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Author
Wilson S Colucci, MD
Section Editor
Stephen S Gottlieb, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC
INTRODUCTION — Randomized trials have shown that blockade of beta adrenergic receptors leads to symptomatic improvement, reduced hospitalization and enhanced survival in many patients with heart failure (HF) and systolic dysfunction [1-3]. Therefore, beta blockers are an important component of standard HF therapy in patients with current or prior symptoms of HF and depressed left ventricular (LV) systolic function.
Recommendations for the use of beta blockers in heart failure due to systolic dysfunction are presented here. The rationale for and clinical trials of beta blockers in HF due to systolic dysfunction, an overview of the treatment of heart failure (HF) due to systolic dysfunction (table 1), and the possible role of beta blockers in asymptomatic left ventricular dysfunction and in patients with diastolic dysfunction are discussed separately. (See "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction" and "Overview of the therapy of heart failure due to systolic dysfunction" and "Evaluation and management of asymptomatic left ventricular systolic dysfunction" and "Treatment and prognosis of diastolic heart failure".)
IMPROVEMENT IN PATIENT SURVIVAL — After initial observations suggesting a survival benefit with beta blockers in HF [4], a number of major trials confirmed this benefit with several beta blockers (extended release metoprolol succinate, carvedilol, and bisoprolol) in selected patients with symptomatic HF and LV systolic dysfunction.
The range of benefit can be illustrated by findings from a meta-analysis that included 22 trials involving more than 10,000 patients with left ventricular ejection fraction (LVEF) <35-45 percent, almost all of whom had NYHA class II or III HF and were also treated with ACE inhibitors [1]. The following findings were noted:
* Beta blockers significantly reduced total mortality at one year (odds ratio 0.65, 95% CI 0.53-0.80) and two years (odds ratio 0.72, 95% CI 0.61-0.84). Assuming a mortality rate of 12 percent in the placebo group at one year (derived from the three largest and most recent trials), beta blocker therapy saved 3.8 lives in the first year per 100 patients treated.
* Beta blockers also reduced hospitalization for HF (odds ratio 0.64, 95% CI 0.53-0.79) with an absolute benefit of four fewer hospitalizations in the first year per 100 patients treated.
Similar findings were noted in a meta-analysis limited to large randomized trials [2]. Clinical trials of beta blocker therapy are discussed in detail separately. (See "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction".)
INDICATIONS FOR THERAPY
Major society guidelines — Major societies have issued similar recommendations regarding the use of beta blockers in HF due to systolic dysfunction.
* The 2005 ACC/AHA guidelines recommended beta blockers in patients with current or prior symptoms of HF and left ventricular systolic dysfunction (table 2A-B) [3]. This recommendation was unchanged by the 2009 focused update. Symptomatic patients should have no or minimal evidence of fluid retention, be on an ACE inhibitor, and should not have required recent intravenous inotropic therapy. (See "Overview of the therapy of heart failure due to systolic dysfunction", section on 'ACE inhibitors or beta blockers first'.)
* The 2006 Heart Failure Society of America (HFSA) guidelines included similar recommendations for patients with HF and an LVEF ≤40 percent [5]. Initiation in stable patients in hospital prior to discharge is recommended when possible.
* The 2008 European Society of Cardiology (ESC) guidelines recommended beta blocker therapy in patients with NYHA functional class II to IV HF and an LVEF ≤40 percent [6].
Our recommendations — In the absence of a contraindication, we recommend carvedilol, extended release metoprolol succinate, or bisoprolol for patients with current or prior HF and an LVEF ≤40 percent. These patients should also be treated with an ACE inhibitor and, if necessary for symptom control, digoxin, and diuretics (table 2A-B). Beta blockers with intrinsic sympathomimetic activity should be avoided [1].
Relative contraindications — The controlled trials of beta blocker therapy excluded patients with absolute or relative contraindications to beta blocker use [1]. Relative contraindications in patients with HF include:
- Heart rate <60 bpm
- Symptomatic hypotension
- Greater than minimal evidence of fluid retention
- Signs of peripheral hypoperfusion
- PR interval >0.24 sec
- Second- or third-degree atrioventricular block
- History of asthma or reactive airways
- Peripheral arterial disease with resting limb ischemia
ADMINISTRATION
Initiation of therapy — Before therapy is initiated, the patient should be informed that beta blockers may lead to an initial increase in symptoms. However, initiation of low doses and careful follow-up should minimize these effects. Guidelines for the safe initiation of therapy have been published [7].
