Beta-blockers for the prevention of sudden cardiac death in heart failure patients: a meta-analysis of randomized controlled trials

  • Muaamar Al-Gobari1Email author,

    Affiliated with

    • Chadia El Khatib1,

      Affiliated with

      • François Pillon2 and

        Affiliated with

        • François Gueyffier1, 2

          Affiliated with

          BMC Cardiovascular Disorders201313:52

          DOI: 10.1186/1471-2261-13-52

          Received: 18 February 2013

          Accepted: 10 July 2013

          Published: 13 July 2013

          Abstract

          Background

          In many studies, beta-blockers have been shown to decrease sudden cardiac death (SCD) in heart failure patients; other studies reported mixed results. Recently, several large randomized control trials of beta blockers have been carried out. It became necessary to conduct a systematic review to provide an up-to-date synthesis of available data.

          Methods

          We conducted a meta-analysis of all randomized controlled trials examining the use of beta-blockers vs. placebo/control for the prevention of SCD in heart failure patients. We identified 30 trials, which randomized 24,779 patients to beta-blocker or placebo/control. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Eligible studies had to be randomized controlled trials and provide information on the incidence of sudden cardiac death in heart failure patients. Additional inclusion criteria included: treatment for >30 days and follow-up ≥ 3 months. Studies of patients <18 years, randomization to beta-blocker vs. an angiotensin converting enzyme (without placebo) and/or beta-blocker in both arms were excluded from the analysis. Pre-specified outcomes of interest included SCD, cardiovascular death (CVD), and all-cause mortality and were analyzed according to intention-to-treat.

          Results

          We found that beta-blockers are effective in the prevention of SCD [OR 0.69; 95% CI, 0.62–0.77, P < 0.00001], cardiovascular death (CVD) [OR 0.71; 95% CI, 0.64–0.79, P < 0.00001], and all-cause mortality [OR 0.67; 95% CI, 0.59–0.76, P < 0.00001]. Based on the study analysis, 43 patients must be treated with a beta-blocker to prevent one SCD, 26 patients to prevent one CVD and 21 patients to prevent all-cause mortality in one year.

          Conclusion

          Beta-blockers reduce the risk of sudden cardiac death (SCD) by 31%, cardiovascular death (CVD) by 29% and all-cause mortality by 33%. These results confirm the mortality benefits of these drugs and they should be recommended to all patients similar to those included in the trials.

          Keywords

          Beta Blocker Sudden cardiac death Heart failure Meta Analysis

          Background

          Sudden cardiac death is defined as a non-violent death that cannot be explained, occurring less than 24 hours from the onset of symptoms [1]. Sudden cardiac death accounts for 300 000 to 400 000 deaths annually in the United States, depending on the definition used [2, 3]. When restricted to death <2 hours from the onset of symptoms, 12% of all natural deaths were classified as sudden in one study, and 88% of those were due to cardiac disease [2, 3]. Sudden cardiac death is the most common and often the first manifestation of coronary heart disease and is responsible for ≈50% of the mortality from cardiovascular disease in the United States and other developed countries [4]. The risk of sudden cardiac death (SCD) is most pronounced among patients with heart failure, in whom the 1 year absolute risk of SCD is between 4 and 13% [5]. It is worth mentioning that BEST [6], a randomized trial of the beta-blocker bucindolol in patients with advanced chronic heart failure, reported that it did not reduce sudden cardiac death and/or all-cause mortality. However, BEST included demographically diverse groups and severe heart failure patients [7]. In this study, we intended to quantify the effect of beta-blockers in the risk reduction of sudden cardiac death in patients with heart failure by using pooled analysis techniques. Recently, several large randomized control trials of beta-blockers have been carried out. Therefore, a systematic review is required to provide an up-to-date synthesis of available data.

          Methods

          Study search

          We searched the Cochrane Central Register of Controlled Trials (Central) in the Cochrane Library (Version 2012) and MEDLINE (1966 to March 2012). The bibliographies of identified studies were checked. The Medline query was limited to studies involving human subjects, randomized controlled trials and/or meta-analyses. No language restrictions were applied.

