Mibefradil, a T-type channel-selective calcium antagonist: clinical trials in chronic stable angina pectoris

Pharmacotherapy with nitrates, beta-blockers, and calcium antagonists is the cornerstone of management of patients with chronic stable angina pectoris. While these agents are all effective, their use may be limited by pharmacologic tolerance, side effects, and drug interactions. Mibefradil is a recently developed calcium antagonist with a unique chemical structure, pharmacologic profile, and mode of action. Unlike all previously available calcium antagonists, mibefradil acts primarily by selective blockade of T-type calcium channels, rather than L-type channels, at clinically relevant concentrations. It has been evaluated as a treatment for angina in placebo-controlled and active-controlled clinical trials. Treatment with 50 mg mibefradil resulted in a significant improvement in exercise tolerance test duration in three of the five placebo-controlled trials, and a significant improvement in time to onset of angina in two of the five trials. Time to onset of ischemia as evaluated by 0.1 mV ST-segment depression was increased in all five placebo-controlled trials. Treatment with 100 mg mibefradil resulted in significant improvement in all three exercise tolerance test parameters in all studies. Mibefradil further improved exercise tolerance test duration and other efficacy parameters when administered concomitantly to patients on background beta-blocker or nitrate therapy. In addition, treatment with mibefradil was associated with a dose-dependent decrease in heart rate, double product, frequency of anginal attacks, nitroglycerin consumption, and both frequency and duration of silent ischemic episodes. In comparative trials, 100 mg mibefradil once daily was superior in efficacy to 10 mg amlodipine once daily and was at least equivalent to diltiazem in both efficacy and tolerability. Mibefradil was safe and well tolerated in all studies.