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ABSTRACT

Background Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate–mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.

Methods In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study.

Results The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. Among the 222 patients completing one year of treatment with sildenafil monotherapy, the improvement from baseline at one year in the distance walked in six minutes was 51 m.

Conclusions Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.

Source Information

From the Institute of Cardiology, University of Bologna, Bologna, Italy (N.G., A.B.); University Hospital, Justus-Liebig-University, Giessen, Germany (H.A.G., F.G.); the Institute of Tuberculosis and Lung Disease, Warsaw, Poland (A.T., M.K.); Babies and Children's Hospital, Columbia Presbyterian Medical Center, New York (R.J.B.); the University of California at San Diego, La Jolla (L.J.R.); University of Colorado Health Sciences Center, Denver (D.B.); the University of Washington, Seattle (T.F.); Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (T.P., G.B.); and Hôpital Antoine Béclère, Clamart, France (G.S.).

Address reprint requests to Dr. Galiè at the Institute of Cardiology, University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy, or at n.galie{at}bo.nettuno.it.

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N Engl J Med 2006; 354:1091-1093, Mar 9, 2006. Correspondence

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