          Selection criteria and data abstraction

          A systematic review of the literature with meta-analysis was needed to identify all clinical trials evaluating beta-blockers for heart failure and reporting all-cause mortality. Eligible studies had to be placebo-controlled trials and provide information on the incidence of sudden cardiac death. Additional inclusion criteria included: treatment for >30 days and follow-up ≥3 months. Studies of patients <18 years, randomization to beta-blocker vs. an angiotensin converting enzyme (without placebo), and/or beta-blockers in both arms were excluded from the analysis.

          Abstracted data included eligibility criteria, baseline characteristics, study design (including treatment and control arms), follow-up, and outcomes. Pre-specified outcomes of interest included SCD, cardiovascular death (CVD), and all-cause mortality. Outcomes were analyzed according to intention-to-treat. Study quality was formally evaluated using the Jadad score [8] for the quality assessment of randomized controlled trials. For the purpose of this analysis, studies which had a score of 3/5 or more were considered high quality. The study selection process (according to the PRISMA guidelines) is shown in Figure 1.
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2261-13-52/MediaObjects/12872_2013_588_Fig1_HTML.jpg
          Figure 1

          PRISMA flow diagram for the meta-analysis. Study selection process according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

          Statistical analysis

          The patient was chosen as the individual unit of analysis (as opposed to person years). The effects of beta-blockers on SCD, CVD, and all-cause mortality were determined using fixed-effect and random-effect modeling. Fixed-effect modeling was performed using the Mantel and Haenszel method. Random-effect modeling was conducted using the DerSimonian and Laird method [9]. The results were similar with both methods, so we only reported the random-effect results. Treatment effect was measured using odds ratios (ORs) with 95% confidence intervals (CIs).

          Heterogeneity across the studies was estimated using I-square test [9]. I-square values of 25%, 50%, and 75% correspond to low, moderate, and high levels of heterogeneity [10]. Meta-analysis results were reported only if the I-square value was under 75%. Sensitivity analyses were performed for each outcome measure to assess the contribution of each study to the pooled estimate by excluding individual trials one at a time and recalculating the combined OR for the remaining studies. Statistical testing was two-tailed, and statistical significance was declared with α = 0.05. All analyses were conducted using RevMan software (Version 5.1).

          Results

          Search results

          After searching Medline and the Cochrane Library, we identified 441 abstracts which were reviewed for inclusion and exclusion criteria (Figure 1). Out of these, 361 were excluded for the following reasons: non-randomized study (including observational studies, pharmacokinetic and pharmacodynamic studies, substudies, editorials, etc.; n=349), absence of placebo or inactive control arm (n=11), and inclusion of subjects < 18 years (n=1).

          The full manuscripts of the remaining 81 studies were retrieved for detailed review. Following full manuscript review, an additional 51 studies were excluded: no placebo or control (n= 9), duplicate report or substudy (n= 16), absence of a beta-blocker arm (n=10), outcome of no interest (n=15) and use of beta-blockers in both arms (n= 1).

          Trial characteristics and study quality

          As shown in Table 1, we identified 30 randomized controlled trials of beta-blocker for inclusion in this meta-analysis, which enrolled a total of 24,779 patients [6, 1139]. The mean follow-up duration was 11.51 months (0.96 year) and all trials are placebo controlled except the trial of Anderson et al. [11] which used standard therapy. Using the Jadad score [8], all studies were estimated with score of 3–5 and qualified as high quality. All trials were analyzed according to the intention-to treat paradigm.
          Table 1

          Randomized trials of beta blockers for the prevention of sudden cardiac death

          Trial (Reference)

          Year

          Number of patients

          Name of drug

          Comparator

          Daily maintenance dose (mg)

          Follow-up (months)

