Influence of β -Blockers on Mortality in Chronic Heart Failure

Abstract

Spanish

French

OBJECTIVE:

To briefly discuss the pathophysiology of heart failure and the rationale for the use of β -blockers in the treatment of chronic heart failure. Key morbidity reduction trials are briefly mentioned, and recent mortality reduction trials are reviewed. General recommendations regarding the use of β -blockers in heart failure are also included to guide clinical practice.

STUDY SELECTION/DATA EXTRACTION:

Randomized, placebo-controlled clinical trials and meta-analyses evaluating mortality reduction with β -blockers in the treatment of heart failure were identified using a MEDLINE search from January 1993 to March 2000. Abstracts and presented results from recent scientific meetings were also considered.

DATA SYNTHESIS:

β -Blockers have been shown to decrease hospitalization for worsening heart failure, decrease the need for heart transplant, improve New York Heart Association (NYHA) functional class, and increase left-ventricular ejection fraction. A mortality benefit has recently been demonstrated for patients with chronic heart failure. Carvedilol, bisoprolol, and controlled-release/ extended-release metoprolol decreased the risk of dying by 65%, 34%, and 34%, respectively, in patients with primarily NYHA functional class II or III and systolic dysfunction. The benefit of these agents in patients with class IV heart failure or determining whether one agent has an advantage over another is being investigated in ongoing clinical trials.

CONCLUSIONS:

Several β -blockers have demonstrated mortality reduction in the treatment of patients with NYHA functional class II or III heart failure and systolic dysfunction. β -Blockers should be considered in these patients when they are clinically stable and taking the current standard therapy of a diuretic plus an angiotensin-converting enzyme inhibitor or other vasodilator agent.

Keywords

β -blocking agents bisoprolol carvedilol metoprolol heart failure

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References

American Heart Association. 1998 heart and stroke statistical update. Dallas, TX: American Heart Association, 1997.

Massie

Shah

. Evolving trends in the epidemiologic factors of heart failure: Rationale for preventive strategies and comprehensive disease management. Am Heart J 1997;133:703–12.

O'Connell

Bristow

. Economic impact of heart failure in the United States: Time for a different approach. J Heart Lung Transplant 1994;13(Suppl):S107–12.

Gooding

Jette

. Hospital readmissions among the elderly. J Am Geriatr Soc 1985;33:595–601.

Rich

Freedland

. Effect of DRGs on three-month readmission rate of geriatric patients with congestive heart failure. Am J Public Health 1988;78:680–2.

Lily

, ed. Pathophysiology of heart disease. Malvern, PA: Lea & Febiger, 1993:147–66.

Packer

Cohn

, On behalf of the Steering Committee and Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure. Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999;83(suppl 2A):1A–38A.

Pepper

Lee

. Sympathetic activation in heart failure and its treatment with β -blockade. Arch Intern Med 1999;159:225–34.

Pfeffer

Braunwald

. Influence of chronic captopril therapy on the infarcted left ventricle of the rat. Circ Res 1985;57:84–95.

10.

Pfeffer

Lamas

Vaughan

Parisi

Braunwald

. Effect of captopril on progressive ventricular dysfunction after anterior myocardial infarction. N Engl J Med 1988;319:80–6.

11.

Sabbah

Shimoyama

Kono

Gupta

Sharov

Scicli

Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction. Circulation 1994;89:2852–9.

12.

McDonald

Rector

Carlyle

Francis

Cohn

. Angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade regress established ventricular remodeling in a canine model of discrete myocardial damage. J Am Coll Cardiol 1994;24:1762–8.

13.

Mulder

Richard

Derumeaux

Hogie

Henry

Lallemand

Role of endogenous endothelin in chronic heart failure: Effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. Circulation 1997;96:1976–82.

14.

Packer

. The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20: 248–54.

15.

Kanai

Mesaros

Finkel

Oddis

Birder

Malinski

. Beta-adrenergic regulation of constitutive nitric oxide synthase in cardiac myocytes. Am J Physiol 1997;273(4 pt 1):C1371–7.

16.

Communal

Singh

Pimentel

Colucci

. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the β-adrenergic pathway. Circulation 1998;98:1329–34.

17.

Mancia

. Neurohumoral activation in congestive heart failure. Am Heart J 1990;120:1532–7.

18.

Francis

Goldsmith

Levine

Olivari

Cohn

. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984;101: 370–7.

19.

Pousset

Isnard

Lechat

Kalotka

Carayon

Maistre

Prognostic value of plasma endothelin-1 in patients with chronic heart failure. Eur Heart J 1997;18:254–8.

20.

Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 7th ed. Boston: Little, Brown, 1973:286.

21.

Cohn

Levine

Olivari

Garberg

Lura

Francis

Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819–23.

22.

Heidenreich

Lee

Massie

. Effect of beta-blockade on mortality in patients with heart failure: A meta-analysis of randomized clinical trials. J Am Coll Cardiol 1997;30:27–34.

23.

Lechat

Packer

Chalon

Cucherat

Arab

Boissel

. Clinical effects of β -adrenergic blockade in chronic heart failure. A meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 1998;98:1184–91.

24.

The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302.

25.

Cohn

Johnson

Ziesche

Cobb

Francis

Tristani

A comparison of enalapril with hydralazine—isosorbide dinitrate in the treatment of chronic congestive heart failure (V-HeFT II). N Engl J Med 1991;325:303–10.

26.

2000 Drug topics red book. Montvale, NJ: Medical Economics, 2000.

27.

