Dose-response evaluation of once-daily therapy with a new formulation of diltiazem for stable angina pectoris

Abstract

Diltiazem hydrochloride in a once-daily capsule formulation (DCD) has recently been approved in the United States for the treatment of mild to moderate hypertension and chronic stable angina pectoris. This trial evaluated the dose response of DCD in patients with chronic stable angina pectoris. In a multicenter, randomized, double-blind, parallel-design trial, the effects and tolerability of once-daily therapy with placebo or DCD (60,120, 240, 360, or 480 mg) were evaluated 24 hours after dosing, following 3 weeks of therapy in 227 patients with reproducible stable exertional angina pectoris. A significant linear dose trend (p = 0.004) was present across the 6 treatment groups for the primary end point—time to exercise termination at 24 hours after dosing—using a standard Brace treadmill excercise test. A significant linear dose trend was also seen for time to 1 mm ST-segment depression at 24 hours after dosing. Similar effects on exercise parameters were also seen at 4 hours after dosing. A linear dose trend (p = 0.04) was noted relative to the overall anginal attacks during daily activities and for anginal attacks during exercise (p = 0.02). Overall frequency of treatment-related adverse effects was dose-related and occurred in 24.4% and 17.5% of patients treated with DCD and placebo, respectively. At a dose up to 240 mg/day, improvement in exercise tolerance was achieved without an associated increase in the rate of treatment-related adverse events compared with placebo. The results of the study suggest that 120 mg of DCD would be the starting dose, with careful titration up to 360 mg/day in individual patients for maximal therapeutic efficacy.