          Jadad scoring

          Anderson et al.12

          1985

          50

          Metoprolol

          Control

          61

          19

          3

          ANZ16

          1997

          415

          Carvedilol

          Placebo

          12.5

          19

          4

          BEST6

          2001

          2708

          Bucindolol

          Placebo

          152

          24

          5

          BHAT

          1986

          3837

          Propranolol

          Placebo

          180/240

          25

          5

          Bristow et al.17

          1994

          139

          Bucindolol

          Placebo

          12.5/50/200

          3

          5

          Bristow et al.18

          1996

          345

          Carvedilol

          Placebo

          12.5/25/50

          6

          5

          Capricorn19

          2001

          1959

          Carvedilol

          Placebo

          50

          15.6

          5

          CIBIS II21

          1999

          2647

          Bisoprolol

          Placebo

          10

          15

          5

          CIBIS20

          1994

          641

          Bisoprolol

          Placebo

          5

          23

          5

          CILICARD

          2000

          124

          Celiprolol

          Placebo

          100

          12

          5

          Colucci et al.22

          1996

          366

          Carvedilol

          Placebo

          100

          15

          5

          COPERNICUS8

          2002

          2289

          Carvedilol

          Placebo

          50

          10.4

          5

          de Milliano et al.

          2002

          59

          Metoprolol

          Placebo

          150

          6

          5

          ELANDD

          2011

          116

          Nebivelol

          Placebo

          5/10

          6

          5

          Engleimeir et al.23

          1985

          25

          Metoprolol

          Placebo

          92

          12

          4

          Fisher et al.24

          1994

          50

          Metoprolol

          Placebo

          87

          6

          5

          Hansteen V. et al.25

          1982

          560

          Propranolol

          Placebo

          160

          12

          5

          Krum et al.26

          1995

          49

          Carvedilol

          Placebo

          50

          4

          5

          MDC27

          1993

          383

          Metoprolol

          Placebo

          108/115

          18

          3

          MERIT-HF28

          1999

          3991

          Metoprolol

          Placebo

          159/170

          12

          5

          Metra et al.29

          1994

          40

          Carvedilol

          Placebo

          50

          4

          4

          Olsen et al.30

          1995

          60

          Carvedilol

          Placebo

          81

          4

          5

          Packer et al.31

          1996

          1094

          Carvedilol

          Placebo

          60

          6

          5

          Pollock et al.32

          1990

          19

          Bucindolol

          Placebo

          200

          3

          4

          RESOLVD

          2000

          426

          Metoprolol

          Placebo

          156

          6

          5

          SENIORS14

          2005

          2128

          Nebivelol

          Placebo

          7.7

          21

          5

          Sturm

          2000

          100

          Atenolol

          Placebo

          89

          24

          5

          UHLIR et al.

          1997

          91

          Nebivelol

          Placebo

          2.5/5

          3.5

          5

          Wisenbaugh et al.15

          1993

          24

          Nebivelol

          placebo

          5

          3

          5

          Woodley et al.13

          1991

          50

          Bucindolol

          Placebo

          175

          3

          5

          ANZ: Australian/New Zealand Heart Failure Research Collaborative Group; BEST: Beta-blocker Bucindolol in patients with advanced chronic heart failure; CAPRICORN: Effect of carvedilol on outcome after myocardial infarction inpatients; COPRINCUS: Effect of Carvedilol on the Morbidity of Patients with Severe chronic Heart Failure; MDC: Metoprolol in Dilated Cardiomyopathy Trial study; Merit-HF: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; SENIORS: Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure.

          Baseline patient characteristics

          Baseline patient characteristics (Table 2) were remarkably similar in age and gender in all trials except for Woodley et al. [12] which included younger patients and the SENIORS [13] which included elderly patients.Therefore, the mean age ranged from 28–76 and all trials enrolled mostly men except for Wisenbaugh et al. [14] and ELANDD [35] which enrolled 50% and 65% women respectively. Copernicus [22] and RESOLVD [36] were not evaluated for cardiovascular death outcome due to missing data. Four trials were restricted to patients with non-ischaemic cardiomyopathy, three to ischaemic patients, three not reported, and the remainder enrolled patients with ischaemic and non-ischaemic cardiomyopathy. Mean left ventricular ejection fraction ranged from 16-62%.
          Table 2

          Patient characteristics in randomized trials of beta blockers for the prevention of sudden cardiac death

          Trial (Reference)

          Mean age (Years)

          Male (%)

          Inclusion criteria

          Population (Ischaemic or non-ischaemic)

          Mean EF (%)

          NYHA

          Anderson et al.

