The Effect of Beta-Blocker Post-Myocardial Infarction With Ejection Fraction >40% Pooled Analysis From Seven Arabian Gulf Acute Coronary Syndrome Registries

Abstract

The use of beta-blockers (BB) in reduced left ventricular ejection fraction (LVEF) post-myocardial infarction (MI) is associated with reduced 1-year mortality, while their role in patients with mid-range and preserved LVEF post-MI remains controversial. We studied 31,620 patients who presented with acute coronary syndrome (ACS) enrolled in seven Arabian Gulf registries between 2005 and 2017. Patients with LVEF ≤40% were excluded. The remaining cohort was divided into two groups: BB group (n = 15,541) and non-BB group (n = 2,798), based on discharge medications. Patients in the non-BB group were relatively younger (55.3 vs. 57.4, P = .004) but higher risk at presentation; with higher Global Registry of Acute Coronary Events (GRACE) score (119.2 vs 109.2, P < .001), higher percentage of cardiogenic shock (3.5 vs 1.4%, P < .001), despite lower prevalence of comorbidities, such as hypertension and hyperlipidemia. BB use was associated with lower 1-year mortality in a multivariate logistic regression analysis, adjusting for major confounders [adjusted odds ratio (OR): 0.71 (95% CI 0.51–0.99)]. This remained the case in a sensitivity analysis using propensity score matching [adjusted OR: 0.34 (95% CI 0.16–0.73)]. In this study, using Arabian Gulf countries registries, the use of BB after ACS with LVEF >40% was independently associated with lower 1-year mortality.

Keywords

beta-blocker myocardial infarction secondary prevention

Introduction

Patients presenting with myocardial infarction (MI) often leave the hospital with multiple drugs, including dual antiplatelet agents, statins, and beta-blockers (BB). All have been shown to reduce mortality in all MI patients except the BB, where its role has been questioned in patients with normal and mildly reduced LVEF.^1-3 The data supporting a mortality benefit of BB in patients with MI goes back to 1981 before the revascularization era. Aside from mortality in the pre-revascularization era, there was 1.5% relative reduction in ventricular arrythmias.⁴ However, even at the time of fibrinolysis, there was a controversy about its protective role. A large randomized controlled trial showed that there was no difference in the composite outcome of mortality, reinfarction, or cardiac arrest post-fibrinolysis.⁵ There was a 0.5% reduction in both reinfarction and ventricular arrhythmia in the group treated with BB but came with the expense of 1.1% increase in cardiogenic shock, and therefore, the recommendation based on this trial was to use it 1 day after fibrinolysis in hemodynamically stable patients.⁵

The American College of Cardiology (ACC) and the American Heart Association (AHA) non-ST elevation acute coronary syndrome (NSTE-ACS) 2014 guidelines indicated that it is reasonable to use BB in patients with normal left ventricular (LV) function and NSTE-ACS (Class IIa, Level of Evidence (LOE) C). This recommendation was based on data from meta-analyses that included many studies carried out before coronary stenting was adopted and also included heart failure patients.^6-8 The latest ACC/AHA/Society for Cardiovascular Angiography and Interventions (SCAI) coronary artery revascularization guidelines give a class III recommendation, with no benefit in patients with normal left ventricular function who presented with stable coronary artery disease and underwent revascularization. However, the societies also endorsed an unclear benefit in patients post-MI with preserved ejection function and therefore their use should be on an individualized basis.⁹ The use of BB in patients after MI with preserved ejection fraction remains debatable in the post-revascularization era.

While some data suggest no protective benefit of BB in patients post-MI without heart failure in the reperfusion era,^10-12 others suggest that BB use has a protective role and discontinuation after MI without heart failure may lead to more ACS or mortality.^13-16 Recently published data from SWEDEHEART showed no benefit of using BB beyond 1 year and up to 4.5 years¹⁷ However, the benefit from other trials might vary from short-term <30 days, 2 years, or ≥3 years ^14,15,18,19 Overall, only a few large registry data included a pre-defined LVEF >40%.^15,16,18,19

The present study pooled data from seven Arabian Gulf countries registries, which included patients who presented with ACS. The aim was to establish if patients discharged on BB after ACS admission with ejection fraction >40% have a better survival compared with those who are not on BB at the time of discharge.

