Does Oral Beta-Blocker Therapy Improve Long-Term Survival in ST-Segment Elevation Myocardial Infarction With Preserved Systolic Function? A Meta-Analysis

Abstract

Background:

The effect of oral beta-blocker therapy on long-term mortality in patients with ST-segment elevation myocardial infarction (STEMI) who are treated with primary percutaneous coronary intervention (PCI) and who have preserved left ventricular ejection fraction (LVEF) remains unclear.

Methods:

We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for studies evaluating the effect of oral beta-blocker therapy in patients with STEMI who underwent primary PCI and who had preserved LVEF. The primary outcome was all-cause mortality. Randomized controlled trials and the observational studies that reported an adjusted hazard ratio (or hazard ratio in the propensity score-matched patients) with follow-up duration equal to or more than 6 months were included. Pooled hazard ratio with 95% confidence interval (CI) was calculated using a random effect model.

Results:

No randomized controlled trials met the inclusion criteria. Seven observational studies totaling 10 857 patients met the inclusion criteria. Follow-up duration ranged from 6 months to 5.2 years. Preserved LVEF was defined as 40% in 4 studies and 50% in 3 studies. Based on the pooled estimate, oral beta-blocker therapy was associated with a reduction in all-cause mortality (combined hazard ratio 0.79, 95% CI 0.65-0.97).

Conclusion:

This meta-analysis demonstrates that oral beta-blocker therapy is associated with decreased all-cause mortality in patients with STEMI who are treated with primary PCI and who have preserved LVEF. This supports the current American College of Cardiology Foundation/American Heart Association 2013 Guideline for the Management of STEMI.

Keywords

beta-blocker ST-segment elevation myocardial infarction percutaneous coronary intervention left ventricular ejection fraction meta-analysis

Introduction

A number of randomized trials predating the era of reperfusion have shown that beta-blocker therapy reduces long-term mortality in patients with acute myocardial infarction.^1

–4 Similarly, the benefit of beta-blocker therapy was demonstrated in the era of thrombolysis.^5
–7 Based on this evidence, the current guideline from the American College of Cardiology Foundation/American Heart Association recommends oral beta-blocker as a Class I recommendation in all patients with ST-segment elevation myocardial infarction (STEMI) who have no contraindication.⁸ In the same line, the current guideline from the European Society of Cardiology recommends oral beta-blocker as a Class I recommendation in patients with STEMI having heart failure or left ventricular dysfunction and as a Class IIa recommendation in other patients.⁹

The treatment of STEMI has markedly advanced since the role of oral beta-blocker therapy was first established. Primary percutaneous coronary intervention (PCI) has been shown to significantly decrease long-term mortality compared to thrombolysis.¹⁰ Therefore, one may speculate that the magnitude of oral beta-blocker therapy may be reduced in the current era of primary PCI. Observational studies that assessed the effect of oral beta-blocker on long-term mortality in patients with STEMI undergoing primary PCI demonstrated mortality benefit, but these benefits were mainly observed in high-risk patients such as those with decreased left ventricular ejection fraction (LVEF) or those on diuretics.^11
–13 These findings were consistent with the established mortality benefit of beta-blocker in patients with low LVEF following acute myocardial infarction.¹⁴

In contrast to the data in patients with reduced LVEF, the effect of beta-blocker therapy in patients with STEMI undergoing primary PCI who have preserved LVEF has not been clarified. Given this uncertainty, we conducted a meta-analysis to evaluate the effects of oral beta-blocker therapy on long-term mortality in patients with STEMI who underwent PCI and who had preserved LVEF.

Methods and Materials

We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1996 to January 2015 for studies evaluating the efficacy of oral beta-blocker therapy in patients with STEMI. Our search included both medical subject headings and key words including (1) “myocardial infarction” and (2) “β-blocker” or “beta-blocker” or “adrenergic beta-antagonists” or “beta adrenergic receptor blocking agent.” We had no language restrictions. Studies were also identified through a search of references cited in the screened original articles and relevant review articles.

Two investigators (NM and YK) independently screened all titles and abstracts of the identified articles. After initial screening, full-text articles of potentially relevant studies were reviewed by both investigators to determine their eligibility. Disagreements were resolved through discussion between the two reviewers. The following inclusion criteria were used for study selection: (1) randomized controlled trial or observational study that investigated the effect of oral beta-blocker therapy on long-term mortality in patients with STEMI undergoing primary PCI who were discharged alive; (2) hazard ratio of all-cause death with 95% confidence interval (CI) in patients with preserved LVEF; (3) an adjusted hazard ratio (or hazard ratio in the propensity score-matched patients) is available for an observational study; and (4) median follow-up duration equal to or more than 6 months.

