EFFECTS OF A NEW CALCIUM-ANTAGONIST, MIBEFRADIL (RO-40-5967), ON SILENT ISCHEMIA IN PATIENTS WITH STABLE CHRONIC ANGINA-PECTORIS - A MULTICENTER PLACEBO-CONTROLLED STUDY

Objectives. The purpose of this study was to evaluate the effects of m ibefradil (Ro 40-5967) on the frequency and duration of episodes of as ymptomatic ischemia in patients with stable angina pectoris and to det ermine the most efficient single therapeutic dose of this drug. Backgr ound. Mibefradil is a novel calcium channel antagonist that shows a hi gh bioavailability, induces no reflex tachycardia and has no negative inotropic effects. Methods. In a multicenter, double-blind, placebo-co ntrolled, parallel design trial, 126 patients with chronic stable angi na pectoris were studied. After 1 week of a placebo run-in period, pat ients were randomized to receive 25, 50, 100, 150 mg of mibefradil or placebo for 2 weeks, Ambulatory 48-h electrocardiographic (EGG) monito ring was performed at the end of both the placebo run in period and th e active treatment period. Results. Compared with placebo, mibefradil was associated with significantly less ischemia as manifested during a mbulatory ECG monitoring. In the 150- and 100-mg groups, respectively, the drug resulted in a 73% and 63% reduction in the frequency of epis odes of ST segment depression and a 78% and 58% reduction in the total duration of ST segment depression. Highly significant linear dose-res ponse relations were present across all treatment groups for ischemic episodes and ischemia duration (p < 0.001). Electrocardiographic abnor malities related to treatment were first-degree atrioventricular block , sinus bradycardia and short Wenckebach episodes, observed during sle ep on Holter monitoring. All ECG events were dose related. Conclusions . Mibefradil is a new, safe, well tolerated and very effective dose-de pendent anti-ischemic calcium channel antagonist.