          50

          66

          IDC

          Non-ischaemic

          29

          II-IV

          ANZ13

          67

          80

          chronic heart failure

          Ischaemic

          29

          II-III

          BEST6

          60

          78

          NYHA III-IV, EF ≤ 35%

          Both

          23

          III-IV

          BHAT

          55

          NR

          MI, HF

          NR

          NR

          NR

          Bristow et al.14

          55

          61

          IDC and ISCD

          Both

          24

          I-IV

          Bristow et al.15

          60

          76

          Mild, moderate, chronic heart failure

          Both

          23

          II-IV

          CAPRICORN16

          63

          74

          Acute MI, EF ≤ 40%

          Ischaemic

          32

          NR

          CELICARD

          57

          89.5

          NYHA II- IV, LVEF<40%

          Both

          26

          II-III

          CIBIS II18

          61

          80

          NYHA III or IV, EF ≤ 35%

          Both

          28

          III-IV

          CIBIS17

          60

          83

          IDC, NYHA III-IV, ≤ 40%

          Both

          25

          III-IV

          Colucci et al.19

          54

          85

          Mildly symptomatic heart failure

          Both

          23

          II-III

          COPERNICUS20

          63.3

          79.5

          HF and EF ≤ 25%

          67% ischaemic

          20

          NR

          de Milliano et al.

          65

          60

          HF,, LVEF<35%,

          Both

          25

          II-III

          ELANDD

          66

          35

          HF, age>40 years, LVEF>45%

          Non-ischaemic

          62

          II-III

          Engleimeir et al.21

          50

          64

          IDC

          Both

          17

          II-III

          Fisher et al22

          63

          96

          HF and CAD

          NR

          23

          II-IV

          Hansteen V. et al.23

          58

          84.5

          Acute MI

          NR

          NR

          NR

          Krum et al.24

          55

          78

          Advanced heart failure

          Both

          16

          II-IV

          MDC25

          49

          73

          DCM and EF<40%

          Non-ischaemic

          22

          I-III

          MERIT-HF26

          64

          77

          NYHA II-IV,EF ≤ 40%

          Both

          28

          II-IV

          Metra et al.27

          51

          90

          NYHA II-III, IDC

          Non-ischaemic

          20

          II-III

          Olsen et al.28

          52

          94

          NYHA II-III, IDC/CAD

          Both

          20

          II-IV

          Packer et al.29

          58

          77

          Chronic heart failure

          Both

          23

          II-IV

          CAD Coronary artery disease, CHF congestive heart failure, DCM dilated cardiomyopathy, ISCD ischemic dilated cardiomyopathy, EF ejection fraction, HF Heart failure, IDC ischemic dilated cardiomyopathy, MDC Metoprolol in Dilated Cardiomyopathy, MI myocardial infarction, NR not reported, NYHA 'Classification of' New York Heart Association.

          Efficacy of beta-blockers

          A total of 3,764 deaths occurred in the 24,779 patients included in this analysis, including 1,597 SCDs. The SCD rate was 5.27% (n= 673/12768) in those treated with beta-blockers compared with 7.69% (n = 924/12011) in those treated with placebo/control [OR 0.69; 95% CI, 0.62–0.77, P < 0.00001] as shown in Figure 2(A). Cardiovascular mortality rate was 10.84% (n = 1236 /11398) in those treated with beta-blockers and 14.86% (n =1585/10666) in those assigned to placebo/control [OR 0.71; 95% CI, 0.64–0.79, P < 0.00001] see Figure 2(B). All-cause mortality rate was 12.82% (n = 1626 /12678) in those treated with beta-blockers and 17.80% (n =2138/12011) in those assigned to placebo/control [OR 0.67; 95% CI, 0.59–0.76, P < 0.00001] as shown in Figure 2(C).
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2261-13-52/MediaObjects/12872_2013_588_Fig2_HTML.jpg
          Figure 2

          Efficacy of beta blockers compared with control for the (A) Prevention of sudden death. (B) Cardiovascular death, and (C) all-cause mortality in patients with heart failure.

