title: Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers. The Netherlands Working Group on Cardiovascular Research (WCN).
abstract: The combination of calcium channel blockers and beta blockers is more effective for the treatment of exercise-induced angina pectoris than beta blocker monotherapy. Since ischemia in exercise-induced angina is essentially preceded by an increase in heart rate, calcium channel blockers with 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 and 10 mg, diltiazem XR 200 and 300 mg, and mibefradil 50 and 100 mg treatment added to baseline beta blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. Although none of the calcium channel blockers improved duration of exercise or amount of workload, all of them significantly delayed onset of 1 mm ST segment depression on ETT (p<0.001 for any treatment versus baseline). In addition, mibefradil, both low- and high-dose treatment, produced the largest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, p<0.003 and <0.001, respectively; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, p<0.001 and <0.001, respectively). These effects were linearly correlated to the amount of rate pressure product (RPP) reduction. Serious symptoms of dizziness likewise occurred significantly more frequently with mibefradil (p<0.05) and led 19 patients taking mibefradil to withdraw from the trial. The authors conclude that calcium channel blockers with negative chronotropic property provide better delay of ischemia in patients with exercise-induced angina but that the concomitant risk of intolerable dizziness largely reduces this benefit.
authors.affiliation: Department of Medicine, Merwede Hospital Dordrecht, Academic Hospital, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: van der Vring
authors.forename: M C
authors.initials: MC
authors.lastname: Daniëls
authors.forename: N J
authors.initials: NJ
authors.lastname: Holwerda
authors.forename: P J
authors.initials: PJ
authors.lastname: Withagen
authors.forename: A
authors.initials: A
authors.lastname: Schelling
authors.forename: T J
authors.initials: TJ
authors.lastname: Cleophas
authors.forename: M G
authors.initials: MG
authors.lastname: Hendriks
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D017311:Amlodipine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000787:Angina Pectoris / Q000188:drug therapy* / Q000209:etiology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000145:classification / Q000627:therapeutic use*; D004110:Diltiazem / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D004338:Drug Combinations; D004562:Electrocardiography / Q000187:drug effects; D005080:Exercise Test; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D020748:Mibefradil; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000517:prevention & control; D005082:Physical Exertion / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D004338:Drug Combinations; D013764:Tetrahydronaphthalenes; D017311:Amlodipine; D020748:Mibefradil; D004110:Diltiazem