Synergistic efficacy of enalapril and losartan on exercise performance andoxygen consumption at peak exercise in congestive heart failure

Oxygen consumption at peak exercise (peak VO2) is a strong independent pred ictor of the outcome in congestive heart failure (CHF). Renin-angiotensin s ystem inhibition with either ACE or ATI receptor blockers is effective on p eak VO2. We evaluated whether mechanisms are similar for the 2 categories o f drugs and whether their combination is able to produce a synergistic effe ct. Twenty CHF patients were randomized to receive, in a double-blind fashi on, placebo + placebo (P+P), enalapril (20 mg/day) + placebo (E+P), losarta n (50 mg/ day) + placebo (L+P), and enalapril + losartan (E + L) or the sam e preparations in a reverse order, each for 8 weeks. Two patients did not c omplete the trial. Pulmonary function, cardiopulmonary exercise test, plasm a neurohormones, and quality of life were assessed at the end of each treat ment. 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 fu nction (reduced slope of ventilation vs carbon dioxide production and dead space to tidal volume ratio, and increased alveolar membrane conductance an d tidal volume). Losartan likely activated the exercising muscle perfusion (raised Delta VO2/Delta work rate, which is a measure of aerobic work effic iency). 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 signific antly 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 f or 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 o f this effect were, at least in part, different therapeutic targets that ma y be synergistic when the 2 drugs are combined. (C) 1999 by Excerpta Medica , Inc.