          Based on these data, 43 patients need to be treated (NNT) with beta-blockers to prevent one SCD, 26 patients to prevent one CVD, and 21 patients to prevent all-cause mortality in one year. The forest plot comparison of beta-blockers vs. placebo for SCD and all-cause mortality is shown in Figure 3 and Figure 4 respectively. The I-square test of heterogeneity was relatively low in SCD, CVD, and all-cause mortality with I2 =0%, 20%, and 43% respectively.
          http://static-content.springer.com/image/art%3A10.1186%2F1471-2261-13-52/MediaObjects/12872_2013_588_Fig3_HTML.jpg
          Figure 3

          Funnel plot of SE (log odds ratio) by odds ratio to evaluate publication bias for effect of treatment in sudden cardiac death (SCD).

          http://static-content.springer.com/image/art%3A10.1186%2F1471-2261-13-52/MediaObjects/12872_2013_588_Fig4_HTML.jpg
          Figure 4

          Funnel plot of SE (log odds ratio) by odds ratio to evaluate publication bias for effect of treatment for all-cause mortality.

          Sensitivity analysis

          The BEST trial had the largest relative overall weight of 23.2%, 17.5%, and 11.8% in SCD, CVD and all-cause mortality respectively. Therefore, we conducted a sensitivity analysis to assess the impact of this trial on the results. When excluding the BEST trial from the random-effect estimates, there was no significant difference: OR for SCD [0.64 (95% CI 0.57 -0 .72), p = 0.00001], OR for CVD [0.69 (95% CI 0.62 -0 .77), p = 0.00001] and OR for all-cause mortality [0.65 (95% CI 0.58 -0 .73), p = 0.00001]. I2 = 0%, 7%, and 25% respectively. The Capricorn [18] and Hansteen et al. [25] and BHAT [39] studies included patients with acute myocardial infarction. But when they were excluded from the analysis, no significant difference was found: OR for SCD [0.69 (95% CI 0.61 -0 .78), p = 0.00001], OR for CVD [0.70 (95% CI 0.60 -0 .82), p = 0.00001] and OR for all-cause mortality [0.65 (95% CI 0.55 -0 .77), p = 0.00001]. I2 = 0%, 26%, and 47% respectively. Also, the trial of ELANDD [35] had included patients with LVEF>45%. The sensitivity analysis showed no significant difference: OR for SCD [0.69 (95% CI 0.62 - 0 .77), p = 0.00001], OR for CVD [0.71 (95% CI 0.67–0.79), p = 0.00001] and OR for all-cause mortality [0.67 (95% CI 0.59 - 0 .76), p = 0.00001]. I2 = 0%, 20%, and 43% respectively.

          Publication bias

          To assess a potential existence of publication bias in the effect of beta-blockers in sudden cardiac death and all-cause mortality, a funnel plot as shown in Figure 3 and Figure 4 indicates large symmetry and therefore a publication bias is likely excluded.

          Discussion

          There exist several meta-analyses which evaluated the mortality benefits of beta-blockers among chronic heart failure patients [4044]. One of the eldest is the study of Heidenreich et al. [40] that reported significant reduction in all-cause mortality but had not concluded for sudden cardiac death. This is apparently due to lack of power and sudden death missing data in the studied clinical trials. Also, the meta-analysis of McAllister et al. [41] showed 24% risk reduction of mortality related to the magnitude of heart rate reduction but not to dosing of beta-blockers. A recent meta-analysis by Chatterjee et al. [42] included 21 trials using beta-blockers in patients with heart failure and reduced ejection fraction showing a 31% reduction in overall mortality with no difference among the different agents used. However, this study, like many others, had not evaluated the overall reduction of beta-blockers in the prevention of sudden cardiac death. Another study, Fauchier et al. [44], found similar beneficial effects of beta-blockers in ischemic and non-ischemic cardiomyopathy. Though, the number of clinical trials that classified such patients accounts for <22% in our meta-analysis. Similarly, study of Bonet et al. [43] reported no difference in mortality benefits among ischemic and non-ischemic heart disease and proposed greater benefit of vasodilating beta-blockers compared with the non-vasodilating agents particularly in patients with non-ischemic cardiomyopathy and attributed mortality benefits to significant reduction of pump failure and sudden death. Briefly, previous studies whether had not evaluated overall reduction of beta-blockers in the prevention of sudden cardiac death or need to be updated such as the studies of Bonet et al. [43] and Heidenreich et al. [40] as several recent and large randomized clinical trials have been carried out.

