OTSUKA AMERICA’s VESNARINONE REDUCES RISK OF DEATH BY 62%

Executive Summary

OTSUKA AMERICA's VESNARINONE REDUCES RISK OF DEATH BY 62% in congestive heart failure patients, according to a study presented Nov. 17 at the American Heart Association's 65th Scientific Sessions in New Orleans. The study also was discussed at a Nov. 18 press conference. Lead study investigator Arthur Feldman, MD/PhD, Johns Hopkins, said that "treatment with 60 mg per day of vesnarinone results in a 50% reduction in the risk of death or worsening heart failure, a 62% reduction in the risk of death, and a significant improvement in quality of life." The multicenter, randomized, placebo-controlled trial of the vesnarinone (OPC-8212) involved patients with symptomatic congestive heart failure who were receiving digoxin, a diuretic and an ACE inhibitor. "The prospectively defined outcome variables were all-cause mortality and cardiovascular morbidity over 26 weeks of treatment and quality of life over 12 weeks of treatment," Feldman said. Patients were enrolled in 22 centers in the U.S. They were eligible if they had symptomatic ventricular dysfunction despite taking routine medications and had an ejection fraction of less than or equal to 30%. The patients were randomized to receive placebo, 60 mg of vesnarinone or 120 mg of vesnarinone. "After randomization of 253 patients, the 120 mg treatment group was discontinued at the request of the data and safety monitoring committee because of a trend towards increased mortality in this high dose group," Feldman explained. "However, the committee also recommended continuation of the low dose arm in the study, and a total of 477 patients were subsequently randomized to receive either placebo or 60 mg vesnarinone." After six months of therapy, patients were offered the drug on an open- label basis. "A substantial and statistically significant decrease in the percentage of patients reaching either morbidity or the mortality endpoint" was evident "in the vesnarinone treatment group when compared to those patients who were receiving placebo," Feldman said. Investigators used the Sickness Impact Profile Questionnaire given by telephone interview to assess the drug's impact on quality of life. Feldman stated that "12 weeks of vesnarinone therapy effected an improvement in overall score, physical score and psychosocial score, and all three of these comparisons were statistically significant." During the six month trial, "therapy was discontinued in 10 patients in the placebo group and 23 patients in the vesnarinone group," Feldman noted. "This disparity was partially accounted for by the withdrawal of six patients or 2.5% of the active treatment group because of neutropenia." Feldman stated that "the occurrence of neutropenia was idiosyncratic and reversible in all cases" and that the neutropenia occurred within the first four months of therapy "suggesting that 16 weeks of white blood count monitoring might be adequate in terms of safety." The investigator pointed out that "reversible neutropenia complicates therapy with vesnarinone in 2.5% of patients, but would appear to be a manageable side effect and the risk/benefit ratio for this new agent would appear to favor benefit."