The aim of the present review was to investigate the association between the use of oral β-blockers and prognosis in patients with acute myocardial infarction (AMI) who underwent percutaneous coronary intervention (PCI) treatment. A systematic literature search was conducted in Pubmed (from inception to September 27, 2014) and Embase (Ovid SP, from 1974 to September 29, 2014) to identify studies that compared the outcome of patients with AMI taking oral β-blockers with that of patients not taking after PCI. Systematic review and meta-analysis were performed with random-effects model or fixed-effects model. Ten observational studies with a total of 40,873 patients were included. Use of β-blockers was associated with a reduced risk of all-cause death (unadjusted relative risk 0.58, 95% confidential interval 0.48 to 0.71; adjusted hazard ratio 0.76, 95% confidential interval 0.62 to 0.94). The potential benefit of β-blockers in preventing all-cause death was not similar in all population but was restricted to those with reduced ejection fraction, with low use proportion of other secondary prevention drugs or with non–ST-segment elevation myocardial infarction. The association between the use of β-blockers and improved survival rate was significant in ≤1-year follow-up duration. Rates of cardiac death, myocardial infarction, and heart failure readmission in patients using β-blockers were not significantly different from those in patients without β-blocker therapy. In conclusion, there is lack of evidence to support routine use of β-blockers in all patients with AMI who underwent PCI. Further trials are urgently needed to address the issue.
Oral β-blocker therapy has been recommended as class I indication for all patients who had acute myocardial infarction (AMI) without contraindication, irrespective of receiving revascularization or not. The strength of recommendation implies that most patients with AMI would benefit from oral β-blocker therapy. In general, class I indications are supported by wealth of evidence from randomized controlled trials. However, although studies conducted in pre-reperfusion era demonstrated the efficacy of β-blockers in improving outcomes in patients with AMI, there is scarce evidence in the modern era. Last 2 decades has witnessed substantial changes in management of patients with AMI. Obviously, it is inappropriate to extrapolate the conclusions from pre-perfusion or thrombolytic therapy era to percutaneous coronary intervention (PCI) era. Previous meta-analysis exploring the effect of β-blockers in current practice mixed thrombolytic therapy and PCI together and defined reperfusion era arbitrarily. In that sense, the present systematic review and meta-analysis assembled all the evidence available to investigate the association between oral β-blocker therapy and prognosis in patients with AMI receiving PCI and assess whether the association was similar in patients with different characteristics.
Methods
The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We performed a systematical search in the database of Pubmed (from inception to September 27, 2014) and Embase (Ovid SP, from 1974 to September 29, 2014). The following search terms were used in combination: (“adrenergic beta-antagonists” or “beta adrenergic receptor blocking agent” or “beta blockers” or “β-blockers” or individual β-blocker names) and (“myocardial infarction” or “heart infarction”) and (“percutaneous coronary intervention” or “transluminal coronary angioplasty”).
Our meta-analysis focused on studies that reported oral β-blocker therapy and clinical outcomes in patients with AMI who underwent PCI treatment. The review did not restrict study type. Only studies with sample size >100 and follow-up duration >3 months were included. The primary outcome was all-cause death. The secondary outcomes included cardiac death, myocardial infarction (MI), and heart failure admission.
Two reviewers independently screened the titles or abstracts of the studies from the electronic search. All potentially eligible studies were then retrieved as full texts for detailed review. Studies with mixed revascularization types or mixed study participants (e.g., unstable angina and AMI) were excluded. Although, in the study by Konishi et al, the proportion of PCI was 97%, it was less likely that the remaining reperfusion type (CABG) would influence the results to a great extent; thus, this study was included. Studies that compared the initiation time of the use of oral β-blockers or studies of head-to-head comparisons of the efficacy of different β-blocker types were not considered.
We used Newcastle-Ottawa scale to assess the quality of the observational studies included. The scales included 3 categories: selection of the study groups (4 items), comparability between groups (1 item), and adjudication and assessment of outcomes (3 items). Each item could be assigned maximally with 1 point except for the item within “comparability” category, which could be given 2 points. The aggregate score was used to appraise study quality.