Waagstein

Bristow

Swedberg

Camerini

Fowler

Silver

, for the Metoprolol in Dilated Cardiomyopathy (MDC) trial study group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342:1441–6.

28.

CIBIS Investigators and Committees. A randomized trial of β -blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994;90:1765–73.

29.

Packer

Bristow

Cohn

Colucci

Fowler

Gilbert

, for the US Carvedilol Heart Failure study group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349–55.

30.

Bristow

Gilbert

Abraham

Adams

Fowler

Hershberger

Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996;94:2807–16.

31.

Packer

Colucci

Sackmer-Berstein

Liang

Goldscher

Freeman

, for the PRECISE study group. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: The PRECISE trial. Circulation 1996;94:2793–9.

32.

Colucci

Packer

Bristow

Gilbert

Cohn

Fowler

, For the US Carvedilol Heart Failure study group. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996;94:2800–6.

33.

Cohn

Fowler

Bristow

Colucci

Gilbert

Kinal

, for the Carvedilol Heart Failure study group. Effect of carvedilol in severe chronic heart failure (abstract). J Am Coll Cardiol 1996;27:169A.

34.

CIBIS-II Investigators and Committee. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999;353:9–13.

35.

Merit-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–7.

36.

Hjalmarson

Goldstein

Fagerberg

Wedel

Waagstein

Kjekshus

, for the MERIT-HF study group. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure. JAMA 2000;283:1295–302.

37.

Domanski

Eichhorn

. BEST (Beta-blocker Evaluation of Survival Study). Presented at the 72nd Scientific Sessions of the American Heart Association, Plenary Session XII: Late-Breaking Clinical Trials, Atlanta, GA, November 10, 1999.

38.

Kerr

. Beta-blocker trial in CHF abruptly halted due to survival benefit. Reuters Medical News, March 22, 2000.

39.

Adams

Baughman

Dec

Elkayam

Forker

Gheorghiade

HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction — Pharmacological approaches. J Cardiac Failure 1999;5:357–82.

40.

Bristow

. β -Adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558–69.

41.

Bristow

Ginsburg

Fowler

Minobe

Rasmussen

Zera

β₁- and β₂-adrenergic receptor subpopulations in normal and failing human ventricular myocardium: Coupling of both receptor subtypes to muscle contraction and selective β₁-receptor downregulation in heart failure. Circ Res 1986;59:297–309.

42.

Brodde

Schuler

Kretsch

Brinkmann

Borst

Hetzer

Regional distribution of β-adrenoceptor in the human heart: Coexistence of function β₁- and β₂-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol 1986;8: 1235–42.

43.

Bristow

. Changes in myocardial and vascular receptors in heart failure. J Am Coll Cardiol 1993;22(suppl A):61A–71A.

44.

Mann

Kent

Parsons

Cooper

G IV

. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85:790–804.

45.

Bristow

Abraham

Yoshikawa

White

Hattler

Crisman

Second and third beta blocking agents in the treatment of chronic heart failure. Cardiovasc Drugs Ther 1997;11:291–6.

46.

Gilbert

Abraham

Olsen

Hattler

White

Mealy

Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996;94:2817–25.

47.

Metra

Nodari

Gargellini

Boldi

Rosselli

Zanini

Comparative effects of metoprolol and carvedilol on resting and peak exercise hemodynamics and functional capacity in patients with chronic heart failure (abstract). Circulation 1997;96(suppl I):I–578.

48.

Kukin

Charney

Levy

Buchholz-Varley

Ocampo

Eng

. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 1999;99:2645–51.

49.

Bristow

Larrabee

Minobe

Roden

Skerl

Klein

Receptor pharmacology of carvedilol in the human heart. J Cardiovasc Pharmacol 1992;19(suppl 1):S68–80.

50.

Bristow

Roden

Lowes

Gilbert

Eichenhorn

. The role of third generation β_b-blocking agents in chronic heart failure. Clin Cardiol 1998;21:I-3–I-13.

51.

Lowes

Chidiac

Olsen

Port

Bouvier

Gilbert

Clinical relevance of inverse agonism and guanine nucleotide modulatable binding properties of β-adrenergic blocking agents (abstract). Circulation 1994;90(suppl I):I–543.

52.

Sandberg

Ragnarsson

Jonsson

Sjogren

. Design of a new multiple-unit controlled-release formulation of metoprolol—metoprolol CR/XL. Eur J Clin Pharmacol 1988;33(Suppl):S3–7.

53.

Abrahamsson

Lucker

Olofsson

Regardh

Sandberg

Wieselgren

The relationship between metoprolol plasma concentration and beta-1-blockade in healthy subjects: A study on conventional metoprolol and metoprolol CR/ZOK formulations. J Clin Pharmacol 1990;30(Suppl):S46–54.

54.

Sandberg

Blomqvist

Jonsson

Lundborg

. Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets. Eur J Clin Pharmacol 1988;33(Suppl):S9–14.

55.

Waagstein

Caidahl

Wallentin

Bergh

Hjalmarson

. Long-term β -blockade in dilated cardiomyopathy: Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol. Circulation 1989;80:551–63.

56.

Epstein

Braunwald

. The effect of beta adrenergic blockade on patterns of urinary sodium excretion: Studies in normal subjects and in patients with heart disease. Ann Intern Med 1966;65:20–7.

57.

Weil

J V

Chidsey

. Plasma volume expansion resulting from interference with adrenergic function in normal man. Circulation 1968;37:54–61.