Methods

Study Population and Outcomes

This is a retrospective cohort study using data from seven prospective registries: Saudi Project for Assessment of Coronary Events (SPACE), Gulf Registry of Acute Coronary Events (Gulf RACE), Gulf RACE-2, Gulf RACE-3, Gulf Locals with Acute Coronary Syndrome Events Registry (Gulf COAST), Kuwait Reperfusion in ST-Segment–Elevation Myocardial Infarction (Kuwait REPERFUSE), and Saudi Acute Myocardial Infarction Registry (STARS).^20-29 The registries represent data from seven countries: Saudi Arabia, Kuwait, Bahrain, Qatar, United Arab Emirates, Oman, and Yemen. They enrolled patients with ACS between 2005 and 2017. All seven registries have in-hospital outcomes. Four of the registries have 1-month and 1-year mortality outcomes (Gulf RACE-2, Gulf COAST, Kuwait REPERFUSE, and STARS). All registries are summarized in Supplementary Table 1.³⁰ We excluded patients with heart failure with reduced ejection fraction (HFrEF) (LVEF ≤40%) based on index admission echocardiography. We then divided up the patients to beta-blocker use (BB) or non-beta-blocker use (non-BB) based on their discharge medications, which was at the discretion of the primary physician. Primary outcome was 1-year all-cause mortality. Secondary outcome was 1-month mortality.

Study Variables

Study variable included baseline characteristics (i.e., demographics, smoking history, and comorbidities), presentation (i.e., hemodynamics, GRACE score and Killip class, ACS type, LVEF, cardiogenic shock, and cardiac arrest), in-hospital outcomes (i.e., revascularization, recurrent ischemia, heart failure, stroke, bleeding, discharge status, and medications on discharge), and mortality (1-month and 1-year all-cause mortality).

Statistical Analysis

Continuous data were reported as mean (± standard deviation) and categorical data as numbers (percentages). Student’s t test, Chi Square test, and Fisher’s exact test were used as appropriate to analyze data. Given that statistical significance is an insensitive measure of the effect size that can be misinterpreted when the sample size is large, we quantified the effect size using the standardized mean difference for continuous variables and phi coefficient for categorical variables. 10% or less (≤10%) is considered small effect size for both statistics.^31,32

To assess the independent effect of BB at discharge on 1-year mortality, we used multivariate logistic regression modeling to adjust for important confounders. We included all the variables that were significantly associated with 1-year mortality in univariate analysis. In addition, we included variables that were significantly associated with BB use in univariate analysis. The final model included the following variables: baseline characteristics (age, sex, ethnicity, current smoking, obesity, diabetes mellitus, hypertension, dyslipidemia, history of coronary artery disease, history of chronic kidney disease, history of heart failure, and history of stroke), presentation characteristics (heart rate, systolic blood pressure, acute coronary syndrome type, cardiogenic shock, cardiac arrest, and Killip class), in-hospital outcomes (revascularization, primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), atrial fibrillation, recurrent ischemia, heart failure, stroke, and major bleeding), and medications on discharge (antiplatelet therapy, angiotensin-converting-enzyme (ACE) inhibitors, and statin).

We also performed a sensitivity analysis using propensity score matching. Matching was performed at a ratio of 1:1 using the nearest neighbor method with a caliper width of 0.2 times the standard deviation. Analyses were performed using SAS (version 9.4, The SAS institute, Cary, North Carolina USA). Two-tailed tests were used, and P < .05 was considered statistically significant.

Results

Overall Cohort

A total of 31,620 patients were enrolled in seven Arabian Gulf registries. After excluding patients with LVEF <40%, 18,339 patients were included (15,541 in the BB group and 2,798 in the non-BB group), (Figure 1). Baseline characteristics, presentation, medications on discharge, and hospital course data are summarized in Table 1.

Figure 1.

Flow chart of the study cohort. ACS, acute coronary syndrome LVEF, left ventricular ejection fraction BB, and beta-blocker.

Table 1.

Baseline Characteristics, Presentation, and In-Hospital Outcomes of Patients Discharged on a Beta-Blocker Vs Those Not Discharged on a Beta-Blocker Post-Acute Coronary Syndrome Admission.

	BB (n = 15,541)	Non-BB (n = 2,798)	P Value	Effect size, %
Baseline characteristics
Age (years) **	55.3 ± 12.1	57.4 ± 13.5	<0.001	17
Sex (male)	12510/15538 (80.5%)	2029/2798 (72.5%)	<0.001	7.1
Ethnicity (Arab)	10129/15541 (65.2%)	439/2798 (76.5%)	<0.001	8.6
Current smoker	4026/15517 (26%)	771/2795 (27.6%)	0.07	1.3
Obesity (BMI >25)	4312/14537 (29.7%)	934/2639 (35.4%)	<0.001	4.5
Diabetes mellitus	6725/15464 (43.5%)	1144/2779 (41.2%)	0.023	1.7
Hypertension	7803/15474 (50.4%)	1319/2781 (47.4%)	0.004	2.2
Hypercholesterolemia	5477/14708 (37.2%)	920/2675 (34.4%)	0.005	2.1
History of coronary artery disease	9794/15541 (63%)	1744/2798 (62.3%)	0.487	0.1
History of chronic kidney disease	317/12732 (2.49%)	73/2394 (3.1%)	0.113	1.3
History of stroke	562/15473 (3.6%)	138/2788 (5%)	<0.001	2.5
Presentation characteristics
Heart rate (beats/min) **	83.4 ± 19.4	83 ± 22.6	<0.001	2.0
Systolic blood pressure, mmHg **	140.2 ± 28	135.7 ± 29.4	<0.001	15.9
GRACE score **	109.2 ± 34.9	119.2 ± 41	<0.001	27.7
Type of ACS			<0.001	9.3
- Anterior STEMI	3546/15539 (22.8%)	373/2797 (13.3%)
- Inferior STEMI	3112/15539 (20%)	699/2797 (25%)
- Other STEMI	124/15539 (8%)	172/2797 (6.2%)
- NSTEMI	7641/15539 (49.2%)	1553/2797 (55.5%)
Cardiac arrest	137/15529 (0.9%)	36/2797 (1.3%)	0.042	1.5
Cardiogenic shock	218/15538 (1.4%)	98/2797 (3.5%)	<0.001	5.8
Killip class (class I)	13406/15291(87.7%)	2169/2775 (78.2%)	<0.001	10.0
Discharge medications
Antiplatelet therapy	3731/15490 (24.1%)	943/2668 (35.3%)	<0.001	17.1
- Single	11656/15490 (75.3%)	1588/2668 (59.5%)
- Dual	103/15490 (0.7%)	137/2668 (5.1%)
- None
ACEI or ARB	12667/15538 (64.9%)	1814/2796 (81.5%)	<0.001	14.7
Spironolactone	107/2855 (3.8%)	11/320 (3.4%)	0.781	0.1
Statin	14701/15539 (94.6%)	2354/2713 (86.8%)	<0.001	11.3
In-hospital outcomes
In-hospital revascularization	2443/14175 (17.2%)	256/2482 (10.3%)	<0.001	6.7
Primary PCI for STEMI	1756/7898 (22.2%)	154/1244 (12.4%)	<0.001	8.3
Atrial fibrillation	194/15539 (1.3%)	51/2797 (1.8%)	0.015	1.8
In-hospital recurrent ischemia	1526/15537 (9.8%)	374/2797 (13.4%)	<0.001	4.2
Heart failure	864/15535 (5.6%)	367/2797 (13.1%)	<0.001	10.9
Stroke	55/15508 (0.35%)	16/2796 (0.57%)	0.088	1.3
Major bleeding	94/15538 (0.6%)	28/2798 (1%)	0.018	1.8

*Data shown as n (%) values except as noted. **Data as mean ± SD.

BB, beta-blocker; BMI, body mass index; GRACE, Global Registry of Acute Coronary Events; ACS, acute coronary syndrome; STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST elevation myocardial infarction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; PCI, percutaneous coronary intervention.

Mean age was 57.4 years in the non-BB group vs 55.3 years in the BB group (P < .001). The BB group had a higher prevalence of diabetes mellitus (43.5 vs 41.2%, P = .023), hypertension (50.4 vs 47.4%, P = .004), and hyperlipidemia (37.2 vs 34.4%, P = .005). The non-BB group had higher prevalence of obesity (35.4 vs 29.7%, P < .001), history of stroke (5 vs 3.6%, P < .001), and more presentation of cardiac arrest (1.3 vs 0.9%, P = .042) and cardiogenic shock (3.5 vs 1.4%, P < .001).

Primary PCI for STEMI was higher in the BB group (22.2 vs 12.4%, P < .001) so as in-hospital revascularization (other than primary PCI) 17.2 vs 10.3% in the BB group vs non-BB group (P < .001). Recurrent ischemia was higher in the non-BB group (13.4 vs 9.8%, P < .001) along with in-hospital heart failure incidence (13.1 vs 5.6%, P < .001). The BB group were more likely to be discharged on DAPT (75.3 vs 59.5%, P < .001), statin (94.6 vs 86.8%, P < .001) and less likely to be discharged on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) (64.9 vs 81.5%, P < .001).

Mortality Difference

One-year mortality information was available for 7,332 patients. It was lower in the BB group (4.1 vs 6.5% in the non-BB group) (P < .001) (Table 2). Secondary outcome was 30-day mortality which was available for 8,115 patients and was found to be lower in the BB group, 1.8 vs 3.7% in the non-BB group (P < .001) (Figure 2). BB use was associated with a significant reduction in 1-year mortality in a multivariate logistic regression analysis, adjusting for all important confounders [adjusted odds ratio (OR): 0.71 (95% CI 0.51–0.99)].

Table 2.

Primary and Secondary Outcomes in Beta-Blocker vs Non-Beta-Blocker Groups.

	BB (n = 15,541)	Non-BB (n = 2,798)	P Value	Effect size, %
Primary outcome
1-year mortality	215/6184 (4.1%)	75/1148 (6.5%)	<0.001	4.4
Secondary outcome
1-month mortality	121/6832 (1.8%)	48/1283(3.7%)	<0.001	5.0

^aData shown as n (%).

BB, beta-blocker.

Figure 2.

Primary and secondary outcomes in BB vs non-BB.

Sensitivity Analysis

An additional sensitivity analysis was performed using propensity score matching (Figure 3). As shown in Supplementary Table 2, characteristics were well-balanced after matching, including primary PCI and revascularization with small effect size. Even after adjusting for BP, antiplatelet therapy, BB use was associated with a significant reduction in 1-year mortality [adjusted OR: 0.34 (95% CI 0.16–0.73)].

Figure 3.

Primary and secondary outcomes after propensity score matching in BB vs non-BB.

Subgroup Analysis

Subgroup analysis (Figure 4) showed no significant interaction based on age (<50, 51–75, and >75), sex, ethnicity, obesity, DM, presentation (STEMI and NSTEMI), and LVEF (41–50% and >50%). Although the OR of 1-year mortality was pointing towards a protective BB effect for all the subgroups except for the revascularized subgroup, the CI did not support that finding. The OR of 1-year mortality with BB in the revascularized group was 2.3, pointing towards a non-protective BB effect, but had a wide 95% confidence interval (0.3–17.7) and non-significant P value (P = .242). The subgroup analysis results could be because of smaller samples to see the difference. Moreover, there was a mortality benefit with BB use in the propensity score matching regardless of revascularization.

Figure 4.

Subgroup analysis of BB use and mortality effects.

Discussion

Our data from large multi-center prospective registries showed that BB use was associated with a significant 1-year mortality reduction in patients who presented with ACS with mid-range and preserved LVEF, even after extensive adjustment for confounders and propensity score matching. This is one of the largest studies that used a pre-defined LVEF to address the effect of BB post-ACS with mid-range and preserved LVEF.

The role of BB use post-MI with mid-range or preserved LVEF has been a debatable topic. Summary of previously published data on the effect of BB on mortality is presented in Table 3.

Table 3.

Previously Published Articles on BB Use in ACS Without Heart Failure.

