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Clinical impact of beta-blockers at discharge on long-term clinical outcomes in patients with non-reduced ejection fraction after acute myocardial infarction

Published:August 19, 2022DOI:https://doi.org/10.1016/j.jjcc.2022.08.002

      Highlights

      • The J-MINUET trial is a prognostic study of patients diagnosed with acute myocardial infarction (AMI) based on the new definition.
      • Beta-blockers improved the composite endpoint in AMI patients without reduced left ventricular (LV) dysfunction.
      • Beta-blockers did not affect the incidence of heart failure in patients without LV dysfunction.

      Abstract

      Background

      Beta-blockers are associated with several clinical benefits in patients with reduced left ventricular ejection fraction (REF) after acute myocardial infarction (AMI), such as lower rates of mortality, recurrence of myocardial infarction, and heart failure. However, the long-term prognosis of beta-blockers has rarely been investigated in patients with non-REF after AMI. This study aimed to investigate the clinical benefits of beta-blockers in these patients.

      Methods

      A total of 3281 consecutive patients who were hospitalized within 48 h after AMI were registered in the J-MINUET study. Patients who underwent primary percutaneous coronary intervention (PCI) and had a left ventricular ejection fraction ≥40 % were enrolled, and patients who died during admission were excluded. Included patients were divided into two groups according to the prescription of beta-blockers at discharge. Their characteristics and clinical outcomes were compared.

      Results

      The number of AMI patients treated with beta-blockers was 1353 (70.4 %). Patients who received beta-blockers were younger and had a higher incidence of hypertension, dyslipidemia, and ST-segment elevation myocardial infarction than those who did not receive beta-blockers. The peak creatine kinase level after primary PCI was significantly higher in patients who received beta-blockers. These patients also had a lower incidence of a composite of all-cause death, myocardial infarction, and stroke compared to those that did not receive beta-blockers (7.3 % vs. 11.9 %, p = 0.001). Multivariate analysis showed that beta-blocker use was an independent factor for better clinical outcomes.

      Conclusions

      The J-MINUET study revealed the clinical benefit of beta-blockers in AMI patients with non-REF after primary PCI.

      Graphical abstract

      Keywords

      Introduction

      In recent decades, primary percutaneous coronary intervention (PCI) has been established as the standard treatment for patients with acute myocardial infarction (AMI). It has been reported that early reperfusion of the culprit coronary artery in AMI patients improves clinical outcomes and left ventricular ejection fraction (LVEF) [
      • Loubeyre C.
      • Lefèvre T.
      • Louvard Y.
      • Dumas P.
      • Piéchaud J.F.
      • Lanore J.J.
      • et al.
      Outcome after combined reperfusion therapy for acute myocardial infarction, combining pre-hospital thrombolysis with immediate percutaneous coronary intervention and stent.
      ]. Treatment with renin-angiotensin-system (RAS) blockers, beta-blockers, and statins has also contributed to the improvement of clinical outcomes [
      • Pfeffer M.A.
      • Braunwald E.
      • Moyé L.A.
      • Basta L.
      • Brown Jr., E.J.
      • Cuddy T.E.
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. the SAVE investigators.
      ,
      • Dargie H.J.
      Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
      ,
      • Ridker P.M.
      • Cannon C.P.
      • Morrow D.
      • Rifai N.
      • Rose L.M.
      • McCabe C.H.
      • et al.
      C-reactive protein levels and outcomes after statin therapy.
      ]. Beta-blockers have been used in AMI patients since before the introduction of reperfusion therapy in clinical practice. Beta-blockers act as antiarrhythmic agents and reduce myocardial oxygen demand, which accelerates myocardial necrosis, by controlling heart rate and myocardial contraction during the acute phase of AMI [
      • McMurray J.
      • Køber L.
      • Robertson M.
      • Dargie H.
      • Colucci W.
      • Lopez-Sendon J.
      • et al.
      Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial.
      ]. Beta-blockers are associated with a survival benefit and suppression of left ventricular remodeling in patients with left ventricular dysfunction after AMI [
      • Dargie H.J.
      Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
      ,
      • Doughty R.N.
      • Whalley G.A.
      • Walsh H.A.
      • Gamble G.D.
      • López-Sendón J.
      • Sharpe N.
      Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy.
      ]. Therefore, some guidelines strongly recommend the use of beta-blockers in patients with reduced left ventricular ejection fraction (REF) or heart failure after the onset of AMI (class I) including ST-segment elevation myocardial infarction (STEMI) and non-STEMI [
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • Casey Jr., D.E.
      • Ganiats T.G.
      • Holmes Jr., D.R.
      • et al.
      2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ,
      • O’Gara P.T.
      • Kushner F.G.
      • Ascheim D.D.
      • Casey Jr., D.E.
      • Chung M.K.
      • de Lemos J.A.
      • et al.
      2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ,
      • Kimura K.
      • Kimura T.
      • Ishihara M.
      • Nakagawa Y.
      • Nakao K.
      • Miyauchi K.
      • et al.
      JCS 2018 guideline on diagnosis and treatment of acute coronary syndrome.
      ]. However, the benefits of beta-blockers in AMI patients with non-REF after primary PCI are unclear. Therefore, beta-blockers are not strongly recommended for patients without heart failure and with left ventricular ejection fraction >40 % because of a lack of evidence [
      • Jneid H.
      • Addison D.
      • Bhatt D.L.
      • Fonarow G.C.
      • Gokak S.
      • Grady K.L.
      • et al.
      2017 AHA/ACC clinical performance and quality measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures.
      ]. Recent guidelines recommend the use of cardiac troponin for the diagnosis of AMI [
      • Alpert J.S.
      • Thygesen K.
      • Antman E.
      • Bassand J.P.
      Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.
      ]. Most previous studies that investigated the efficacy of beta-blockers in patients with AMI did not include non-STEMI patients without creatine kinase (CK) elevation because these patients were treated as unstable angina.
      This study aimed to investigate the clinical benefit of beta-blockers in patients with troponin-positive AMI without LV dysfunction in the era of primary PCI.

