Combination of calcium channel blockers and beta-blockers for patients with exercise-induced angina pectoris: beneficial effect of calcium channel blockers largely determined by their effect on heart rate.
The combination of calcium channel blockers and beta-blockers is more effective for the treatment of exercise-induced angina pectoris than beta-blocker monotherapy. As ischemia in exercise-induced angina is essentially preceded by an increase in heart rate, calcium channel blockers with a negative chronotropic property may perform better for this purpose than nonchronotropic compounds. A 335-patient, 10-week, double-blind, parallel-group comparison of amlodipine 5 mg and 10 mg, diltiazem 200 mg and 300 mg, and mibefradil 50 mg and 100 mg treatment added to baseline beta-blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. All of the calcium channels blockers significantly delayed the onset of 1 mm ST-segment depression on ETT (p < 0.001 for any treatment vs. baseline). In addition, mibefradil, in both low- and high-dose treatments, produced the largest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 seconds, respectively, p < 0.003 and < 0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 seconds, respectively, p < 0.001 and < 0.001). A stepwise logistic regression analysis revealed that this beneficial effect of calcium channel blockers was largely dependent on their effect on heart rate. Serious symptoms of dizziness likewise occurred significantly more frequently on mibefradil (p < 0.05 vs. diltiazem) and urged no fewer than 19 patients on mibefradil to withdraw from the trial. The authors conclude that calcium channel blockers with a negative chronotropic property provide a better delay of ischemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness may reduce this benefit.
The Netherlands Working Group on Cardiovascular Research (WCN), Dordrecht.
T J
TJ
Cleophas
J
J
van der Sluijs
J A
JA
van der Vring
M C
MC
Daniëls
K J
KJ
Holwerda
A J
AJ
Withagen
A
A
Schelling
M G
MG
Hendriks
A H
AH
Zwinderman
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D017311:Amlodipine / Q000627:therapeutic use; D000787:Angina Pectoris / Q000188:drug therapy* / Q000209:etiology; D001562:Benzimidazoles / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D003645:Death, Sudden / Q000209:etiology; D004110:Diltiazem / Q000627:therapeutic use; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015444:Exercise; D005080:Exercise Test; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D020748:Mibefradil; D008875:Middle Aged; D012044:Regression Analysis; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D017311:Amlodipine; D020748:Mibefradil; D004110:Diltiazem