Study	Publication year	Total number of patients	Total number of patients on BB	Study type	% revascularized	Follow-up (median)	Primary outcome	Mortality benefit of BB	Included pre-defined LVEF
Bangalore et al.¹¹	2014	102,003 (48,806 post-perfusion era)	Not mentioned	Meta-analysis, 60 randomized studies (12 post-reperfusion era), (1966–2005)	Majority not reported	10 months	Post-reperfusion era: Mortality incident RR 0.98; (95% CI, 0.92 to 1.05)	No mortality benefit post-reperfusion era	No
Choo et al.¹⁵	2014	3,019	2,424 (80%)	Retrospective, propensity score matching (2004–2009)	100% PCI	3 years	All-cause mortality and cardiac mortality in non-BB vs BB (10.8 vs 5.7%, P < .001), (7.6 vs 2.6%, P < .001)	Yes	Yes, ≥50%
Raposeiras et al.¹⁶	2015	3,236	2,277 (70%)	Retrospective, propensity score matching(2003–2012)	65.2% PCI	5.2 years	All-cause mortality: 25.2% (non-BB) vs 11.6% (BB), (P < .001)	Yes	Yes, ≥50%
Konishi et al.¹⁸	2015	424	197 (46%)	Retrospective, propensity score matching (1997–2011)	100% PCI	4.7 years	Cardiac mortality – lower in the BB group (HR 0.40 (95% CI, 0.14 to 0.97; P = .04)	Yes	Yes, >40%
Huang et al.³⁷	2015	40,873		Meta-analysis, 10 observational trials (1974–2014)	100% PCI	<1 year	Unadjusted RR for all-cause mortality with the use of BB in preserved LVEF was 0.79 (95% CI: 0.59 to 1.07; I² = 61%, P = .026)	Not for preserved LVEF	Yes (except 2 studies), 43–63%
Puymirat et al. ¹⁹	2016	2,679	2,050 (77%)	Retrospective analysis of prospective registry (FAST-MI),Multivariate analysis and propensity score matching, (2005)	48.7% PCI	30 days,1 year,5 years	30-day mortality lower in BB (adjusted HR 0.46, 95% CI 0.26 to 0.82),1-year mortality adjusted HR 0.77, (95% CI 0.46–1.30)5-year mortality adjusted HR 1.19, (95% CI 0.65–2.18)	Yes- 1 monthNo- 1 and 5 years	Yes, LVEF >40%
Abi Khalil et al.³⁴	2017	4,208	3,520 (84%)	Retrospective analysis of GULF RACE-2 registry (2008–2009)	27% (PCI and CABG)	1 year	1-year mortality lower in the BB group (4.1 vs 10.6%, OR 0.64, 95% CI, 0.48–0.87, P = .001)	Yes	Yes, LVEF ≥40%
Dondo et al. ³⁸	2017	179,810	170,475 (95%)	Retrospective analysis of national English and Welsh registry data from the myocardial ischemia national Audit project, propensity score analysis, (2007–2013)	40% PCI or CABG (20% missing data)	1 month, 6 months,1 year	Adjusted 1-year mortality was not statistically significant between the BB and non-BB groups. (Average treatment effect (ATE) coefficient: 0.07; 95% CI: −0.60 to 0.75; P = .827)	No	Not in all patients, LVEF >30%
Neumann et al.¹³	2018	73,450	63,041 (86%)	Retrospective, Propensity score matching (2007–2012)	95.2% PCI6.5% CABG	3.8 years	Adjusted HR for all-cause mortality with BB discontinuation 1.13 (95% CI, 0.94 to 1.36)	Yes	No
Dahl et al.¹²	2019	189,385	164,408 (87%)	Meta-analysis, 16 observational studies, (2000–2017)	48.7–100%	2.7 years	Adjusted rate ratio (RR) for all-cause mortality 0.90, (95% CI 0.77 to 1.04), moderate heterogeneity (I² = 67.4%)	No	Yes for 10/16 studies, LVEF 48.9–60.4%
Montenegro et al.³⁵	2019	9,429	7,692 (82%)	Retrospective, multivariate logistic regression (2010–2016)	70% PCI	In-hospital (median 3–5 days)	In-hospital mortality OR 0.3, (95% CI 0.1 to 0.6; P = .003) for LVEF 40–49% on BB	Yes, for LVEF 40–49% but not for LVEF >50%	Yes, 3 groups (LVEF >50%, LVEF 40–49% and LVEF <40%)
Kim et al¹⁴	2020	28,970	22,707 (78%) on BB >1 year	Retrospective, multivariable mixed-effects cox regression analysis (2010–2015)	100%	3.5 years	All-cause mortality lower in the BB use beyond 1 year, HR = 0.50 (95% CI 0.46 to 0.55; P < .001)Persisted mortality benefit beyond 2 years but not beyond 3 years	Yes	No
Abi Khalil et al.³⁶	2020	2,028	1,123 (55%)	Retrospective gulf COAST registry, propensity score matching. (2012–2013)	27% PCI	1 month6 months1 year	1-month mortality was significantly reduced by BB use with OR 0.25, (95% CI 0.09 to 0.67, P = .006)6-month and 12-month mortality not reduced by BB use with OR 0.86 (95% CI 0.4 to 1.86) and OR 0.74 (95% CI 0.35 to 1.55) respectively	Yes for 1 monthNo benefit at 6 and 12 months	Yes, ≥40%
Chen et al³³	2021	2,397	2,060 (86%)	Retrospective, propensity score matching and inverse probability treatment weighting. (2010–2017)	100% PCI	727 days	Adjusted HR for all-cause mortality with BB use HR = 0.53; (95% CI: 0.29 to 0.98, P = .044)	Yes	Yes, >50%
El nasasra et al.³⁹	2021	7,392	6,007 (80%)	Retrospective, multivariate analysis.(2000–2016)	87.3% PCI4.6% CABG	1 year	MACE^a rates at 30 days 9% BB and 9.5% no BB (no difference) -1-year mortality on BB HR 0.8, 95% CI 0.58 to 1.11, P = .18)	No	Yes, >40%
Holt et al.¹⁰	2021	30,177	24,770 (82%)	Retrospective, multivariate logistic regression analysis (2003–2018)	83.8% PCI	3 months-3 years	Cardiovascular mortality 1.4% (no BB) vs 1.5% (BB), ARD 0.1% (95% CI −0.3% to 0.5%)	No	No
Ishak et al.¹⁷	2022	43,618	34,253 (78.5%)	Retrospective, nationwide cohort study (SWEDEHEART) (2005–2016)	78% PCI3.3% CABG	1 year- 4.5 years	Composite of all-cause mortality, recurrent MI, unscheduled revascularization, or heart failure hospitalization = 18.9% (BB) vs 21.7% (non-BB) (HR 0.99; 95% CI 0.93 to 1.04)	No	Yes, LVEF ≥ 50%
Al-Bawardy et al	2023	31, 620 (18,339 after excluding patients with LVEF <40%)	15,541 (85%)	Retrospective, multi-center registries, multivariate logistic regression analysis and propensity score matching (2005–2017)	18%	1 month1 year	1-month mortality 3.7% (non-BB) vs 1.8% (BB) (P < .001)1-year mortality 6.5% (non-BB) vs 4.1% (BB) (P < .001)	Yes	Yes, >40%