      Methods

      Study design and subjects

      The Japanese registry of acute Myocardial Infarction diagnosed by Universal dEfiniTion (J-MINUET) was a prospective and multicenter study conducted in 28 Japanese medical institutions (UMIN000010037). A total of 3283 consecutive patients admitted within 48 h after the onset of AMI were enrolled between July 2012 and March 2014. Patients who underwent primary PCI were included in this study. Patients without LVEF measurement (n = 514), REF (LVEF <40 %) (n = 245), patients who did not undergo primary PCI (n = 453), and those who died during admission (n = 213) were excluded. Patients with non-REF were defined as those with an LVEF ≥40 %. Finally, 1955 patients with non-REF were studied and divided into two groups according to whether they did (n = 1353, beta-blocker group) or did not (n = 570, non-beta-blocker group) receive beta-blockers at discharge (Fig. 1). Three-year clinical outcomes were compared between the two groups. Clinical follow-up after the index admission was performed through a review of medical records, telephone contact, and mailed questionnaires.
      Fig. 1
      Fig. 1Study flow chart.
      AMI, acute myocardial infarction; LVEF left ventricular ejection fraction; PCI, percutaneous coronary intervention; REF, reduced left ventricular ejection fraction.
      The design, inclusion criteria, and results of the J-MINUET study have been previously reported [
      • Ishihara M.
      • Fujino M.
      • Ogawa H.
      • Yasuda S.
      • Noguchi T.
      • Nakao K.
      • et al.
      Clinical presentation, management and outcome of Japanese patients with acute myocardial infarction in the troponin era - Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET).
      ]. Briefly, AMI was diagnosed using a universal definition, in which cardiac troponin (cTn) was used as a reliable biomarker for detecting myocardial injury [
      • O’Gara P.T.
      • Kushner F.G.
      • Ascheim D.D.
      • Casey Jr., D.E.
      • Chung M.K.
      • de Lemos J.A.
      • et al.
      2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ]. STEMI was diagnosed based on the presence of new ST elevation at the J point in at least two contiguous leads ≥0.2 mV in men or ≥0.15 mV in women in leads V2–3, or ≥0.1 mV in another two contiguous leads [
      • O’Gara P.T.
      • Kushner F.G.
      • Ascheim D.D.
      • Casey Jr., D.E.
      • Chung M.K.
      • de Lemos J.A.
      • et al.
      2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ,
      • Alpert J.S.
      • Thygesen K.
      • Antman E.
      • Bassand J.P.
      Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.
      ]. A new or presumably new left bundle branch block was considered equivalent to STEMI. Treatment-related data, such as coronary interventions and medications, were recorded. Urgent coronary angiography (CAG) was performed within 48 h of admission. LVEF was measured using either ultrasound or left ventricular angiography during hospitalization. If the patients had two or more LVEF measurements during admission, the latest LVEF value was used.
      The primary outcome was the composite of all-cause death, nonfatal MI, and non-fatal stroke in this study. The secondary outcomes included all-cause death, cardiovascular death, non-fatal MI, non-fatal stroke, heart failure admission, unstable angina pectoris with revascularization, and the composite of all-cause death, non-fatal MI, non-fatal stroke, and heart failure admission.
      This study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of each participating institution.

