Future of Clinical Trials for Pulmonary Hypertension

> “It is better to lose the battle and win the war.” > > —Sun Tzu (circa 6th century BCE Chinese General and military strategist) In 1995, the first successful randomized controlled trial (RCT) for pulmonary arterial hypertension (PAH) led to the approval of the pulmonary vasodilator epoprostenol.1 Under the assumption that PAH was a disease of inappropriate pulmonary vasoconstriction, testing a drug that had vasodilator properties seemed reasonable. The 6-minute walk test was the primary end point in the trial because it was in keeping with the Food and Drug Administration precedent that an outcome assessment in a patient with cardiopulmonary disease needs to reflect how the patient feels, functions, or survives. Article see p 2985 There are now 7 vasodilator therapies for PAH, all approved because they improved exercise capacity for 3 to 4 months.2 Whether they affect long-term survival remains a valid question.3 Recently, a sobering report from a highly respected referral center in France noted that the current 3-year survival for patients with pulmonary hypertension managed with state-of-the-art multiple drug therapy was only 58%, marginally better than in 1980s when there were no treatments at all.4 In addition, it appears that these drugs do not protect patients from developing severe pulmonary vascular disease.5,6 Our knowledge of the pathobiology of PAH today is quite different from what it was 20 years ago. Scientific studies have demonstrated that cellular proliferation, inflammation, and thrombosis are the dominant underlying pathobiological processes and that chronic pulmonary vasoconstriction appears to play a relatively minor role.7 It is therefore understandable why the RCT by Kawut et al8 in this issue of Circulation chose to study the safety and efficacy of simvastatin and/or aspirin, therapies directed at normalizing endothelial cell function and platelet activation, as a treatment for …