(Circulation. 1999;99:990-992.)
© 1999 American Heart Association, Inc.
Brief Rapid Communication |
Addition of Angiotensin II Receptor Blockade to Maximal Angiotensin-Converting Enzyme Inhibition Improves Exercise Capacity in Patients With Severe Congestive Heart Failure
From the Departments of Medicine, Divisions of Cardiology, The Albert Einstein College of Medicine, Bronx, NY (G.H., I.B., R.B., R.P., S.T., T.H.L.); Columbia Presbyterian Medical Center, New York, NY (S.D.K., D.M.); Hôpital Ambroise Paré, Paris, France (G.J.); and the University of Nebraska Medical Center, Omaha (M.T.O.).
Correspondence to Thierry H. Le Jemtel, MD, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background—Incomplete suppression of the renin-angiotensin system during long-term ACE inhibition may contribute to symptomatic deterioration in patients with severe congestive heart failure (CHF). Combined angiotensin II type I (AT1) receptor blockade and ACE inhibition more completely suppresses the activated renin-angiotensin system than either intervention alone in sodium-depleted normal individuals. Whether AT1 receptor blockade with losartan improves exercise capacity in patients with severe CHF already treated with ACE inhibitors is unknown.
Methods and Results—Thirty-three patients with severe CHF despite
treatment with maximally recommended or tolerated doses of ACE
inhibitors were randomized 1:1 to receive 50 mg/d
losartan or placebo for 6 months in addition to standard
therapy in a multicenter, double-blind trial. Peak aerobic capacity
(
O2) during symptom-limited treadmill
exercise and NYHA functional class were determined at baseline and
after 3 and 6 months of double-blind therapy. Peak
O2 at baseline and after 3 and 6 months
were 13.5±0.6, 15.1±1.0, and 15.7±1.1 mL ·
kg-1 · min-1, respectively, in
patients receiving losartan and 14.1±0.6, 14.3±0.9, and
13.6±1.1 mL · kg-1 · min-1,
respectively, in patients receiving placebo (P<0.02 for
treatment group–by-time interaction). Functional class improved by at
least one NYHA class in 9 of 16 patients receiving losartan and
1 of 17 patients receiving placebo.
Conclusions—Losartan enhances peak exercise capacity and alleviates symptoms in patients with CHF who are severely symptomatic despite treatment with maximally recommended or tolerated doses of ACE inhibitors.
Key Words: angiotensin • heart failure • trials • exercise
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Marked elevation of angiotensin II, norepinephrine, and aldosterone plasma levels and progression of left ventricular dilatation in patients with congestive heart failure (CHF) treated with recommended doses of ACE inhibitors suggests that long-term ACE inhibition may only partially suppress the activated renin-angiotensin system.1 2 3 Mild activation of the renin-angiotensin system in sodium-depleted normotensive volunteers is more completely suppressed by combined administration of losartan, an angiotensin II type I (AT1) receptor antagonist, and captopril, an ACE inhibitor, than by either intervention alone.4
Losartan is well tolerated by patients with severe CHF who are maximally treated with ACE inhibitors in addition to standard therapy,5 but the effects of combined therapy on functional capacity in patients with severe CHF are unknown. Accordingly, the present study was undertaken to determine the effects of losartan versus placebo on exercise capacity and functional class in patients with CHF who were severely symptomatic despite treatment with optimal doses of ACE inhibitors, digoxin, and diuretics.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The study was a prospective, double-blind, randomized, placebo-controlled trial conducted at 4 centers (Appendix). The study was approved by the ethical review board at each site; all patients gave written informed consent before participation.
Patient Population
Thirty-three patients whose symptoms of CHF were compatible with
functional class III to IV of the New York Heart Association (NYHA)
were studied. In addition to digoxin and diuretics, all
patients had been treated with ACE inhibitors at maximally
recommended or tolerated doses for 
3 months. Clinical characteristics
and medications are detailed in Tables 1
and 2. None of the patients had
participated in a physical conditioning program. Patients randomized to
losartan and placebo were similar except for a preponderance of
men and a higher dose of captopril in the losartan group.
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Study Design
Randomization to losartan or placebo was preceded by a
2-week single-blind tolerability phase, which has been reported
previously.5 All patients tolerated losartan 50
mg/d. Patients were then randomized to therapy with losartan 50
mg or placebo for 6 months. Clinical assessments and laboratory
evaluations were performed weekly for 1 month and monthly thereafter.
Peak oxygen uptake (O2,
mL · kg-1 ·
min-1) during symptom-limited maximal
treadmill exercise was measured at baseline in duplicate and
subsequently after 3 and 6 months of double-blind therapy.
Study End Points and Data Analysis
The primary end points of the study were peak
O2 and NYHA functional class.
Secondary end points were laboratory safety parameters and
doses of concomitant background medications. Prerandomization peak
O2 was determined as the
highest value of 2 exercise tests with <10% variation. Peak
O2 at months 3 and 6 was
derived from a single maximal exercise test.
