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Corresponding author: Dr Cynthia Jackevicius, Western University of Health Sciences, College of Pharmacy, 309 E Second St, Pomona, California 91766, USA. Tel.: +1-909-469-5527; fax: +1-909-469-5539.
Department of Pharmacy Practice and Administration, College of Pharmacy, Western University of Health Sciences, Pomona, California, USAInstitute for Clinical Evaluative Sciences, Toronto, Ontario, CanadaVeterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USAInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, CanadaUniversity Health Network, Toronto, Ontario, Canada
Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut, USADepartment of Epidemiology and Public Health, Section of Health Policy and Administration, New Haven, Connecticut, USARobert Wood Johnson Clinical Scholars Program, New Haven, Connecticut, USA
Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut, USADepartment of Internal Medicine, Section of General Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
Institute for Clinical Evaluative Sciences, Toronto, Ontario, CanadaInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
Institute for Clinical Evaluative Sciences, Toronto, Ontario, CanadaInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
Institute for Clinical Evaluative Sciences, Toronto, Ontario, CanadaInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
Institute for Clinical Evaluative Sciences, Toronto, Ontario, CanadaInstitute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, CanadaDivision of Cardiology, Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
It is uncertain whether beta-blockers (BBs) are beneficial in contemporary stable patients with prior myocardial infarction (MI). Therefore, we sought to examine the effectiveness of BB use in this population.
Methods
We conducted a cohort study with the use of administrative databases of patients ≥ 65 years of age, alive on April 1, 2012 (index date) with a hospital discharge diagnosis of MI within the previous 3 years. The primary outcome was time to death or hospitalization for MI or angina 1 year after the index date, with inverse probability of treatment weighting.
Results
We included 33,811 patients with prior MI, of whom 21,440 (63.4%) were dispensed a BB. The median age was 78 years, and 56% were male. There was no difference in the 1-year hazard of death/hospitalization for MI or angina (14.8% vs 14.7%, hazard ratio 1.00, 95% confidence interval 0.94-1.07; P = 0.90) in those receiving vs not receiving BB. Similarly, there was no difference in the individual end points in composite nor in 3-year outcomes. Subgroup analysis by age, sex, MI timing, MI type, heart failure, and atrial fibrillation found no benefit. Patients with a history of revascularisation treated with BBs had a lower rate of the composite outcome compared with those without such history (P = 0.006 for interaction) at 1 year but not at 3 years.
Conclusions
In this large contemporary population-based observational study of older stable patients with prior MI, BBs were not associated with a reduction in major cardiovascular events or mortality in those with MI within the previous 3 years. This study supports the need to conduct contemporary clinical trials evaluating the use of BBs after MI.
Résumé
Contexte
On ne sait pas avec certitude si les bêtabloquants (BB) sont bénéfiques chez les patients contemporains qui présentent des antécédents d’infarctus du myocarde (IM) et dont l’état est stable. Nous avons donc cherché à examiner l’efficacité des BB au sein de cette population.
Méthodologie
Nous avons utilisé des bases de données administratives afin de mener une étude de cohorte portant sur des patients de 65 ans et plus qui étaient vivants en date du 1er avril 2012 (date de référence) et qui avaient reçu un diagnostic d’IM à leur sortie de l’hôpital au cours des trois années précédentes. Le paramètre d’évaluation principal était le temps écoulé avant le décès ou l’hospitalisation pour cause d’IM ou d’angine un an après la date de référence, avec pondération par probabilité inverse de traitement.
Résultats
Nous avons inclus 33 811 patients présentant des antécédents d’IM, dont 21 440 (63,4 %) avaient reçu des BB. L’âge médian était de 78 ans, et 56 % des patients étaient de sexe masculin. Aucune différence n’a été notée quant au risque de décès ou d’hospitalisation pour cause d’IM ou d’angine sur un an (14,8 % vs 14,7 %, rapport des risques instantanés : 1,00, intervalle de confiance à 95 % : 0,94-1,07; p = 0,90) chez les patients traités par des BB par rapport à ceux qui ne l’étaient pas. De même, aucune différence n’a été observée au regard de chaque paramètre d’évaluation dans les résultats composites ni dans les résultats à trois ans. Une analyse de sous-groupes en fonction de l’âge, du sexe, du moment de survenue de l’IM, du type d’IM, de l’insuffisance cardiaque et de la fibrillation auriculaire n’a mis en évidence aucun bienfait. Les patients présentant des antécédents de revascularisation traités par des BB, comparativement à ceux qui ne présentaient pas de tels antécédents, avaient un taux de résultats composites moins élevé (p = 0,006 pour l’interaction) à un an, mais pas à trois ans.