Timing — Prior to initiation of therapy, the patient should have no or minimal evidence of fluid retention and should not have required recent intravenous inotropic therapy.
An ACE inhibitor is generally instituted before beta blocker therapy. The preference for this approach is largely based upon clinical trials with ACE inhibitors being performed before trials of beta blockers. However, subsequent randomized trials (eg, CIBIS III) suggest that the outcomes may be similar if beta blockers are given first. This issue is discussed in detail elsewhere. (See "Overview of the therapy of heart failure due to systolic dysfunction", section on 'ACE inhibitors or beta blockers first'.)
The results from the IMPACT-HF trial and the OPTIMIZE-HF registry support the initiation of a beta blocker in stable patients prior to hospital discharge [8,9]. The IMPACT-HF demonstrated that the initiation of beta blockade in the hospital, compared to later initiation, was associated with more frequent use of beta blockers at 60 days without any increase in the rates of worsening HF, hypotension, bradycardia, or drug discontinuation [8].
Choice of beta blocker — We recommend use of carvedilol, bisoprolol, or extended release metoprolol succinate since these beta blockers have been shown to reduce all-cause mortality and decrease hospitalization in patients with HF and left ventricular systolic dysfunction (LVEF ≤ 35-40 percent) in randomized controlled trials.
Limited data are available on the comparative efficacy of these three beta blockers. Indirect evidence suggests that carvedilol may produce greater improvement in LVEF than metoprolol. Patients with low blood pressure may be less likely to tolerate carvedilol because of its vasodilatory activity. Conversely, carvedilol may be preferred in patients with higher blood pressure. (See "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction", section on 'Comparison with other beta blockers',Retrospective data suggest that some beta blockers other than those with proven benefit in randomized trials (eg, atenolol but not short-acting metoprolol tartrate) may be beneficial in HF. However these observations are not sufficient to support a recommendation for use of beta blockers without benefit established by randomized studies.
Dosing — Therapy should be begun in very low doses and the dose doubled at regular intervals (eg, every two to three weeks) until the target dose is reached or symptoms become limiting [10]. Initial and target doses are as follows:
* For carvedilol, 3.125 mg twice daily with target dose of 25 to 50 mg twice daily (the higher dose being used in subjects over 85 kg)
* For extended release metoprolol succinate, 12.5 or 25 mg daily with target dose of 200 mg/day
* For bisoprolol, 1.25 mg once daily with target dose of 5 to 10 mg once daily
The patient should weigh himself or herself daily and call the physician if there has been a 1 to 1.5 kg weight gain. Weight gain alone may be treated with diuretics, but resistant edema or more severe decompensation may require beta blocker dose reduction or cessation (possibly transient). (See 'Worsening of HF symptoms' below.)
Every effort should be made to achieve the target dose. The proportion of patients who reach the target dose is higher in clinical trials than in the general population in which the patients are older and have more comorbid disease. However, although not optimal, even low doses appear to be of benefit and should be used when higher doses are not tolerated.
Duration of therapy — Although evidence establishing the optimum duration of beta blocker therapy in HF are lacking, available data support continuation of beta blocker therapy in patients with left ventricular systolic dysfunction and history of HF [3,11,12].
Use with other HF drugs — ACE inhibitors, angiotensin II receptor blockers (ARBs), and aldosterone antagonists, as well as combination hydralazine and nitrate therapy in blacks, improve survival in patients with HF due to systolic dysfunction. The benefit from each of these drugs appears to be additive to that of beta blockers. (See "Overview of the therapy of heart failure due to systolic dysfunction" and "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction".)
ACE inhibitors — Treatment of HF with ACE inhibitor and beta blocker combination therapy is more effective than use of either therapy alone [13].
ARBs — Combination therapy with an ARB and a beta blocker appears to be more effective than either agent alone [14]. (See "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use".)
