Admission Heart Rate Is a Determinant of Effectiveness of Beta-Blockers in Acute Myocardial Infarction Patients

Abstract

Background: Beta-blockers are standard therapy for acute myocardial infarction (AMI). However, despite current advances in the management of AMI, it remains unclear whether all AMI patients benefit from β-blockers. We investigated whether admission heart rate (HR) is a determinant of the effectiveness of β-blockers for AMI patients.

Methods and Results: We enrolled 3,283 consecutive AMI patients who were admitted to 28 participating institutions in the Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) study. According to admission HR, we divided patients into 3 groups: bradycardia (HR <60 beats/min, n=444), normocardia (HR 60 to ≤100 beats/min, n=2,013), and tachycardia (HR >100 beats/min, n=342). The primary endpoint was major adverse cardiac events (MACE), including all-cause death, non-fatal MI, non-fatal stroke, heart failure (HF), and urgent revascularization for unstable angina, at 3-year follow-up. Beta-blocker at discharge was significantly associated with a lower risk of MACE in the tachycardia group (23.6% vs. 33.0%; P=0.033), but it did not affect rates of MACE in the normocardia group (17.8% vs. 18.4%; P=0.681). In the bradycardia group, β-blocker use at discharge was significantly associated with a higher risk of MACE (21.6% vs. 12.7%; P=0.026). Results were consistent for multivariable regression and stepwise multivariable regression.

Conclusions: Admission HR might determine the efficacy of β-blockers for current AMI patients.

Beta-blockers are recommended for long-term management of patients with acute myocardial infarction (AMI),^1–4 but many of the studies that established the effectiveness of β-blockers for AMI patients were conducted several decades ago.^5–8 During the past few decades, advances in the management of AMI, such as reperfusion therapy, and the use of statins, and angiotensin-converting enzyme inhibitors, have dramatically improved the clinical outcomes of AMI patients. Many observational studies of long-term β-blocker therapy for current AMI patients have been conducted, but the results are inconsistent.^9–18 Some of these observational studies have suggested that β-blockers are no longer effective for all AMI patients, but that their use is associated with improved outcomes for some specific subgroups, such as patients with reduced left ventricular ejection fraction (EF), multivessel disease, or high Global Registry of Acute Coronary Events (GRACE) risk scores.^17,18 These findings indicated the importance of current evidence-based therapy and that not all patients should be treated with β-blockers after AMI.

Recent data for 6,168 patients presenting with MI in a German registry showed that admission tachycardia or bradycardia was associated with adverse outcomes. Furthermore, higher heart rate (HR) at discharge was associated with an increased risk of death.^19,20 Resting HR reduction was also shown to be a driving factor of the beneficial effects of β-blockers.^21,22 Therefore, we evaluated whether admission HR is a determinant of the effectiveness of β-blockers for AMI patients in a retrospective analysis of the Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) study.

Methods

Study Design and Subjects

The analyses were based on data from the J-MINUET study (the design and primary results of the J-MINUET study have been published previously^23,24). Briefly, the J-MINUET study was a prospective observational multicenter study conducted at 28 nationwide institutions; 3,283 consecutive AMI patients were enrolled between July 2012 and March 2014. AMI was diagnosed according to the European Society of Cardiology, ACC Foundation, American Heart Association, and World Heart Foundation Task Force for the Universal Definition of Myocardial Infarction.²⁵ ST-segment elevation AMI (STEMI) was diagnosed in the presence of new ST elevation at the J point in at least 2 continuous leads of ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V2–3 and/or of ≥1 mm (0.1 mV) in other contiguous chest leads or the limb leads.^2,26 A new or presumably new left bundle branch block was considered as a STEMI equivalent. Up to 3 years of clinical follow-up data were obtained from medical records, telephone contact, and mailed questionnaires. The indications for and methods of revascularization and the use of β-blockers were at the discretion of the treating physicians. The J-MINUET study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the ethics committee of each participating institution.