Conclusions
Dans le cadre de cette vaste étude d’observation de population contemporaine portant sur des patients âgés présentant des antécédents d’IM et dont l’état est stable, les BB n’étaient pas associés à une réduction des événements cardiovasculaires majeurs ou de la mortalité chez les patients qui avaient subi un IM au cours des trois années précédentes. Cette étude confirme qu’il est nécessaire de mener des essais cliniques contemporains visant à évaluer l’utilisation de BB après un IM.
The benefit of oral beta-blockers (BBs) in patients with heart failure with reduced ejection fraction (HFrEF) and acute myocardial infarction (MI) is well established. However, recent observational studies, with highly heterogeneous results on meta-analysis, have raised uncertainty about the use of BB therapy in stable patients after MI.
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.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
The vast majority of the clinical trial evidence demonstrating morbidity and mortality reduction with the use of BBs originates from older randomized trials that preceded the current reperfusion era, the current statin era, and the introduction of troponin assays to diagnose acute MI.
The most recent BB trial, the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), which studied the early use of BBs in a largely ST-segment-elevation myocardial infarction (STEMI) patient population, does not help to answer the question regarding the utility of BB therapy in contemporary stable patients chronically with prior MI because it was conducted from 1999 to 2005 in a setting with minimal reperfusion, primarily with the use of the fibrinolytic streptokinase, and focused on early outcomes with intravenous BB therapy at 1 month.
COMMIT Collaborative Group Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.
The American College of Cardiology/American Heart Association guidelines for acute coronary syndromes and for chronic secondary prevention treatment of ischemic heart disease began questioning use of BBs in stable post-MI patients owing to concerns about long-term patient tolerability.
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.
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.
AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
Their 2011 secondary prevention guidelines were the first to make a change in recommending the continuation of BBs for only 3 years after MI rather than indefinitely as in previous guidelines, unless patients have other compelling reasons for ongoing BB therapy.
AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
Subsequent stable ischemic heart disease and STEMI guidelines followed suit in 2012 and 2013, limiting the duration of BB therapy while maintaining the class IA recommendation, respectively.
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.
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.
The European Society of Cardiology STEMI and non–ST-segment-elevation acute coronary syndrome guidelines in 2015 further questioned the utility of chronic BB use after MI by recommending chronic use only in those patients with heart failure or left ventricular dysfunction, generating further uncertainty given the discrepancies in professional society recommendations surrounding BB use.
ESC Document Group 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).
ESC Scientific Document Group 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).
Their justification was that BBs have been investigated in contemporary randomized trials only in MI patients with heart failure or without normal left ventricular function.
The observational studies that have questioned the usefulness of BBs in patients with prior MI have been limited in size, resulting in confidence intervals that cannot exclude a potentially clinically meaningful benefit.
In order to improve generalizability, certainty, and precision regarding the estimate of treatment effect for this important clinical decision, we used multiple linked health care databases to evaluate the effectiveness of BBs in a large, contemporary population-based cohort of stable patients with prior MI.
Methods
Study design and data sources
We conducted a population-based observational cohort study linking multiple health care databases and used inverse probability of treatment weighting (IPTW) with the use of the propensity score to account for confounding. The data sources have been widely used for health services and outcomes research.
To identify patients for eligibility for cohort entry and to document cardiac risk factors and comorbidities, we used the Canadian Institute for Health Information (CIHI) Discharge Abstract Database, which contains primary and secondary discharge diagnoses for all hospital admissions in Ontario, including cardiac procedures, such as percutaneous coronary intervention and coronary catheterization. To ascertain medication use, we used the Ontario Drug Benefit prescription claims database, which contains outpatient prescriptions dispensed for all elderly patients (≥ 65 years of age) in Ontario, as well as those on social assistance. The Ontario Health Insurance Plan database contains data on physician services. The Ontario Registered Persons database contains information on vital status of all Ontario residents and was used to ascertain death. The Statistics Canada census database contains demographic and socioeconomic data, and was used to determine geographic location and median neighbourhood income of patients according to their location of residence. These datasets were linked using unique encoded identifiers and analyzed at the Institute for Clinical Evaluative Sciences, Toronto.
