Author + information
- Received September 27, 2013
- Revision received November 15, 2013
- Accepted December 1, 2013
- Published online June 1, 2014.
- Jeong Hoon Yang, MD∗,†,
- Joo-Yong Hahn, MD∗∗ (, )
- Young Bin Song, MD∗,
- Seung-Hyuk Choi, MD∗,
- Jin-Ho Choi, MD∗,
- Sang Hoon Lee, MD∗,
- Joo Han Kim, MD‡,
- Young-Keun Ahn, MD‡,
- Myung-Ho Jeong, MD‡,
- Dong-Joo Choi, MD§,
- Jong Seon Park, MD‖,
- Young Jo Kim, MD‖,
- Hun Sik Park, MD¶,
- Kyoo-Rok Han, MD#,
- Seung Woon Rha, MD∗∗ and
- Hyeon-Cheol Gwon, MD∗
- ∗Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- †Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- ‡Division of Cardiology, Department of Medicine, Chonnam National University Hospital, Gwangju, South Korea
- §Division of Cardiology, Department of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
- ‖Department of Medicine, Yeungnam University Hospital, Daegu, South Korea
- ¶Department of Medicine, Kyungpook National University Hospital, Daegu, South Korea
- #Department of Medicine, Kangdong Sacred Heart Hospital, Seoul, South Korea
- ∗∗Department of Medicine, Korea University Medical Center, Seoul, South Korea
- ↵∗Reprint requests and correspondence:
Dr. Joo-Yong Hahn, Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea.
Objectives This study sought to investigate the association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI).
Background Limited data are available on the efficacy of beta-blocker therapy for secondary prevention in STEMI patients.
Methods Between November 1, 2005 and September 30, 2010, 20,344 patients were enrolled in nationwide, prospective, multicenter registries. Among these, we studied STEMI patients undergoing primary PCI who were discharged alive (n = 8,510). We classified patients into the beta-blocker group (n = 6,873) and no–beta-blocker group (n = 1,637) according to the use of beta-blockers at discharge. Propensity-score matching analysis was also performed in 1,325 patient triplets. The primary outcome was all-cause death.
Results The median follow-up duration was 367 days (interquartile range: 157 to 440 days). All-cause death occurred in 146 patients (2.1%) of the beta-blocker group versus 59 patients (3.6%) of the no–beta-blocker group (p < 0.001). After 2:1 propensity-score matching, beta-blocker therapy was associated with a lower incidence of all-cause death (2.8% vs. 4.1%, adjusted hazard ratio: 0.46, 95% confidence interval: 0.27 to 0.78, p = 0.004). The association with better outcome of beta-blocker therapy in terms of all-cause death was consistent across various subgroups, including patients with relatively low-risk profiles such as ejection fraction >40% or single-vessel disease.
Conclusions Beta-blocker therapy at discharge was associated with improved survival in STEMI patients treated with primary PCI. Our results support the current American College of Cardiology/American Heart Association guidelines, which recommend long-term beta-blocker therapy in all patients with STEMI regardless of reperfusion therapy or risk profile.
The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend beta-blockers for secondary prevention in patients with ST-segment elevation myocardial infarction (STEMI) without regard to reperfusion therapy (1). However, evidence supporting this recommendation originated from studies conducted before the introduction of reperfusion therapy or studies in patients treated with fibrinolysis (2,3). In the present era of primary percutaneous coronary intervention (PCI), there are no prospective randomized studies looking at the effects of long-term beta-blocker therapy on clinical outcomes in STEMI patients. Moreover, results from registry data and post-hoc analysis on beta-blocker therapy in patients undergoing primary PCI are inconsistent (4,5). In particular, the beneficial effect of long-term beta-blocker therapy has not been well established in patients with relatively low risk, such as preserved left ventricular systolic function or single-vessel disease. Therefore, we investigated the association of beta-blocker therapy at discharge with clinical outcomes in STEMI patients after primary PCI, using data from a nationwide, large registry series dedicated to MI.