Study Populations

Based on the admission HR, patients with data regarding β-blocker use at discharge were divided into 3 groups: bradycardia (HR <60 beats/min), normocardia (HR, 60 to ≤100 beats/min) or tachycardia (HR >100 beats/min). Furthermore, each of these groups was divided into 2 subgroups based on β-blocker use at discharge: the β-blocker group and the no β-blocker group. Figure 1 shows the study flowchart. The primary endpoint was major adverse cardiac events (MACE) such as all-cause death, non-fatal MI, non-fatal stroke, heart failure (HF), and urgent revascularization for unstable angina at the 3-year follow-up. Non-fatal MI included only type 1 (spontaneous MI) and type 2 (MI secondary to an ischemic imbalance).²⁵ HF was defined as HF requiring hospital admission. The secondary endpoints included the following: death; composite of death and non-fatal MI; composite of death, non-fatal MI, and non-fatal stroke; and composite of death, non-fatal MI, non-fatal stroke, and HF.

Figure 1.

Flowchart of patients enrolled in the registry. AMI, acute myocardial infarction; BB, β-blocker; HR, heart rate on admission.

Statistical Analysis

All continuous variables are described as median values and interquartile range. All categorical variables are described using absolute and relative frequency distributions. Differences between groups of continuous variables were evaluated with the Kruskal-Wallis test. The chi-square test was used for non-continuous and categorical variables. We created Kaplan-Meyer curves for patients treated with or without β-blockers, and the differences between groups were assessed by the log-rank test. Univariate and multivariate Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (CI) for all events. Because differences in baseline characteristics could significantly affect outcomes, sensitivity analyses were performed to adjust for confounders using 2 Cox regression models. In the first model, we selected covariates (age, sex, STEMI, urgent revascularization, multivessel disease, Killip class >2, and MI history) based on their potential to be associated with cardiac events. In the second model, we selected covariates that were significantly different (P<0.1) among 3 HR groups. In this model, we used stepwise-backward selection with probability to remove the effect of regression at P>0.05. Throughout the present study, P<0.05 was considered significant. Statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), and STATA (version 12; StataCorp LP, College Station, TX, USA).

Results

Among the 3,283 patients registered in the J-MINUET study, we identified 2,799 consecutive patients with data regarding admission HR and β-blocker use at discharge. Of them, 444 patients (15.9%) were classified into the bradycardia group, 2,013 (71.9%) into the normocardia group, and 342 (12.2%) into the tachycardia group. Baseline clinical characteristics and management according to admission HR are shown in Table 1. There were several important differences among the groups. Complete atrioventricular block was more frequently observed in the bradycardia group, whereas ventricular tachycardia, fibrillation, and atrial fibrillation were more frequently observed in the tachycardia group. The proportions of STEMI and urgent revascularization were highest in the bradycardia group and lowest in the tachycardia group. The prevalences of hypertension, diabetes, chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m²) and high Killip class (>2) were highest in the tachycardia group. Medications at discharge are also shown in Table 1. Most patients were prescribed evidence-based secondary prevention medications such as renin-angiotensin-aldosterone system inhibitors and statins. In the tachycardia group, β-blockers were more likely to be prescribed, whereas angiotensin-converting enzyme inhibitors were less likely to be prescribed. The Kaplan-Meier curves for death and the primary endpoint according to admission HR are shown in Supplementary Figure. At the 3-year follow-up, the tachycardia group had significantly higher incidences of death (bradycardia group vs. normocardia group vs. tachycardia group: 4.8% vs. 8.8% vs. 13.6%; log-rank test P<0.001) and the primary endpoint (bradycardia group vs. normocardia group vs. tachycardia group: 24.3% vs. 23.9% vs. 35.7%; log-rank test P<0.001).

