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REVIEW ARTICLE

Beta Blockers for Congestive Heart Failure
Daulat Manurung, Hana B. Trisnohadi

ABSTRACT which will damage the myocardium. Beta blockers
The prognosis remains poor for many patients with may block sympathetic nervous system activity and
congestive heart failure, despite maximal medical treatment slow the progression of disease, improve symptoms
with ACE inhibitor, diuretics and digitalis. In heart failure, and increase survival.
activation of sympathetic nervous system has been described Several large clinical trials have demonstrated that
as one of the most important pathophysiologic abnormalities beta blockers decrease mortality in patients who have
in patients with congestive heart failure and as one of the
already received standard heart failure therapy such as
most important mechanisms that may be responsible for
progression of heart failure. The use of beta blockers which
diuretics, ACE inhibitors with or without digoxin.2,3
may inhibit sympathetic activity, might reduce the risk of Current guidelines recommend that beta blockers should
disease progression in heart failure, improve symptoms and be used in mild to moderate heart failure, class II or
increase survival. III NYHA (New York Heart Association).4 Recent trial
Several large clinical trials with metoprolol, carvedilol and COPERNICUS demonstrated that beta blocker is also
bisoprolol have shown that long term use of these agents can beneficial in severe heart failure (Class IV NYHA)
improve left ventricular function and symptoms of CHF, it may and another trial CAPRICORN showed the benecial
also reduce hospital readmission and decrease mortality. effects of beta blockers in mild heart failure (Class
Current guidelines recommend the use of beta blocker I NYHA).5,6
in mild, moderate and severe CHF, in the absence of
contraindications or tolerance in combination with ACE
inhibitor and diuretics. Beta blocker should be initiated in RATIONALE FOR BETA BLOCKER THERAPY IN
patients after maximal medical therapy with diuretics, ACE HEART FAILURE
inhibitor and digitalis and patients already stabilized and in Left ventricular systolic dysfunction in heart failure
compensated conditions. Beta blocker should be started in will be compensated by activating the sympathetic
low doses and require slow titration over weeks or months nervous system and increasing adrenergic activity to
before patients can attain maintenance doses. improve cardiac performance.2,3,6 This compensatory
mechanism may improve contractility and provide
Key words: beta blockers, congestive heart failure. hemodynamic support in short term. However, chronic
adrenergic stimulation can be deleterious because it
INTRODUCTION may cause myocardial damage due to changes in left
The role of beta blockers has changed dramatically ventricular remodeling, loss of myocardial cells and
in the management of heart failure.1 In the past, beta abnormal gene expression.7 Sympathetic activation is
blockers were contraindicated in patients with heart also associated with positive chronotropic effects, which
failure, because the negative inotropic effects of beta will deplete the energy stores of the myocardium and
blocker will decrease further the left ventricular function have direct effects on myocardial cells, thereby adversely
and will worsen the course of this disease. However, affecting outcome and accelerating progression to
pathophysiology of heart failure has changed. In heart advanced heart failure.8 Attenuation of these mechanisms
failure there was an increase of neurohormonal activity is associated with improvement in survival.
Adrenergic stimulation will affect the heart via three
adrenergic receptors: beta1, beta2 and alpha1, which
present in human cardiac myocytes. Beta blockers func-
Division of Cardiology, Department of Internal Medicine, Faculty of tion by reversibly binding with beta-adrenergic receptors
Medicine, Indonesia University/Dr.Cipto Mangunkusumo Hospital,
Jakarta.
to block the response to sympathetic nerve impulses or
catecholamines (norepinephrine or epinephrine).9

