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Effects of Beraprost Sodium, an Oral Prostacyclin Analogue, in Patients

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Effects of Beraprost Sodium, an Oral Prostacyclin Analogue, in Patients View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 39, No. 9, 2002 © 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)01786-2 Pulmonary Hypertension Effects of Beraprost Sodium, an Oral Prostacyclin Analogue, in Patients With Pulmonary Arterial Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial Nazzareno Galie`, MD,* Marc Humbert, MD,† Jean-Luc Vachie´ry, MD,‡ Carmine Dario Vizza, MD,§ Meinhard Kneussl, MD,࿣ Alessandra Manes, MD,* Olivier Sitbon, MD,† Adam Torbicki, MD,¶ Marion Delcroix, MD,# Robert Naeije, MD,‡ Marius Hoeper, MD,** Ari Chaouat, MD,†† Sophie Morand, MD,‡‡ Bruno Besse, MD,‡‡ Gerald Simonneau, MD,† for the Arterial Pulmonary Hypertension and Beraprost European Trial (ALPHABET) Study Group Bologna, Italy; Clamart, Strasbourg and Paris, France; Brussels and Leuven, Belgium; Rome, Italy; Vienna, Austria; Warsaw, Poland; and Hannover, Germany OBJECTIVES The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH). BACKGROUND Pulmonary arterial hypertension is a life-threatening disease for which continuous intrave- nous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system. METHODS In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 ␮g four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class. RESULTS Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p ϭ 0.036). The difference in the mean change of Borg dyspnea index was Ϫ0.94 (95% CI: Ϫ1.63 to Ϫ0.24, p ϭ 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p ϭ 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period. CONCLUSIONS Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension. (J Am Coll Cardiol 2002;39:1496–502) © 2002 by the American College of Cardiology Foundation Pulmonary arterial hypertension (PAH) is defined, accord- and pulmonary hypertension associated with various condi- ing to the 1998 World Health Organization classification tions such as collagen vascular diseases (5), congenital (1), as a group of diseases characterized by a progressive systemic-to-pulmonary shunts (6), portal hypertension (7) increase of pulmonary vascular resistance leading to right and human immunodeficiency virus (HIV) infection (8). All ventricular failure and death (2,3). Pulmonary arterial hy- these conditions share virtually identical obstructive patho- pertension includes primary pulmonary hypertension (2,4) logic changes of the pulmonary microcirculation (9). Pros- tacyclin is an endogenous substance produced by vascular From the *Institute of Cardiology, University of Bologna, Bologna, Italy; †Division of Pulmonary and Critical Care Medicine, Antoine Be´cle`re Hospital, Clamart, endothelium that has vasodilating, antiplatelet aggregation Paris-Sud University, Clamart, France; ‡Departement de Cardiologie et Laboratoire and antiproliferative effects (10–12). A dysregulation of de Physiologie, Hoˆpital Erasme, Universite´ Libre de Bruxelles, Brussels, Belgium; prostacyclin metabolic pathways has been demonstrated in §Department of Cardiology, University of Roma “La Sapienza,” Rome, Italy; ࿣Allgemeines Krankenhaus der Stadt Wien, University of Vienna, Vienna, Austria; patients with PAH (13) and in experimental models of ¶Department of Chest Medicine, National Institute of Tuberculosis and Lung pulmonary hypertension (14,15). Recently, therapy with Disease, Warsaw, Poland; #Department of Pneumology, Gasthuisberg University continuous intravenous prostacyclin (epoprostenol) has been Hospital, Leuven, Belgium; **Abteilung Pneumologie, Medizinische Hochschule Hannover, Hannover, Germany; ††Service de Pneumologie, Centre Hospitalier shown to improve symptoms and prognosis in New York Hautepierre, Strasbourg, France; ‡‡Laboratoire Aventis, Paris, France. Supported by Heart Association (NYHA) functional class III and IV a grant from Laboratoire Aventis, Paris, France. Manuscript received November 6, 2001; revised manuscript received January 28, patients with different types of PAH (16–20). However, 2002, accepted February 6, 2002. epoprostenol requires permanent intravenous catheters and JACC