Table 1. Baseline Characteristics and Management of AMI According to Admission Heart Rate

	Bradycardia group (n=444)	Normocardia group (n=2,013)	Tachycardia group (n=342)	P value
Age (years)	70 (63–79)	69 (60–77)	69 (58–78)	0.028
Male	339 (76.4%)	1,541 (76.6%)	246 (71.9%)	0.177
Vitals
SBP (mmHg)	120 (100–144)	142 (122–162)	147 (120–171)	<0.001
HR (beats/min)	52 (45–56)	78 (69–87)	112 (106–122)	<0.001
Arrhythmia on admission
Atrial fibrillation	26 (5.9%)	71 (3.5%)	37 (10.8%)	<0.001
Ventricular tachycardia/fibrillation	15 (3.4%)	51 (2.5%)	29 (8.5%)	<0.001
Complete AV block	78 (17.6%)	23 (1.1%)	1 (0.3%)	<0.001
Concomitant diseases
Hypertension	278 (62.9%)	1,350 (67.2%)	241 (71.1%)	0.051
Diabetes	139 (31.7%)	704 (35.5%)	154 (45.6%)	<0.001
Dyslipidemia	230 (52.0%)	1,076 (53.8%)	184 (54.3%)	0.768
CKD	215 (48.4%)	770 (38.3%)	185 (54.1%)	<0.001
Previous history
Previous MI	43 (9.7%)	251 (12.5%)	49 (14.4%)	0.120
Prior stroke	46 (10.6%)	209 (10.7%)	41 (12.4%)	0.658
Previous PAD	20 (4.7%)	74 (3.9%)	25 (7.6%)	0.009
Diagnosis				<0.001
NSTEMI	103 (23.2%)	633 (31.4%)	139 (40.6%)
STEMI	341 (76.8%)	1,380 (68.6%)	203 (59.4%)
Killip class >2	61 (13.7%)	126 (6.3%)	107 (31.5%)	<0.001
Multivessel disease	188 (44.2%)	782 (41.4%)	155 (52.2%)	0.002
Urgent revascularization	407 (91.7%)	1,773 (88.1%)	270 (78.9%)	<0.001
Medications at discharge
β-blockers	278 (62.6%)	1,387 (68.9%)	254 (74.3%)	0.002
ACEIs	249 (57.1%)	1,031 (52.1%)	158 (47.0%)	0.02
ARBs	112 (25.9%)	569 (28.7%)	97 (28.7%)	0.495
Statins	384 (87.5%)	1,758 (87.8%)	278 (82.2%)	0.018
Aspirin	423 (95.5%)	1,926 (96.2%)	315 (92.9%)	0.025
P2Y12 inhibitors	346 (82.0%)	1,551 (79.9%)	246 (73.7%)	0.013

ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin II receptor blocker; AV, atrioventricular; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; HR, heart rate; MI, myocardial infarction; NSTEMI, non-ST-elevated myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; STEMI, ST-elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.

Bradycardia Group

Among the 444 patients included in the bradycardia group (HR <60 beats/min), 278 (62.6%) were treated with β-blockers at discharge. Figure 2 and Figure 3 show the Kaplan-Meier curves for the primary endpoint and the secondary endpoints at 3 years. At 3-year follow-up, the β-blocker group had a significantly higher incidence of the primary endpoint (β-blocker group vs. no β-blocker group: 21.6% vs. 12.7%; log-rank test P=0.026; unadjusted hazard ratio, 1.74; 95% CI, 1.06–2.87; P=0.028). In terms of the secondary endpoints, both groups had comparable outcomes. Sensitivity analyses using multivariable Cox regression and stepwise Cox regression showed a significantly higher incidence of the primary endpoint (Table 2).

Figure 2.

Unadjusted Kaplan-Meier curves for MACE according to β-blocker use for each heart rate subgroup. In the bradycardia group, patients who used β-blockers had a significantly higher incidence of MACE at 3 years. In contrast, in the tachycardia group, patients who used β-blockers had a significantly lower incidence of MACE at 3 years. In the normocardia group, there was no significant difference between patients who did or did not use β-blockers. The P-value for the interaction between β-blocker use and admission heart rate for MACE was significant (P=0.003). MACE included all-cause death, non-fatal myocardial infarction, non-fatal stroke, heart failure, and revascularization for unstable angina. The red line and black line indicate the β-blocker group and no β-blocker group, respectively. MACE, major adverse cardiac events.

Figure 3.