      Statistical analysis

      All continuous variables are described as mean with standard deviation for parametric results, and median with interquartile range (25th–75th percentile) for non-parametric results. All categorical or non-continuous variables are described as counts with percentages (%). For comparisons between two groups, the chi-square test was applied for categorical results, the t-test was applied for parametric continuous results, and the Mann–Whitney U test was applied for non-parametric continuous results. Kaplan–Meyer analysis was conducted to analyze the time to event occurrence in both groups, and the difference between the two groups was assessed by the log-rank test. Univariate and multivariate Cox proportional hazard models were used to calculate the hazard ratios. To study the efficacy of beta-blockers on the primary endpoint, a subgroup analysis was performed according to sex, LVEF, estimated glomerular filtration rate (eGFR), and age (divided by median value). Statistical analyses were performed using JMP® 13 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at p < 0.05.

      Results

      Baseline clinical characteristics

      Among 1955 non-REF patients, 1353 (70.1 %) received beta-blockers at discharge. Baseline clinical characteristics on admission are shown in Table 1. Patients who received beta-blockers were significantly younger and showed a significantly higher incidence of coronary risk factors such as hypertension and dyslipidemia compared to those who did not. The incidence of STEMI was higher in the beta-blocker group than in the non-beta-blocker group.
      Table 1Baseline clinical characteristics on admission.
      Non-beta-blocker group (n = 570)Beta-blocker group (n = 1353)p-value
      Age, years68.6 ± 12.367.0 ± 12.10.007
      Male75.8 %77.0 %0.562
      Hypertension61.1 %67.7 %0.006
      Diabetes mellitus35.7 %36.1 %0.789
      Dyslipidemia47.9 %55.5 %0.002
      CKD37.0 %36.7 %0.906
      Current smoker38.7 %37.0 %0.487
      Past history
      Prior MI7.7 %10.6 %0.053
      Prior PCI12.2 %13.7 %0.353
      Prior CABG1.8 %2.2 %0.512
      Atrial fibrillation4.4 %3.7 %0.470
      Stroke9.0 %9.4 %0.813
      PAD3.8 %2.9 %0.305
      Medications on admission
      Anti-platelet therapy22.6 %22.5 %0.938
      Dual anti-platelet therapy5.8 %6.2 %0.726
      Oral anti-coagulation therapy4.0 %2.5 %0.072
      ACE inhibitor4.4 %6.4 %0.081
      ARB24.0 %25.6 %0.478
      MR blocker0.5 %1.1 %0.226
      Diuretics6.0 %7.7 %0.182
      Statin22.8 %22.4 %0.833
      Oral anti-diabetic agent16.8 %17.4 %0.750
      Insulin3.7 %4.2 %0.592
      Presentation<0.001
      STEMI70.0 %78.6 %
      non-STEMI+CK14.2 %13.5 %
      non-STEMI–CK15.8 %7.9 %
      Systolic BP, mm Hg136.7 ± 31.1140.1 ± 32.40.034
      Heart rate, bpm73.5 ± 18.577.6 ± 20.0<0.001
      Killip classification0.774
      Class 184.0 %83.3 %
      Class 28.6 %8.0 %
      Class 32.5 %3.0 %
      Class 44.9 %5.8 %
      Onset to admission, min137

      [70–360]
      158

      [75–370]
      0.372
      Values are mean ± SD, median [inter quartile range] or percentage.
      CKD, chronic kidney disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; PAD, peripheral artery disease; RAS blocker, renin-angiotensin-system blocker; MR blocker, mineralocorticoid-receptor blocker; STEMI, ST-segment elevation myocardial infarction; non-STEMI+CK, non-ST-segment elevation myocardial infarction with creatine kinase (CK) elevation; non-STEMI-CK, non-ST-segment elevation myocardial infarction without CK elevation; BP; blood pressure.
      The laboratory findings are shown in Table 2. Patients who received beta-blockers showed significantly higher levels of hemoglobin than those who did not. There were no significant differences in the lipid profile, hemoglobin A1c, and eGFR levels between groups. Patients who received beta-blockers showed significantly higher peak CK and lower LVEF than those who did not.
      Table 2Laboratory findings.
      Non-beta-blocker group (n = 570)Beta-blocker group

      (n = 1353)
      p-value
      Hb, g/dl13.7 ± 1.914.1 ± 4.30.034
      TC, mg/dl187.9 ± 37.8188.5 ± 43.80.784
      HDL-C, mg/dl47.1 ± 14.146.5 ± 12.60.412
      LDL-C, mg/dl119.5 ± 36.2120.1 ± 37.30.761
      TG, mg/dl123.1 ± 98.3128.5 ± 117.70.350
      HbA1c, %6.3 ± 1.46.3 ± 1.30.797
      eGFR, ml/min/m267.5 ± 28.670.3 ± 39.40.130
      Peak CK, IU/L1180

      [403–2429]
      1918

      [847–3563]
      <0.001
      LVEF, %59.1 ± 9.055.6 ± 9.1<0.001
      Values are mean ± SD, or median [inter quartile range].
      Hb, hemoglobin; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; HbA1c, hemoglobin A1c; eGFR, estimated glomerular filtration rate; CK, creatine kinase; LVEF, left ventricular ejection fraction.