The study population was selected from the KAMIR (Korean Acute Myocardial Infarction Registry), and its successor, KorMI (Korea Working Group on Myocardial Infarction) registry. The KAMIR is the first nationwide, prospective, multicenter online registry in patients presenting with acute MI from November 2005 to December 2007 (6,7). The KAMIR was conducted at 52 university or community hospitals. The KorMI is the second nationwide online registry, conducted at 53 university or community hospitals from January 2008 to September 2010 (8). Participating centers of the 2 registries have high volumes of patients with facilities for primary PCI and onsite cardiac surgery. The protocols of the 2 prospective cohorts were similar. Between November 2005 and September 2010, 20,344 consecutive patients with acute MI were prospectively enrolled in these registries. Clinical, laboratory, and outcome data were collected by a trained study coordinator using a standardized case report form and protocol. Angiographic parameters such as TIMI (Thrombolysis In Myocardial Infarction) flow grade or ACC/AHA lesion type were assessed by the operator. If necessary, additional information was documented by contacting the principal investigators in each hospital and/or by review of hospital records and telephone interviews. Clinical follow-up was performed at 1, 6, and 12 months in KAMIR and at 1, 6, 12, and 24 months in the KorMI registry after the PCI procedure. These registries were sponsored by the Korean Society of Cardiology and managed by the Korean Working Group of Acute Myocardial Infarction. The local institutional review board at each hospital approved the study protocol.
Inclusion criteria for the present analysis were: 1) consecutive patients 18 years of age or older; 2) patients with ST-segment elevation >1 mm in at least 2 contiguous leads or presumably new left bundle branch block with elevated cardiac enzymes (troponin or myocardial band fraction of creatine kinase); and 3) patients undergoing primary PCI. Exclusion criteria were: 1) in-hospital death; and 2) missing beta-blocker information. Among the patients registered, 8,510 were finally included in this analysis. The patient flow of the study is shown in Figure 1. Subjects were divided by use of beta-blockers at discharge into the beta-blocker group and no–beta-blocker group.
Coronary interventions were performed according to current standard procedural guidelines. All patients received a 300-mg loading dose of aspirin and a 300- to 600-mg loading dose of clopidogrel before the coronary intervention unless they had previously received these antiplatelet medications. Anticoagulation therapy during PCI was performed according to current practice guidelines by the Korean Society of Interventional Cardiology. The treatment strategy and the use of glycoprotein IIb/IIIa receptor inhibitors or intravascular ultrasound were all left to the operator's discretion. Drug-eluting stents were used without restriction. Duration of dual antiplatelet therapy was determined by the operators.
Definitions and outcomes
Primary PCI was defined as percutaneous coronary revascularization within 24 h of symptom onset without antecedent treatment with a fibrinolytic agent as the initial therapy (9,10). All-cause death was defined as any death during or after the procedure and was considered to be of cardiac origin unless a definite noncardiac cause could be established. Recurrent MI was defined as recurrent symptoms with new electrocardiographic changes compatible with MI or cardiac markers at least twice the upper limit of normal (11). Any revascularization was defined as revascularization on either target or non-target vessels. All events were identified by the patient's physician and confirmed by the principal investigator of each hospital.
The primary outcome was all-cause death during follow-up. Secondary outcomes included cardiac death, recurrent MI, any revascularization with PCI or coronary artery bypass graft, and major adverse cardiac events (MACE), a composite of all-cause death, recurrent MI, and any revascularization during follow-up.
Comparisons for continuous variables were made using the t test or Wilcoxon rank-sum test when applicable. Categorical data were tested using the chi-square test. Survival curves were constructed using Kaplan-Meier estimates and compared with the log-rank test. The Cox proportional hazard model was used to compare the risks of adverse cardiac events between the use of beta-blockers and no use of beta-blockers. The propensity scores were estimated using multiple logistic-regression analysis. A full nonparsimonious model was developed that included age, sex, hospital groups according to the number of enrolled patients, hypertension, previous MI, previous PCI, left ventricular ejection fraction, creatinine, use of aspirin, clopidogrel, renin-angiotensin receptor blockade, spironolactone and statins at discharge, infarct-related artery PCI with stent, maximal stent diameter, use of vasopressor, and intra-aortic balloon pump in Tables 1 and 2⇓. A 2:1 matching ratio (beta-blocker group to no–beta-blocker group) was used to retain a large sample, which maximizes the study power while maintaining a balance in covariates between the 2 groups (12). Cox regression analysis using triplets matched by a greedy algorithm and the nearest available triplet-matching method among patients with an individual propensity score was also performed to evaluate the reduction in outcome risk. The covariate balance achieved by matching was assessed by calculating the absolute standardized differences in covariates between the use of beta-blockers and no use of beta-blockers. An absolute standardized difference of <10% for the measured covariate suggests appropriate balance between the groups. In the propensity score-matched population, continuous variables were compared with a 2-way analysis of variance or the median regression test, as appropriate; categorical variables were compared using McNemar or Bowker tests of symmetry, as appropriate; and the reduction in the risk of outcome was compared by use of the stratified Cox regression model, with prognostic covariates having an absolute standardized difference of >1.0% considered as candidate variables for inclusion in the multivariate models because the combination of regression adjustment in matched samples generally produces the least biased estimate (13,14). Cumulative incidence rates of individual clinical outcomes and composite outcomes were estimated by the Kaplan-Meier method and compared by the paired Prentice-Wilcoxon test. Statistical analyses were performed with SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). All tests were 2-tailed, and p < 0.05 was considered statistically significant.