Unadjusted Kaplan-Meier curves according to β-blocker use in the bradycardia group. Kaplan-Meier curve for (A) mortality shows no difference between patients who did or did not use β-blockers. Kaplan-Meier curves for (B) composite of mortality and non-fatal MI, (C) composite of mortality, non-fatal MI, and non-fatal stroke, and (D) composite of mortality, non-fatal MI, non-fatal stroke, and heart failure show trends towards a higher incidence of each outcome for patients who used β-blockers. However, the differences were not statistically significant. MI, myocardial infarction.

Table 2. Comparison of the Primary Endpoint According to Beta-Blocker Use

	Beta-blocker group	No-β-blocker group	Unadjusted		Multivariable-Adjusted		Stepwise-Adjusted
			Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value
Bradycardia group	(n=278)	(n=166)
Primary endpoint	60 (21.6%)	21 (12.7%)	1.74 (1.06–2.87)	0.028	1.72 (1.02–2.89)	0.040	1.67 (1.00–2.79)	0.048
Normocardia group	(n=1,387)	(n=626)
Primary endpoint	247 (17.8%)	115 (18.4%)	0.95 (0.77–1.19)	0.681
Tachycardia group	(n=254)	(n=88)
Primary endpoint	60 (23.6%)	29 (33.0%)	0.62 (0.40–0.97)	0.035	0.57 (0.34–0.95)	0.032	0.49 (0.28–0.85)	0.011

The primary endpoint includes all-cause death, non-fatal myocardial infarction, non-fatal stroke, heart failure, and urgent revascularization for unstable angina at 3 years.

Normocardia Group

Among the 2,013 patients included in the normocardia group (HR 60 to ≤100 beats/min), 1,387 (69.2%) were treated with β-blockers at discharge. Figure 2 and Figure 4 show the Kaplan-Meier curves for the primary endpoint and the secondary endpoints at 3 years. At 3-year follow-up, the β-blocker group had a comparable incidence of the primary endpoint (β-blocker group vs. no β-blocker group: 17.8% vs. 18.4%; log-rank test P=0.681; unadjusted hazard ratio, 0.95; 95% CI, 0.77–1.19; P=0.681). The significant risk reduction in the β-blocker group was only observed in the composite endpoint of death, non-fatal MI, and non-fatal stroke (Table 2).

Figure 4.

Unadjusted Kaplan-Meier curves according to β-blocker use for the normocardia group. Kaplan-Meier curves for (A) mortality, (B) composite of mortality and non-fatal MI, and (D) composite of mortality, non-fatal MI, non-fatal stroke, and heart failure show no significant differences between patients who used β-blockers and who did not use β-blockers. Only the Kaplan-Meier curve for (C) the composite of mortality, non-fatal MI, and non-fatal stroke shows a slightly lower incidence of the composite outcome at 3 years for patients who used β-blockers. MI, myocardial infarction.

Tachycardia Group

Among the 342 patients included in the tachycardia group (HR >100 beats/min), 254 (74.3%) were treated with β-blockers at discharge. Figure 2 and Figure 5 show the Kaplan-Meier curves for the primary endpoint and the secondary endpoints at 3 years. At 3-year follow-up, the β-blocker group had a significantly lower incidence of the primary endpoint (β-blocker group vs. no β-blocker group: 23.6% vs. 33.0%; log-rank test P=0.033; unadjusted hazard ratio, 0.62; 95% CI, 0.40–0.97; P=0.035). In terms of secondary endpoints, including all-cause death, the β-blocker group had significantly better outcomes (Figure 4). Sensitivity analyses using multivariable Cox regression and stepwise Cox regression showed a significantly lower incidence of the primary endpoint (Table 2).

Figure 5.

Unadjusted Kaplan-Meier curves according to β-blocker use for the tachycardia group. Kaplan-Meier curves for (A) mortality, (B) composite of mortality and non-fatal MI, (C) composite of mortality, non-fatal MI, and non-fatal stroke, and (D) composite of mortality, non-fatal MI, non-fatal stroke, and heart failure show a significantly lower incidence of each outcome at 3 years for patients who used β-blockers. MI, myocardial infarction.