      Procedural findings and medications at discharge

      Compared with the non-beta-blocker group, the beta-blocker group showed a lower incidence of radial approach, higher incidence of left anterior descending coronary artery (LAD) lesion and multi-vessel disease, and worse initial thrombolysis in myocardial infarction (TIMI) flow. Patients who received beta-blockers showed significantly shorter door-to-device times, but the onset-to-device time was similar between the two groups (Table 3).
      Table 3Procedural findings and medications at discharge.
      Non-beta-blocker group (n = 570)Beta-blocker group (n = 1353)p-value
      Radial approach41.8 %29.6 %<0.001
      LAD lesion36.3 %50.5 %<0.001
      Multi-vessel disease37.2 %42.6 %0.029
      Initial TIMI flow 0–160.0 %65.8 %0.015
      Final TIMI flow 0–26.7 %6.4 %0.835
      Door to device time, min80

      [52–132]
      70

      [51–111]
      0.003
      Onset to device time, min262

      [157–566]
      262

      [155–536]
      0.802
      Medications at discharge
       Anti-platelet therapy96.7 %98.9 %<0.001
       Dual anti-platelet therapy77.0 %85.3 %<0.001
       Oral anti-coagulation therapy8.8 %11.3 %0.109
       RAS blocker74.6 %85.9 %<0.001
       MR blocker1.1 %0.8 %0.637
       Diuretics1.4 %1.4 %0.934
       Statin85.6 %92.0 %<0.001
       Oral anti-diabetic agent22.5 %25.7 %0.140
       Insulin4.3 %4.5 %0.823
      Values are median [inter quartile range] or percentage.
      LAD, left anterior descending artery; TIMI, thrombolysis in myocardial infarction; RAS blocker, renin-angiotensin-system blocker; MR blocker, mineralocorticoid-receptor blocker.
      More than 95 % of the patients received antiplatelet therapy at discharge. Patients who received beta-blockers had a higher incidence of administration of antiplatelet therapy, dual antiplatelet therapy, RAS blockers, and statins than those who did not.

      Three-year clinical outcomes

      During a 3-year follow-up, 170 patients (8.7 %) experienced clinical events. The incidence of the primary outcome, a composite of all-cause death, non-fatal MI, and non-fatal stroke was significantly lower in patients who received beta-blockers than in those who did not (7.3 % vs. 11.9 %, p = 0.001). The patients who received beta-blockers had a lower incidence of all-cause death (3.5 % vs. 6.0 %, p = 0.009), non-fatal stroke (2.5 % vs. 4.2 %, p = 0.047), and a composite of the primary outcome and heart failure admission (10.1 % vs. 13.9 %, p = 0.018). The patients who received beta-blockers tended to have a lower incidence of cardiovascular death (2.4 % vs. 3.2 %, p = 0.144) and non-fatal MI (1.0 % vs. 1.8 %, p = 0.370). However, the incidence of heart failure admission was similar between the two groups (Table 4 and Fig. 2).
      Table 4Three-year clinical outcomes.
      Non-beta-blocker group (n = 570)Beta-blocker group (n = 1353)p-value
      Primary outcome, composite of all cause death, non-fatal MI, and non-fatal stroke11.9 %7.3 %0.001
      All-cause death6.0 %3.5 %0.009
      Cardiovascular death1.8 %1.0 %0.144
      Non-fatal MI3.2 %2.4 %0.370
      Non-fatal stroke4.2 %2.5 %0.047
      Heart failure admission3.2 %3.4 %0.787
      UAP revascularization5.4 %6.5 %0.376
      Composite of all-cause death, non-fatal MI, non-fatal stroke, and heart failure admission13.9 %10.1 %0.018
      Values are percentages.
      MI, myocardial infarction; UAP, unstable angina pectoris.
      Fig. 2
      Fig. 2Event-free Kaplan-Meier survival curves. (A) Primary outcome: composite of all-cause death, non-fatal MI and non-fatal stroke. (B) All-cause death. (C) Non-fatal MI. (D) Non-fatal stroke. (E) Heart failure admission. (F) Cardiovascular death, non-fatal MI, non-fatal stroke.
      BB, beta-blocker; MI, myocardial infarction.

