Milton Packer1, Christopher O'Connor1, John J V McMurray1, Janet Wittes1, William T Abraham1, Stefan D Anker1, Kenneth Dickstein1, Gerasimos Filippatos1, Richard Holcomb1, Henry Krum1, Aldo P Maggioni1, Alexandre Mebazaa1, W Frank Peacock1, Mark C Petrie1, Piotr Ponikowski1, Frank Ruschitzka1, Dirk J van Veldhuisen1, Lisa S Kowarski1, Mark Schactman1, Johannes Holzmeister1. 1. From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.), and Baylor College of Medicine, Houston (F.P.) - both in Texas; Inova Heart and Vascular Institute, Falls Church, VA (C.O.); the Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P.); Statistics Collaborative, Washington, DC (J.W., L.S.K., M.S.); Ohio State University Heart and Vascular Center, Columbus (W.T.A.); Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany (S.A.); the Division of Cardiology, University of Bergen, Stavanger University Hospital, Stavanger, Norway (K.D.); Faculty of Medicine, National and Kapodistrian University of Athens, Athens (G.F.); private consultant, Wayzata, MN (R.H.); Centre of Cardiovascular Research and Education in Therapeutics, Monash University, Melbourne, VIC, Australia (H.K.); Centro Studi, Associazione Nazionale Medici Cardiologi Ospedalieri, Fondazione Per il Tuo Cuore HCF ONLUS, Florence, Italy (A.P.M.); University Paris 7 Diderot, Assistance Publique-Hôpitaux de Paris, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint-Louis Lariboisière, U 942 INSERM, Paris (A.M.); Wroclaw Medical University, Wroclaw, Poland (P.P.); the Department of Cardiology, University Hospital Zurich, Zurich (F.R., J.H.), and Cardiorentis, Zug (J.H.) - both in Switzerland; and the University Medical Center Groningen, Groningen, the Netherlands (D.J.V.).
Abstract
BACKGROUND: In patients with acute heart failure, early intervention with anintravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis. METHODS: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive acontinuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS:Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in theplacebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634 .).
RCT Entities:
BACKGROUND: In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis. METHODS: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS:Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634 .).
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