Baseline and procedural characteristics
Beta-blockers were prescribed at discharge to 6,873 patients (80.8%), but not prescribed to 1,637 patients (19.2%). Baseline clinical characteristics are shown in Table 1 and angiographic and procedural characteristics in Table 2. Symptom onset to balloon time (beta-blocker group vs. no–beta-blocker group: median: 267 min, interquartile range [IQR]: 172 to 451 min vs. median: 260 min, IQR: 179 to 444 min, p = 0.97) and door-to-balloon time (median: 78 min, IQR: 58 to 110 min vs. median: 77 min, IQR: 57 to 112 min, p = 0.77) were similar in both groups. Overall, patients in the no–beta-blocker group were higher-risk subjects. Compared with patients in the beta-blocker group, those in the no–beta-blocker group were older and had a higher prevalence of previous MI, Killip class ≥III, low left ventricular ejection fraction, elevated serum creatinine, and post-procedural TIMI flow grade of 0 to 1. In addition, patients in the no–beta-blocker group were less likely to receive aspirin, clopidogrel, renin-angiotensin system blockade, statins, or PCI with a stent, but they were more likely to receive a stent with a small size diameter, vasopressors, intra-aortic balloon pump, defibrillator/cardioversion, or temporary pacemaker.
After performing propensity-score matching for the entire population, a total of 1,325 matched triplets of patients were created (Tables 1 and 2). The C-statistic for the propensity score model was 0.68, suggesting that use of beta-blockers was relatively random and that would make the analysis more reliable. Symptom onset–to-balloon time (beta-blocker group vs. no–beta-blocker group: median: 270 min, IQR: 179 to 454 min vs. median 260 min, IQR: 178 to 435 min, p = 0.41) and door-to-balloon time (median: 78 min, IQR: 59 to 112 min vs. median: 77 min, IQR: 57 to 113 min, p = 0.28) were similar in both groups. There were no significant differences in baseline clinical, angiographic, and procedural characteristics between the 2 groups for the propensity-matched subjects. On the other hand, for nonincluded patients in propensity-matched analysis, patients in the no–beta-blocker group were higher-risk groups as expected (Online Tables 1 and 2).
The median follow-up duration was 367 days (IQR: 157 to 440 days). Table 3 shows cumulative clinical outcomes of the study groups. All-cause death occurred in 205 patients (2.4%) during follow-up. The beta-blocker group had a significantly lower incidence of all-cause death (beta-blocker group vs. no–beta-blocker group: 2.1% vs. 3.6%, unadjusted hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.38 to 0.70, p < 0.001) (Fig. 2). The incidence of cardiac death was significantly lower in the beta-blocker group than in the no–beta-blocker group (1.1% vs. 2.4%, unadjusted HR: 0.41, 95% CI: 0.28 to 0.60, p < 0.001), whereas both groups had comparable incidences of MI and any coronary revascularization. Although all-cause death or MI occurred less frequently in the beta-blocker group than in the no–beta-blocker group (3.1% vs. 4.7%, unadjusted HR: 0.58, 95% CI: 0.45 to 0.75, p < 0.001), there was no significant difference between the 2 groups in the rates of MACE. To reinforce the strength of the analysis, we compared the clinical outcomes between excluded patients due to missing information on beta-blocker and study population during follow-up period, and there were no significant differences between the 2 groups in the rates of all-cause death and MACE (Online Table 3).