Pooled analyses of absolute numbers of events between comparison groups without adjusting for confounders were presented with relative risk (RR) and 95% confidential intervals (CIs). For adjusted effect size provided by original researches, pooled hazard ratio (HR) was calculated. Heterogeneity between studies was detected using the chi-square test, and the degree was quantified using I 2 statistic. p Value <0.1 indicated the existence of heterogeneity. Methods of meta-analysis calculation were chosen according to magnitude of heterogeneity. When I 2 >50%, random-effects model was used with the method by DerSimonian and Laird, whereas when I 2 ≤50%, fixed-effects model was used with the method by Mantel-Haenszel. Several methods were used to explore the reasons responsible for the heterogeneity. At first, sensitivity analyses were performed based on several vital characteristics of study participants. Second, subgroup analyses were conducted according to sample size, duration of follow-up, and left ventricular ejection fraction (LVEF) of patients. Finally, univariate meta-regression analyses were performed to test the potential covariates that could explain the variances between studies: age, female percentage, sample size, follow-up duration, AMI types, proportion of the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) or antiplatelet drugs, proportion of patients receiving early revascularization, and percentage of patients discharged alive. We estimated the degree of contribution of each covariate for the heterogeneity by investigating the changes of tau 2 value. The likelihood of publication bias was estimated by visual inspection of funnel plot and analyzed with Egg’s test. A p value <0.1 indicated significant publication bias. Statistical analyses were conducted using RevMan 5.2 (Cochrane Collaboration, Oxford, United Kingdom) and Stata 12.0 software packages (Stata Corporation, College Station, Texas).
Results
The database searches identified 5,019 records. After duplicates removal and preliminarily screening based on the titles and abstracts, 30 potentially eligible articles were retrieved for full text assessment. Of these, 10 observational studies met the inclusion criteria. The screening flow chart was displayed in Figure 1 .
Principle characteristics of the included studies were summarized in Table 1 . A total of 10 studies comprising 40,873 participants were included into the analyses. Seven studies recruited patients with ST-segment elevation myocardial infarction (STEMI), whereas 3 studies recruited patients with AMI without specific subtypes. Early revascularization was performed in 8 studies. For the remaining 2 studies, no information about PCI time was available. Seven studies only recruited patients who were alive at discharge, whereas 2 studies included patients with inhospital death. Survival status at discharge was not clear in 1 study. The type of β-blockers used varied between studies; nevertheless, half of the included studies did not report details about the type. Carvediol was the most used type of β-blockers. All the studies compared patients using β-blockers with those not using β-blockers. With regard to outcomes, all-cause death was reported in all the studies. Six studies showed the data about cardiac death, 7 studies reported MI, whereas 3 studies reported heart failure needing hospitalization. The follow-up duration varied between 1/2, 1, 3, and 4 years. Details of the quality assessment for each of the 10 included studies were presented in Table 2 .
| Study | Participants (No) | Study type | Age | Female (%) | β-blockers | On Aspirin (%) | On Clopidogrel (%) | Other antiplatelet drugs (%) | On ACEI/ARB (%) | On Statin (%) | LVEF (%) | Killp≥III (%) | length of follow-up (years) | Covariates adjustment |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Konishi 2011 | STEMI patients with PCI (97%) (251) | Retrospective | 65 | 21 | Carvedilol, bisoprolol | β: 100; no-β:100 | β: 60; no-β:63 | Ticlopidine: β: 33; no-β:34 | β: 100; no-β:100 | β: 98; no-β:99 | β:43; no-β:44 | β:39; no-β:36 | 1 | No |
| Chen 2000 | AMI patients with PTCA (13997) | Retrospective | 73 | 43 | NA | All:84 | NA | NA | All:28 | NA | <55%: All:63% | NA | 1 | Adjusted |
