Therapy for Pulmonary Arterial Hypertension: The More, the Merrier?

Without effective therapy, patients with pulmonary arterial hypertension (PAH) have inexorably worsening dyspnea and declining exercise capacity and can die, most often of right heart failure. The disease involves dysregulated endothelial and vascular smooth-muscle cell growth, in situ thrombosis, and an imbalance of vasodilators and constrictors. The result is a noncompliant, markedly narrowed blood vessel that resists blood flow from a progressively weakening right ventricle. Less than 20 years ago, the mean survival of patients with idiopathic PAH (formerly called primary) was only 2.8 years. There was little to offer beyond supplemental oxygen, anticoagulants, and diuretics (1).

Since then, the pace of research has accelerated, and we now have 6 drugs approved by the U.S. Food and Drug Administration that target 3 of many pathways implicated in PAH (2, 3). Deficient production of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation and smooth-muscle proliferation, can be ameliorated with the prostacyclin analogues epoprostenol, iloprost, or treprostinil. Each improves hemodynamic measurements and exercise capacity, and a randomized, controlled trial (RCT) of epoprostenol demonstrated improved survival (4). Currently, however, these drugs require intravenous, subcutaneous, or inhaled administration. In a second pathway, deficient synthesis of nitric oxide can be managed with oral sildenafil, which slows the breakdown of nitric oxide's vasodilating metabolites. A third pathway involves endothelin, a potent vasoconstrictor in which overexpression in PAH might also contribute to cell growth, fibrosis, and inflammation. Oral bosentan or ambrisentan inhibit this pathway. In addition, calcium-channel antagonists are effective in a small minority of patients.

Although the number of drugs available for treating PAH has grown, the drugs remain inadequate. Although the mortality rate has improved, it remains very high. Even with continuous intravenous epoprostenol, approximately 50% of patients with idiopathic PAH die within 5 years (5). Those who improve with …