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The trial was terminated early when an analysis 45 . Assuming a dysfunction (ejection fraction less than 35%) and mortality rate in the placebo group was 12% in one NYHA class II and IV symptoms were enrolled in year. 95% CI 0.3 per- term therapy resulted in improvements in LVEF.14 Similar improvements have been improved.53 to 0.001). There was also reduction in the hospital- index and LV stroke work.9 percent) in the metoprolol group.9 vs carvedilol. is a morbidity and mortality in heart failure. Beta blocker also reduced the standard therapy for heart failure consisting of the hospitalization for heart failure (odds ratio 0.20 failure is being the fundamental basis for the rationale MERIT-HF Trial use of beta-adrenergic antagonists. The results showed beta of carvedilol on morbidity and mortality in patients with blockers signicantly reduced mortality in one year congestive heart failure.15-17 6. The mean dose was 159 mg and overall clinical status. to 7 patients with congestive cardiomyopathy resulted in beginning with 12. resulted in deterioration of clinical conditions.23 (metoprolol.11 the discontinuation of patients taking active drug was 14 Subsequent reports consistently conrmed these percent in one year.79 ) with an absolute benet randomly assigned to of 4 fewer hospitalization in the rst year per receive carvedilol in a target dose of 25 to 50 mg twice 100 patients treated. p < 0.2 versus 11 percent for placebo. When analyzed by mode of deaths. demonstrating that beta blocker administration because signicant benets had already been noted in could improve LVEF and hemodynamic condition over the metoprolol group.53 to 0. investigated the outcomes in congestive heart failure thetic drive and stopping the adverse effects of chronic patients randomly assigned to receive either beta adrenergic stimulation in chronic congestive heart blockers or placebo therapy. p < 0. a beta1 selective adrenoreceptor blocker was compared with placebo CLINICAL TRIALS OF BETA BLOCKADE for the treatment of heart failure. NYHA functional class also improved in bucindolol p < 0.22 Improvement in Patients Survival Carvedilol Trials During the last few years many studies have shown that beta-adrenergic blockade dramatically reduced the Carvedilol a third generation beta blocker. 19 Three large mortality trials daily or placebo. fraction of less than 40 percent who were receiving Ventricular Performance digoxin.000 failure have been shown in the 1996 US Carvedilol patients almost all of whom had NYHA class II or III Heart Failure Study. carvedilol and bisoprolol).18 A meta analysis The benets of carvedilol for the treatment of heart that included 22 trials involving more than 10. p = dilated cardiomyopathy.8 lives in the first year this carvedilol study. 95% CI 0. Bucindolol is a nonselective 0.12-14 One study performed double The results showed that in the metoprolol group blind. Long point of death and need for transplant (7. there demonstrated with metoprolol and bisoprolol and were signicantly fewer sudden cardiac death (3.72.22 In this trial. Beta blocker safed 3. The NYHA class and quality of life was group (p < 0.5 versus 10.21.Vol 39 • Number 1 • January . a number of nonselective beta-receptor antagonist that also blocks trials conrmed this benet with several beta blockers alpha receptors and has unique antioxidant properties. Patients continued to receive per 100 patients treated.24 This study was a compilation of heart failure and were also treated with standard therapy results from four smaller trials that evaluated the effect including ACE inhibitors.21. The study was terminated early ndings.5 vs 2.61 to 0. while withdrawal of the drug daily.5 or 25 mg daily and titrated up to improvement in left ventricular ejection fraction (LVEF) 200 mg daily or placebo.001) or for heart failure (10 versus 15 percent.64. diuretics and ACE inhibitors and were 95% CI 0.01). an ACE inhibitor and a diuretics were randomly Waagstein reported that administration of metoprolol assigned to therapy with extended release metoprolol. placebo controlled comparing bucindolol with there was 34 percent decrease in all cause mortality placebo plus standard therapy for heart failure due to at 12 months (7. while mean pulmonary ization for cardiovascular causes (20 versus 25 percent. a 3 to 6 month period. In MERIT-HF trial metoprolol.March 2007 Beta Blockers for Congestive Heart Failure Treatment is aimed at halting this increased sympa. use of digoxin.80) and two years A total of 1094 patients with left ventricular systolic (odds ratio 0. capillary wedge pressure and heart rate decreased. there was also reduction in the combined end beta blocker with direct vasodilatory activity.006).84). 3991 Various studies have been shown benecial effects patients with class II to IV heart failure and an ejection of beta blocking agents in patients with heart failure.001).65.17. cardiac cent. with 64 percent of patients receiving target dose.25-27 (odds ratio 0.6%) and fewer deaths from worsening of heart failure (1.

