibitors Nitric Oxide Pathway Arachidonic Acid Prostacyclin Synthase Vasodilatation and Antiproliferation Prostacyclin cAMP Prostacyclin Derivatives Prostacyclin Derivatives Prostacyclin Pathway

12. PAH Determinants of Risk McLaughlin VV, McGoon MD. Circulation . 2006;114:1417-1431. Lower Risk Determinants of Risk Higher Risk No Clinical evidence of RV failure Yes Gradual Progression Rapid II, III WHO class IV Longer (>400 m) 6MW distance Shorter (<300 m) Minimally elevated BNP Very elevated Minimal RV dysfunction Echocardiographic findings Pericardial effusion, significant RV dysfunction Normal/near normal RAP and CI Hemodynamics High RAP, low CI

13. Choice of Initial PAH Therapy

14. PAH: Randomized Control Trials of Approved Agents Headache, flushing, dyspepsia 6 MWD CPH Symptoms Double-blind, placebo 12 wks 278 IPAH,CT CHD II, III SUPER Sildenafil Citrate (20, 40 or 80 mg tid) PDE-5 Inhibitor Pain, erythema at infusion site Side effects 6 MWD Symptoms CPH Double-blind 12-wk 470 PAH II-IV SQ Treprostinil / SQ placebo Prostacyclin analogue Administration 6 to 9 times daily Composite Endpoint 6 MWD, sx Double-blind 12-week 203 PH III-IV Inhalational Iloprost / Placebo Prostacyclin analogue Hepatic toxicity (11%; transient, reversible) 6 MWD Symptoms Clinical Worsening CPH Double- Blind 16-wk 213 PAH III,IV BREATHE-1 Oral Bosentan / placebo ET-1 Antagonist Indwelling central line Pump (infection,malf) Side effects Disadvantages 6 MWD Symptoms CPH Survival Open- Label 12-wk 81 PPH III,IV IV Epoprostenol / Conventional Rx Prostacyclin Positive Results Design N Eunctional Class Study/ Drug Class of Drug

15. PAH-specific drug therapy European Heart Journal (2009) 30, 2493–2537

16. IV epoprostenol (flolan)

20. Relationship Between The Mean 6 MWD at Baseline and Rate of Fatal Events During 3-Month Follow Up (Adjusted R² = 0.5519, P = .0109) Macchia, et al. Am Heart J 2007; 153:1037-1047

21. Suggested assessments and timing for the follow-up of patients with PAH European Heart Journal (2009) 30, 2493–2537

22. PAH: Composite Score Predicts Disease Progression Anderson D, et al. AJRCCM 2008

25. Combination Therapy: Ongoing or Recently Completed Clinical Trials

26. Overview of Combination Therapy Trials for PAH + 20 m 235 RCT Bosentan + Inhaled Treprostinil TRIUMPH-1 + 26 m 267 RCT Sildenafil and IV Epoprostenol PACES NS 33 RCT Bosentan and IV Epoprostenol BREATHE-2 NS 40 RCT Iloprost/Beraprost and Bosentan COMBI + 26 m 67 RCT Iloprost inhalation and Bosentan STEP + 19 m 29 RCT Bosental and Sildenafil EARLY

28. New Treatments on the Horizon

29. Pulmonary Arterial Hypertension Cellular Processes Newman JH. Circulation 2004;109:2947-2952

32. THANKS