There are conflicting data on the value of adding an ARB to patients already treated with an ACE inhibitor and beta blocker [15,16]. We regard the data supporting addition of ARB therapy as more definitive. We suggest the addition of an ARB, if tolerated, to a regimen including ACE inhibitors and beta blockers, in patients with persistent class II to III HF if the patient has normal renal function and low to normal serum potassium. (See "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use".)
Aldosterone antagonists — Evidence from the EPHESUS and RALES trials supports a benefit of aldosterone antagonists in patients taking beta blockers [17,18]. Similarly, patients taking an aldosterone antagonist appear to benefit from addition of beta blocker therapy [19]. (See "Use of diuretics in heart failure".)
Hydralazine plus nitrate — Evidence from the AHeFT trial supports a benefit of hydralazine plus nitrate therapy in African American patients taking beta blockers [20,21].
Use with aspirin — Some concern has been raised that aspirin may interfere with treatment of HF although evidence for such an interaction is limited.
* A posthoc analysis suggested that aspirin use may reduce the beneficial impact of beta blocker (carvedilol) therapy on LVEF [22].
* A potential interaction between aspirin and ACE inhibitors has also been investigated. However, most of the available evidence does not support an inhibitory effect of aspirin on the long-term outcome benefits of ACE inhibitors in HF. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use".)
Given the demonstrated value of aspirin and the confounding features of available evidence, it would be premature to modify recommendations for aspirin use until further data are available.
(See "Drugs that should be avoided or used with caution in patients with heart failure".)Aspirin).
ADVERSE EFFECTS — Potential side effects of beta blockers include worsening of HF, bradycardia, hypotension, bronchospasm, and exacerbation of peripheral vascular disease. Concern about adverse effects of beta blockade may deter clinicians from prescribing them despite the recognized benefits [23]. (See "Major side effects of beta blockers".)
The rate of withdrawal of beta blockers during the run-in period in clinical HF trials has been about 5 percent [1]. The overall all-cause withdrawal rate for patients on active therapy has been 16 percent, which is actually less than that seen among placebo recipients (18 percent) [24]. Side effects that have been significantly more common with beta blockers in clinical trials are dizziness (22 versus 17 percent with placebo) and bradycardia (6 versus 2 percent) [24].
Worsening of HF symptoms
During beta blocker initiation — Patients may have a period of worsening of HF symptoms lasting two weeks to two months after the initiation of beta blocker therapy. This is minimized by starting at extremely low doses and titrating up every two weeks until target doses are reached.
The chief factor limiting titration is bradycardia. Adverse effects appear decreased after two months of beta blocker administration [10].
* Similarly, a low rate of adverse events during carvedilol initiation was observed in an analysis of COPERNICUS trial of patients with class III to IV HF [25,26]. During the first eight weeks of the trial (the dose initiation and titration period), the rate of death or hospitalization for any reason was not higher in the carvedilol group than the placebo group (12.3 versus 14.4 percent) [26]. During the first eight weeks, the carvedilol arm was comparable to the placebo arm in the rate of worsening HF (5.1 versus 6.4 percent).
The low rates of worsening HF are likely due to the requirement for clinical euvolemia before enrollment and vigorous efforts to maintain euvolemia during the trial. Furthermore, the investigators who managed trial patients were highly experienced in the treatment of HF. Cautious management is important in the initiation of beta blocker therapy, especially in patients with advanced HF.
During maintenance therapy — A separate issue is the management of an exacerbation of HF in a patient who has been stable on a beta blocker for more than three months. Given the benefits of beta blockade, the ACC/AHA guidelines and many cardiologists recommend continuing the beta blocker and intensifying diuretics and other therapies if the exacerbation is primarily due to fluid overload without hemodynamic instability [3,27]. On the other hand, temporary cessation of beta blocker therapy is reasonable if the exacerbation is characterized by hypoperfusion, bradycardia, or the requirement for inotropic drugs. Inotropes that act independent of the beta adrenergic receptor, such as the phosphodiesterase inhibitor milrinone, may be preferable in this setting. Reintroduction of the beta blocker is warranted if the patient stabilizes. (See "Treatment of acute decompensated heart failure", section on 'Beta blockers'.)
