High-dose monotherapy and combination therapy with calcium channel blockers for angina. A comprehensive review of the literature.
Clinical experience with the calcium channel-blocking agents has established their efficacy in the therapy of painful and silent myocardial ischemia. Questions have arisen, however, about side-effect characteristics of these medications as clinical practice has led to utilization of higher doses of individual drugs than employed in large numbers of patients in early clinical trials as well as combinations with other antianginal agents including beta-blockers. A study was undertaken to examine the published literature regarding side effects associated with high-dose versus low-dose therapy with nifedipine and diltiazem and the use of these agents in combination with beta-blockers. This investigation demonstrated that utilization of high-dose diltiazem (more than 240 mg per day) as opposed to low-dose diltiazem (no more than 240 mg per day) was associated with an increased incidence of atrioventricular block, and increased peripheral vasodilatory effects. In contrast, the use of high-dose nifedipine (more than 60 mg per day) was not associated with atrioventricular block. At clinically high dosage levels, the incidence of peripheral edema was comparable for both nifedipine and diltiazem, although low-dose nifedipine resulted in a significantly greater incidence of edema compared with low-dose diltiazem. This analysis also demonstrated that bradyarrhythmia is associated with the combination of a beta-blocking agent and either low- or high-dose diltiazem, but not with nifedipine-beta-blocker combinations. Clinical experience suggests caution in the combined use of diltiazem and a beta-blocking agent because of the demonstrated additional adverse negative chronotropic and dromotropic effects. No additional adverse electrophysiologic effects have been noted for nifedipine-beta-blocker combinations. The literature analysis supports and mirrors widespread clinical experience obtained since nifedipine and diltiazem were introduced. It should be noted, though, that combination therapy with calcium channel blockers and beta-blockers should be done with caution, since there have been occasional reports of congestive heart failure or exacerbation of angina with this combination.