Data were abstracted including the following information: first author’s name, year of publication, study period, country, study design, number of patients, clinical characteristics of the study population, type of beta-blocker and dose, definition of preserved LVEF, duration of follow-up, an adjusted hazard ratio of all-cause death with 95% CI (or equivalent) in patients with preserved ejection fraction, clinical variables used for multivariate adjustment, or propensity score matching. When the potentially eligible studies did not report an adjusted hazard ratio with 95% CI in patients with preserved LVEF, authors were contacted. Data abstraction was performed by one author (NM) and verified by another (YK).

Hazard ratios of all-cause death were used as the measure of efficacy of oral beta-blocker therapy. The natural log of the hazard ratios of each study were pooled across the studies using the inverse variance method. The standard errors were estimated from the CI provided in each original study. The I² index was used to summarize the proportion of the total variability in the estimate.¹⁵ We used random-effect model to calculate the pooled hazard ratio, which allows for heterogeneity between studies. We also performed subgroup analyses to evaluate associations between the effect size and study characteristics such as definitions of preserved LVEF and follow-up duration. Publication bias was estimated visually by funnel plot and with the Begg test. All analyses were performed using R software version 3.0.1 (The R Foundation for Statistical Computing, Vienna, Austria).

Results

The results of our search strategy are shown in Figure 1. Of the 4951 articles, 124 potentially eligible articles were reviewed in full text. As a result, 7 observational studies totaling 10 857 patients met the inclusion criteria.^{11,12,16

–20} No randomized controlled trials met the inclusion criteria. Additional data were obtained through contact with the authors in the 2 studies.^11,19 Four studies that reported only nonadjusted hazard ratio for all-cause mortality in patients with preserved LVEF were not included in the analysis.^13,21
–23

Figure 1.

Flow diagram of the systematic overview process.

The characteristics of the included studies are shown in Table 1. Among the 7 studies, 1 was a retrospective analysis of patients included in randomized trials comparing PCI versus thrombolysis,¹¹ 4 were prospective multicenter registries,^12,16
–18 and 2 were single-center studies.^19,20 Three studies specifically included patients with preserved LVEF,^18
–20 and the other 4 studies reported the results of subgroup analyses of the patients with preserved LVEF. Two studies that included patients with non-ST-segment elevation acute myocardial infarction or acute coronary syndrome reported the results of subgroup analyses of the population with STEMI.^18,19 All of the patients except for 4 patients in Raposeiras-Roubín et al study¹⁹ underwent primary PCI. Preserved LVEF was defined as >40% in 4 studies^12,16,17,20 and >50% in 3 studies.^11,18,19 Mean follow-up duration ranged from 6 months to 5.2 years. Of the 7 studies, 3 studies reported the type of beta-blocker, and carvedilol was most commonly used in all of the 3 studies.^12,16,18

Table 1.

Characteristics of the Studies Included in the Meta-Analysis.