| Yang 2014 | STEMI patients with primary PCI (8510) | Prospective | 63 | 25 | NA | β:99; no-β:98 | β:98; no-β:97 | NA | β:89; no-β:69 | β:82; no-β:80 | β:51; no-β:50 | β:11; no-β:16 | 1 | Propensity-matched cohort, age, sex, IRA, number of coronary arteries narrowed, pre-procedural TIMI flow grade on culprit vessel, use of GP IIb/IIIa inhibitor |
| Choo 2014 | AMI patients with preserved systolic function treated by PCI (3019) | Prospective | 61 | 27 | Carvedilol, bisoprolol, atenolol, or other β-blockers | β:100; no-β:100 | β:100; no-β:100 | Cilostazol: β:49; no-β:46 | β: 86; no-β:65 | β:91; no-β:89 | β: 60; no-β:60 | β: 5; no-β:10 | 3 | Propensity score, important covariables for risk with significant effects ( p<0.1) in the univariate analysis |
| Kernis 2004 | STEMI patients with pPCI (2442) | Retrospective | 61 | 26 | NA | NA | NA | NA | NA | NA | β:49; no-β:48 | β:2; no-β:3 | 0.5 | Age, gender, current smoker, diabetes, PVD, COPD, prior angina, PCI, stent or CABG, Killip class >1, multi-vessel CAD, EF≤50%, final residual stenosis, systolic blood pressure < 100, IRA in the LCX or RCA, the propensity score |
| Nakatani 2013 | STEMI patients with pPCI (5628) | Prospective | 65 | 23 | Carvedilol , metoprolol, bisoprolol, atenolol, and others | β: 96; no-β:93 | NA | Dual-antiplatelet therapy: β:77; no-β:64 | β:83; no-β:71 | β: 52; no-β:36 | NA | Killip class ≥II: β: 17; no-β:13 | 4 | Variables with p values <0.20 between groups and propensity score. |
| De Luca 2005 | STEMI patients with primary angioplasty (1513) | Prospective | 60 | 22 | Metoprolol, other β-blockers | NA | NA | NA | β: 52; no-β:60 | β: 62; no-β:40 | β: 43; no-β:43 | Killip class≥II: β:6; no-β:17 | 1 | Adjusted |
| Ozasa 2010 | STEMI patients with pPCI (910) | Prospective | 67 | 24 | NA | β:99; no-β:98 | NA | Thienopyridine: β:94; no-β:95 | β:80; no-β:74 | β:63; no-β:48 | β:51; no-β:53 | NA | 3 | Propensity score for use of β blockers |
| Ellis 2003 | AMI patients with PCI (934) | Retrospective | 60 | 30 | NA | NA | NA | NA | NA | NA | NA | NA | 0.5 | Propensity scores, age, hypertension, diabetes, PVD, prior revascularization, prior MI, randomization to abciximab, pre-procedure aspirin, anticoagulant or nitrate use, BMI |
| Bao 2013 | STEMI patients with PCI (3692) | Prospective | 67 | 25 | Carvedilol, other β-blockers | β:100; no-β:99 | β:9; no-β:8 | Ticlopidine: β:88; no-β:89 Cilostazol: β:34; no-β:37 | β:83; no-β:70 | β:64; no-β:51 | β:52; no-β:54 | NA | 3 | Clinical characteristics, procedural characteristics, and discharge medication |
| Study | Selection | Comparability | Outcome |
|---|---|---|---|
| Konishi 2011 | **** | ** | ** |
| Chen 2000 | **** | * | ** |
| Yang 2014 | **** | * | *** |
| Choo 2014 | **** | * | ** |
| Kernis 2004 | *** | * | ** |
| Nakatani 2013 | **** | * | *** |
| De Luca 2005 | **** | ** | *** |
| Ozasa 2010 | **** | ** | *** |
| Ellis 2003 | *** | * | *** |
| Bao 2013 | **** | * | *** |
Ten studies reported unadjusted event rate of all-cause death. Pooled data showed that the use of β-blockers was associated with a 42% reduced risk of all-cause death (RR 0.58, 95% CI 0.48 to 0.71); however, there was significantly statistical heterogeneity (I 2 = 74%; Figure 2 ). To explore the sources of heterogeneity, meta-analyses focusing on special characteristics were rerun. After excluding the study by Konishi et al, the result consistently showed that the treatment of β-blockers was associated with reduced risk of all-cause death (RR 0.60, 95% CI 0.49 to 0.73; I 2 = 75%). In the 7 studies that included exclusively patients discharged alive, β-blocker therapy was associated with a 34% reduction in all-cause death (RR 0.66, 95% CI 0.55 to 0.80; I 2 = 71%). In the 8 studies that enrolled patients who underwent early revascularization, β-blockers was associated with a 42% decrease in all-cause death (RR 0.58, 95% CI 0.44 to 0.76; I 2 = 79%). Seven studies exclusively included patients with STEMI; meta-analysis showed similar benefits of β-blockers (RR 0.59, 95% CI 0.43 to 0.80; I 2 = 80%). Further analysis for the 7 studies with ACEI prescription rate >50% (RR 0.64, 95% CI 0.50 to 0.82; I 2 = 72%) and 6 studies with antiplatelet drug use rate >90% (RR 0.69, 95% CI 0.55 to 0.88; I 2 = 68%) consistently demonstrated improved survival rate when using β-blockers.
