Antianginal and anti-ischemic effects of mibefradil in the treatment of patients with chronic stable angina pectoris.
Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either beta blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of mibefradil. The 25-mg dose of mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic beta-blocker or long-acting nitrate therapy. Taken together, these studies indicate that mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.
Alpert
J S
JS
University of Arizona Health Sciences Center, Tucson 85724-5035, USA.
Bakx
A L
AL
Braun
S
S
Frishman
W H
WH
Schneeweiss
A
A
Tzivoni
D
D
Kobrin
I
I
D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy*; D001562:Benzimidazoles / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015716:Electrocardiography, Ambulatory; D005080:Exercise Test; D005260:Female; D006801:Humans; D008297:Male; D020748:Mibefradil; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil