A COMPARISON OF CONTINUOUS INTRAVENOUS EPOPROSTENOL ( PROSTACYCLIN ) WITH CONVENTIONAL THERAPY FOR PRIMARY PULMONARY HYPERTENSION

Background. Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. Methods. We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Results. Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P 0.01). Hemodynamics improved at 12 weeks in the epoprostenoltreated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were 8 percent and 3 percent, respectively (difference in mean change, 6.7 mm Hg; 95 percent confidence interval, 10.7 to 2.6 mm Hg; P 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were 21 percent and 9 percent, respectively (difference in mean change, 4.9 mm Hg per liter per minute; 95 percent confidence interval, 7.6 to 2.3 mm Hg per liter per minute; P 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. Conclusions. As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension. (N Engl J Med 1996;334:296-301.)  1996, Massachusetts Medical Society. From the Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York (R.J.B.); the Department of Medicine, University of Maryland, Baltimore (L.J.R.); the Department of Pediatrics, University of North Carolina, Chapel Hill (W.A.L.); the Department of Medicine, Mayo Medical Center, Rochester, Minn. (M.D.M.); the Department of Medicine, University of Illinois at Chicago (S.R.); the Department of Medicine, University of Colorado Health Sciences Center, Denver (D.B.B., B.M.G.); the Department of Medicine, Duke University Medical Center, Durham, N.C. (V.F.T.); the Department of Medicine, University of Alabama, Birmingham (R.C.B.); the Department of Medicine, Harbor–UCLA Medical Center, Torrance, Calif. (B.H.B.); the Department of Medicine, Cedars–Sinai Medical Center, Los Angeles (S.K.K.); the Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal (D.L.); the Department of Medicine, Baylor College of Medicine, Houston (C.A.K.); the Department of Medicine, Presbyterian–University Hospital, University of Pittsburgh, Pittsburgh (S.M., B.F.U.); and the Medical Division, Burroughs Wellcome, Research Triangle Park, N.C. (L.M.C., M.M.J., S.D.B., D.S., J.W.C.). Address reprint requests to Dr. Barst at the Division of Pediatric Cardiology, Department of Pediatrics, BH 262N, Columbia University College of Physicians and Surgeons, 3959 Broadway, New York, NY 10032. Supported in part by Burroughs Wellcome, Research Triangle Park, N.C. Dr. Rubin is the recipient of an academic award in vascular disease from the National Heart, Lung, and Blood Institute. Dr. Badesch is the recipient of a clinical investigator award from the National Institutes of Health. *The members of the Primary Pulmonary Hypertension Study Group are listed in the Appendix. P RIMARY pulmonary hypertension is a disease characterized by the progressive elevation of pulmonary-artery pressure and vascular resistance, ultimately producing right ventricular failure and death. 1-3 A variety of treatments have been used, including vasodilators, 4-7 anticoagulant agents, 6,8 and lung or heart–lung transplantation, 9-13 but none have resulted in improved survival in a prospective, randomized trial. Epoprostenol (formerly called prostacyclin or prostaglandin I 2 ) is a potent, short-acting vasodilator and inhibitor of platelet aggregation that is produced by vascular endothelium. Short-term infusions of epoprostenol decrease pulmonary vascular resistance in a dosedependent manner in patients with primary pulmonary hypertension, and this response has been used to determine whether long-term oral vasodilator therapy is warranted. 14 In an eight-week prospective, randomized trial, the continuous intravenous infusion of epoprostenol produced hemodynamic and symptomatic improvement. 15 Patients treated with epoprostenol for up to three years appeared to live longer than historical controls from the Registry on Primary Pulmonary Hypertension of the National Institutes of Health (NIH) who received standard therapy. 16 The objective of this study was to evaluate the effects of the continuous infusion of epoprostenol on exercise capacity, quality of life, hemodynamics, and survival in a 12-week open-label, prospective, randomized, multicenter study of patients with severe primary pulmonary hypertension who continued to be in New York Heart Association (NYHA) functional class III or IV despite conventional therapy.