Congestive Heart Failure
Synergistic efficacy of enalapril and losartan on exercise performance and oxygen consumption at peak exercise in congestive heart failure

https://doi.org/10.1016/S0002-9149(99)00495-6Get rights and content

Abstract

Oxygen consumption at peak exercise (peak VO2) is a strong independent predictor of the outcome in congestive heart failure (CHF). Renin-angiotensin system inhibition with either ACE or AT1 receptor blockers is effective on peak VO2. We evaluated whether mechanisms are similar for the 2 categories of drugs and whether their combination is able to produce a synergistic effect. Twenty CHF patients were randomized to receive, in a double-blind fashion, placebo + placebo (P+P), enalapril (20 mg/day) + placebo (E+P), losartan (50 mg/day) + placebo (L+P), and enalapril + losartan (E+L) or the same preparations in a reverse order, each for 8 weeks. Two patients did not complete the trial. Pulmonary function, cardiopulmonary exercise test, plasma neurohormones, and quality of life were assessed at the end of each treatment. Compared with P+P, E+P, and L+P similarly (16% and 15%, respectively) and significantly (p <0.01) augmented peak VO2. Enalapril improved lung function (reduced slope of ventilation vs carbon dioxide production and dead space to tidal volume ratio, and increased alveolar membrane conductance and tidal volume). Losartan likely activated the exercising muscle perfusion (raised ΔVO2/Δwork rate, which is a measure of aerobic work efficiency). In combination, they further increased peak VO2, 10% from E+P (p <0.05) and 11% from L+P (p <0.05). Compared with run-in, E+P and L+P significantly reduced plasma norepinephrine by 70 ± 14 pg/ml and 100 ± 16 pg/ml and aldosterone by 1.6 ± 0.7 ng/dl and 1.6 ± 0.8 ng/dl. These changes were significantly greater when the drugs were combined (140 ± 20 pg/ml for norepinephrine, and 5.6 ± 0.9 ng/dl for aldosterone). Quality-of-life score did not improve significantly at each treatment step. Thus, lorsartan and enalapril similarly increased peak VO2 in CHF patients, but mediators of this effect were, at least in part, different therapeutic targets that may be synergistic when the 2 drugs are combined.

Section snippets

Study design and data acquisition

This was a double-blind, randomized, crossover, and placebo-controlled study. Figure 1 shows the study design. During a single-blind, placebo run-in period of 14 days, clinical stability was confirmed and patients’ characteristics were collected. A preliminary cardiopulmonary exercise test was performed for familiarization purposes, and the Minnesota living with heart failure quality-of-life questionnaire was filled out. Clinical stability was defined as unchanged New York Heart Association

Results

Two of the 20 patients who fulfilled the entry criteria were withdrawn from the study because of adverse reactions (hypotension with the drug combination, in 1 case, and cough while on enalapril, in the other case). They were excluded from the final analysis. The order of drug administration was uninfluential on the overall results, and data of each corresponding treatment step were pooled together independently of the sequence. The baseline characteristics of the patient population are listed

Discussion

In CHF, which causes exercise limitation (baseline peak VO2 was 13.4 ±4.0 ml/min/kg), a combination of losartan and enalapril yielded a better physical performance and exercise oxygen uptake compared with either drug alone. It also produced an additive inhibitory effect on plasma neurohormones, suggesting that neurohumoral modulation is more effective than with losartan or enalapril alone.

Cardiopulmonary exercise testing in CHF allows quantification of exercise intolerance, as well as

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    This study was supported in part by a grant from the National Research Council, Rome, and the Monzino Foundation, Milan, Italy.

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