Author	Year	Country	Study Period	Total Study Population	Age	PCI Rate	Definition of Preserved LVEF
Kernis et al¹¹	2004	United States	1991-1998	2442	61	100%	>50%
Bao et al¹⁶	2012	Japan	2005-2007	3692	67	100%	>40%
Nakatani et al¹²	2013	Japan	1998-2011	5628	65	100%	≥40%
Yang et al¹⁷	2014	South Korea	2005-2010	8510	63	100%	>40%
Choo et al¹⁸	2014	South Korea	2004-2009	3019	62	100%	≥50%
Raposeiras-Roubín et al¹⁹	2014	Spain	2003-2012	3236	65	99%	≥50%
Konishi et al²⁰	2015	Japan	1997-2011	424	64	100%	>40%
Author	No. of Patients With Preserved LVEF Included in the Analysis	Follow-Up Duration	Death in Beta	Death in no Beta	Adjusted HR for Death (or HR in propensity score matching)
Kernis et al	1489	6 months	13/1013	7/476	0.93 (0.20-4.27)
Bao et al	2494	955 days (median)	46/1137	71/1357	0.87 (0.56-1.37)
Nakatani et al	2606	1430 days (median)	68/1294	71/1312	0.923 (0.662–1.287)
Yang et al	3073	367 days (median)	NA	NA	0.56 (0.29-1.07)
Choo et al	678	3 years	21/340	29/338	0.72 (0.41-1.26)
Raposeiras-Roubín et al	311	5.2 years (median)	NA	NA	0.689 (0.357-1.330)
Konishi et al	206	4.7 years (median)	14/103	24/103	0.63 (0.31-1.23)
Author		Type of Beta-Blocker			Dose of Beta-Blocker
Kernis et al		NA			NA
Bao et al		Carvedilol (90.2%)			Carvedilol 5 mg/d (median)
Nakatani et al		Carvedilol (72.0%), metoprolol (19.4%), bisoprolol (4.7%), and atenolol (1.1%)			NA
Yang et al		NA			NA
Choo et al		Carvedilol (81.0%), bisoprolol (10.6%), atenolol (7.5%)			NA
Raposeiras-Roubín et al		NA			NA
Konishi et al		NA			NA
Author		Variables adjusted for (or variables used for propensity score estimation)
Kernis et al		13 variables (baseline demographics, risk factors, and angiographic findings)
Bao et al		39 variables (baseline demographics, risk factors, LVEF, angiographic findings, and medication at discharge)
Nakatani et al		32 variables (baseline demographics, risk factors, angiographic findings, and medication at discharge)
Yang et al		17 variables (baseline demographics, risk factors, LVEF, angiographic findings, and medication at discharge)
Choo et al		30 variables (baseline demographics, risk factors, LVEF, angiographic findings, medication at discharge)
Raposeiras-Roubín et al		17 variables (baseline demographics, risk factors, angiographic findings, and medication at discharge)
Konishi et al		18 variables (baseline demographics, risk factors, LVEF, angiographic findings, and medication at discharge)

Abbreviations: LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; HR, hazard ratio; NA, not applicable.

Figure 2 shows the Forest plot reporting the hazard ratio estimate with 95% CI for all-cause mortality in patients with preserved LVEF. Pooled analysis of the 7 studies revealed a significant reduction in all-cause mortality in patients on oral beta-blocker therapy (combined hazard ratio 0.79, 95% CI: 0.65-0.97). There was no heterogeneity among the studies (I² = 0%). Subgroup analysis showed that the pooled estimate of the hazard ratio did not vary substantially with the exclusion of the study with follow-up duration less than 1 year (combined hazard ratio 0.79, 95% CI 0.64-0.97).¹¹ Another subgroup analysis stratified according to the definition of preserved LVEF showed similar pooled estimates of hazard ratio (LVEF >40%; combined hazard ratio 0.82, 95% CI 0.65-1.03, LVEF >50%: combined hazard ratio 0.72, 95% CI 0.48-1.09).

Figure 2.

Forest plot reporting the hazard ratio estimate with 95% confidence interval for all-cause mortality in patients with ST-segment elevation myocardial infarction (STEMI) having preserved left ventricular ejection fraction.

Funnel plot is shown in Figure 3. Visual assessment of Funnel plot suggested a possible publication bias. The Begg test showed that P value was .18.

Figure 3.

Funnel plot of all studies included in the meta-analysis.

Discussion

In the present meta-analysis of 7 observational studies consisting of 10 857 patients with STEMI undergoing primary PCI who have preserved LVEF, we found that oral beta-blocker was associated with decreased all-cause mortality. To our knowledge, this is the first meta-analysis that has evaluated the association between oral beta-blocker therapy and mortality in this specific population.

Based on the results of randomized trials predating the era of reperfusion, oral beta-blocker therapy is indicated for patients with STEMI according to the current guidelines.^8,9 Observational studies in the era of PCI that assessed the effect of oral beta-blocker on long-term mortality in patients with STEMI demonstrated mortality benefit, but these benefits were mainly observed in high-risk patients such as those with decreased LVEF or those on diuretics.^11
–13 In fact, not a single study included in this meta-analysis showed statistically significant reduction in an adjusted all-cause mortality in patients on oral beta-blocker therapy who have preserved LVEF. However, all of the studies showed a similar trend for decreased mortality in patients on oral beta-blocker therapy. This similar trend for decreased mortality observed in all studies and the lack of heterogeneity among studies suggest that the statistically significant reduction in all-cause mortality observed in this meta-analysis was led by increased number of study population. Although the definition of preserved LVEF ranged from 40% to 50% among studies, subgroup analyses showed similar trends toward reduction in all-cause death in either subgroup. The result of our meta-analysis supports the use of oral beta-blocker therapy in patients with STEMI who are treated with primary PCI and have preserved LVEF, as recommended by the current guidelines.