Discussion

In this prospective, observational multicenter study including consecutive patients who were hospitalized within 48 h of the onset of MI and mostly treated with urgent revascularization and evidence-based medical therapy, the use of β-blockers at discharge was significantly associated with a lower risk of death and MACE for patients with tachycardia (HR >100 beats/min) on admission; however, β-blocker use did not affect long-term mortality or MACE for patients with normocardia (HR 60 to ≤100 beats/min) on admission. Moreover, interestingly, for patients with bradycardia (HR <60 beats/min) on admission, the use of β-blockers at discharge was associated with a higher risk of MACE.

The current American Heart Association guidelines recommend oral β-blockers as a Class I indication for all AMI patients without contraindications.^1,2 However, these recommendations are mainly based on evidence from AMI patients before the reperfusion era; therefore, the evidence for β-blocker use in current AMI patients is lacking.^5–8 Although the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) study²⁷ and the CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) study²⁸ are recent randomized trials suggesting beneficial effects of β-blockers for AMI patients in the reperfusion era, those study populations are still crucially different from the current AMI population; fibrinolysis was mainly used and the reperfusion therapy was administered to only 45–55%.^27,28 Therefore, European guidelines have downgraded the level of the recommendation from Class I to Class IIa for AMI patients without left ventricular systolic dysfunction or HF.^3,4

Some recent observational studies and meta-analyses have suggested that β-blockers are no longer effective for all AMI patients.^12,14,15 A post hoc analysis of 2,332 AMI patients who underwent successful primary PCI was the first to show significant benefits of β-blockers even after successful primary PCI necessitated by reduced EF or multivessel disease.¹⁷ Furthermore, a post hoc analysis of 5,628 STEMI patients who were treated with primary PCI suggested that β-blockers were associated with a significantly lower mortality risk for high-risk patients with Global Registry of Acute Coronary Events (GRACE) risk scores ≥121 or those administered diuretics, but not for patients at lower risk.¹⁸ A meta-analysis of 10 observational studies comprising 40,873 AMI patients who underwent PCI suggested that the beneficial effects of β-blockers were restricted to those with reduced EF, STEMI, and infrequent use of evidence-based secondary prevention medications.¹² Therefore, for contemporary management of AMI, it is important to know who should be treated with β-blockers and who should not.

To date, several studies have shown that elevated HR, regardless of the timing, was associated with an increased risk of long-term mortality after AMI.^{19,20,29–31} and our results were consistent with those studies. Moreover, a meta-analysis of 14 randomized trials of β-blockers and calcium-channel blockers for AMI patients suggested that the magnitude of resting HR reduction was associated with the beneficial effects of β-blockers.²² In the BEAUTIFUL (ivabradine for patients with stable coronary artery disease and left ventricular systolic dysfunction) study, the beneficial effects of rate reduction by ivabradine for patients with stable coronary artery disease and left ventricular dysfunction were observed only in patients with HR ≥70 beats/min.³² More recently, a retrospective analysis of 2,310 STEMI patients who were treated with PCI at a regional tertiary center showed that β-blockers improved the post-discharge survival of patients with elevated admission HR.³³ Those findings support our results indicating that β-blockers reduce overall mortality and MACE in patients with tachycardia on admission.

In the normocardia group, no significant differences according to β-blocker use were observed for overall mortality and MACE. Although the results were consistent with those of previous studies,^12,14,15 β-blocker use was associated with significant reduction of the composite endpoint of death, non-fatal MI, and non-fatal stroke in this patient group. This was because the incidence rates of death, non-fatal MI, and non-fatal stroke were numerically lower in the β-blocker group, whereas the incidence rates of HF and urgent revascularization for unstable angina were numerically higher in the β-blocker group (Supplementary Table 1). However, none of the components showed significant difference. These numerical differences might be explained by residual confounding factors. Careful interpretation seems to be necessary to conclude the effectiveness of β-blockers in this patient group.

In the bradycardia group, indications for β-blockers should be more carefully considered because β-blockers are known to be a cause of iatrogenic bradycardia such as acquired complete atrioventricular block.^34–37 In most randomized trials of β-blockers, including the COMMIT trial, low baseline HR was an exclusion criterion.^27,38,39 Therefore, the effectiveness of β-blockers for AMI patients with bradycardia is far more unclear. In our retrospective analysis, β-blockers did not affect the long-term mortality of patients with bradycardia on admission. Moreover, they were associated with an increased risk of MACE. The results were consistent even when excluding patients with complete atrioventricular block (Supplementary Table 2). The comparison of each component of the endpoints is shown in Supplementary Table 1. The incidence rates of death and HF were numerically higher and the incidence rates of non-fatal MI and urgent revascularization for unstable angina were significantly higher in the β-blocker group. To the best of our knowledge, this is the first study suggesting that β-blockers can have adverse effects in AMI patients. However, this seems to be acceptable because β-blockers can be associated with extreme bradycardia which might cause coronary events through the decrease in coronary blood flow.⁴⁰

Study Limitations

Our study had several important limitations that should be noted when interpreting the findings. First, this was not a randomized controlled study; therefore, potential biases in measured and unmeasured variables existed. Statistical techniques may not have been sufficient to adjust for these confounding factors. Second, this study lacked important data regarding β-blockers. We only knew whether patients were using β-blocker therapy at discharge. Unfortunately, there was no information regarding the type or dose of β-blocker, the timing of initial administration, discontinuation, adherence, dose change, or new prescription after discharge, which can affect the long-term efficacy of β-blocker therapy. Third, there were too many missing EF values. When considering the effectiveness of β-blockers for AMI patients, the EF value, which is a well-known strong predictor of the effectiveness of β-blockers, is critically important. However, in our registry data, missing EF values were observed for approximately one-third of the total population; therefore, we considered it inappropriate to add this value to our analysis. Finally, the initial diagnosis and adverse clinical events were not centrally adjudicated in our registry. All diagnoses and events were identified by physicians and confirmed by the principal investigator of each hospital. Therefore, inaccuracies in diagnoses and clinical events were possible.

Conclusions

In our multicenter registry data, β-blocker therapy at discharge was associated with improved long-term survival and clinical outcomes for current AMI patients with tachycardia on admission. In contrast, for patients with bradycardia on admission, β-blocker therapy was associated with worse long-term clinical outcomes. Our study suggested that admission HR might be a determinant of the efficacy of β-blocker therapy for current AMI patients. However, further investigations are warranted to confirm our findings.

Acknowledgments

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

Grant

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

Disclosures

• Dr. Tanabe: Remuneration – Abbott Vascular, Daiich-Sankyo, Tanabe Mitsubishi Pharma.

• Dr. Ozaki: Research fund – Bayer, Research Institute for Production Development. Scholarship fund – Daiichi-Sankyo, Dainippon Sumitomo.

• Dr. Ako: Remuneration – Tanabe Mitsubishi Pharma, Daiichi-Sankyo, Actelion, Sanofi, Takeda Pharmaceutical, Mochida Pharmaceutical, Shionogi, Kaneka, Astra Zeneca, Astellas Pharma, Volcano, Terumo, Eisai, Bristol-Myers Squibb, St. Jude Medical, Kyowa Hakko Kirin, Pfizer, Ono Pharmaceutical, Abbott Vascular Japan, Toa Eiyo, JIMRO, Kissei, Sumitomo Dainippon Pharma. Scholarship funds: Astellas Pharma, Mediphysics, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Kyowa Hakko Kirin, Bayer, Eisai, Teijin, Kowa Pharmaceutical, Mochida Pharmaceutical, Abbott Vascular Japan, Medtronic Japan, Asahi Intec, Astra Zeneca, Sumitomo Dainippon Pharma, Otsuka Pharmaceutical, Tanabe Mitsubishi Pharma, Takeda Pharmaceutical, Japan Lifeline.

• Dr. Saito: Scholar fund – Takeda Pharmaceutical, Teijin Pharma, Ono Pharmceutical, Tanabe Mitsubishi, Eisai, ZERIA Pharmaceutical, Shionogi, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Kyowa Hakko Kirin, Astellas Pharma, Daiichi-Sankyo, Boston Scientific Japan. Affiliation with Endowed Department – MSD, a subsidiary of Merck & Co.

