Combination therapy with calcium-channel blockers and beta blockers for chronic stable angina pectoris

Combination therapy using calcium-channel blockers and β blockers in patients with refractory chronic stable angina has gained much popularity, but remains highly controversial because of the potential for serious additive deleterious hemodynamic or electrophysiologic reactions. In studies involving patients with preserved left ventricular function receiving chronic oral β blockers, short-term administration of intravenous verapamil has been shown to cause a further lowering in heart rate and blood pressure while prolonging atrioventricular node conduction; additive cardiodepressant effects were noted, including a tendency toward increased left and right heart filling pressures. Nifedipine, on the other hand, when added acutely to β blockers, causes an increase in heart rate, a decrease in blood pressure and either no change or a slight improvement in most cardiac performance variables. Controlled, double-blind clinical trials have demonstrated that combinations of calcium-channel blockers and β blockers result in augmented symptom benefit compared with either drug class alone. The predominant mechanism responsible for such improvement is increased lowering of myocardial oxygen demand by virtue of additive diminution in heart rate, blood pressure and, consequently, pressure-rate product both at rest and during exercise. Verapamil (and possibly diltiazem) plus β blockers appears to have the greatest therapeutic efficacy but also the highest frequency of harmful adverse cardiac effects, whereas nifedipine plus β blockers is generally safer but also less efficacious. Factors that should be carefully considered by clinicians contemplating combination therapy are the choice of calcium-channel blocker, the dose of calcium-channel blocker and β blocker, the presence of antecedent left ventricular dysfunction or conduction system disease and the possibility of drug interactions. Concomitant calcium-channel blocker and β-blocker therapy is an important contribution to the pharmacologic management of resistant patients who remain symptomatic during single drug treatment. However, the possibility of additive adverse cardiac effects mandates careful patient selection and close clinical monitoring.