Vol. 39, No. 9, 2002 Galie` et al. 1497 May 1, 2002:1496–502 Beraprost Sodium in Pulmonary Hypertension 20 ␮g or matching placebo four times a day each week. In Abbreviations and Acronyms case of intolerable side effects, the dose was reduced to that CI ϭ confidence interval of the previous week, and this was considered as the HIV ϭ human immunodeficiency virus maximal tolerated dose. Therefore, the up-titration was ϭ PAH pulmonary arterial hypertension based on side effects and not on clinical efficacy, in order to NYHA ϭ New York Heart Association administer the highest tolerated dose. The maximal dose allowed in the study was 120 ␮g four times a day at week 6. The maximal tolerated dose was kept constant during the portable pumps and is associated with several side effects maintenance period between week 7 and week 12. Side and potentially serious complications. For these reasons, effects limiting dose increase were moderate to severe alternatives to intravenous prostacyclin have been sought, flushing, headache and diarrhea and usually occurred 1 to and this has led to analogues, which can be administered 2 h after single-dose intake. All patients were enrolled in an subcutaneously (treprostinol), by inhalation (iloprost) or open-label study with beraprost sodium after the comple- orally (beraprost sodium) (21). tion of the randomized study. Beraprost sodium is the first chemically stable and orally Outcome measures. Patients were evaluated at baseline, active prostacyclin analogue (22). In experimental studies, week 6 and week 12. The primary efficacy parameter was beraprost sodium has been shown to exert a protective effect exercise capacity measured by the distance a patient could on the development of monocrotaline-induced pulmonary walk in 6 min (6-min walk test) at week 12. The 6-min walk hypertension (23). Uncontrolled and retrospective experi- test was performed after standardized procedures (26) 2 to ences in patients with primary pulmonary hypertension have 4 h after drug intake. preliminarily shown that long-term oral treatment with Secondary measures of efficacy included the Borg dyspnea beraprost sodium improves hemodynamics (24) and prog- index (27) assessed immediately after completion of the nosis (25). 6-min walk test and cardiopulmonary hemodynamics mea- We report on the results of a randomized, double-blind, sured by right heart catheterization at baseline and week 12. placebo-controlled, multicenter study designed to deter- Cardiac index (l/min/m2) was computed as cardiac output mine the effects of 12-week oral administration of beraprost divided by body surface area; pulmonary vascular resistance sodium on exercise capacity, symptoms and cardiopulmo- index (U/m2) was calculated using standard formula: mean nary hemodynamics in NYHA class II and III patients with pulmonary artery pressureϪpulmonary capillary wedge PAH. pressure/cardiac index. Secondary measures of efficacy also METHODS included the NYHA functional class and the reduction in all-cause mortality or hospitalization for worsening of Patients selection. Patients eligible for this study were symptoms related to pulmonary hypertension. Safety was males or females over 8 years of age with PAH (1) in assessed by adverse event recording and laboratory assess- NYHA functional classes II and III, including primary ment. pulmonary hypertension, pulmonary hypertension associ- Statistical analysis. The sample size was estimated under ated with collagen vascular disease, congenital systemic-to- the assumptions of a two-sided alpha probability of 0.05, an pulmonary shunts, portal hypertension and HIV infection. 80%-power, an expected treatment difference for the change A baseline 6-min walking distance between 50 and 500 m, from baseline in 6-min walk test of 40 m and an SD of a mean pulmonary artery pressure Ͼ25 mm Hg and a 70 m. Under these conditions, the study’s 1:1 randomization pulmonary capillary wedge pressure Ͻ15 mm Hg were required a sample size of at least 50 evaluable patients in required for inclusion. Patients were excluded if they had each group. Assuming a 10% drop-out rate, planned recruit- received long-term treatment with other prostacyclin ana- ment was for a total of 110 patients
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