      Predictors for the primary outcome

      Multivariate analysis was performed to predict the primary outcome. Younger age, the use of beta-blockers and RAS blockers at discharge, better LVEF, and STEMI were independent negative predictors of the primary outcome (Table 5).
      Table 5Predictors for primary outcome.
      PredictorUnivariate modelMultivariate model
      HR95 % CIp-valueHR95 % CIp-value
      Age1.041.02–1.05<0.0011.031.01–1.04<0.001
      RAS-blocker at discharge0.500.36–0.70<0.0010.610.42–0.890.012
      Beta-blocker at discharge0.600.44–0.820.0010.660.47–0.940.021
      LVEF, %0.990.97–1.000.0170.980.96–1.000.033
      STEMI0.630.46–0.870.0050.700.49–1.000.048
      CKD1.631.21–2.200.0021.330.95–1.860.102
      Multi-vessel disease1.411.04–1.900.0261.330.96–1.850.087
      Statin0.530.36–0.810.0040.780.50–1.240.282
      LAD lesion0.870.63–1.200.3981.010.72–1.410.973
      HR, hazard ratio; CI, confidence interval; RAS blocker, renin-angiotensin-system blocker; LVEF, left ventricular ejection fraction; STEMI, ST-segment elevation myocardial infarction; CKD, chronic kidney disease; LAD, left anterior descending artery.

      Primary endpoint for selected subgroups

      In the subgroup analysis, patients with LVEF ≥50 % and elderly patients who received beta-blockers showed a better primary endpoint than those who did not (Fig. 3).
      Fig. 3
      Fig. 3The effect of beta-blocker on primary endpoint.
      EF, ejection fraction; eGFR, estimated glomerular filtration rate.

      Discussion

      The J-MINUET study included consecutive patients diagnosed with AMI based on a universal definition. One of the biggest differences from previous studies is that the J-MINUET study included patients with non-STEMI without CK elevation, and showed that patients with non-STEMI without CK elevation also had a poor long-term prognosis [
      • Ishihara M.
      • Nakao K.
      • Ozaki Y.
      • Kimura K.
      • Ako J.
      • Noguchi T.
      • et al.
      Long-term outcomes of non-ST-elevation myocardial infarction without creatine kinase elevation - the J-MINUET Study.
      ]. Previous studies have shown that beta-blockers have a positive impact on prognosis, but most of these were limited to patients who had a reduced LVEF and were diagnosed with STEMI or AMI, including STEMI and non-STEMI with CK elevation [
      • Dargie H.J.
      Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
      ]. However, whether beta-blockers are clinically useful in AMI patients without LV dysfunction after primary PCI is unclear. In this era of primary PCI, the effect of beta-blockers on the long-term prognosis of patients with AMI diagnosed according to the new definition needs to be investigated. The main findings are as follows: 1) the incidence of the primary outcome, a composite of all-cause death, non-fatal MI, and non-fatal stroke, was significantly lower in patients who received beta-blockers than in those who did not; 2) patients who received beta-blockers had a lower incidence of all-cause death; 3) patients who received beta-blockers had a lower incidence of non-fatal stroke; 4) there was a similar incidence of heart failure admission between the two groups; 5) the use of beta-blockers was one of the independent predictors of the primary outcome; and 6) the benefit of beta-blockers was seen in patients with LVEF ≥50 % and elderly patients.

      Clinical presentation

      In this study, 70.4 % of AMI patients with non-REF were prescribed beta-blockers. Compared with AMI patients who did not receive beta-blockers, patients who received beta-blockers had a higher incidence of hypertension; however, contrary to expectations, there was no significant difference in the history of atrial fibrillation. The beta-blocker group had a higher incidence of STEMI, greater peak CK, and lower LVEF than the non-beta-blocker group. These findings suggested that beta-blockers were aggressively prescribed with the expectation that they would inhibit myocardial damage and left ventricular remodeling. The higher incidence of LAD lesions as AMI culprit lesions, multi-vessel disease, and worse initial TIMI flow at emergent CAG in the beta-blocker group indicated a poorer condition. In fact, patients who received beta-blockers were aggressively treated with anti-atherosclerotic agents and cardio-protective agents, such as antiplatelet therapy, RAS blockers, and statins.