Study population
Our study included patients ≥ 65 years of age who were alive on April 1, 2012. We created a cohort of stable patients who had been discharged with an acute MI within the 3 years before April 1, 2012, the cohort index date, as identified with the use of the codes I21 and I22 from the International Classification of Disease, 10th Revision, in the CIHI Discharge Abstract Database. We excluded patients with a presumed history of HFrEF, which was defined by those prescribed carvedilol (which in Ontario is reserved for the treatment of HFrEF). We also excluded patients older than 105 years and those with an invalid Ontario health insurance number.
Exposure
BB exposure was defined as dispensation of a BB prescription within 100 days before the index date of April 1, 2012. All BBs qualified for exposure with the exceptions of sotalol and carvedilol. Sotalol is generally used as an antiarrhythmic rather than for purposes of atherosclerotic cardiovascular risk reduction, and in Ontario, carvedilol is recommended exclusively for patients with HFrEF. Because our intention was to examine a post-MI cohort that did not already have a compelling indication for a BB, we excluded patients prescribed carvedilol.
Outcomes
The primary outcome was death or hospitalization for MI or angina within 1 year after April 1, 2012. Secondary outcomes included death alone and death or hospitalization for MI. Primary and secondary hospitalization outcomes were ascertained from CIHI discharge abstract data. Death was determined from the Ontario Registered Persons Database. Follow-up for ascertainment of outcomes began on April 1, 2012, the time of cohort entry, and patients were followed for events up to 1 year after cohort entry for the primary outcome. A secondary analysis also followed patients for 3 years after cohort entry.
Statistical analysis
In the overall cohort, baseline demographic and clinical variables were compared between those using BBs and those not using BBs by means of the chi-square test for proportions, 1-way analysis of variance for means, and Kruskal-Wallis test for medians of continuous variables. Potential confounders measured at baseline were adjusted for IPTW with the use of the propensity score. The propensity score (the probability of receiving BB therapy conditional on relevant baseline and clinical characteristics) was estimated with the use of a multivariable logistic regression model based on the baseline demographic and clinical characteristics listed in Table 1. Patients were weighted by the inverse of the probability of receiving the treatments that they actually received. To determine whether the treatment groups were balanced after weighting, we estimated the weighted standardised differences for each baseline covariate.
Moving toward best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
Weighted Kaplan-Meier curves were estimated in each group to compare outcomes between groups. Cox proportional hazard models were constructed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the estimates of treatment effect between the BB and no-BB groups for the primary and secondary outcomes. IPTW was incorporated into the models. A robust variance estimator was used to account for the weighted nature of the sample.
We also conducted subgroup analyses to compare the BB treatment effect according to age (< 75 years, ≥ 75 years), sex (male, female), timing of prior MI, history of coronary revascularisation (percutaneous coronary intervention or coronary artery bypass surgery), heart failure, and history of atrial fibrillation and tested for interactions. As a further analysis, we restricted the sample to those patients treated with BBs and compared outcomes in patients who received high- or standard-dose with those who received low-dose BBs, thereby allowing us to explore a dose-response effect. This analysis used a new IPTW analysis with a new propensity score estimated for use of high- or standard-dose BB vs low-dose BB. (Dose thresholds are presented in Supplemental Table S1.) All analyses were conducted with the use of SAS version 9.3 (SAS Institute, Cary, NC, USA). A P value of < 0.05 was considered to be statistically significant. The use of data in this project was authorized under section 45 of Ontario’s Personal Health Information Protection Act, which does not require review by a Research Ethics Board.
Results
We included 33,811 patients in the present cohort, and of these, 21,440 (63.4%) had been dispensed BBs (Fig. 1). The baseline characteristics were well balanced after IPTW, with all standardized differences < 0.1. (Table 1; Supplemental Table S2) In the weighted cohort, the median age was 78 years, 56% were male, ~ 70% had NSTEMI, and the median time to the most recent MI was 16.1 months (interquartile range 7.3–25.8 months). Patients had many common cardiovascular risk factors, including hypertension (89.3%), diabetes (43.5%), and dyslipidemia (52.9%). Approximately 74% of patients had undergone coronary catheterization, and 43% had undergone percutaneous coronary intervention. Within the 100 days before the cohort index date, 68% of patients had filled a prescription for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and 76% had filled a prescription for statins. The most common BB dispensed was metoprolol (61.5%), followed by bisoprolol (30.0%) and atenolol (6.3%). Of those receiving BBs, 60.9% received a high or standard dose of BB. Mean proportion of days covered for all those in the BB group was 87.2% at 1 year, 85.4% at 2 years, and 84.0% at 3 years after the index date of cohort entry.