Other adverse effects — The risk of adverse effects of beta blockade other than exacerbation of HF has been small in clinical trials. In a pooled analysis of nine studies, side effects caused more often by beta blockers than placebo included hypotension (7.6 versus 6.1 percent), dizziness (21.5 versus 16.6 percent), and bradycardia (5.7 versus 1.8 percent) [24].
If symptomatic hypotension develops with carvedilol, a trial of metoprolol succinate or bisoprolol should be considered. A reduction in dose of other hypotensive agents (other than ACE inhibitors or ARBs) such as nitrates and diuretics should be considered [6].
SPECIFIC PATIENT SUBSETS
General approach — Less evidence is available to support beta blocker use in specific patients subsets. As recommended in the 2005 ACC/AHA guidelines, groups of patients including a) high-risk ethnic minorities (eg, blacks), b) groups underrepresented in clinical trials, and c) any groups believed to be underserved should, in the absence of specific evidence to the contrary, receive therapy identical to that applied to the broader population [3].
Available evidence supports beta blocker use for treatment of HF due to systolic dysfunction in patients with ischemic and nonischemic cardiomyopathies, stable class IV HF, diabetes, women, blacks, and elderly patients.
Use in ischemic and nonischemic cardiomyopathies — Clinical trials have demonstrated that improvements in exercise duration, stabilization of LV function, and mortality are similar in ischemic and nonischemic cardiomyopathies [28-30].
Class IV HF — The mortality benefit of beta blockade appears to extend to patients with severe class III and stable class IV HF (table 1) [25,31,32].
Combination with dobutamine — Patients with advanced HF who decompensate may be treated with dobutamine. In this setting, pretreatment with carvedilol markedly reduced the inotropic response to dobutamine, whereas metoprolol had only a slight inhibitory effect [33]. Alternatively, use of inotropes that act independent of the beta adrenergic receptor, such as the phosphodiesterase inhibitor milrinone, may be preferable in this setting. (See "Inotropic agents in heart failure due to systolic dysfunction".)
Use in women — Women have been underrepresented in the beta blocker trials, but appear to benefit to the same degree as men [34,35].
Use in blacks — Beta blocker use in black HF patients is supported by data from carvedilol, metoprolol succinate and bisoprolol HF trials [35,36].
Results from the BEST trial suggest that bucindolol, a beta blocker with partial beta agonist activity [37], may have differing effects in white and black HF patients. In the BEST trial there was no significant mortality benefit in the treatment group as a whole or in black patients although there was a significant benefit in white patients [38]. However, results of subgroup analysis should be interpreted with caution given the potential effect of chance. (See "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction", section on 'Use in blacks'.)
Use in diabetes — In a meta-analysis including 1883 diabetics and 7042 nondiabetics, the survival benefit with beta blocker therapy was significant for both those with diabetes and for those without (relative risk 0.77 and 0.65, respectively) [35]. (See "Heart failure in diabetes mellitus", section on Drug therapy.)
Use in patients with COPD — Beta-1 selective beta blockers (eg, metoprolol or atenolol) appear to be safe in patients with COPD, even when there is a bronchospastic component. In a meta-analysis of major trials, no changes in FEV1, respiratory symptoms, or the use of inhaled beta agonists were seen [39,40]. More limited data suggest that non-specific beta blockade (eg, carvedilol) may be safe in the setting of COPD as well, but less well tolerated in patients with asthma [41].
Use in elderly adults — All of the major randomized trials included many elderly patients who appeared to derive similar benefit as younger patients.
The SENIORS trial evaluated the efficacy of nebivolol, a novel beta 1 blocker (and beta 3 agonist) with vasodilating activity in patients ≥70 years of age with history of hospital admission for HF within the previous year OR known LVEF ≤35 percent) [42]. Nebivolol therapy produced a significant reduction in the primary end point of all-cause mortality or cardiovascular hospital admission and there was a trend toward decrease in all-cause mortality. (See "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction", section on 'Use in elderly adults'.)
