Medical therapeutics for pulmonary arterial hypertension: from basic science and clinical trial design to evidence-based medicine

Pulmonary arterial hypertension is a severe disease with poor prognosis, caused by obliteration of the pulmonary vasculature as a result of pulmonary-vascular remodeling, active vasoconstriction and in situ thrombosis. Left untreated, pulmonary arterial hypertension results in right-ventricular failure and death. There has been dramatic progress in the treatment of pulmonary arterial hypertension during recent years. A remarkable number of randomized-controlled trials with agents known to target specific abnormalities present in pulmonary arterial hypertension have been completed. Most commonly, therapeutic efficacy was judged by the ability of the drug under study to improve exercise capacity and to decrease the rate of severe complications. Completed clinical trials have mainly evaluated patients with relatively advanced disease. Despite these advances, responses to therapy in pulmonary arterial hypertension are not uniformly favorable and frequently incomplete. In addition, the methods of delivery and the adverse effect profile of the currently available pulmonary arterial hypertension-specific drugs create further management difficulties. Based on newly identified pathobiologic abnormalities in the pulmonary vasculature, future studies are likely to focus on the discovery of new therapeutic targets. Clinical trial design will continue to evolve in an attempt to enable inclusion of patients with less advanced disease and evaluation of treatment combinations or comparisons of the currently approved drugs.