Figure 1Flowchart of cohort creation according to inclusion and exclusion criteria. AMI, acute myocardial infarction.
There were a total of 3,748 deaths and 1,591 admissions due to MI or angina. There was no difference in the rate of occurrence of the primary composite outcome of death or hospitalization for MI or angina between the BB group and the no-BB group at 1 year (14.8% vs 14.7%, IPTW-adjusted hazard ratio [aHR] 1.00, 95% CI 0.94-1.07; P = 0.90). (Table 2) There was also no difference in the 1-year hazard of death (11.1% vs 11.1%, HR 1.00, 95% CI 0.93-1.08; P = 1.00) or of death or hospitalization for MI (13.7% vs 13.9%, HR 0.98, 95% CI 0.92-1.05; P = 0.64) between the groups. When outcomes were examined at 3 years after the study index date, there were also no differences found between groups in the primary or the secondary outcomes. There was no difference in the composite outcome of death or hospitalization for MI or angina in the BB group compared with the no-BB group at 3 years (33.5% vs 33.4%, aHR 1.00, 95% CI 0.96-1.05; P = 0.92). There was also no difference in the hazard of death (27.8% vs 28.0%, HR 0.99, 95% CI 0.95-1.04; P = 0.80) or of death or hospitalization (31.9% vs 31.9%, HR 1.00, 95% CI 0.96-1.05; P = 1.00) for MI between the BB and no-BB groups at 3 years. (Table 2) We also found no difference in outcomes between high-dose and low-dose BBs.
Table 2One- and 3-year cardiovascular and death outcomes
Outcome
Unadjusted, n (%)
Model with IPTW using robust variance
β-Blocker
No β-blocker
β-Blocker KM rate, %
No β-blocker KM rate, %
Absolute risk difference, %
HR (95% CI)
P value
n
21,440
12,371
1 year after Apr 1, 2012
Death
2355 (11.0)
1393 (11.3)
11.1
11.1
0
1.00 (0.93-1.08)
1.00
Death/hospitalization for MI
2948 (13.8)
1679 (13.6)
13.7
13.9
0.2
0.98 (0.92-1.05)
0.64
Death/hospitalization for MI or angina
3195 (14.9)
1758 (14.2)
14.8
14.7
0.1
1.00 (0.94-1.07)
0.90
3 years after Apr 1, 2012
Death
5928 (27.6)
3373 (27.3)
27.8
28.0
0.2
0.99 (0.95-1.04)
0.80
Death/hospitalization for MI
6847 (31.9)
3825 (30.9)
31.9
31.9
0
1.00 (0.96-1.05)
1.00
Death/hospitalization for MI or angina
7198 (33.6)
3979 (32.2)
33.5
33.4
0.1
1.00 (0.96-1.05)
0.92
Data are expressed as n (%) unless otherwise noted.
IPTW, inverse probability of treatment weighting; KM, Kaplan-Meier; MI, myocardial infarction.
Subgroup analyses that were conducted according to age, sex, timing of MI, type of MI, heart failure, and atrial fibrillation found no interactions to identify a specific subgroup that benefited from BB use. (Fig. 2) A significant interaction was found in treatment effect for the composite outcome at 1 year for the subgroup of those with vs without a history of coronary revascularisation with percutaneous coronary intervention or coronary artery bypass graft surgery (revascularisation history HR 0.90, 95% CI 0.80-1.00, vs no revascularisation history HR 1.09, 95% CI 1.00-1.18; P = 0.006 for interaction). However, at 3 years, this effect did not persist.
Figure 2Forest plot of the subgroup results for the composite end point of death or hospitalization for myocardial infarction (MI) or angina at 1 year. CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.
