Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure

Packer, Milton; Colucci, Wilson S.; Sackner‐Bernstein, Jonathan; Liang, Chang‐seng; Goldscher, David A.; Freeman, Israel; Kukin, Marrick; Kinhal, Vithal; Udelson, James E.; Klapholz, Marc; Gottlieb, Stephen S.; Pearle, David L.; Cody, Robert J.; Gregory, John J.; Kantrowitz, Nikki E.; LeJemtel, Thierry H.; Young, Sarah; Lukas, Mary Ann; Shusterman, Neil H.

doi:10.1161/01.cir.94.11.2793

Cited by 558 publications

(272 citation statements)

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“…However, exercise tolerance has not been consistently improved with carvedilol in clinical trials in heart failure,28, 29, 30 and treatments that have improved symptoms and exercise tolerance have not produced striking effects on cachexia.…”

Section: Discussionmentioning

confidence: 99%

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Clark

Coats

Krum

et al. 2017

J cachexia sarcopenia muscle

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BackgroundCardiac cachexia frequently accompanies the progression of heart failure despite the use of effective therapies for left ventricular dysfunction. Activation of the sympathetic nervous system has been implicated in the pathogenesis of weight loss, but the effects of sympathetic antagonism on cachexia are not well defined.MethodsWe prospectively evaluated changes in body weight in 2289 patients with heart failure who had dyspnoea at rest or on minimal exertion and a left ventricular ejection fraction <25%. Patients were randomly assigned (double‐blind) to receive either placebo (n = 1133) or carvedilol (n = 1156) and were followed for the occurrence of major clinical events for up to 29 months (COPERNICUS trial). Patients were not enrolled if they had signs of clinically significant fluid retention due to heart failure.ResultsPatients in the carvedilol group were 33% less likely than patients in the placebo group to experience a further significant loss of weight (>6%) (95% confidence interval: 14–48%, P = 0.002) and were 37% more likely to experience a significant gain in weight (≥5%) (95% confidence interval: 12–66%, P = 0.002). Carvedilol's ability to prevent weight loss was most marked in patients with increased body mass index at baseline, whereas its ability to promote weight gain was most marked in patients with decreased body mass index at baseline. Increases in weight were not accompanied by evidence of fluid retention. Baseline values for body mass index and change in body weight were significant predictors of survival regardless of treatment.ConclusionsCarvedilol attenuated the development and promoted a partial reversal of cachexia in patients with severe chronic heart failure, supporting a role for prolonged sympathetic activation in the genesis of weight loss.

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Section: Discussionmentioning

confidence: 99%

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Clark

Coats

Krum

et al. 2017

J cachexia sarcopenia muscle

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“…29 Left ventricular hypertrophy can be reduced by the peripheral and coronary vasodilating effect of ␣-blockade. 11,28,30 The beneficial effect of adrenergic suppression on mortality and hospitalization rates in adults has been demonstrated in several large-scale studies with metoprolol 13,14 and bisoprolol. 15,16 In adults with CHF who were treated with digoxin, diuretics and ACE inhibitors, the addition of carvedilol significantly reduced mortality and hospitalization rates.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies 8 -10 in adult patients have suggested that sympathetic activation plays an important role in the genesis and progression of heart failure. This, combined with the results of several clinical trials, [11][12][13][14][15][16] has led to the addition of ␤-sympathetic antagonists to the armamentarium of pharmacologic treatments for heart failure in adults. Carvedilol is a third generation non-selective ␤-antagonist with ␣ 1 -adrenergic blocking and anti-oxidant activity.…”

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confidence: 99%

“…[17][18][19][20][21] When combined with diuretics, digoxin and ACE inhibitors, carvedilol has been shown to be effective in decreasing hospitalization rates and improving survival in adults with congestive heart failure (CHF). 8,10,11 The efficacy and safety of carvedilol in pediatric patients with CHF due to either dilated CMP or end-stage congenital heart defects has not been fully established. The purpose of this study is to report our experience using carvedilol in managing children with dilated CMP, and to evaluate its dosing, safety and efficacy.…”

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confidence: 99%

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Carvedilol in children with cardiomyopathy: 3-year experience at a single institution