To date, there has been no randomized controlled trial of oral beta-blocker therapy in patients with STEMI undergoing PCI, likely reflecting the clear recommendation for beta-blocker in patients with STEMI on the current guidelines. The first randomized controlled trial assessing the efficacy of oral beta-blocker therapy (carvedilol) in patients with STEMI who have preserved LVEF (≥40%) after primary PCI is now ongoing (NCT01155635). This study is planning to recruit 1300 patients and is hoping to be completed in 2018.

In our meta-analysis, we evaluated the effect of oral beta-blocker therapy in specific patients with STEMI who underwent primary PCI and who had preserved LVEF. This population partially overlaps with patients having stable coronary artery disease with prior myocardial infarction. Several studies have evaluated the effect of oral beta-blocker therapy in patients with stable coronary artery disease having prior myocardial infarction. Bangalore et al evaluated the effect of oral beta-blocker using propensity score matching in 6758 patients with stable coronary artery disease having prior myocardial infarction from the Reduction of Atherothrombosis for Continued Health (REACH) Registry.²⁴ They reported that all-cause mortality and cardiovascular mortality were not significantly different in patients with beta-blocker use compared to those without beta-blocker use at a median follow-up of 44 months (hazard ratio for all-cause mortality 0.93, 95% CI 0.80-1.08, P = .34; hazard ratio for cardiovascular mortality 0.91, 95% CI 0.76-1.09, P = .31). Bauters et al also evaluated the effect of oral beta-blocker using propensity score matching in 1678 patients with stable coronary artery disease, of which about a half of the patients had prior myocardial infarction.²⁵ Their study demonstrated that the use of beta-blocker was associated with a lower risk of cardiovascular mortality at 2-year follow-up (hazard ratio 0.43, 95% CI 0.22-0.82, P = .011). Bauters et al theorized that the disagreement regarding mortality benefit of beta-blocker between their study and REACH registry beta-blocker analysis might be related to the difference in the covariates used to estimate the propensity score, and LVEF was controlled in their study but not in the study by the REACH investigators.²⁵ Since patients with a low LVEF are also more likely to receive beta-blocker, the lack of adjustment for LVEF might have disadvantaged the beta-blocker group in the analysis by the REACH investigators. A post hoc analysis from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial showed that beta-blocker use in patients with prior myocardial infarction but no heart failure was associated with better clinical outcomes driven by lower risk of recurrent myocardial infarction without statistically significant difference in mortality (hazard ratio for all-cause mortality 0.77, 95% CI 0.52-1.14, P = .197).²⁶ These lines of evidence suggest a potential clinical benefit of oral beta-blocker therapy in patients with stable coronary artery disease having prior myocardial infarction; however, further studies are warranted to elucidate the role of beta-blocker in patients with stable coronary artery disease having prior myocardial infarction.

There are several limitations in this meta-analysis. First, we used an adjusted hazard ratio (or hazard ratio in the propensity score-matched patients) as a measure of effect, since only observational studies were available to address this clinical question. Multivariate analysis or propensity score matching can control measured confounding variables, but it cannot account for unmeasured confounders. Patients who did not receive beta-blockers were more likely to have had a contraindication to beta-blocker such as hypotension, bradycardia, or decompensated heart failure. Therefore, we cannot exclude the possibility that these potential biases might have inflated the mortality benefit associated with oral beta-blocker therapy observed in this meta-analysis. In addition, several studies used a subgroup analysis of the propensity-matched population, which is another potential cause of bias. Second, beta-blocker therapy was defined as a beta-blocker prescription at the time of discharge, which may not be representative of long-term beta-blocker therapy. The studies included in this meta-analysis only enrolled patients who were discharged alive. Finally, we could not exclude the possibility of existence of publication based on the visual assessment of Funnel plot, although Begg test did not show significant publication bias. Considering the lack of randomized control trial assessing the efficacy of oral beta-blocker therapy in this specific population, this meta-analysis would be the current most comprehensible evidence supporting oral beta-blocker therapy in patients with STEMI who are treated with primary PCI and have preserved LVEF, as recommended by the current guidelines. However, our results should be considered as hypothesis generating because of these study limitations.

Conclusion

This meta-analysis demonstrates that oral beta-blocker is associated with decreased all-cause mortality in patients with STEMI who are treated with primary PCI and who have preserved LVEF. We conclude that it would be prudent to prescribe oral beta-blocker in all patients with STEMI, unless contraindicated, as recommended by the current guidelines, while awaiting the results of a randomized controlled trial.