^aMACE = 30-day mortality, recurrent MI, ischemia, stent thrombosis, stroke, and urgent revascularization.

BB, beta-blocker; RR, risk ratio; LVEF, left ventricular ejection fraction; CI, confidence interval; PCI, percutaneous coronary intervention; HR, hazard ratio; FAST-MI, French registry of Acute ST- and non-ST-elevation Myocardial Infarction; CABG, coronary artery bypass graft; Gulf RACE, Gulf Registry of Acute Coronary Events; Gulf COAST, Gulf Locals with Acute Coronary Syndrome Events Registry.

Data with Evidence That BB Have a Protective Role

There is data to support the findings of our study. Several small observational studies showed mortality benefit of BB when used post-MI with pre-defined LVEF.^15,16,18,33 Larger registries from Korea and France showed potential protective role with the use of BB in patients who present with AMI and undergo revascularization with no HF.

A Korean registry of 3,109 patients with AMI who underwent PCI and had pre-defined LVEF ≥50% found a reduction in all-cause mortality and cardiac mortality beyond 3 years in patients treated with BB compared with those who are not (5.7 vs 10.8%, P < .001, 2.6 vs 7.6%, P < 001).¹⁵ Another observational study of 3,236 patients with pre-defined LVEF ≥50% showed that the use of BB in patients post-MI with normal LVEF is associated with lower long-term mortality with a median follow-up of 5 years (11.6 vs 25.2%; P < .001).¹⁶ A smaller additional study of 424 patients with pre-defined LVEF >40% post-MI found that the use of BB significantly reduced cardiac mortality with a median follow-up of 4.7 years.¹⁸