There were 128 all-cause deaths with a median follow-up of 364 days in the matched patients. Beta-blocker therapy was still associated with a lower incidence of all-cause death in the matched cohort of patients (2.8% vs. 4.1%, adjusted HR: 0.46, 95% CI: 0.27 to 0.78, p = 0.004) (Table 4, Fig. 3). Cardiac death occurred less frequently in the beta-blocker group than in the no–beta-blocker group (1.5% vs. 2.8%, adjusted HR: 0.39, 95% CI: 0.19 to 0.79, p = 0.01). There were no differences between the 2 groups in the rates of MI, any coronary revascularization, and MACE. In the stratified Cox regression model with prognostic covariates adjustment, significant predictors of all-cause death were age (HR: 1.06, 95% CI: 1.03 to 1.09, p < 0.001), left anterior descending artery as the infarct-related artery (HR: 2.51, 95% CI: 1.36 to 4.65, p = 0.003), and no use of beta-blocker at discharge (HR: 2.19, 95% CI: 1.29 to 3.72, p = 0.004).
To determine whether the outcomes according to beta-blocker therapy observed in the overall population were consistent, we calculated the unadjusted HR for death in various complex subgroups (Fig. 4). The association with better outcome of beta-blocker therapy in terms of all-cause death was consistent across various subgroups including patients with relatively low-risk profile such as left ventricular ejection fraction >40% or single-vessel disease. There were no significant interactions between the use of beta-blocker at discharge and all-cause death among all of the subgroups. The association with better outcome of beta-blocker therapy in terms of all-cause death was also consistent across various subgroups in propensity-matched populations (Fig. 5).
In the present study, we investigated the association of beta-blocker therapy with clinical outcomes in STEMI patients who underwent primary PCI using data from large, prospective, multicenter registry series in Korea. Beta-blocker therapy at discharge was associated with lower mortality, and this result was maintained in propensity-matched populations. Furthermore, the association with better outcome of beta-blocker therapy in terms of all-cause death was consistent across various subgroups.
Although outcomes of patients with MI have greatly improved after the introduction of primary PCI, optimal medical therapy after successful reperfusion in patients with STEMI is very important (15). Beta-blockers have been reported to reduce life-threatening arrhythmias, relieve recurrent ischemia, and reduce mortality, including sudden cardiac death, in studies performed in the pre-PCI era (16–18). Based on this evidence, the ACC/AHA guidelines recommend beta-blockers for secondary prevention in all patients with STEMI unless absolutely contraindicated or not tolerated (1). However, evidence supporting routine beta-blocker therapy for secondary prevention is lacking in the primary PCI era. There are no prospective randomized studies addressing this issue, and results from nonrandomized studies are inconsistent (4,5). Moreover, previous studies had several major limitations such as relatively small sample size or lower rates of use of thienopyridine medication and stent, unlike the current practice. The recently published observational REACH (Reduction of Atherothrombosis for Continued Health) registry showed that the use of beta-blockers was not associated with a lower risk of adverse events in stable patients with a previous history of MI (19). However, the REACH registry did not reflect the early association of beta-blocker therapy with the clinical outcomes of STEMI, because only stable outpatients were selectively enrolled in this registry and there were no data on onset, type, and risk profile of MI (20). Therefore, in the present study, we investigated the associations of beta-blocker therapy at discharge with clinical outcomes using data from the nationwide MI registries of Korea, and we demonstrate that beta-blocker therapy at discharge was associated with benefits to mortality in STEMI patients undergoing primary PCI. A large sample size and reflection of current real-world practice such as high rates of use of statins, renin-angiotensin system blockades, or dual antiplatelet therapy are the strengths of our study.
Considering that beta-blockers have anti-ischemic, antiarrhythmic, and antiadrenergic properties (17,21,22), our results appear to be relevant. However, patients who did not receive beta-blockers in the present study were characterized as having relatively high-risk factors such as older age, Killip class ≥III on admission, and low left ventricular ejection fractions. Therefore, the observed benefit of beta-blockers in our study may result from differences in baseline characteristics. To address this, we performed propensity score-matching to adjust for the differences in baseline characteristics between the groups. After propensity score-matching, baseline characteristics were well balanced between the groups, and the result was consistent in all patients and propensity-matched populations. Moreover, patients who died during the index hospitalization were not included by study design in the present study, which reduced possible bias due to differences in baseline characteristics between the groups. Taken together, the association with better outcome of beta-blocker therapy in terms of all-cause mortality cannot be attributed to differences in baseline characteristics between the 2 groups. It is uncertain why there were no significant differences between the groups in the incidences of MI and revascularization. Unrestricted use of drug-eluting stents, complete revascularization, and medication other than beta-blockers such as statins, renin-angiotensin system blockades, or dual antiplatelet therapy may explain the low and similar incidences of MI and revascularization in both groups.