          In this meta-analysis of 24,779 randomized patients, we found that beta-blockers are effective in the prevention of SCD with [OR 0.69; 95% CI, 0.62–0.77, P < 0.00001], CVD [OR 0.71; 95% CI, 0.64–0.79, P < 0.00001], and all-cause mortality [OR 0.67; 95% CI, 0.59–0.76, P < 0.00001]. Ventricular arrhythmias (including non-sustained ventricular tachycardia) have been documented in up to 85% of patients with severe congestive heart failure [45]. As antiarrhythmic agents, beta-blockers have been shown to reduce morbidity and mortality in patients with chronic heart failure in randomized controlled trials, and consistently reduce the risk of SCD by 40–55% [20, 28]. However, our meta-analysis showed a 32% reduction of SCD risk. As indicated earlier, the 1-year absolute risk of SCD in heart failure patients is 4-13% [5]. In our study, the 1-year absolute risk of SCD in the beta-blocker group and placebo/control group is 5.5% and 8.10% respectively. Mortality rates increase the higher the New York Heart Association (NYHA) class, but the proportion of patients dying suddenly (rather than from progressive pump failure) is highest among those with less severe heart failure (NYHA class II or III) [28]. The evaluation of clinical benefits for patients at different stages of heart failure by subgroup analysis merits further investigation. Our study included two clinical trials with acute myocardial infarction patients. When they were excluded from the meta-analysis, no significant differences were found in a sensitivity analysis of the remaining trials. Our study provides a high level of evidence given the large number of randomized patients included.

          Clinical implications

          American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines recommend the use of beta-blockers to reduce sudden death and especially in patients with heart failure [46, 47]. Our results support such recommendations with a high level of argument.

          Conclusion

          Out of all antiarrhythmic agents, only beta-blockers have been shown to be effective at reducing the risk of SCD. Beta-blockers reduce the risk of SCD by 31%, CVD by 29%, and all-cause mortality by 33% and therefore, this meta-analysis study confirms beta-blockers’ clinical benefits and should be recommended to all patients similar to those included in the trials.

          Abbreviations

          ANZ: 

          Australia/New Zealand Heart Failure Study

          BEST: 

          Beta-blocker evaluation survival trial

          CAPRICORN: 

          Carvedilol post-infarct survival control in LV dysfunction study

          CIBIS I: 

          Cardiac insufficiency bisoprolol study

          CIBIS-II: 

          Cardiac insufficiency bisoprolol study II

          COPERNICUS: 

          Carvedilol prospective randomized cumulative survival study

          HF: 

          Heart failure

          LV: 

          Left ventricular

          MDC: 

          Metoprolol in idiopathic dilated cardiomyopathy study

          MDC: 

          Metoprolol in dilated cardiomyopathy trial study

          MERIT-HF: 

          Metoprolol CR/XL randomized intervention trial in congestive heart failure

          MI: 

          Myocardial infarction

          NYHA: 

          New York Heart Association

          RCTs: 

          Randomized controlled trials

          SENIORS: 

          Study of the effects of nebivolol intervention on outcomes and rehospitalisation in seniors with heart failure study.

          Declarations

          Acknowledgement

          We would like to thank Mr. Kent Neal for technical assistance and proofreading the manuscript.

          Funding

          MA received a research grant from the scholarship program of YEMEN LNG COMPANY LTD, Sana’a; Yemen. This study was supported by a student grant from UMR 5558, Biometry and Evolutionary Biology Laboratory, Lyon, France.