In this study, in a contemporary population-based cohort, BBs were not associated with a reduction in major cardiovascular events, namely, death or hospitalization for MI or angina in a stable population with prior MI. A large impact on cardiovascular events was not expected in our contemporary cohort, because patients were already well treated with other evidence-based risk reduction medications, with more than 70% of patients receiving statins and nearly 70% receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and many had undergone coronary revascularisation. The results were consistent across multiple subgroups, although in one subgroup, those with prior coronary revascularisation, BBs were associated with a modest reduction in major cardiovascular events at 1 year, though not at 3 years. Although it is possible that those who were revascularised may represent a higher-risk population, this subgroup finding should be considered as hypothesis generating because it could be a chance finding given the multiple subgroups that we analyzed in our comprehensive evaluation.
Whereas most previous research included patients immediately after MI enrolled in MI registries, we focused on examining a stabilized cohort with MI within the previous 3 years, with the majority of patients having their most recent MI ~ 1.5 years before cohort entry.
Thus, our study examined the association of BB use with clinical outcomes beyond the acute MI period. In a subgroup analysis, we compared patients with a more recent AMI (< 1 year before) vs those with a more remote AMI (≥ 1 year before) and found no statistical interaction to suggest a beneficial association between BB use and clinical outcomes in either group. The current American College of Cardiology/American Heart Association secondary prevention guidelines recommend limiting BB therapy to a duration of 3 years because the original prospective BB randomized controlled trials that demonstrated morbidity and mortality benefits were of 3 years’ duration.
AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
Ongoing clinical trials, such as REDUCE-SWEDEHEART, are examining the benefit of BBs in a contemporary well treated population 1-7 days after MI, but the question of longer-term optimal chronic BB use (beyond 1-3 years) remains unanswered.
Until further clinical trials address this issue, our findings add to the growing observational literature questioning the utility of BB use chronically after MI.
We summarize the results of our current study for death and acute coronary syndrome events along with the results of previous studies of BB use from cohort studies of populations with prior MI in Figure 3. Two other cohort studies examined a composite end point of major cardiovascular events and death. Andersson et al.,
using a time-varying Cox model, found a significant 8% reduction in composite events primarily in the recent MI subgroup of a mixed cohort from 2000-2008 of post–acute MI patients and those undergoing revascularisation. In contrast, Bangalore et al.,
in a propensity score-matched analysis with the use of a smaller cohort of 6,758 post–acute MI patients from the REACH (Reduction of Atherothrombosis for Continued Health) registry, found a modest, but nonsignificant, 10% reduction in composite events, with CIs that did not preclude a possible treatment effect (HR 0.90, 95% CI 0.79-1.03). In our larger cohort of 33,811 patients at an average of 1.5 years after MI, we found no difference for the composite end point of death or hospitalization for MI or angina, with a greater precision around the HR estimate (HR 1.00, 95% CI 0.94-1.07).
Figure 3Point estimates and confidence intervals for the outcomes of death, myocardial infarction (MI), or acute coronary syndromes (ACS) or of death alone for the present study and previous published cohort studies examining the use of beta-blockers in post-MI patients.
Six cohort studies examined a mortality end point and found conflicting results. One of these 6 studies examined the association with BB discontinuation rather than BB initiation or use with outcomes.
(Fig. 3). The point estimates for mortality varied widely, from an HR as low as 0.57 to one as high as 0.93, with the lowest estimate representing a 7% and the highest estimate representing a 43% relative hazard reduction in mortality. CIs ranging from a lower interval of 0.36 (64% mortality reduction) to an upper interval of 1.78 (78% mortality increase) reflect the imprecision of estimates of previous studies because of small sample size or few events, and they illustrate the inability to exclude a possible beneficial BB treatment effect. Our findings in a large, population-based, contemporary, and well balanced cohort of well treated patients with prior MI reports a more precise estimate showing no treatment effect for BBs both for a composite end point of major cardiovascular events and for mortality alone.
It has been suggested that type of BB may be an important variable in achieving a favourable BB effect after MI. Analogous to that for the heart failure indication, some preliminary research suggests improved outcomes in MI populations with the use of noncardioselective BBs and vasodilating BBs, both attributes of carvedilol.
A systematic review of selective and nonselective beta blockers for prevention of vascular events in patients with acute coronary syndrome or heart failure.
Benefit of vasodilating β-blockers in patients with acute myocardial infarction after percutaneous coronary intervention: nationwide multicenter cohort study.