Use in patients on hemodialysis — Available evidence including a small randomized carvedilol trial suggests that beta blocker therapy is beneficial in dialysis patients with HF due to systolic dysfunction [43]. (See "Myocardial dysfunction in end-stage renal disease", section on Pharmacologic therapy.)
INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Heart failure causes, symptoms, and diagnosis" and "Patient information: Heart failure treatments".) We encourage you to print or e-mail these topic reviews, or to refer patients to our public website, www.uptodate.com/patients, which includes these and other topics.
SUMMARY AND RECOMMENDATIONS
* Use of certain beta blockers in patients with HF due to systolic dysfunction, particularly carvedilol, metoprolol succinate, and bisoprolol, reduces hospitalizations for HF and improves survival. (See 'Improvement in patient survival' above.)
* Available evidence also supports beta blocker use for treatment of HF due to systolic dysfunction in subgroups including patients with ischemic and nonischemic cardiomyopathies, stable class IV HF, women, blacks, patients with diabetes, and elderly adults.
* In patients with current or prior HF and an LVEF ≤40 percent, we recommend therapy with a beta blocker (Grade 1A). We believe that clinicians should choose one of the beta blockers of proven benefit (including reduction in all-cause mortality) in randomized trials (ie, carvedilol, extended release metoprolol succinate, or bisoprolol).
* Prior to initiation of therapy, the patient should have no or minimal evidence of fluid retention. Beta blocker therapy should be initiated in stable patients prior to hospital discharge.
* Beta blocker therapy provides incremental benefit in patients with HF treated with an ACE inhibitor or ARB or aldosterone antagonist. (See 'Use with other HF drugs' above.)
* ACE inhibitor therapy should generally be instituted before beta blocker therapy is initiated. Data supporting initiation of beta blocker therapy first is limited.
* Beta blocker therapy should be begun at very low doses and the dose doubled at regular intervals (for example, every two to three weeks) until the target dose is reached or symptoms (worsening HF) become limiting or symptomatic hypotension or excessive bradycardia (rate <50 beats/min) develops. Initial and target doses are:
- For carvedilol, 3.125 mg twice daily; target of 25 to 50 mg twice daily (the higher dose being used in subjects over 85 kg)
- For extended release metoprolol, 12.5 or 25 mg daily; target of 200 mg/day
- For bisoprolol, 1.25 mg once daily; target of 5 to 10 mg once daily
* Every effort should be made to achieve the target doses through individualized dose titration. When target doses are not tolerated, even low doses appear to be of benefit, although they are not optimal.
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REFERENCES
1. Brophy, JM, Joseph, L, Rouleau, JL. Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 2001; 134:550.
2. Foody, JM, Farrell, MH, Krumholz, HM. beta-Blocker therapy in heart failure: scientific review. JAMA 2002; 287:883.
3. Hunt, SA, Abraham, WT, Chin, MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119:e391.
4. Swedberg, K, Waagstein, F, Hjalmarson, A, Wallentin, I. Prolongation of survival in congestive cardiomyopathy by beta receptor blockade. Lancet 1979; 1:1374.
5. Heart Failure Society Of America. Heart failure in patients with left ventricular systolic dysfunction. J Card Fail 2006;12:e38.
6. Dickstein, K, Cohen-Solal, A, Filippatos, G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008; 29:2388.
7. Eichhorn, EJ, Bristow, MR. Practical guidelines for initiation of beta-adrenergic blockade in patients with chronic heart failure. Am J Cardiol 1997; 79:794.
8. Gattis, WA, O'Connor, CM, Gallup, DS, et al. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004; 43:1534.
9. Fonarow, GC, Abraham, WT, Albert, NM, et al. Carvedilol use at discharge in patients hospitalized for heart failure is associated with improved survival: an analysis from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J 2007; 153:82.
10. Gottlieb, SS, Fisher, ML, Kjekshus, J, et al. Tolerability of beta-blocker initiation and titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Circulation 2002; 105:1182.
11. Morimoto, S, Shimizu, K, Yamada, K, et al. Can beta-blocker therapy be withdrawn from patients with dilated cardiomyopathy? Am Heart J 1999; 138:456.
12. Eichhorn, EJ. Beta-blocker withdrawal: the song of Orpheus. Am Heart J 1999; 138:387.
13. Exner, DV, Dries, DL, Waclawiw, MA, et al. Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: A post hoc analysis of the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1999; 33:916.