          Authors’ Affiliations

          (1)
          Laboratoire de Biologie et Biométrie Evolutive - Equipe Modélisation des Effets Thérapeutiques, UMR 5558 Université Claude Bernard Lyon1
          (2)
          Service de Pharmacologie Clinique et essais thérapeutiques, Hospices Civils de Lyon

          References

          1. The International Classification of Diseases Version 10 ( ICD-10; Code No. 146.1). Geneva, Switzerland: WHO Press; 2010.
          2. Englestein E, Zipes D, Zipes D: Sudden Cardiac Death. Edited by: Alexander RW, Schlant RC, Fuster V, Alexander RW, Schlant RC, Fuster V. New York, NY: McGraw-Hill; 1998.
          3. Myerburg RJ, Castellanos A: Cardiac Arrest and Sudden Death. 9th edition. Philadelphia: WB Saunders; 1997. [In: Braunwald E, Ed. Heart Disease: A Textbook of Cardiovascular Medicine.]
          4. Zipes DP, Wellens HJ: Sudden cardiac death. Circulation 1998, 98:2334–2351.PubMedView Article
          5. Piccini JP, Berger JS, O’Connor CM: Amiodarone for the prevention of sudden cardiac death: a meta-analysis of randomized controlled trials. Eur Heart J 2009, 30:1245–1253.PubMedView Article
          6. Beta-Blocker Evaluation of Survival Trial Investigators: A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001, 344:1659–1667.View Article
          7. Domanski MJ, Krause-Steinrauf H, Massie BM, Deedwania P, Follmann D, Kovar D, Murray D, Oren R, Rosenberg Y, Young J, Zile M, Eichhorn E, BEST Investigators: A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS. J Card Fail 2003, 9:354–363.PubMedView Article
          8. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996, 17:1–12.PubMedView Article
          9. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986, 7:177–188.PubMedView Article
          10. Higgins JPT, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 2003, 327:557–560.PubMedView Article
          11. Anderson JL, Lutz JR, Gilbert EM, Sorensen SG, Yanowitz FG, Menlove RL, Bartholomew M: A randomized trial of low-dose beta-blockade therapy for idiopathic dilated cardiomyopathy. Am J Cardiol 1985, 55:471–475.PubMedView Article
          12. Woodley SL, Gilbert EM, Anderson JL, O’Connell JB, Deitchman D, Yanowitz FG, Mealey PC, Volkman K, Renlund DG, Menlove R: Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation 1991, 84:2426–2441.PubMedView Article
          13. Flather MD, Shibata MC, Coats AJS, Van Veldhuisen DJ, Parkhomenko A, Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J, Tavazzi L, Spinarova L, Toman J, Böhm M, Anker SD, Thompson SG, Poole-Wilson PA, SENIORS Investigators: 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, 26:215–225.PubMedView Article
          14. Wisenbaugh T, Katz I, Davis J, Essop R, Skoularigis J, Middlemost S, Röthlisberger C, Skudicky D, Sareli P: Long-term (3-month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol 1993, 21:1094–1100.PubMedView Article
          15. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group Lancet 1997, 349:375–380.
          16. Bristow MR, O’Connell JB, Gilbert EM, French WJ, Leatherman G, Kantrowitz NE, Orie J, Smucker ML, Marshall G, Kelly P: Dose–response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Bucindolol Investigators. Circulation 1994, 89:1632–1642.PubMedView Article
          17. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N: Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996, 94:2807–2816.PubMedView Article
          18. Dargie HJ: Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001, 357:1385–1390.PubMedView Article
          19. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees Circulation 1994, 90:1765–1773.
          20. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial Lancet 1999, 353:9–13.
          21. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA: Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation 1996, 94:2800–2806.PubMedView Article
          22. Packer M, Fowler MB, Roecker EB, Coats AJS, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL, Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group: 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, 106:2194–2199.PubMedView Article
          23. Engelmeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM: Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation 1985, 72:536–546.PubMedView Article
          24. Fisher ML, Gottlieb SS, Plotnick GD, Greenberg NL, Patten RD, Bennett SK, Hamilton BP: Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol 1994, 23:943–950.PubMedView Article
