From short-term benefits to long-term outcomes: the evolution of clinical trials in pulmonary arterial hypertension.

Abstract Over the past 2 decades, major advances in our understanding of pulmonary arterial hypertension (PAH) have led to the development of new targeted therapeutics and management strategies that have provided benefits to patients with this devastating disease. Despite such improvements, no therapies are curative, and PAH remains a progressive disease associated with high morbidity and suboptimal survival in many patients. Clinical research in PAH is currently at a crossroads. To move forward, not only are new therapies needed, but novel approaches to clinical trial design are also required. Trials should be designed to assess the longer-term benefits of investigational therapies in what has become a chronic disease. Moreover, there is a need to consider moving away from short-term trials that use markers such as the 6-minute walk distance as a measure of exercise capacity as primary end points to longer-term, event-driven trials with composite end points made up of clinically relevant measures that better reflect the ultimate goals of reducing morbidity and mortality. A shift in trial design may also be useful in overcoming some of the muted results from recent pivotal phase III studies of combination therapy by allowing the potential of these regimens to be more comprehensively assessed.