      Beta-blockers and clinical outcomes in AMI patients without LV dysfunction

      In recent decades, the benefits of beta-blockers have been unclear in AMI patients without LV dysfunction after primary PCI. The benefits of beta-blockers on long-term mortality in STEMI patients were confirmed in patients with a high GRACE score [
      • Nakatani D.
      • Sakata Y.
      • Suna S.
      • Usami M.
      • Matsumoto S.
      • Shimizu M.
      • et al.
      Impact of beta blockade therapy on long-term mortality after ST-segment elevation acute myocardial infarction in the percutaneous coronary intervention era.
      ], those with reduced EF [
      • Ozasa N.
      • Kimura T.
      • Morimoto T.
      • Hou H.
      • Tamura T.
      • Shizuta S.
      • et al.
      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.
      ], those with anterior infarction [
      • De Luca G.
      • de Boer M.J.
      • Ottervanger J.P.
      • van’t Hof A.W.
      • Hoorntje J.C.
      • Gosselink A.T.
      • et al.
      Impact of beta-blocker therapy at discharge on long-term mortality after primary angioplasty for ST-segment elevation myocardial infarction.
      ], and those with multi-vessel disease [
      • Kernis S.J.
      • Harjai K.J.
      • Stone G.W.
      • Grines L.L.
      • Boura J.A.
      • O’Neill W.W.
      • et al.
      Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty?.
      ]. Since the cardioprotective effects of beta-blockers correspond to a reduction in oxygen demand mediated by suppression of LV contractility, negative chronotropic action, and left ventricular remodeling, the clinical benefits were clearly proven in patients with LV dysfunction [
      • Ozasa N.
      • Kimura T.
      • Morimoto T.
      • Hou H.
      • Tamura T.
      • Shizuta S.
      • et al.
      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.
      ]. Our current study showed the significant benefits of beta-blockers on the primary endpoint, a composite of all-cause death, non-fatal MI, and non-fatal stroke in AMI patients without LV dysfunction after primary PCI. In addition, there were significant benefits of beta-blockers with respect to all-cause death and non-fatal stroke. This effect may be due to the preventive effects of beta-blockers on ventricular tachycardia, atrial fibrillation, and recurrent MI onset. In fact, our study found a 1.8-fold higher incidence of cardiovascular death and a 1.3-fold higher incidence of non-fatal MI in AMI patients who did not receive beta-blockers than in those who received beta-blockers. Though we have no data for the type of beta-blockers in our study, most patients were commonly administered either carvedilol or bisoprolol in Japan. Several previous studies have shown that newer generation beta-blockers have been shown to have good effects on glycemic control, insulin sensitivity, prevention of atherosclerosis progression, lipid metabolism, vasodilatory effect, or improvement of endothelial function, in contrast to traditional or earlier generations of beta-blocker [
      • Leonetti G.
      • Egan C.G.
      Use of carvedilol in hypertension: an update.
      ,
      • Messerli F.H.
      • Grossman E.
      Beta-blockers in hypertension: is carvedilol different?.
      ,
      • Giugliano D.
      • Acampora R.
      • Marfella R.
      • De Rosa N.
      • Ziccardi P.
      • Ragone R.
      • et al.
      Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial.
      ,
      • Vrablik M.
      • Corsini A.
      • Tůmová E.
      Beta-blockers for atherosclerosis prevention: a missed opportunity?.
      ]. Beta-blockers may reduce the onset of fatal arrhythmia and fatal MI, as well as embolic events, by preventing the onset of atrial fibrillation. A previous large cohort study concluded a non-significant effect of beta-blocker on clinical outcomes in AMI patients with LVEF >50 % [
      • Kernis S.J.
      • Harjai K.J.
      • Stone G.W.
      • Grines L.L.
      • Boura J.A.
      • O’Neill W.W.
      • et al.
      Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty?.
      ]. The discrepancy between the previous study and our study might have occurred by the difference in the follow-up period and the number of study patients. The previous study had a shorter follow-up period (6 months vs 3 years) and a smaller study population (1081 vs 1955 patients).

      Beta-blockers and heart failure admission in AMI patients without LV dysfunction

      Several studies on patients with heart failure and an LVEF ≥40 % reported that beta-blockers did not improve a composite of cardiovascular death and unplanned hospitalization for heart failure [
      • Lund L.H.
      • Benson L.
      • Dahlström U.
      • Edner M.
      • Friberg L.
      Association between use of β-blockers and outcomes in patients with heart failure and preserved ejection fraction.
      ,
      • Pitt B.
      • Pfeffer M.A.
      • Assmann S.F.
      • Boineau R.
      • Anand I.S.
      • Claggett B.
      • et al.
      Spironolactone for heart failure with preserved ejection fraction.
      ]. Furthermore, when the subjects were limited to patients with an LVEF ≥50 %, beta-blocker prescriptions were associated with an increased risk of heart failure admission [
      • Silverman D.N.
      • Plante T.B.
      • Infeld M.
      • Callas P.W.
      • Juraschek S.P.
      • Dougherty G.B.
      • et al.
      Association of β-blocker use with heart failure hospitalizations and cardiovascular disease mortality among patients with heart failure with a preserved ejection fraction: a secondary analysis of the TOPCAT Trial.
      ]. Some studies also reported that beta-blockers for patients with non-REF increased brain natriuretic peptide levels [
      • Silverman D.N.
      • Plante T.B.
      • Infeld M.
      • Callas P.W.
      • Juraschek S.P.
      • Dougherty G.B.
      • et al.
      Association of β-blocker use with heart failure hospitalizations and cardiovascular disease mortality among patients with heart failure with a preserved ejection fraction: a secondary analysis of the TOPCAT Trial.
      ,
      • Bergström A.
      • Andersson B.
      • Edner M.
      • Nylander E.
      • Persson H.
      • Dahlström U.
      Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC).
      ,
      • Deary A.J.
      • Schumann A.L.
      • Murfet H.
      • Haydock S.
      • Foo R.S.
      • Brown M.J.
      Influence of drugs and gender on the arterial pulse wave and natriuretic peptide secretion in untreated patients with essential hypertension.
      ]. In our study, there was also a trend of increasing incidence of heart failure hospitalizations in patients who received beta-blockers, although the difference was not significant. When beta-blockers are introduced for AMI patients with preserved EF, heart failure may occur in a few cases.