A French registry found that out of all patients (n = 73,450) who presented with AMI without HF and underwent revascularization, the discontinuation of BB after a year with follow-up up to 3.8 years had higher rates of all-cause mortality or ACS (adjusted HR for mortality of ACS 1.17 (95% CI, 1.01–1.35). However, the difference did not reach statistical significant for all-cause mortality (adjusted HR 1.13 (95% CI, 0.94–1.36).¹³ Nonetheless, one of the main limitations of the study was the lack of pre-defined LVEF. Another Korean registry followed 28,970 patients for a year after presenting with AMI resulting in coronary revascularization. Receiving BB beyond a year was also associated with a lower HR (0.81, 95% CI 0.72–0.91) for all-cause mortality, which was persistent beyond 2 years as well but not beyond 3 years.¹⁴ This study also lacked pre-defined LVEF.

Similar to our findings, Abi Khalil and colleagues saw a difference in mortality favoring BB with pre-defined LVEF ≥40% after ACS.³⁴ However, their sample size is smaller with 4,208 patients.

Is the Benefit Short-Term Only?

Our study showed both 1-month and 1-year mortality benefit with BB use in patients with AMI and LVEF ≥40%. The short-term mortality benefit was also supported by other studies. A Portuguese national registry data enrolling 9,429 ACS patients showed an in-hospital mortality benefit with the use of BB post-ACS with LVEF 40–49% but not for >50%.³⁵ Nonetheless, the study did not have long-term outcome to see if it is a sustainable benefit. A French registry enrolled 2,679 patients post-MI with pre-defined LVEF >40% and found that BB use reduced 30-day mortality.¹⁹ However, its discontinuation after 1 year did not increase mortality at 1-year and 5 years.¹⁹ This was an older study from 2005 and had fewer patients compared with our study. Our study did not go beyond 1-year follow-up to look for a difference beyond a year.

Another registry from the Gulf region (GULF COAST registry) showed 30-day mortality benefit in patients treated with BB after their ACS presentation with LVEF >40% compared with those who were not.³⁶ However, that mortality benefit faded away at 1 year and was no longer significant.³⁶ It is important to mention the study was smaller than ours with 2,028 patients.

In summary, the studies that showed short-term benefit only had fewer patients than ours.

Data With No Protective Role of BB

There is also data supporting a lack of protective role of BB in patients post-MI without heart failure. Several meta-analyses carried out had multiple limitations such as including observational studies and pre-reperfusion old studies with missing pre-defined LVEF.

An old meta-analysis published in 2014 showed no mortality or net benefit of BB in MI patients without heart failure in the reperfusion era compared to pre-reperfusion era.¹¹ Although there was a decrease in MI and angina in the reperfusion era, it came with the expense of more heat failure and cardiogenic shock as well as higher drug discontinuation.¹¹ Although the exclusion criteria of this meta-analysis included post-MI heart failure trials, not all included trials studied preserved LVEF patients only. Most importantly, they were mainly old trials, of which only two trials were published after 2005.

A subsequent meta-analysis published the following year in 2015 showed that all-cause and cardiac mortality was lower in the group treated with BB compared with no BB, but the finding was restricted to those with reduced LVEF.³⁷ Nevertheless, they included observational studies, some prior to the reperfusion era.

Another more recent meta-analysis published in 2019 with all 16 studies published in the 2000s found that there was 26% reduction in all-cause mortality with BB after MI with no heart failure. However, that effect disappeared when controlling for bias.¹² Most studies included did not have pre-defined LVEF and only four had pre-defined LVEF >40% (2 of them with LVEF ≥50%).¹²

There are several registries published that also support the lack of BB protective effect. However, some limitations include the lack of pre-defined LVEF. One example is a large registry data from the UK with >170,000 patients admitted with AMI between 2007 and 2013 that showed an overall higher mortality at 1 year, 5.2%, which is similar to our cohort.³⁸ Although the unadjusted 1-year mortality was lower in the BB group compared with those not on a BB (4.9 vs 11.2%; P < .001), the adjusted mortality was similar in the two groups.³⁸ One of their limitations is that the definition of heart failure for their study was based on the hospital records, which did not always include a pre-defined LVEF and included clinical heart failure definition.³⁸ Another example of the lack of pre-defined LVEF is a Danish registry published in 2021 that showed that the use of BB medications beyond 3 months post-MI in patients without HF did not affect cardiovascular mortality, recurrent MI, or composite of the two outcomes after 3 years compared with patients who are not on BB after 3 months of their MI and up to 3 years.¹⁰ However, their outcomes which included cardiovascular mortality at 3 years were very low in both groups <2% compared with our mortality rates.¹⁰

