Mibefradil: A New and Promising Calcium Antagonist
December 1, 1997 5 minutes read
Mibefradil: A New and Promising Calcium Antagonist
ABSTRACT & COMMENTARY
Synopsis: The 100 mg and 150 mg doses of mibefradil were highly effective in improving ischemic parameters on exercise and reducing silent ischemic episodes.
Source: Tzivoni D, et al. Circulation 1997;96: 2557-2564.
Mibefradil dihydrochloride is a unique calcium antagonist (CA) that has just been released by Roche Laboratories (Posicor). This agent has both L- and T-type calcium channel inhibiting activity, binding to a unique receptor site that competitively interferes with the rate slowing CA verapamil and diltiazem. This report represents a large, randomized, double-blind, placebo controlled trial involving 23 centers in seven countries, comparing mibefradil in three dosages to amlodipine and placebo. Three hundred nine patients were randomized; all subjects had chronic stable exercise-induced angina and ST depression with proven coronary artery disease. After a washout and a one-week placebo run-in, patients underwent serial exercise testing and 48 hour ambulatory ECG monitoring. Eligible subjects had to have two positive treadmill tests with total exercise duration within 15%, and they did not have to have ambulatory ischemia. Patients were randomized into five treatment groups: placebo; three doses of mibefradil once a day; or amlodipine daily. After one week, starting doses were all increased to target, which was 10 mg for amlodipine and 50 mg, 100 mg, and 150 mg for mibefradil. After an additional two weeks at the maximal dose level, patients had repeat baseline exercise testing and 48-hour ambulatory recordings. Stress tests were performed approximately 24 hours after drug administration. Patients kept a weekly diary of NTG consumption and angina attacks. The primary endpoint in this intent to treat study was the change from baseline in total exercise test duration at week 3. Numerous secondary efficacy parameters were evaluated, including time to onset of angina and ischemia, number and duration of episodes of silent ischemia, and weekly angina and nitroglycerin rates. Multiple statistical analyses were carried out, including an unusual probabilistic predictive power analysis in attempt to correlate ambulatory ischemia with exercise parameters.
The results were strongly favorable for the 100 mg and 150 mg doses of mibefradil, which provided robust decreases in all ischemic parameters, and in most instances were better than amlodipine 10 mg daily. The higher doses of the new CA increased the primary endpoint of total exercise duration compared to placebo by approximately 30% vs. 19% for amlodipine (P > 0.05). A variety of other endpoints were also favorable for the 100 mg and 150 mg doses of mibefradil, including time to onset of angina and ischemia. Mibefradil produced a highly significant (P < 0.001) linear dose response at all doses for each ETT parameter. Robust decreases in time to onset of ischemia and chest pain approaching 50% improvement were found for mibefradil, which in each case, was greater than amlodipine. Mibefradil decreased resting and, importantly, peak exercise heart rate in a dose-dependent fashion. For instance, at the 150 mg dose, mean heart rate at peak exercise was decreased by 17 beats per minutefor the 100 mg dose, nine beats per minute; the CA decreased diastolic blood pressure significantly. Thus, double product was substantially diminished for mibefradil after 100 mg and 150 mg doses and was not changed with amlodipine.
Treatment differences between mibefradil and amlodipine favored the higher doses of the new CA for all parameters. Silent ischemia data paralleled the treadmill tests. Overall, silent ischemia was documented in 171 of the original cohort (thus, > 50% had ST depression on Holter recording). The 100 mg and 150 mg doses of mibefradil produced a marked decrease in both the number and duration of ischemic episodes (> 70%), compared to baseline. While amlodipine decreased silent ischemia, it was less potent than the new CA. Using the probabilistic statistical analysis technique, there was concordance between the exercise test parameters and the probability decreasing silent ischemia. Clinical parameters of nitroglycerin consumption and angina symptoms decreased in all mibefradil groups but not with amlodipine. Adverse effects were noteworthy, in that 5-10% of individuals receiving mibefradil developed first degree block or greater. Heart rate was decreased by mibefradil with a 12% incidence of sinus bradycardia at the highest dose and a 10% incidence of first degree block at this dose. Leg edema developed in 12% of the amlodipine patients and virtually none of the mibefradil patients. Dizziness was noted in 11% of the high-dose mibefradil individuals and none with amlodipine. Tzivoni and colleagues conclude that the 100 mg and 150 mg doses were highly effective in improving ischemic parameters on exercise and reducing silent ischemic episodes.
COMMENT BY JONATHAN ABRAMS, MD
This a well designed trial with a large number of patients in each group. Clearly, a new and effective calcium antagonist is at hand. One aspect of mibefradil, not evaluated in this trial, is the lack of significant negative inotropic activity at standard doses (Abernathy D. Am J Cardiol 1997;80(4B):4C-11C) with potential safety and efficacy in congestive heart failure. An ongoing trial, MACH-1, is evaluating the drug in heart failure; amlodipine is also being tested in dilated cardiomyopathy subjects (PRAISE-2). The present trial indicates that the new CA at doses of 100 mg and 150 mg daily is highly effective in reducing myocardial ischemia induced by exercise or with daily life.
The data also suggest that mibefradil was superior to amlodipine in almost every category. Of note, amlodipine did not decrease the low baseline frequency of angina and nitroglycerin consumption compared to placebo. The adverse effects of mibefradil seem acceptable. In patients with sinus node disease or baseline AV nodal dysfunction, higher doses need to be used with considerable caution. More experience will be necessary to find out whether AV block and sinus bradycardia will be major problems, but clinicians must be aware of this potential adverse effectparticularly at the higher doses. This trial, as well as other studies, indicates that the 50 mg dose of mibefradil is probably not effective, although patients could be up titrated, particularly if there is concern about sinus or AV nodal function.
Finally, mibefradil is metabolized by the P-450 system, which could lead to QT prolongation and torsades de pointes if certain long-acting antihistamines are used concommitantly.
Tzivoni et al are to be congratulated for a large and well designed study that clearly supports the efficacy of mibefradil. This study suggests that mibefradil may be more effective than amlodipine, but more data are clearly indicated. Whether a traditional L channel CA should be used in conjunction with mibefradil remains to be established, but theoretically, this could be an effective combination with dihydropyridines. At the very least, it appears that there is a new calcium blocker that has clinical promise, and if these data predict clinical experience, mibefradil will be a major addition to our angina armamentarium.
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