Mibefradil in the Treatment of Chronic Stable Angina Pectoris: Comparative Studies With Other Calcium Antagonists

Abstract

The ability of mibefradil, a new T-channel-selective calcium antagonist, to improve exercise tolerance and silent ischemic parameters in patients with chronic stable angina was compared in 3 separate trials with 2 other commonly used calcium antagonists: diltiazem SR (120 mg/twice daily) and amlodipine (10 mg/day). Compared with amlodipine, mibefradil 100 mg given once daily over a 3-week period resulted in a statistically significantly larger increase from baseline in total exercise tolerance test (ETT) duration (treatment difference of 40.9 sec, p = 0.04), time to onset of angina (treatment difference 61.2 sec, p <0.001), and time to onset of ischemia (treatment difference of 54.4 sec, p = 0.004). The decrease in weekly anginal episodes was 58% with mibefradil versus 19% with amlodipine, and the reduction in nitroglycerin consumption was 58% with mibefradil versus a 10% increase with amlodipine. The decrease in the number of silent ischemic episodes detected by a 48-hour Holter recording was significantly larger (p = 0.03) with mibefradil 100 mg (88%) compared with amlodipine 10 mg (38%). Similarly, a larger decrease in the duration of silent ischemia was observed with mibefradil (69%) compared with that seen with amlodipine (38%). The preliminary results of a second trial comparing mibefradil with amlodipine were consistent with the first demonstrating that the improvement for all 3 ETT parameters was larger for mibefradil (ETT duration: 55.2 sec; delay in onset angina: 74.2 sec; time to onset of ischemia: 63.6 sec), but in this trial the treatment differences did not reach statistical significance. In the trial comparing mibefradil (100 mg once daily) with diltiazem SR (120 mg twice daily), both compounds had equivalent effects on all ETT parameters tested. Mibefradil produced a 21% increase in exercise duration compared with a 20% increase with diltiazem. Although mibefradil yielded larger increases in the time to onset of angina and the time to onset of 1-mm ST-segment depression (42% and 38%, respectively) than did diltiazem (34% and 25%, respectively), the treatment differences did not reach statistical significance. Both mibefradil and diltiazem SR were associated with at least a 70% reduction from baseline in anginal frequency and nitroglycerin consumption. Mibefradil-treated patients showed greater decreases in heart rate and the rate-pressure product at each stage of the ETT than patients treated with amlodipine or diltiazem SR. All 3 drugs were well tolerated. However, compared with mibefradil, amlodipine and diltiazem SR produced a higher incidence of leg edema. In conclusion, the effectiveness of mibefradil in improving all 3 ETT parameters was greater than that of amlodipine and equivalent to that of diltiazem SR. Moreover, mibefradil provided greater reductions in the heart rate and cardiac workload than did the other 2 drugs.