Subgroup analyses were conducted based on sample size (≤1,000 and >1,000), follow-up duration (6 months, 1 year, and >1 year), and LVEF (preserved and reduced) ( Table 3 ). Overall, β-blocker therapy was associated with reduced risk of all-cause death for all subgroups, expect those with sample size ≤1,000 and those with preserved LVEF. Meta-regression analysis was performed to further identify the reasons for the heterogeneity. Univariate meta-regression models demonstrated that age, female proportion, sample size, AMI type (STEMI or STEMI/non–ST-segment elevation myocardial infarction [NSTEMI]), the percentage of ACEI/ARB and antiplatelet drugs use, and proportion of patients receiving early revascularization were not responsible for the high degree of heterogeneity, whereas follow-up duration and the percentage of patients discharged alive explained most of the heterogeneity between studies. When both the 2 covariates were included in the meta-regression models, tau 2 was reduced to 0.02417 from the original 0.0665, indicating that the 2 covariates explained 63.7% heterogeneity. It seemed that benefits driven from β-blockers decreased as the follow-up duration went on ( Table 3 ). Also, in comparison with studies exclusively enrolling patients discharged alive, those including patients with inhospital death showed higher benefits driven from β-blockers (RR 0.34, 95% CI 0.24 to 0.48; I 2 = 0%).
| Subgroup | Study | No. of Studies | Sample size | Heterogeneity | Meta-analysis | ||
|---|---|---|---|---|---|---|---|
| I 2 | P-value | Effect size | 95%CI | ||||
| Sample size | ≤1000 | 3 | 2095 | 73% | 0.02 | RR 0.52 | 0.24-1.13 |
| >1000 | 7 | 38778 | 78% | 0.0001 | RR 0.59 | 0.47-0.73 | |
| Follow-up | 6 months | 2 | 3353 | 0% | 0.67 | RR 0.35 | 0.24-0.50 |
| 1 year | 4 | 24271 | 50% | 0.11 | RR 0.59 | 0.52-0.67 | |
| >1 year | 4 | 13249 | 68% | 0.02 | RR 0.76 | 0.59-0.98 | |
| LVEF | Preserved | 6 | 16645 | 61% | 0.026 | RR 0.79 | 0.59-1.07 |
| Reduced | 5 | 3299 | 65% | 0.023 | RR 0.60 | 0.36-1.00 | |
As observational studies have inherent limitations of selective bias, meta-analyses were rerun based on the studies that fully adjusted for confounders. Seven studies reported adjusted HR of β-blocker therapy. Overall, users of β-blockers showed superior survival rate compared with nonusers (HR 0.76, 95% CI 0.62 to 0.94), but evident statistical heterogeneity was detected (I 2 = 65%; Figure 3 ). Six studies including patients discharged alive showed potential benefits of β-blockers in reducing all-cause death (HR 0.82, 95% CI 0.68 to 0.99; I 2 = 54.3%). In the 6 studies enrolling exclusively patients who underwent early revascularization, similar survival benefit driven from β-blockers was found (HR 0.73, 95% CI 0.55 to 0.97; I 2 = 69.3%). However, there was no significantly statistical difference in all-cause death between β-blockers group and no β-blockers group in the 5 studies including exclusive patients with STEMI (HR 0.75, 95% CI 0.53 to 1.06; I 2 = 71.5%), in the 5 studies with ACEI/ARB prescription rate >50% (HR 0.80, 95% CI 0.61 to 1.05; I 2 = 62.9%), and in the 5 studies with antiplatelet drugs use rate >90% (HR 0.80, 95% CI 0.61 to 1.05; I 2 = 62.9%). Meta-analysis of studies with sample size >1,000 demonstrated that β-blocker therapy was associated with a 26% reduction of all-cause death (HR 0.74, 95% CI 0.59 to 0.92; I 2 = 68.7%). Subgroup analyses according to follow-up duration showed varied results. Although benefit with β-blocker therapy in improving survival was similar as main analysis in the studies with follow-up duration ≤1 year (HR 0.58, 95% CI 0.34 to 0.98; I 2 = 81.0%), it disappeared when the analysis was repeated for the studies with follow-up >1 year (HR 0.87, 95% CI 0.74 to 1.02; I 2 = 47.9%).
