Evidence-Based Pharmacologic Management of Pulmonary Arterial Hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is a debilitating chronic disorder of the pulmonary vasculature characterized by elevated mean pulmonary arterial pressure, right-sided heart failure, and early mortality. Objectives: This paper reviews the available information on PAH, including its pathophysiology, classification of its severity, current treatment options, drug interactions, pharmacokinetics, and cost considerations. The results of clinical trials of the available treatments are summarized, and a suggested treatment algorithm is provided as a guide to the medical management of PAH. Methods: Pertinent articles were identified by a search of MEDLINE through May 2007 using the terms primary pulmonary hypertension, pulmonary arterial hypertension, prostacyclin, pulmonary vasodilators, endothelin-receptor antagonists, and phosphodiesterase inhibitors. Trials with prospective, randomized designs were given precedence, and prospective studies having nonrandomized, open-label designs or using historical controls were included if they contributed useful knowledge. Retrospective studies were not included. Results: In two 12-week, randomized, open-label trials in patients with moderate to severe PAH (N = 81 and N = 111), exercise capacity, measured on the 6-minute walk test (6-MWT), was significantly improved with intravenous epoprostenol compared with conventional therapy (+31 vs −29 m, respectively, in one study [ P = 0.002]; +46 vs −48 m in the other [P < 0.001]). In one of these trials, intravenous epoprostenol also was associated with a significant survival benefit ( P < 0.003). In a 12-week, randomized, doubleblind, placebo-controlled trial in 470 patients with moderate to severe PAH, subcutaneous treprostinil plus conventional therapy was associated with a significant improvement on the 6-MWT compared with conventional therapy alone (+10 vs 0 m, respectively; P = 0.006). In a 16-week, randomized, double-blind, placebo-controlled trial in 213 patients with mild to moderate symptoms, the oral endothelin-receptor antagonist bosentan was associated with a significant improvement on the 6-MWT compared with placebo (+36 vs −8 m, respectively; P ≤ 0.001) and significantly less clinical worsening at 28 weeks (9/144 vs 14/69; P = 0.002). In a 12-week, prospective, randomized, double-blind, placebo-controlled trial in 277 patients with PAH, sildenafil 20, 40, and 80 mg TID were associated with significant improvements on the 6-MWT compared with placebo (all, P < 0.001). In a prospective trial in 76 patients with idiopathic PAH, the inhaled prostacyclin iloprost was associated with overall survival rates of 93%, 79%, 70%, 59%, 59%, and 49% at 3 months and 1, 2, 3, 4, and 5 years, respectively. In an early trial in 64 patients receiving highdose calcium channel blockers, those who had responded to initial drug challenge (defined as a > 20% decrease in pulmonary arterial pressure and pulmonary vascular resistance immediately after challenge) had a survival rate of 94% at 1, 3, and 5 years. Conclusions: Patients who respond to an acute trial of a vasodilator may be treated with an oral calcium channel blocker, whereas oral therapies such as sildenafil and bosentan have been effective in patients with mild to moderate symptoms. Infusions of the prostacyclin analogues epoprostenol and treprostinil appear to be the treatment of choice for moderate to severe PAH, and agents with alternate routes of delivery such as inhaled iloprost may be advantageous in adjunctive roles. Future trials that focus on the long-term effects of currently available agents, as well as on combination therapy, are needed.