Dose-response relation of antianginal activity of isosorbide dinitrate

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Eleven men with angiographic evidence of coronary heart disease and stable, exercise-induced angina pectoris were given placebo (P) or isosorbide dinitrate (ISDN) in a daily dose of 30, 120, 240 or 480 mg, in a randomized single-blind trial. The daily doses were administered 6 times a day as single oral doses of 5, 20, 40 and 80 mg. Each dose or placebo was given for 7 days. Before therapy was begun, and on the seventh day of each treatment period, an exercise ECG with standardized level and duration of exercise was recorded. Subsequently, a 4-week treatment period with 480 mg/day was carried out at the end of which another stress test was performed. This was followed by a final 2-week placebo period. The frequency of anginal attacks per week tended to decrease with increasing nitrate doses, but decreased significantly only after the highest dose (480 mg/day) compared with placebo. Continuation of therapy with 480 mg/day maintained the reduced rate of anginal attacks. The ischemic response, expressed as the sum of ST-segment depressions in the exercise ECG, revealed a dose-dependent reduction of 26% (30 mg/day), 39% (120 mg/day) (p < 0.01), 63% (240 mg/day) (p < 0.01) and 72% (480 mg/day) (p < 0.01), respectively. At the end of the 4-week treatment period with 480 mg/day, antianginal efficacy was found to be moderately reduced, showing a 56% reduction of ischemic response compared to the placebo trial. The time of onset of angina during exercise testing was also delayed in relation to the dosage given. These findings suggest that in patients with stable angina pectoris, orally administered ISDN exerts a dose-dependent effect on the frequency of angina and on ischemic variables. The antianginal efficacy of oral high-dose ISDN (480 mg/day) was only moderately reduced after 4 weeks of continuous treatment compared with 1 week of therapy with the same dose. Oral high-dose treatment with ISDN can be recommended in patients with severe stable angina pectoris, and dosage should be individually increased according to the frequency and severity of the complaints.