A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure

Background Vesnarinone, an inotropic drug, was shown in a short-term placeb o-controlled trial to improve survival markedly in patients with severe hea rt failure when given at a dose of 60 mg per day, but there was a trend tow ard an adverse effect on survival when the dose was 120 mg per day. In a lo nger-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 Associ ation class III or IV heart failure and a left ventricular ejection fractio n of 30 percent or less despite optimal treatment. The mean follow-up was 2 86 days. Results There were significantly fewer deaths in the placebo group (242 dea ths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 2 2.9 percent) and longer survival (P=0.02). The increase in mortality with v esnarinone was attributed to an increase in sudden death, presumed to be du e 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 measure s of the quality of life in the 30-mg vesnarinone group were similar to tho se in the 60-mg group but not significantly different from those in the pla cebo group. Agranulocytosis occurred in 1.2 percent of the patients given 6 0 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnari none. Conclusions Vesnarinone is associated with a dose-dependent increase in mor tality among patients with severe heart failure, an increase that is probab ly 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 therap eutic goal in treating heart failure. (N Engl J Med 1998;339:1810-6.) (C) 1 998, Massachusetts Medical Society.