OBJECTIVE The purpose of this study was to evaluate the effects of mibefradil (Ro 40-5967) on the frequency and duration of episodes of asymptomatic ischemia in patients with stable angina pectoris and to determine the most efficient single therapeutic dose of this drug. BACKGROUND Mibefradil is a novel calcium channel antagonist that shows a high bioavailability, induces no reflex tachycardia and has no negative inotropic effects. METHODS In a multicenter, double-blind, placebo-controlled, parallel-design trial, 126 patients with chronic stable angina pectoris were studied. After 1 week of a placebo run-in period, patients were randomized to receive 25, 50, 100, 150 mg of mibefradil or placebo for 2 weeks. Ambulatory 48-h electrocardiographic (ECG) monitoring was performed at the end of both the placebo run-in period and the active treatment period. RESULTS Compared with placebo, mibefradil was associated with significantly less ischemia as manifested during ambulatory ECG monitoring. In the 150- and 100-mg groups, respectively, the drug resulted in a 73% and 63% reduction in the frequency of episodes of ST segment depression and a 78% and 58% reduction in the total duration of ST segment depression. Highly significant linear dose-response relations were present across all treatment groups for ischemic episodes and ischemia duration (p < 0.001). Electrocardiographic abnormalities related to treatment were first-degree atrioventricular block, sinus bradycardia and short Wenckebach episodes, observed during sleep on Holter monitoring. All ECG events were dose related. CONCLUSIONS Mibefradil is a new, safe, well tolerated and very effective dose-dependent anti-ischemic calcium channel antagonist.