          25. Hansteen V, Møinichen E, Lorentsen E, Andersen A, Strøm O, Søiland K, Dyrbekk D, Refsum AM, Tromsdal A, Knudsen K, Eika C, Bakken J Jr, Smith P, Hoff PI: One year’s treatment with propranolol after myocardial infarction: preliminary report of Norwegian multicentre trial. Br Med J (Clin Res Ed) 1982, 284:155–160.View Article
          26. Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD: Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation 1995, 92:1499–1506.PubMedView Article
          27. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A: Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993, 342:1441–1446.PubMedView Article
          28. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet 1999, 353:2001–2007.
          29. Metra M, Nardi M, Giubbini R, Dei Cas L: Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994, 24:1678–1687.PubMedView Article
          30. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR: Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol 1995, 25:1225–1231.PubMedView Article
          31. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996, 334:1349–1355.PubMedView Article
          32. Pollock SG, Lystash J, Tedesco C, Craddock G, Smucker ML: Usefulness of bucindolol in congestive heart failure. Am J Cardiol 1990, 66:603–607.PubMedView Article
          33. Witchitz S, Cohen-Solal A, Dartois N, Weisslinger N, Juste K, Darmon JY: Treatment of heart failure with celiprolol, a cardioselective beta blocker with beta-2 agonist vasodilatory properties. The CELICARD Group. Am J Cardiol 2000, 85:1467–1471.PubMedView Article
          34. de Milliano PAR, de Groot AC, Tijssen JGP, van Eck-Smit BLF, Van Zwieten PA, Lie KI: Beneficial effects of metoprolol on myocardial sympathetic function: evidence from a randomized, placebo-controlled study in patients with congestive heart failure. Am Heart J 2002, 144:E3.PubMedView Article
          35. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, Vardas PE, Böhm M, Dei Cas L: Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail 2012, 14:219–225.PubMedView Article
          36. Effects of metoprolol CR in patients with ischemic and dilated cardiomyopathy: the randomized evaluation of strategies for left ventricular dysfunction pilot study Circulation 2000, 101:378–384.
          37. Sturm B, Pacher R, Strametz-Juranek J, Berger R, Frey B, Stanek B: Effect of beta 1 blockade with atenolol on progression of heart failure in patients pretreated with high-dose enalapril. Eur J Heart Fail 2000, 2:407–412.PubMedView Article
          38. Uhlir O, Dvorak I, Gregor P, Malek I, Spinarova L, Vojacek J, Van Nueten L: Nebivolol in the treatment of cardiac failure: a double-blind controlled clinical trial. J Card Fail 1997, 3:271–276.PubMedView Article
          39. Chadda K, Goldstein S, Byington R, Curb JD: Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation 1986, 73:503–510.PubMedView Article
          40. Heidenreich PA, Lee TT, Massie BM: 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.PubMedView Article
          41. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW: Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009, 150:784–794.PubMedView Article
          42. Chatterjee S, Biondi-Zoccai G, Abbate A, D’Ascenzo F, Castagno D, Van Tassell B, Mukherjee D, Lichstein E: Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ 2013, 346:f55.PubMedView Article
          43. Bonet S, Agustí A, Arnau JM, Vidal X, Diogène E, Galve E, Laporte JR: 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, 160:621–627.PubMedView Article
          44. Fauchier L, Pierre B, de Labriolle A, Babuty D: Comparison of the beneficial effect of beta-blockers on mortality in patients with ischaemic or non-ischaemic systolic heart failure: a meta-analysis of randomised controlled trials. Eur J Heart Fail 2007, 9:1136–1139.PubMedView Article
          45. Singh SN, Carson PE, Fisher SG: Nonsustained ventricular tachycardia in severe heart failure. Circulation 1997, 96:3794–3795.PubMed
          46. Ball TA, Kerns JW, Nashelsky J, Saseen J: Clinical inquiries. Do antiarrhythmics prevent sudden death in patients with heart failure? J Fam Pract 2003, 52:719–721.PubMed
          47. Hunt SA, American College of Cardiology, American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005, 46:e1-e82.PubMedView Article
          48. Pre-publication history

            1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2261/​13/​52/​prepub

          Copyright

          © Al-Gobari et al.; licensee BioMed Central Ltd. 2013

          This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.