Discordance of anti-ischemic and hemodynamic effects of captopril in stable coronary artery disease

Abstract

Background: The role of angiotensin converting enzyme (ACE) inhibition in patients with coronary artery disease without concomitant disease such as heart failure or hypertension has not been elucidated. In this double-blind, cross-over, randomized trial of the ACE inhibitor captopril, its antianginal and anti-ischemic effects were studied during monotherapy and in the presence of an organic nitrate.

Methods: Thirty-seven patients (34 men, three women) with stable coronary artery disease and exercise-induced ST-segment depression were enrolled. After a washout phase without medication they received placebo, isosorbide dinitrate (ISDN) 20 mg twice daily, captopril 12.5 mg twice daily, and the combination of both for 1 week each, after which exercise tolerance, blood pressure and heart rate (supine, standing and 24 h profile), and peripheral arterial vasodilatation (finger pulse plethysmography) were assessed.

Results: Thirty-three patients completed all phases of the study. Exercise-induced anginal symptoms occurred in 17 patients, and asymptomatic ischemia was seen in the other 16 men. In comparison with ISDN, the anti-ischemic effects of captopril were minimal, despite a similar reduction in blood pressure. Compared with baseline, 1 week of placebo reduced the sum of ST-segment depression, the main efficacy parameter, by 10% (NS), captopril by 19% (NS), ISDN by 37% (P < 0.001) and the combination of captopril and ISDN by 42% (P < 0.001; NS versus ISDN). No patient remained completely free of exercise-induced angina during treatment with captopril; however, three patients after ISDN and seven patients after the combination did (P < 0.05). Blood pressure at rest decreased at peak effect by 9-10% systolic (P < 0.001) with monotherapy and by up to 7% diastolic (P < 0.001), and during combined therapy with captopril and ISDN by 18% systolic (P < 0.001) and 12% diastolic (P < 0.001). Significantly enhanced circulatory effects of captopril plus ISDN versus ISDN were found for blood pressure (P < 0.001) and peripheral arterial vasodilation (P < 0.01). The reflex tachycardia induced by ISDN in the upright position (5 beats/min) was not blocked by captopril during combined therapy.

Conclusions: The antianginal and anti-ischemic effects of captopril alone were marginal, despite significant circulatory effects after short-term administration. Although captopril in combination with ISDN resulted in a significant further blood-pressure-lowering effect and increased peripheral arterial vasodilatation, the magnitude of potentiation of the anti-ischemic nitrate effects was, in contrast, small. Only exercise-induced angina was further improved by the use of the combination. No paradoxical worsening of ischemia or angina was seen after captopril. Thus, although captopril has no place as first-line therapy for ischemia, its use in combination with ISDN could be advantageous for long-term prognosis.