Two registries found no protective role of BB with pre-defined LVEF. The first is a smaller registry (n = 7,392) from Israel that showed also no 30-day or 1-year mortality benefit with BB use in patients with AMI and LVEF 40–49% or >50%. However, the study cohort included patients as early as 2000 and one main difference with our study is the very low rates of 30-day mortality (0.6%) and 1-year mortality (2.7%) to possibly detect a difference.³⁹

The second and largest registry (n = 43,618) that showed no protective role of BB with pre-defined LVEF comes from SWEDEHEART. They found no benefit in the use of BB in patients post-MI with normal LVEF starting 1 year and up to median of 4.5 years on composite outcomes that included all-cause mortality, recurrent MI, unscheduled revascularization, and heart failure hospitalization.¹⁷ However, their study addressed the effect of BB use beyond 1 year of MI and excluded mid-range LVEF but had higher rates of revascularization compared with our study.

In summary, most of the studies that showed no benefit of BB on mortality in patients without heart failure were either beyond a year with normal LVEF, limited by small numbers of events or lacked a pre-defined LVEF. In comparison, we have included large number of patients with pre-defined LVEF in the mid-range or preserved. Our mortality rates were higher than some of previous studies which could potentially explain the difference in outcomes.^10,39 However, we had low numbers of revascularization compared with previously mentioned trials (40–92 vs 18%), which may have contributed to our finding of protective BB role with possible residual CAD.^10,17,38,39 Nonetheless, as described above, even with 100% revascularization rates, some studies have shown the benefit of BB on mortality.^15,18,33 It remains unclear if revascularization lessens the effects of BB on mortality in those with mid-range and preserved LVEF.

Although this study is a large study that includes multiple registries, it carries the expected limitations of registries. The 30-day and 1-year mortality were not available for all the registries. We do not have data on adherence to medications that could affect the interpretation of the reported outcomes. Another limitation of our study is the missing data on residual CAD after PCI and whether BB play a protective role in that patient population. Although with matched cohort and similar comorbidities, the extent of CAD is likely similar in the two groups. We also have low percentage of revascularization that could have affected the generalizability of our results due to recruitment of non-PCI hospitals in the registries. The revascularization rates could be higher than reported, as they will not be captured if patients were transferred to PCI centers. However, even with propensity score matching regardless of revascularization, there was a mortality benefit of BB in mid-range and normal LVEF post-MI up to a year post-MI. We do not have data beyond 1 year and it is unclear if the benefit fades away after a year.

In conclusion, our study shows 1-month and 1-year mortality benefit of BB use in the Gulf population patients after ACS with mid-range and preserved LVEF. The mortality benefit remained statistically significant even after propensity score matching with adjustment for residual confounders. Randomized controlled trials will be needed to address this question and produce definitive answers.

Supplemental Material

Supplemental Material - The Effect of Beta-Blocker Post-Myocardial Infarction With Ejection Fraction >40% Pooled Analysis From Seven Arabian Gulf Acute Coronary Syndrome Registries

Supplemental Material for The Effect of Beta-Blocker Post-Myocardial Infarction With Ejection Fraction >40% Pooled Analysis From Seven Arabian Gulf Acute Coronary Syndrome Registries by Rasha Al-Bawardy, MD, MSc, Wael Alqarawi, MD, MSc, Jassim Al Suwaidi, MBChB, Wael Almahmeed, MD, Mohammad Zubaid, MBChB, Haitham Amin, MD, Kadhim Sulaiman, MD, Ahmad Al-Motarreb, MD, and Khalid Alhabib, MBBS in Angiology.

Footnotes

Acknowledgments

The authors acknowledge the Gulf Heart Association, the Saudi Heart Association, the College of Medicine Research Center at King Khalid University Hospital, and the King Saud University, Riyadh, Saudi Arabia for their support with the initial registries.

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.

ORCID iDs

Rasha Al-Bawardy

Mohammad Zubaid

Supplemental Material

Supplemental material for this article is available online.

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