Case reports were centrally collected, and data were analyzed
by Lynn Sleeper, ScD (New England Research Institute, Watertown, Mass).
Repeated-measures ANOVA (SAS Institute Inc, PROC MIXED) was used to
analyze peak O2,
laboratory safety parameters, and doses of background
medications. An SAS macro for repeated-measures cumulative logistic
regression was used to analyze NYHA functional class. The daily
dose of furosemide was square root–transformed to meet the normality
assumption because of the wide dosing range for this agent. Probability
values reported are from models that incorporate time as a continuous
covariate. Values are expressed as mean±SEM.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Primary End Points
Peak
O2 at baseline and
after 3 and 6 months was 13.5±0.6, 15.1±1.0, and 15.7±1.1 mL
· kg-1 · min-1,
respectively, in patients receiving losartan and 14.1±0.6,
14.3±0.9, and 13.6±1.1 mL · kg-1
· min-1, respectively, in patients receiving
placebo (P<0.02 for treatment group–by-time interaction,
Figure 1). Functional class improved by
1 NYHA class in 9 of 16 patients receiving losartan and 1 of
17 patients receiving placebo. Functional class at baseline and after 3
and 6 months was 3.2±0.4, 2.9±0.6, and 2.5±0.8, respectively, in
patients receiving losartan and 3.0±0.4, 3.0±0.5, and
3.0±0.5, respectively, in patients receiving placebo
(P<0.001 for treatment group–by-time interaction, Figure 2).
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) and
placebo (
).
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Secondary End Points
Serum electrolytes, creatinine, and blood urea
nitrogen were unchanged in both treatment groups. The furosemide dose
(square root–transformed) at baseline and after 3 and 6 months was
11.5±1.1, 10.9±1.1, and 10.5±1.2, respectively, in patients
receiving losartan and 9.9±1.0, 10.0±1.1, and 10.8±1.1,
respectively, in patients receiving placebo (P<0.05 for
treatment group–by-time interaction). Doses of other background
medications were unchanged in both treatment groups. The combination of
study drug and ACE inhibitors in both treatment groups was
well tolerated, without adverse side effects.
Four patients in the placebo group and 3 patients in the losartan group did not complete the study. In the placebo group, 1 patient died suddenly, 1 underwent cardiac transplantation, 1 was no longer willing to take the study drug because of impotence, and 1 was lost to follow-up. In the losartan group, 2 patients withdrew from the study (1 was diagnosed with AIDS; the other experienced nausea), and 1 was lost to follow-up.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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The present data indicate that losartan improves peak aerobic capacity and relieves symptoms in patients with CHF who are severely symptomatic despite treatment with optimal doses of ACE inhibitors, digoxin, and loop diuretics.
The therapeutic efficacy of losartan has been demonstrated in patients with CHF in the absence of ACE inhibitors.6 7 8 9 10 Acute administration of losartan results in arterial and venous dilatation comparable to that with ACE inhibition.6 The acute hemodynamic effects of losartan are greatest at a dose of 50 mg and persist without attenuation for 12 weeks.7 In patients in whom previous ACE inhibition therapy was withdrawn, losartan and enalapril have comparable effects on exercise performance.8 9
The present study assessed the long-term effects of AT1 receptor blockade in patients with severe CHF receiving optimal doses of ACE inhibitors. Data collected from previous clinical trials have suggested that an escape phenomenon may occur during prolonged ACE inhibition.1 2 3 Whether partial deactivation is attributable to an escape from ACE inhibition during long-term therapy or to other metabolic pathways for biosynthesis of angiotensin II cannot be ascertained from the present study.11 Our findings are consistent with the additive effects of combined ACE inhibition and AT1 receptor blockade on blood pressure and renin release in sodium-depleted normotensives and with the preliminary results of the RESOLVD trial.4 12 In the RESOLVD trial, combined ACE inhibition and AT1 receptor blockade prevented left ventricular dilatation and lowered plasma brain natriuretic peptide levels to a greater extent than either intervention alone.12 Enhanced functional capacity in our patients treated with losartan is thus likely to be, at least in part, centrally mediated. Patients randomized to losartan were receiving higher doses of ACE inhibitors than those randomized to placebo. Whether such baseline imbalance affected our results is difficult to ascertain in view of the small patient population.
In summary, the present data demonstrate that addition of AT1 receptor blockade to optimal ACE inhibition therapy improves peak exercise performance and function capacity in patients with severe heart failure. These striking findings in 33 patients require confirmation in larger trials.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Trial Centers and Investigators
Albert Einstein College of Medicine: Glenn Hamroff, MD; Ira Blaufarb, MD; Rachel Bijou, MD; Rajoo Patel, MD; Sylvia Thomas, MS, RPh; and Thierry H. Le Jemtel, MD. Columbia Presbyterian Hospital Center: Stuart D. Katz, MD; and Donna Mancini, MD. University of Nebraska Medical Center: Maria-Teresa Olivari, MD. Hôpital Ambroise Paré: Guillaume Jondeau, MD.
Received October 1, 1998; revision received December 22, 1998; accepted January 8, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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