      Beta-blockers and stroke in AMI patients without LV dysfunction

      Our study demonstrated that beta-blockers were effective for the primary prevention of stroke, and the incidence of stroke was 2.1-fold higher in the non-beta-blocker group than in the beta-blocker group. Many studies have been conducted to evaluate the usefulness of beta-blockers for cerebrovascular diseases. Although some studies have shown that beta-blockers reduce the risk of stroke compared to placebo [
      • Psaty B.M.
      • Smith N.L.
      • Siscovick D.S.
      • Koepsell T.D.
      • Weiss N.S.
      • Heckbert S.R.
      • et al.
      Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis.
      ], they are less effective than other antihypertensive agents and are no longer the first-line treatment for primary hypertension [
      • Dahlöf B.
      • Sever P.S.
      • Poulter N.R.
      • Wedel H.
      • Beevers D.G.
      • Caulfield M.
      • et al.
      Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
      ,
      • Carlberg B.
      • Samuelsson O.
      • Lindholm L.H.
      Atenolol in hypertension: is it a wise choice?.
      ]. However, the main beta-blockers used in these comparative trials were older generation medications such as propranolol or atenolol, and meta-analyses using each type of beta-blocker have shown different results [
      • Neal B.
      • MacMahon S.
      • Chapman N.
      Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration.
      ]. It is well known that there are three generations of beta-blockers, which have different affinities towards the three beta-adrenoreceptor isotypes and two alpha-adrenoreceptor isotypes, and with different effects. Some studies have shown that the inferiority of beta-blockers to other antihypertensive drugs is due to their influence on central blood pressure elevation, lipid control, or insulin control [
      • Williams B.
      • Lacy P.S.
      • Thom S.M.
      • Cruickshank K.
      • Stanton A.
      • Collier D.
      • et al.
      Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study.
      ,
      • Bulas J.
      • Potocarova M.
      • Kupcova V.
      • Gaspar L.
      • Wimmer G.
      • Murin J.
      Central systolic blood pressure increases with aortic stiffness.
      ,
      • Vlachopoulos C.
      • Aznaouridis K.
      • O’Rourke M.F.
      • Safar M.E.
      • Baou K.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis.
      ], but these studies included the older generation beta-blockers. Since newer generation beta-blockers, which are commonly used in Japan, have positive effects on lipid control, insulin control, prevention on atherosclerosis progression, vasodilation, antioxidant effects, and lowering of central blood pressure [
      • Leonetti G.
      • Egan C.G.
      Use of carvedilol in hypertension: an update.
      ,
      • Messerli F.H.
      • Grossman E.
      Beta-blockers in hypertension: is carvedilol different?.
      ,
      • Giugliano D.
      • Acampora R.
      • Marfella R.
      • De Rosa N.
      • Ziccardi P.
      • Ragone R.
      • et al.
      Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial.
      ,
      • Vrablik M.
      • Corsini A.
      • Tůmová E.
      Beta-blockers for atherosclerosis prevention: a missed opportunity?.
      ], these beta-blockers might provide a better prognosis for stroke prevention.

      The benefit of beta-blockers in subgroups

      Subgroup analyses showed the efficacy of beta-blockers in patients with LVEF ≥50 % and elderly patients. The reason for this might be that beta-blockers in these subgroups are likely to maintain sinus rhythm and prevent cardiovascular events.

      Limitations

      This study has several limitations. First, this was not a randomized controlled study; therefore, a selection bias in prescribing beta-blockers existed. Some non-beta blockers, such as patients with hypotension, bradycardia, atrioventricular block, and chronic obstructive pulmonary disease might be contraindicated to beta-blocker use or some of patients with malignancy had given up taking beta-blockers. Second, the incidence of the primary outcome was relatively small; therefore, some clinical benefits of beta-blockers in patients with AMI without LV dysfunction might not be observed. Third, this study did not evaluate whether patients continued beta-blocker therapy, although it is well known that persistent beta-blocker therapy after AMI is associated with better mortality outcomes [
      • Kim J.
      • Kang D.
      • Park H.
      • Kang M.
      • Park T.K.
      • Lee J.M.
      • et al.
      Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study.
      ]. Fourth, the type and dose of beta-blockers were not recorded, and we did not evaluate the effect of dose or type of beta-blockers on clinical outcomes. It is certain that most Japanese cardiologists use either carvedilol or bisoprolol for the patients after AMI [
      • Konishi M.
      • Haraguchi G.
      • Yoshikawa S.
      • Kimura S.
      • Inagaki H.
      • Isobe M.
      Additive effects of β-blockers on renin-angiotensin system inhibitors for patients after acute myocardial infarction treated with primary coronary revascularization.
      ]. Fifth, the change in LVEF during the follow-up period was not documented. The change in LVEF may affect clinical outcomes after the onset of AMI. Sixth, since the exact reasons for mortality were not recorded, we could not determine the incidence of sudden cardiac death. Further studies are required to confirm this hypothesis.