• Dr. Shimizu: Remuneration – Daiichi-Sankyo, Boehringer Ingelheim Japan, Bayer, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer. Scholarship fund – Daiichi-Sankyo, Boehringer Ingelheim Japan, Ono Pharmaceutical, Otsuka Pharmaceutical, Eisai, Tanabe Mitsubish Pharma, Astellas Pharma, St. Jude Medical.

• Dr. Kimura: Remuneration – Astra Zeneca, Toa Eiyo, Bayer, Daiichi-Sankyo. Scholarship fund – MSD, Daiichi-Sankyo, Ono Pharmaceutical, Pfizer, Bayer, Takeda Pharmaceutical, Boehringer Ingelheim Japan, Tanabe Mitsubishi, Astellas.

• Dr. Saito: Remuneration – Otsuka Pharmaceutical, Kowa Pharmaceutical, Daiichi-Sankyo, Tanabe Mitsubishi Pharma, Pfizer Japan, Novartis Pharma.

• Dr. Tsujita: Remuneration – Bayer, MSD, Sanofi, Amgen Astellas BioPharma, Daiichi-Sankyo. Research funds – AstraZeneca. Scholarship fund – Astellas, Bayer, Boehringer Ingelheim Japan, Boston Scientific Japan, Chugai, Daiichi-Sankyo, Eisai, Kowa, Tanabe Mitsubishi, MSD, Pfizer, Sanofi, Shionogi, Takeda Pharmaceutical.

• Dr. Ishihara: Remuneration – Bayer, MSD, Astra Zeneca, Astellas. Scholarship fund – Abbott Vascular, Boston Scientific, Sanofi, MSD, Astellas, Bayer, Pfizer, Daiichi-Sankyo, MID, Goodman