14. Granger, CB, McMurray, JJ, Yusuf, S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003; 362:772.
15. McMurray, JJ, Ostergren, J, Swedberg, K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362:767.
16. Cohn, JN, Tognoni, G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345:1667.
17. Pitt, B, Remme, W, Zannad, F, Neaton, J. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309.
18. Pitt, B, Zannad, F, Remme, WJ, et al, for the Randomized Aldactone Evaluation Study Investigators. The Effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341:709.
19. Krum, H, Mohacsi, P, Katus, HA, et al. Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study. Am Heart J 2006; 151:55.
20. Taylor, AL, Ziesche, S, Yancy, C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351:2049.
21. Taylor, AL, Ziesche, S, Yancy, CW, et al. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American Heart Failure Trial. Circulation 2007; 115:1747.
22. Lindenfeld, J, Robertson, AD, Lowes, BD, Bristow, MR. Aspirin impairs reverse myocardial remodeling in patients with heart failure treated with beta-blockers. J Am Coll Cardiol 2001; 38:1950.
23. Chatterjee, K. The fear of beta-blocker therapy in heart failure: time to forget. Arch Intern Med 2004; 164:1370.
24. Ko, DT, Hebert, PR, Coffey, CS, et al. Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials. Arch Intern Med 2004; 164:1389.
25. Packer, M, Coats, AJ, Fowler, MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344:1651.
26. Krum, H, Roecker, EB, Mohacsi, P, et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study. JAMA 2003; 289:712.
27. Farrell, MH, Foody, JM, Krumholz, HM. Beta-blockers in heart failure: clinical applications. JAMA 2002; 287:890.
28. Packer, M, Bristow, MR, Cohn, JN, et al 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.
29. Bonet, S, Agusti, A, Arnau, JM, et al. Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and non-vasodilating agents according to patients' characteristics: a meta-analysis of clinical trials. Arch Intern Med 2000; 160:621.
30. Fisher, ML, Gottlieb, SS, Plotnick, GD, et al. Beneficial effects of metoprolol in heart failure associated with coronary artery disease: A randomized trial. J Am Coll Cardiol 1994; 23:943.
31. Goldstein, S, Fagerberg, B, Hjalmarson, A, et al. Metoprolol controlled release/extended release in patients with severe heart failure. Analysis of the experience in the MERIT-HF study. J Am Coll Cardiol 2001; 38:932.
32. Packer, M, Fowler, MB, Roecker, EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation 2002; 106:2194.
33. Metra, M, Nodari, S, D'Aloia, A, et al. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol 2002; 40:1248.
34. Ghali, JK, Pina, IL, Gottlieb, SS, et al. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation 2002; 105:1585.
35. Shekelle, PG, Rich, MW, Morton, SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol 2003; 41:1529.
36. Yancy, CW, Fowler, MB, Colucci, WS, et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med 2001; 344:1358.
37. Andreka, P, Aiyar, N, Olson, LC, et al. Bucindolol displays intrinsic sympathomimetic activity in human myocardium. Circulation 2002; 105:2429.
38. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001; 344:1659.
39. Salpeter, S, Ormiston, T, Salpeter, E. Cardioselective beta-blockers for reversible airway disease. Cochrane Database Syst Rev 2002; :CD002992.
40. Salpeter, SR, Ormiston, TM, Salpeter, EE. Cardioselective beta-blockers in patients with reactive airway disease: a meta-analysis. Ann Intern Med 2002; 137:715.
41. Kotlyar, E, Keogh, AM, Macdonald, PS, et al. Tolerability of carvedilol in patients with heart failure and concomitant chronic obstructive pulmonary disease or asthma. J Heart Lung Transplant 2002; 21:1290.
42. Flather, MD, Shibata, MC, Coats, AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005; 26:215.
43. Cice, G, Ferrara, L, Di Benedetto, A, et al. Dilated cardiomyopathy in dialysis patients--beneficial effects of carvedilol: a double-blind, placebo-controlled trial. J Am Coll Cardiol 2001; 37:407.
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