CAPRICORN Investigators Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
We could not explore this further, because we excluded patients receiving carvedilol from our cohort to examine a non–heart failure population; future research can explore this hypothesis. There is renewed interest in targeting specific heart rates in various cardiovascular populations.
Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post–myocardial infarction: a meta-regression of randomized clinical trials.
Although we did not have data on heart rate, we did not identify a dose-response gradient in our subgroup analysis, similarly to most previous research in post-MI populations.
We now have improved medical and interventional MI therapies, including more advanced coronary reperfusion approaches, particularly primary percutaneous coronary intervention for STEMI, as well as potent dual-antiplatelet therapy and high-intensity statins.
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.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
Furthermore, with the advent first of troponin and then of high-sensitivity troponin assays, our ability to detect smaller myocardial injury is now yielding a lower-risk MI population compared with MI that occurred in the era in which BBs were originally found to be beneficial.
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.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
The use of BBs indefinitely after MI has been ingrained in our therapeutic approach, but a reevaluation of this practice appears to be necessary to reflect the contemporary MI setting.
The present study has several limitations. As an observational study, there is the possibility for residual confounding. We cannot know why some patients were treated with BB and others were not. However, our use of IPTW methods and use of a large unselected population-based database, with all standardized differences well below 0.1, indicate the creation of a well balanced cohort. Furthermore, potential confounding would most likely bias toward finding a benefit with BB, whereas we found no difference. Thus, residual confounding is unlikely to explain our findings. We did not have information on some cardiac risk factors, such as weight, smoking, and exercise status, given that these data are not typically available in administrative data sources. However, our cohort was well balanced for all other known baseline covariates and was also balanced for high levels of use of contemporary evidence-based medications for cardiovascular risk reduction. We did not have data available on ejection fraction. However, our exclusion of patients receiving carvedilol primarily excluded HFrEF patients from our population because carvedilol is used in Ontario solely for HFrEF. Therefore, our study results are applicable to patients without HFrEF. Furthermore, should some HFrEF patients have been included in our BB group, this again would have biased our findings toward benefit.
Conclusion
In summary, this large population-based cohort provides a precise estimate of treatment effect, finding that the use of BBs was not associated with a reduction in major cardiovascular events or mortality in stable patients with prior MI who were well treated with other evidence-based cardiovascular risk-reduction therapies. The conflicting results of recent observational studies and importance of this clinical question supports the conduct of randomized clinical trials of chronic BB use in a contemporary cohort of patients with prior MI.
Acknowledgements
This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Part of this material is based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI). The analyses, conclusions, opinions, and statements expressed herein are those of the authors and not necessarily those of CIHI. The authors acknowledge Dr Jack V. Tu (deceased May 30, 2018), who made contributions to the initial design of this study.
Funding Sources
This study was funded by a grant (G-14-0005977) from the Heart and Stroke Foundation of Canada and by Foundation Grants (154333 and 154333) from the Canadian Institutes of Health Research.
Disclosures
Detailed disclosures for H.C.K. and J.S.R. are provided in the Supplemental Appendix. P.C.A. and D.T.K. are each supported by their own Mid-Career Investigator Award from the Heart and Stroke Foundation, Ontario Provincial Office. The other authors have no conflicts of interest to disclose.
Supplemental Tables S1 and S2 and Supplemental Appendix
References
O’Gara P.T.
Kushner F.G.
Ascheim D.D.
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.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
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.
AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
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).
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).
Moving toward best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
A systematic review of selective and nonselective beta blockers for prevention of vascular events in patients with acute coronary syndrome or heart failure.
Benefit of vasodilating β-blockers in patients with acute myocardial infarction after percutaneous coronary intervention: nationwide multicenter cohort study.
Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post–myocardial infarction: a meta-regression of randomized clinical trials.
Patients with myocardial infarction (MI) are at an increased risk for cardiovascular events, including sudden cardiac death, ventricular arrhythmias, reinfarction, and heart failure. These risks are particularly high in the near term after MI and decreases over time. Increased sympathetic activation in patients with MI occurs frequently as part of compensatory mechanism due to chest discomfort, dyspnea, anxiety, and impaired cardiac function. However, prolonged sympathetic activation plays a major role in mediating many of the adverse outcomes after an MI.
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