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0995

References

• 1.   Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130: 2354–2394.
• 2.   O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, 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. J Am Coll Cardiol 2013; 61: e78–e140.
• 3.   Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the Management of Acute Myocardial Infarction in Patients Presenting with ST-segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39: 119–177.
• 4.   Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267–315.
• 5.   A randomized trial of propranolol in patients with acute myocardial infarction. I: Mortality results. JAMA 1982; 247: 1707–1714.
• 6.   A randomized trial of propranolol in patients with acute myocardial infarction. II: Morbidity results. JAMA 1983; 250: 2814–2819.
• 7.   Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981; 304: 801–807.
• 8.   Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: An overview of the randomized trials. Prog Cardiovasc Dis 1985; 27: 335–371.
• 9.   Choo EH, Chang K, Ahn Y, Jeon DS, Lee JM, Kim DB, et al. Benefit of beta-blocker treatment for patients with acute myocardial infarction and preserved systolic function after percutaneous coronary intervention. Heart 2014; 100: 492–499.
• 10.   Yang JH, Hahn JY, Song YB, Choi SH, Choi JH, Lee SH, et al. Association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. JACC Cardiovasc Interv 2014; 7: 592–601.
• 11.   Goldberger JJ, Bonow RO, Cuffe M, Liu L, Rosenberg Y, Shah PK, et al. Effect of beta-blocker dose on survival after acute myocardial infarction. J Am Coll Cardiol 2015; 66: 1431–1441.
• 12.   Huang BT, Huang FY, Zuo ZL, Liao YB, Heng Y, Wang PJ, et al. Meta-analysis of relation between oral beta-blocker therapy and outcomes in patients with acute myocardial infarction who underwent percutaneous coronary intervention. Am J Cardiol 2015; 115: 1529–1538.
• 13.   Puymirat E, Riant E, Aissoui N, Soria A, Ducrocq G, Coste P, et al. β blockers and mortality after myocardial infarction in patients without heart failure: Multicentre prospective cohort study. BMJ 2016; 354: i4801.
• 14.   Dondo TB, Hall M, West RM, Jernberg T, Lindahl B, Bueno H, et al. Beta-blockers and mortality after acute myocardial infarction in patients without heart failure or ventricular dysfunction. J Am Coll Cardiol 2017; 69: 2710–2720.
• 15.   Bangalore S, Makani H, Radford M, Thakur K, Toklu B, Katz SD, et al. Clinical outcomes with beta-blockers for myocardial infarction: A meta-analysis of randomized trials. Am J Med 2014; 127: 939–953.
• 16.   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. Am J Cardiol 2010; 106: 1225–1233.
• 17.   Kernis SJ, Harjai KJ, Stone GW, Grines LL, Boura JA, O’Neill WW, et al. Does beta-blocker therapy improve clinical outcomes of acute myocardial infarction after successful primary angioplasty? J Am Coll Cardiol 2004; 43: 1773–1779.
• 18.   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. Am J Cardiol 2013; 111: 457–464.
• 19.   Antoni ML, Boden H, Delgado V, Boersma E, Fox K, Schalij MJ, et al. Relationship between discharge heart rate and mortality in patients after acute myocardial infarction treated with primary percutaneous coronary intervention. Eur Heart J 2012; 33: 96–102.
• 20.   Seronde MF, Geha R, Puymirat E, Chaib A, Simon T, Berard L, et al. Discharge heart rate and mortality after acute myocardial infarction. Am J Med 2014; 127: 954–962.
• 21.   Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol 1986; 57: 43f–49f.
• 22.   Cucherat M. Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post-myocardial infarction: A meta-regression of randomized clinical trials. Eur Heart J 2007; 28: 3012–3019.
• 23.   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). Circ J 2015; 79: 1255–1262.
• 24.   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. Circ J 2017; 81: 958–965.
• 25.   Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60: 1581–1598.
• 26.   Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined: A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–969.
• 27.   Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 2005; 366: 1622–1632.
• 28.   Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001; 357: 1385–1390.
• 29.   Fosbol EL, Seibaek M, Brendorp B, Moller DV, Thune JJ, Gislason GH, et al. Long-term prognostic importance of resting heart rate in patients with left ventricular dysfunction in connection with either heart failure or myocardial infarction: The DIAMOND study. Int J Cardiol 2010; 140: 279–286.
• 30.   Parodi G, Bellandi B, Valenti R, Memisha G, Giuliani G, Velluzzi S, et al. Heart rate as an independent prognostic risk factor in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Atherosclerosis 2010; 211: 255–259.
• 31.   Li J, Becker R, Rauch B, Schiele R, Schneider S, Riemer T, et al. Usefulness of heart rate to predict one-year mortality in patients with atrial fibrillation and acute myocardial infarction (from the OMEGA trial). Am J Cardiol 2013; 111: 811–815.
• 32.   Fox K, Ford I, Steg PG, Tendera M, Ferrari R, Investigators B. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 807–816.
• 33.   Noman A, Balasubramaniam K, Das R, Ang D, Kunadian V, Ivanauskiene T, et al. Admission heart rate predicts mortality following primary percutaneous coronary intervention for ST-elevation myocardial infarction: An observational study. Cardiovasc Ther 2013; 31: 363–369.
• 34.   Gheorghiade M, Colucci WS, Swedberg K. Beta-blockers in chronic heart failure. Circulation 2003; 107: 1570–1575.
• 35.   Lee JH, Ryu HM, Bae MH, Kwon YS, Lee JH, Park Y, et al. Prognosis and natural history of drug-related bradycardia. Korean Circ J 2009; 39: 367–371.
• 36.   Sagie A, Strasberg B, Kusnieck J, Sclarovsky S. Symptomatic bradycardia induced by the combination of oral diltiazem and beta blockers. Clin Cardiol 1991; 14: 314–316.
• 37.   Lu HT, Kam J, Nordin RB, Khelae SK, Wang JM, Choy CN, et al. Beta-blocker use and risk of symptomatic bradyarrhythmias: A hospital-based case-control study. J Geriatr Cardiol 2016; 13: 749–759.
• 38.   Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–1658.
• 39.   A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS): CIBIS Investigators and Committees. Circulation 1994; 90: 1765–1773.
• 40.   Schneider HJ, Pfeiffer D, Hagendorff A. The influence of bradycardia and normofrequent ventricular pacing on myocardial blood flow and energy demand in rats. Cardiology 2003; 100: 67–72.