Discordance of anti-ischemic and hemodynamic effects of captopril in stable coronary artery disease.
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.
Winkelmann
B R
BR
Abteilung für Kardiologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany.
Matheis
G
G
Kleist
P
P
Pötter
S
S
Wohltmann
D
D
Kaltenbach
M
M
D000368:Aged; D000787:Angina Pectoris / Q000150:complications / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005080:Exercise Test; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007548:Isosorbide Dinitrate / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged
D002216:Captopril; D007548:Isosorbide Dinitrate