Footnotes

Acknowledgments

The authors would like to thank Kamyar Arasteh for statistical analysis support and Raposeiras-Roubín Sergio for providing data for this analysis.

Author Contribution

Misumida, N and Kanei, Y contributed to conception or design, acquisition, analysis, or interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Harjai, K and Kernis, S contributed to acquisition, analysis, or interpretation; critically revised the manuscript; gave final approval; and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304(14):801–807.

A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA. 1982;247(12):1707–1714.

Hjalmarson

Herlitz

Holmberg

. The Göteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation. 1983;67(6 pt 2):I26–I32.

Yusuf

Peto

Lewis

Collins

Sleight

. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27(5):335–371.

Boissel

Leizorovicz

Picolet

Ducruet

. Efficacy of acebutolol after acute myocardial infarction (the APSI trial). The APSI Investigators. Am J Cardiol. 1990;66(9):24C–31C.

Pfisterer

Cox

Granger

. Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries. J Am Coll Cardiol. 1998;32(3):634–640.

Freemantle

Cleland

Young

Mason

Harrison

. beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318(7200):1730–1737.

O’Gara

Kushner

Ascheim

. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2013;82(1): e1–e27.

Steg

James

Atar

. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569–2619.

10.

Keeley

Boura

Grines

. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13–20.

11.

Kernis

Harjai

Stone

. Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty? J Am Coll Cardiol. 2004;43(10):1773–1779.

12.

Nakatani

Sakata

Suna

. Impact of beta blockade therapy on long-term mortality after ST-segment elevation acute myocardial infarction in the percutaneous coronary intervention era. Am J Cardiol. 2013;111(4):457–464.

13.

Ozasa

Kimura

Morimoto

. Lack of effect of oral beta-blocker therapy at discharge on long-term clinical outcomes of ST-segment elevation acute myocardial infarction after primary percutaneous coronary intervention. Am J Cardiol. 2010;106(9):1225–1233.

14.

Dargie

. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357(9266):1385–1390.

15.

Higgins

JPT

Thompson

Deeks

Altman

. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560.

16.

Bao

Ozasa

Morimoto

. β-Blocker therapy and cardiovascular outcomes in patients who have undergone percutaneous coronary intervention after ST-elevation myocardial infarction. Cardiovasc Interv Ther. 2013;28(2):139–147.

17.

Yang

Hahn

J-Y

Song Y

Bin

. Association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. JACC Cardiovasc Interv. 2014;7(6):592–601.

18.

Choo

Chang

Ahn

. Benefit of β-blocker treatment for patients with acute myocardial infarction and preserved systolic function after percutaneous coronary intervention. Heart. 2014;100(6):492–499.

19.

Raposeiras-Roubín

Abu-Assi

Redondo-Diéguez

. Prognostic Benefit of Beta-blockers After Acute Coronary Syndrome With Preserved Systolic Function. Still Relevant Today? Rev Esp Cardiol (Engl Ed). 2015;68(7):585–591.

20.

Konishi

Miyauchi

Kasai

. Long-term effect of β-blocker in ST-segment elevation myocardial infarction in patients with preserved left ventricular systolic function: a propensity analysis[published online January 9, 2015]. Heart Vessels. 2015.

21.

De Luca

de Boer

M-J

Ottervanger

. Impact of beta-blocker therapy at discharge on long-term mortality after primary angioplasty for ST-segment elevation myocardial infarction. Am J Cardiol. 2005;96(6):806–809.

22.

Siu

C-W

Pong

Jim

M-H

. Beta-blocker in post-myocardial infarct survivors with preserved left ventricular systolic function. Pacing Clin Electrophysiol. 2010;33(6):675–680.

23.

Konishi

Haraguchi

Yoshikawa

Kimura

Inagaki

Isobe

. Additive effects of β-blockers on renin-angiotensin system inhibitors for patients after acute myocardial infarction treated with primary coronary revascularization. Circ J. 2011;75(8):1982–1991.

24.

Bangalore

Steg

Deedwania

. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA. 2012;308(13):1340–1349.

25.

Bauters

Lemesle

Meurice

Tricot

de Groote

Lamblin

. Prognostic impact of ß-blocker use in patients with stable coronary artery disease. Heart. 2014;100(22):1757–1761.

26.

Bangalore

Bhatt

Steg

. β-blockers and cardiovascular events in patients with and without myocardial infarction: post hoc analysis from the CHARISMA trial. Circ Cardiovasc Qual Outcomes 2014;7(6):872–881.