Long-term beta-blocker treatment after acute myocardial infarction and preserved left ventricular ejection fraction: The REDUCE-AMI Trial

Reported from ACC.24

REDUCE-AMI is a multicentre, registry-based, prospective open-label parallel-group randomised clinical trial evaluating the benefit of beta-blocker treatment in patients with acute MI and an ejection fraction >50% treated with a contemporary reperfusion strategy.

Nicola Ryan and Ali Nazmi Calik provide their take on the results which were presented at ACC.24 in Atlanta and simultaneously published in the NEJM.

PICOT analysis of REDUCE-AMI - Courtesy of Nicola Ryan and Ali Nazmi Calik - Source: PCRonline.com

Why this study – the rationale/objective?

The beneficial role of beta blockers in patients with heart failure reduced ejection fraction is well established. Prior trials (1–3), the majority carried out prior to modern reperfusion and pharmacotherapy strategies such as high-intensity statins, antithrombotic regimens and ACE/ARBs have suggested that long-term beta-blocker treatment reduces mortality post-MI. Importantly a significant proportion of patients in these trials had impaired ejection fractions. The optimal strategy for beta-blockers in patients presenting with AMI with preserved ejection fractions in contemporary clinical practice has not been adequately studied.

How was it executed - the methodology

Patients presenting with an acute myocardial infarction with obstructive coronary artery disease at angiography, (stenosis >50%, FFR <0.80, iFR <0.89) and a preserved ejection fraction, ≥50%, on echocardiogram, were eligible for randomisation. Recruitment occurred in three countries: Sweden, Estonia and New Zealand. The main exclusion criteria was an indication for a beta-blocker or a contraindication to a beta-blocker. Patients were treated with beta-1-receptor selective beta-blockers (metoprolol or bisoprolol).

The primary endpoint was a composite of all-cause death and new myocardial infarction.
The key secondary endpoints were all-cause death, cardiovascular death, MI, hospitalisation for atrial fibrillation and hospitalisation for heart failure.
Safety endpoints were hospitalisation for bradycardia, second or third-degree AV block, hypotension, syncope or implantation of a pacemaker, hospitalisation for asthma or COPD, and hospitalisation for stroke.

What is the main result?

From September 2017 to May 2023, 5020 patients were included, 2508 randomised to beta blockers and 2512 to no beta blockers. Overall loss to follow-up was similar amongst both arms. At 6-10 weeks follow up 90% of the beta-blocker group were still taking beta-blockers, whilst 11.3% of the no beta-blocker group were taking beta-blockers, at 11-13 months follow up the figures were 81.9% and 14.3% respectively. A little over 22% of the population were female with a mean age of 65 years, 35% presented with STEMI, with low rates of prior MI, PCI or CABG. The majority of participants had single-vessel disease, with 95% treated with PCI. There were high rates of prescription of contemporary medical therapy at discharge with statins 98%, aspirin 97%, P2Y12 inhibitors 97% and ACE/ARB 80%. The median follow-up time was 3.5 years (IQR 2.2-4.7)

At a median of 3.5 years there was no difference in the primary endpoint of all-cause death or MI between the beta-blocker group 7.9% vs no beta-blocker group 8.3% (HR 0.96 95% CI 0.76-1.16 p=0.64)
Secondary endpoints were similar between groups, with no differences in cardiovascular death (BB 1.5% vs no BB 1.3% HR 1.15, 95% CI 0.72-1.84) or MI (BB 4.5% vs no BB 4.7%, HR 0.96, 95% CI 0.96 0.74-1.24)
The safety endpoint of hospitalisation for bradycardia, second or third-degree AV block, hypotension, syncope or implantation of a pacemaker was similar between groups (BB 3.4% vs no BB 3.2%, HR 1.08 95% CI 0.79-1.46)

Critical reading and the relevance for clinical practice

The results of this trial show that in patients presenting with an acute MI with a preserved ejection fraction treated with modern pharmacotherapy and reperfusion strategies beta blockers do not lead to a reduced incidence of all-cause death or MI. Importantly the population included in the trial were a lower cardiovascular risk group who were well treated with evidence-based pharmacotherapy at discharge. The majority of patients had since vessel disease with 95% treated with PCI. In the beta-blocker group, 62.2% received metoprolol (median dose 100mg) and 37.8% bisoprolol (median dose 5mg).

The statistical design of the trial assumed a 7.3% event rate per year in the no beta-blocker group however during the trial the blinded observed rate was lower leading to a protocol adjustment from a 16.7% lower risk to 25% lower risk in the beta-blocker group to be clinically important. Overall the annual event rates in both groups were low (2.4% in beta-blocker group and 2.5% in no-beta-blocker group) with no differences between groups. Pre-specified subgroup analysis including STEMI versus NSTEMI, complete versus incomplete revascularisation and prior atrial fibrillation demonstrated similar treatment effects.

The population enrolled was relatively homogenous due to the trial design of only including patients with an early invasive strategy and patients with ejection fractions >50%. Therefore it is not possible to generalise these results to patients who do not receive an early invasive strategy. Definition of preserved ejection fraction varies between trials with other ongoing trials of beta-blockers including patients with an ejection fraction >40% (4–6). Whether patients with a mid-range ejection fraction may benefit from beta-blockers is yet to be determined.

Some important limitations need to be borne in mind including those associated with randomised registry trials including the lack of central adjudication of endpoints. There was a cross-over rate in both arms with 14% of the no-beta-blocker group taking beta-blockers at one year and 18% of the beta-blocker group not taking beta-blockers at one year which may influence the neutral outcome however this likely reflects real-world practice. This analysis does not include compliance with beta-blocker randomisation post one-year.

Overall this trial suggests that treatment with beta-blockers does not reduce the incidence of all-cause death or myocardial infarction in patients presenting with acute myocardial infarction and an ejection fraction >50% treated with an early invasive strategy.

References

Timolol-Induced Reduction in Mortality and Reinfarction in Patients Surviving Acute Myocardial Infarction | New England Journal of Medicine [Internet]. [cited 2024 Apr 7].
Hjalmarson Å, Herlitz J, Málek I, Rydén L, Vedin A, Waldenström A, et al. EFFECT ON MORTALITY OF METOPROLOL IN ACUTE MYOCARDIAL INFARCTION: A Double-blind Randomised Trial. The Lancet. 1981 Oct 17;318(8251):823–7.
A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA. 1982 Mar 26;247(12):1707–14.
Munkhaugen J, Ruddox V, Halvorsen S, Dammen T, Fagerland MW, Hernæs KH, et al. BEtablocker Treatment After acute Myocardial Infarction in revascularized patients without reduced left ventricular ejection fraction (BETAMI): Rationale and design of a prospective, randomized, open, blinded end point study. Am Heart J. 2019 Feb;208:37–46.
Kristensen AMD, Bovin A, Zwisler AD, Cerquira C, Torp-Pedersen C, Bøtker HE, et al. Design and rationale of the Danish trial of beta-blocker treatment after myocardial infarction without reduced ejection fraction: study protocol for a randomized controlled trial. Trials. 2020 May 23;21:415.
Rossello X, Raposeiras-Roubin S, Latini R, Dominguez-Rodriguez A, Barrabés JA, Sánchez PL, et al. Rationale and design of the pragmatic clinical trial tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT). European Heart Journal - Cardiovascular Pharmacotherapy. 2022 May 1;8(3):291–301.