      Conclusions

      The J-MINUET study showed a better clinical impact of beta-blockers for improving the composite long-term prognosis in AMI patients without LV dysfunction who underwent primary PCI.

      Acknowledgments

      The authors thank all the enrolled patients, participating cardiologists, medical and other staff who have contributed to this study.

      Sources of funding

      This study was supported by the Intramural Research Fund , grant number 23-4-5 , for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center.

      Declaration of competing interest

      Yoshihiko Saito: grants from MEXT KAKENHI Grant Number JP19155855 , grants from Health Labour Sciences Research Grant Number 19189094 , grants from Health Labour Sciences Research Grant Number 17933459 , grants from AMED under Grant Number JP19ek0210080 , grants from AMED under Grant Number JP19ek0210118 , grants from AMED under Grant Number JP19ek0210121 , grants from AMED under Grant Number JP19ek0210115 , grants from AMED under Grant Number JP19ek0109367 , grants from AMED under Grant Number JP19ek0109406 , grants from AMED under Grant Number JP19km0405009 , during the conduct of the study; grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from Bristol-Myers Squibb Company, grants from Actelion Pharmaceuticals Japan Ltd., grants from Kyowa Kirin Co., Ltd., grants and personal fees from Kowa Pharmaceutical Co., Ltd., grants from Shionogi & Co., Ltd., grants from Dainippon Sumitomo Pharma Co., Ltd., grants and personal fees from Teijin Pharma Ltd., grants from Chugai Pharmaceutical Co., Ltd., grants from Eli Lilly Japan K.K., grants from Nihon Medi-Physics Co., Ltd., grants, personal fees and other from Novartis Pharma K.K., grants and personal fees from Pfizer Japan Inc., grants from Fuji Yakuhin Co., Ltd., grants, personal fees and other from Bayer Yakuhin, Ltd., other from Amgen Astellas BioPharma K.K., other from Actelion Pharmaceuticals Japan Ltd., other from Roche Diagnostics K.K., personal fees from Alnylam Japan K.K., personal fees from AstraZeneca K.K., personal fees from Tsumura & Co., personal fees from Toa Eiyo Ltd., personal fees from Nippon Shinyaku Co., Ltd., personal fees from Nippon Boehringer Ingelheim Co., Ltd., personal fees from Mochida Pharmaceutical Co., Ltd. Kengo Tanabe: personal fees from Abbott Vascular, personal fees from Boston Scientific, personal fees from Medtronic, personal fees from Terumo, personal fees from Kaneka, from Japan Lifeline. Hisao Ogawa: personal fees from Towa Pharmaceutical Co., Ltd., personal fees from Bristol-Meyers Squibb Co., Ltd., personal fees from Pfizer Co., Ltd., personal fees from Toa Eiyo Co., Ltd., personal fees from Bayer Yakuhin Co., Ltd., personal fees from Novartis Pharma Co., Ltd. Masaharu Ishihara: grants from Abbott Vascular Japan Co., Ltd., grants and personal fees from Amgen Astellas Bio Pharma K.K., grants from Astellas Pharma Inc., grants and personal fees from Bayer Yakuhin, Ltd., grants from Boston Scientific Japan K.K., grants and personal fees from Daiichi Sankyo Company, Limited, grants from Fukuda Denshi Co., Ltd., grants from Goodman Co., LTD., grants from Japan Lifeline Co., Ltd., grants from Kowa Pharmaceutical Co., Ltd., grants from MID, Inc., grants from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from MSD K.K., grants from Nippon Shinyaku Co., Ltd., grants from Nipro Corporation, grants from Otsuka Pharmaceutical Co., Ltd., grants from Ono Pharmaceutical Co., Ltd., grants from Pfizer Japan Inc., grants and personal fees from Sanofi K.K., grants from Shionogi & Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Takeda pharmaceutical Co. Ltd., grants from Teijin Pharma Ltd., grants from Terumo Corporation, grants from Abbott Medical Japan Co., Ltd., grants from Medtronic Japan Co., Ltd., grants from Nippon Boehringer Ingelheim Co., Ltd.

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