early when analysis showed a signicant reduction in MERIT-HF. tachycardia. There was also reduction of nonfatal myocardial infarction of 41% (p = 0.014) and INITIATION OF THERAPY the combined end point of all cause mortality and nonfatal If a patient is considered suitable for beta blocker MI was reduced by 29% (p = 0. 3%-45%. (3. a second generation B1 trial was prematurely terminated because a signicant selective adrenoreceptor blocker were analyzed for mortality reduction from carvedilol compared with the efcacy in decreasing all cause mortality in heart placebo (annual mortality rate 11. p=0. et al Acta Med Indones-Indones J Intern Med showed that overall mortality was signicantly lower regardless of ejection fraction or patients with reduced among patients taking carvedilol than among those ejection fraction with or without recent myocardial taking placebo.29 was 65% (96% CI. Beta.6% in the placebo group the benet of metoprolol for severe heart failure was (95%CI. of mortality with bisoprolol. The In this study bisoprolol. patients with severe class III and stable class IV NYHA. ACE 46 .21. or cardiogenic shock. 19%-46%.001) in patients The benet of beta blockade appears to extend to treated with carvedilol over a period of 6.29 Beta blocker therapy Ventricular Dysfunction (CAPRICORN) study.8%). CIBIS II. The ACC/AHA therapy.22 Similar results were seen with failure therapy. severe asthma and The results showed that all cause mortality was reduced severe chronic obstructive pulmonary disease.5 months.30 prescribed to patients with asymptomatic left ventricular Patients should first be stable on standard therapy dysfunction with a recent myocardial infarction for congestive heart failure. sudden cardiac death (5.3 years. The reduction of death infarction. all patients had left ventricular in the hospital and were less likely to develop serious ejection fraction equal or less than 35% and were adverse effects such as sudden death.0001).3 vs 7% and the number of hospital- failure.28 2647 patients who had NYHA class III or patients treated with carvedilol also spent fewer days IV were evaluated.3 vs 18.2 vs 7. 95% CI. 156 (11. The investigators concluded that carvedilol reduced Metoprolol reduced total mortality (11. P < 0.4 Patients were randomly These ndings were conrmed in a pooled data assigned to bisoprolol therapy at target dose of 10 mg analysis of 3836 patients NYHA functional class III/IV once daily or to placebo.8%) patients 18% with placebo. There was a 27% risk reduction for hospitalization In a subgroup analysis of 795 patients with severe for cardiovascular causes among the carvedilol group heart failure (NYHA class III/IV) in MERIT-HF study. carvedilol in COPERNICUS trial.1%) compared with 19. which specically assessed the efcacy of beta blockade in 2289 patients CIBIS-II with class IV heart failure and LVEF less than 25%.blockade was associated all cause mortality in the bisoprolol group.4% vs 18. Again this trial was stopped and LVEF less than 25% enrolled in COPERNICUS.036).098). Primarily due to the reduction in sudden death (p = 0.5%). averaging 1. similar to that seen in the entire study population. compared with 228 worsening of symptoms may be more common in patients (17. including diuretics.5 1959 patients with proven myocardial patient should be stabilized and in compensated condition.002). INDICATIONS FOR BETA BLOCKERS Class I and Class IV Heart Failure Beta blockers should be administered in all patients The major mortality trials have not included patients with mild. But in a recent trial left ventricular systolic dysfunction in the absence of the Carvedilol Post Infarct Survival Control in Left contraindications or tolerance. 39-80%. by 23% (p = 0. After with a signicant reduction in total mortality (13 vs follow up.031). who had already received the standard heart ization (15% vs 25%). symptomatic bradycardia without pacemaker. assessed should be initiated in patients after adequate diuresis the effect of beta blockers in patient with mild or and generally following ACE inhibitor treatment and the no symptoms. infarction and a left ventricular ejection fraction Contraindications for beta blocker treatment: cardiogenic less than 40% were shock. randomized to carvedilol (n =975) or placebo (n = 984) second and third degree AV block.72) however initial in the bisoprolol group had died.Daulat Manurung. a careful initiation and gradual increases of beta guidelines suggested that beta blockers should be blocker dose are crucial to avoid clinical deterioration.5 vs 9.350) in the placebo group (34% reduction patients with severe disease. moderate and severe heart failure due to with NYHA class I symptoms.2% the risk of death and the risk of hospitalization for for placebo). p < 0. The failure. (14.8%). ventricular being treated with ACE inhibitors and diuretics. relative risk 0. death cardiovascular causes in patients with congestive heart from heart failure (3.

344: 1651-8. Activation of the be appropriate. Metra M. Am guidelines recommend the use of beta blockers in Heart J. et al. et al. Gilbert EM. Br Heart J. Circulation. Packer M. for patients who weigh less than 85 kg. class III or IV) a starting dose of 12. Chronic beta-blocker- but also they improve survival in patients with severe vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: A double blind. bucindolol versus placebo. 2003.5 mg once daily may 2. on Evaluation and Management of Heart Failure). ogy and the American Heart Association. drive.125 demonstrated that beta blocker was also benecial in mg twice daily for two weeks then the dose is increase patients with stable severe heart failure in reducing every two weeks until target level of 25 mg twice daily mortality and improving symptoms. Circulation. 1990. 25 mg once daily and the dose is increased at 2 week Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee intervals until a goal of 200 mg once daily is reached. Currently. Bisoprolol is started at 1. the mechanism of disease progression in heart failure. which is chronically increased in heart failure. N Engl J Med. Varnauskus E. by Circulation.88:223-9. randomized study of symptomatic heart failure.94(9):2286-96. Malloy CR. Packer M. Improvements in hemodynamic. Mechanisms contributing those asymptomatic LV systolic dysfunction and those to the progression of left ventricular dysfunction to end-stage with severe symptomatic disease. Ceconi C.37:1022. Circulation. Curello S. A rationale for the use European Society of Cardiology clinical practice of beta blockers as standard treatment for heart failure.35 These guidelines heart failure.139(3):511-21. Fowler MB. Coats AJS.94(9):2285-96. Most occur at 2-3 weeks interval and patients should undergo of the large clinical trials were done in patients with mild reevaluation before any adjustments are made. Guidelines from the American College of Cardiol. with few 10. Eur Heart J. low starting dose that is gradually increased until the Because beta blockers administration may induce acute maintenance level derived from the mortality trials are hemodynamic effects. 2000. A beta blocker is then added at disturbing and interrupting neurohormonal pathways. only patients with absolute biological properties of the chronically failing heart: a contraindications to these drugs or patients with new era in the treatment of heart failure.5(1):114-21. Beta-adrenergic receptor blockade in chronic emphasize that the majority of patients with heart failure heart failure. Kilter H. Not only these chronic beta-adrenergic receptor blockade in congestive agents benecial in patients with mild to moderate cardiomyopathy. Eichhom EJ. 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