Although the association of beta-blocker therapy with better outcome was reported to be greatest in the relatively high-risk group with low ejection fraction or multivessel coronary artery disease (4), the implications of long-term beta-blocker therapy in relatively low-risk patients has not been well established. In the present study, the association of beta-blocker therapy with better outcome was consistent, and there were no significant interactions between use of beta-blockers at discharge and death across various subgroups. Statistical significance was found in patients with left ventricular ejection fraction >40%, Killip class I or II, and single-vessel disease in whom the association with better outcome of beta-blocker therapy has not been demonstrated in previous studies (4,5). The large sample size of our study made subgroup analysis possible and demonstrated the association with better outcome of beta-blocker therapy in these populations. Although the findings are hypothesis-generating, our results support the current ACC/AHA guidelines, which recommend long-term beta-blocker therapy in all patients with STEMI regardless of risk profile.
First, the study lacks data on specific beta-blockers and doses. Also, we do not know how long beta-blockers continued to be taken after discharge. Second, the nonrandomized nature of the registry data could have resulted in selection bias. Although we performed propensity score-matched analysis to adjust for these potential confounding factors, we were not able to correct for unmeasured variables. In particular, we did not have information on several important variables such access site and comorbidities such as cancer, history of asthma, or chronic obstructive pulmonary disease due to the limitations of the databases. However, the association with better outcome of beta-blocker therapy was demonstrated in terms of cardiac mortality as well as all-cause mortality in the present study. Large-scale, prospective, randomized-controlled trials are needed to clarify the effects of long-term beta-blocker therapy in patients with STEMI undergoing primary PCI. Third, adverse clinical events were not centrally adjudicated in our registries. All events were identified by the patient's physician and confirmed by the principal investigator of each hospital. Considering the limitation of possible inaccuracy in determining cause of death, we selected “all-cause mortality” as the primary outcome instead of “cardiac mortality.” Finally, the clinical data encompassed a 12-month period in KAMIR and a 24-month period in the KorMI registry. A median follow-up of 12 months may be too short for conclusive determination of the long-term efficacy of beta-blockers in the setting of STEMI. Accordingly, the long-term prognostic outcomes of the 2 groups beyond 1 year after the index event remain unclear because median follow-up duration was approximately 1 year.
Beta-blocker therapy at discharge was associated with improved survival in patients with STEMI undergoing primary PCI. Our results support the current ACC/AHA guidelines, which recommend long-term beta-blocker therapy for all patients with STEMI regardless of reperfusion therapy or risk profile.
The authors thank Seonwoo Kim, PhD, and Joonghyun Ahn, MS, at the Samsung Biomedical Research Institute for their excellent statistical support.
This study was supported by the Korean Society of Cardiology. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- American College of Cardiology
- American Heart Association
- confidence interval
- hazard ratio
- interquartile range
- major adverse cardiac events
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Thrombolysis In Myocardial Infarction
- Received September 27, 2013.
- Revision received November 15, 2013.
- Accepted December 1, 2013.
- American College of Cardiology Foundation
- O'Gara P.T.,
- Kushner F.G.,
- Ascheim D.D.,
- et al.
- Kernis S.J.,
- Harjai K.J.,
- Stone G.W.,
- et al.
- Ozasa N.,
- Kimura T.,
- Morimoto T.,
- et al.,
- for the j-Cypher Registry Investigators
- Chen K.Y.,
- Rha S.W.,
- Li Y.J.,
- et al.,
- for the Korean Acute Myocardial Infarction Registry Investigators
- Antman E.M.,
- Anbe D.T.,
- Armstrong P.W.,
- et al.
- Kim J.Y.,
- Jeong M.H.,
- Ahn Y.K.,
- et al.,
- for the Other Korea Acute Myocardial Infarction Registry
- Lee K.H.,
- Jeong M.H.,
- Kim H.M.,
- et al.,
- for the KAMIR Investigators
- López-Sendón J.,
- Swedberg K.,
- McMurray J.,
- et al.,
- for the Task Force on Beta-Blockers of the European Society of Cardiology
- McMurray J.,
- Køber L.,
- Robertson M.,
- et al.