Rusconi

Gómez-Marı́n

Rossique-Gonzalez

et al. 2004

The Journal of Heart and Lung Transplantation

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Background: Carvedilol reduces mortality and hospitalization in adults with congestive heart failure. Limited information is available about its use in children. Methods:We reviewed the medical records of 24 children with dilated cardiomyopathy and left ventricular ejection fraction of Յ40%, who were treated with carvedilol as adjunct therapy to angiotensinconverting enzyme inhibitors, digoxin and diuretics. Results:Carvedilol was initiated 14.3 Ϯ 23.3 (mean Ϯ SD) months after the diagnosis of cardiomyopathy. Mean age at initiation of therapy was 7.2 Ϯ 6.4 years. The mean initial and maximum doses were 0.15 Ϯ 0.09 and 0.98 Ϯ 0.26 mg/kg/day. Adverse effects occurred in 5 patients (21%). Two patients (8%) required discontinuation of the drug within 5 weeks of the initial dose. The remaining 22 patients tolerated carvedilol for a mean follow-up period of 26.6 Ϯ 14.7 months. Among these 22 patients, mean left ventricular ejection fraction improved from 24.6 Ϯ 7.6% to 42.2 Ϯ 14.2% (p Ͻ 0.001), and mean sphericity index from 0.86 Ϯ 0.11 to 0.74 Ϯ 0.10 (p Ͻ 0.001). New York Heart Association functional class improved in 15 patients (68%). One patient (4%) died and 3 (14%) were transplanted. Conclusions: Carvedilol, in addition to standard therapy for dilated cardiomyopathy in children improves cardiac function and symptoms; it is well tolerated, with minimal adverse effects, but close monitoring is necessary as it might worsen congestive heart failure and precipitate asthma. Control studies are necessary to assess the effect of carvedilol on mortality and hospitalization rates.

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“…Because HF hospitalization can be defined in various ways, and in order to ensure sufficient data for a meaningful analysis, data for surrogate measures of HF hospitalization were used in a number of studies 4, 5, 6, 7, 8, 9. The surrogate measures consisted of ‘ worsening heart failure requiring intravenous diuretic therapy or discontinuation of the study ’, ‘ intravenous furosemide for the control of acute exacerbations or symptoms ’, ‘ heart failure episode/decompensation ’, ‘ hospitalization for cardiovascular causes/reasons ’, ‘ cardiovascular hospitalization ’, and ‘ severe/resistant heart failure ’.…”

Section: Methodsmentioning

confidence: 99%

Varying effects of recommended treatments for heart failure with reduced ejection fraction: meta‐analysis of randomized controlled trials in the ESC and ACCF/AHA guidelines

2016

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The aim of this paper is to evaluate the treatment effects of recommended drugs and devices on key clinical outcomes for patients with heart failure with reduced ejection fraction (HFREF). Randomized controlled trials (RCTs) listed in the 2012 HF guideline from the European Society of Cardiology as well as the 2013 HF guideline from the American College of Cardiology Foundation and American Heart Association were evaluated for use in the meta‐analysis. RCTs written in English evaluating recommended drugs and devices for the treatment of patients with HFREF were included. Meta‐analyses, based on the outcomes of all‐cause mortality and hospitalization because of HF, were performed with relative risk ratio as the effect size. In the identified 47 RCTs, patients were on average 63 years old and 22% were female. Drugs targeting the renin‐angiotensin‐aldosterone system, beta‐blockers, cardiac resynchronization therapy (CRT), and intracardiac defibrillator devices (ICDs) significantly reduced the risk of death with reductions of 14–19, 23, 20, and 20%, respectively. Drugs targeting the renin‐angiotensin‐aldosterone system, beta‐blockers, digoxin, and CRT significantly reduced the risk of HF hospitalization with reductions of 24–37, 22, 60, and 36%, respectively, while ICDs significantly increased the risk with 34%. Ivabradine showed no significant effects on either outcome. As such, the majority of recommended HFREF treatments offered significant treatment benefits. However, many of the included studies were from the 1990s or earlier, and one must therefore be cautious when extrapolating these results to contemporary patients with HF.

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Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure

Abstract: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.

Cited by 558 publications

References 40 publications

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Carvedilol in children with cardiomyopathy: 3-year experience at a single institution

Varying effects of recommended treatments for heart failure with reduced ejection fraction: meta‐analysis of randomized controlled trials in the ESC and ACCF/AHA guidelines

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