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European Heart Journal 2002 23(17):1360-1368; doi:10.1053/euhj.2001.3112
Copyright © 2002 by the European Society of Cardiology.
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A mechanistic investigation of ACE inhibitor dose effects on aerobic exercise capacity in heart failure patients

G.A. Cookea, S.G. Williamsa, P. Marshalla, J.K. Al-Timmana, J. Shelbourneb, D.J. Wrighta and L.-B. Tana,f1

a School of Medicine, University of Leeds, Yorkshire Heart Centre, Leeds General Infirmary, Leeds, U.K.
b Parexel S-cubed, Sheffield, U.K.

revised November 27, 2001; accepted November 28, 2001

Abstract

Background Angiotensin converting enzyme inhibitors at high doses have been shown to improve prognosis of heart failure patients. Their beneficial effects on exercise capacity have been less convincing in large parallel group studies. The objective of this investigation was to explore the mechanisms involved in dose-related functional effects and to test the hypothesis that a trial recommended high dose of lisinopril would improve aerobic exercise capacity and cardiovascular function more than with a low dose.

Methods Twelve patients with symptomatic heart failure completed a randomized double-blind crossover trial of lisinopril 5mg o.d. and 20mg o.d. for 24 weeks, crossing over the doses at 12 weeks. The primary end-point was aerobic exercise capacity, and the secondary end-points were cardiac performance at peak exercise and dobutamine stimulation.

Results The aerobic exercise capacity (primary end-point) was significantly higher during the 5mg per day dosage compared to the 20mg (1696 vs 1578ml.min–1, P=0·016), equivalent to a rise of 1·53ml.kg–1min–1 from the 19·6ml.kg–1min–1 with 20mg when normalized by body weight. Seventy-three percent of patients showed greater peak oxygen consumption and peak cardiac power output with the 5mg per day dose than the 20mg, and none showed the opposite. In terms of cardiac performance, although the results were not statistically significant, there was a consistent pattern showing the same directional changes in favour of the lower dose in peak exercise cardiac power output and cardiac power output at maximal dobutamine. There were no significant differences in the resting values. A total of 24 adverse reactions were reported during the 5mg phase compared to 38 during the 20mg phase.

Conclusions Contrary to expectation, the aerobic exercise capacity of patients was found to be greater with the lower dose of lisinopril, suggesting that therapy with ACE inhibitors for heart failure may require tailoring the doses to the individual to optimize functional benefits in relation to the assumed prognostic benefits. Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

Key Words: ACE inhibitors, congestive heart failure, exercise capacity, oxygen consumption

f1 Correspondence: Dr L. B. Tan, Consultant Cardiologist, Room G-186/8, Jubilee Building, Leeds General Infirmary, Leeds LS1 3EX, U.K.

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