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Original Article
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Volume 339:1810-1816 December 17, 1998 Number 25
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A Dose-Dependent Increase in Mortality with Vesnarinone among Patients with Severe Heart Failure
Jay N. Cohn, M.D., Sidney O. Goldstein, M.D., Barry H. Greenberg, M.D., Beverly H. Lorell, M.D., Robert C. Bourge, M.D., Brian E. Jaski, M.D., Sidney O. Gottlieb, M.D., Frank McGrew, M.D., David L. DeMets, Ph.D., Bill G. White, Ph.D., for The Vesnarinone Trial Investigators

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ABSTRACT

Background Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity.

Methods We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days.

Results There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P<0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those in the 60-mg group but not significantly different from those in the placebo group. Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone.

Conclusions Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia. A short-term benefit in terms of the quality of life raises issues about the appropriate therapeutic goal in treating heart failure.


Source Information

From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis (J.N.C.); the Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Hospital, Detroit (S.O. Goldstein); the Department of Cardiology, University of California, San Diego, Medical Center, San Diego (B.H.G.); the Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston (B.H.L.); the Division of Cardiology, Department of Medicine, University of Alabama, Birmingham (R.C.B.); the San Diego Cardiac Center Medical Group, San Diego, Calif. (B.E.J.); the Division of Cardiology, Department of Medicine, University of Maryland Hospital, Baltimore (S.O. Gottlieb); the Stern Cardiovascular Center, Memphis, Tenn. (F.M.); the Department of Statistics and Biostatistics, University of Wisconsin Medical School, Madison (D.L.D.); and Clinical Cardiovascular Research, McLean, Va. (B.G.W.).

Address reprint requests to Dr. Cohn at the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St., SE, Minneapolis, MN 55455.

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