Beta-blocker therapy after acute myocardial infarction with preserved ejection fraction : observational and clinical studies

Background

Cardiovascular disease, with its feared primary presentation of acute myocardial infarction (AMI), remains the leading cause of morbidity and mortality globally. Despite its routine use worldwide, the scientific evidence for beta-blocker therapy in patients with AMI and preserved left ventricular ejection fraction (LVEF) is surprisingly limited. Large, randomized trials are required to form a more solid base and to support recommendations.

Methods and results

Study I. An observational study linking data from multiple Swedish national registries assessed dose-dependent effects of beta-blockers on death from any cause and new AMI. A total of 97,575 patients with first-time AMI were included, where 33,126 (33.9%) patients were discharged with >50% of the target beta- blocker dose, and 64,449 (66.1%) patients with <50% of the target beta-blocker dose. Multivariable adjusted one-year follow-up estimates using mixed-effects Cox regression showed that patients treated with >50% of the target dose had a similar risk of the composite endpoint (HR, 1.03; 95% CI, 0.99 to 1.08; P = 0.18) compared with patients on <50% of the target beta-blocker dose.

Study II. A register-based, randomized, parallel, open-label, multicentre trial that evaluated the effect of routine initiation of beta-blocker treatment, in patients with AMI and preserved LVEF, in reducing the risk of death from any cause, or new AMI. The trial was performed at 38 centres in Sweden, one in Estonia, and six in New Zealand. From September 2017 through May 2023, 5020 patients were randomly assigned to either long-term beta-blocker treatment or no beta- blocker treatment. Baseline characteristics were well balanced between the two groups, the median age of the population was 65 years and 22.5% were women. Unadjusted Cox proportional hazards regression analysis showed that beta- blocker treatment did not decrease the risk of the composite endpoint, including death from any cause or new AMI, compared with no beta-blocker treatment (HR, 0.96; 95% CI, 0.79 to 1.16; P=0.64).

Study III. A pre-specified substudy of the trial described in Study II, designed to evaluate the effect of beta-blockers on health-related quality of life (HRQoL) in patients with AMI and preserved LVEF. Responses to EQ-5D questionnaires were obtained at 6-10 weeks and 11-13 months after AMI. A total of 4,080 patients answered the forms, out of which 2,023 (49.6%) patients were randomized to beta-blockers. Baseline characteristics were similar to those in the main trial. The study reported results from intention-to-treat (ITT) and on-treatment analyses using the Wilcoxon rank sum test and adjusted ordinal regression analyses. The main outcome, median EQ-5D index score, did not differ between the groups at follow-up one (6-10 weeks after the AMI) (OR, 1.00; 95% CI, 0.89 to 1.13; P = 0.94). At the second follow-up (11-13 months after AMI), the results remained unchanged (OR, 1.02; 95% CI, 0.90 to 1.15; P = 0.78). The findings were robust in on-treatment analyses and across relevant subgroups.

Study IV. A pre-specified substudy of the trial described in Study II, where conventional echocardiographic parameters and global longitudinal strain (GLS) measurements were obtained from routine echocardiographic examinations during the index hospitalization at four participating centres. The analysis addressed the question of whether or not GLS measurement in addition to LVEF improves outcome prediction. A likelihood ratio (LR) test between models adjusted for age, sex, hypertension, smoking, diabetes, previous AMI, and multivessel disease was used to compare LVEF and GLS as prognostic methods. A Cox regression model was used to evaluate the impact of beta-blocker treatment on the composite endpoint of death from any cause, or new AMI. A total of 1,436 patients (28.6% of the total population) were included. The LR test showed no significant difference (P = 0.56) when comparing the combination of GLS and LVEF to LVEF alone. The results were robust when adding beta-blocker randomization status as an independent variable.

Conclusions

This thesis provides new evidence that routine initiation of beta-blockers in patients with AMI and preserved LVEF does not decrease the risk of death from any cause, or new AMI, compared with no beta-blocker use. Even when complemented with more advanced echocardiographic measurements, no additive prognostic value regarding these endpoints was found. In addition, beta-blockers do not seem to affect HRQoL in this patient population. If beta-blockers are used, it appears that higher doses are not associated with improved cardiovascular outcomes.

List of scientific papers

I. Mars K, Wallert J, Held C, Humphries S, Pingel R, Jernberg T, Olsson EMG, Hofmann R. Association between ß-blocker dose and cardiovascular outcomes after myocardial infarction: insights from the SWEDEHEART registry. Eur Heart J Acute Cardiovasc Care. 2020. https://doi.org/10.1093/ehjacc/zuaa002

II. Yndigegn T, Lindahl B, Mars K, Alfredsson J, Benatar J, Brandin L, Erlinge D, Hallen O, Held C, Hjalmarsson P, Johansson P, Karlström P, Kellerth T, Marandi T, Ravn-Fischer A, Sundström J, Östlund O, Hofmann R, Jernberg T. Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction. N Engl J Med. 2024. https://doi.org/10.1056/NEJMoa2401479

III. Mars K, Humphries S, Leissner P, Jonsson M, Karlström P, Lauermann J, Alfredsson J, Kellerth T, Ravn-Fischer A, Erlinge D, Lindahl B, Yndigegn T, Jernberg T, Held C, Olsson EMG, Hofmann R. Effects of beta-blockers on quality of life and well-being in patients with myocardial infarction and preserved left ventricular function - a prespecified substudy from REDUCE-AMI. Eur Heart J Cardiovasc Pharmacother. 2024. https://doi.org/10.1093/ehjcvp/pvae062

IV. Mars K, Hofmann R, Jonsson M, Manouras A, Engvall J, Yndigegn T, Jernberg T, Shahgaldi K/ Sundqvist MG. The prognostic value of global longitudinal strain in patients with myocardial infarction and preserved ejection fraction - a prespecified substudy of the REDUCE-AMI trial. Eur Heart J Cardiovasc Imaging. 2025. https://doi.org/10.1093/ehjci/jeaf015