Do We Still Need Betablockers after AMI

Oral beta-blockers have been a central component of secondary prevention pharmacotherapy following acute myocardial infarction (AMI) irrespective of its severity. Recent international guidelines on the management of coronary disease, both from the European Society of Cardiology (ESC) and the American societies, convey a moderately strong recommendation to their use in the post infarct setting. The foremost reason for slightly downgrading recommendation strength from its previous “must do” grade is the fact that supportive studies in favor of beta-blockers were undertaken before the implementation of modern approaches to AMI, including (i) revolutionary, biochemistry-based diagnostication of AMI, (ii) revascularization strategies with minimized time-delays, and (iii) comprehensive secondary prevention therapies. Nevertheless, beta-blockers remain a cornerstone therapy in patients after AMI, and in certain areas, their utilization is systematically surveyed as a benchmark parameter of quality when discharge from hospital for post-infarction care is scrutinized.

Let us look back in time for a moment: landmark studies which established the rationale for the routine use of long-term oral beta-blockade after AMI were published in the early 1980s. The only randomized large-scale beta-blocker trial conducted in patients following AMI in a relatively modern setting, found no prognostic benefit of early intravenous metoprolol followed by 4 weeks of oral treatment compared with placebo [1]. Yet, as late as in 1999, the renowned group of Cleland and co-workers concluded that beta-blockers are under-utilized in patients who have survived an AMI [2].

A substantial number of studies ensued. At a later stage, now moving forward to the year 2014, a meta-analysis of randomized, controlled trials did no longer find a mortality effect associated with beta-blockers in studies from the reperfusion era, as opposed to a significant reduction in mortality for studies published in the pre-reperfusion era [3].

The latest contribution stems from a 2018-metaanalysis that synthetized the results of 16 observational studies published between 1 January 2000 and 30 October 2017 [4]. Publication bias was evaluated, and heterogeneity between studies examined by meta-regression analyses considering patient-related and study-level variables. The pooled estimate in this work suggested that beta-blocker treatment among 164 408 patients, with a median follow-up time of 2.7 years, showed no association between this therapy (beta-blockers) and all-cause mortality.

With this analysis in mind, we turn back to the initial question in the title: Can the results of observational studies change clinical practice? As already mentioned, the newest ESC guidelines on treatment of both STEMI (2018) and NSTEMI (2017) maintain a clear class II recommendation for long-term beta-blocker use after AMI. Hence, the obvious answer is no: observational studies do not suffice to change established treatment paradigms in modern medicine. Or to put in a different wording: a possible beneficial effect of beta-blockers in today’s contemporarily treated AMI survivors without heart failure needs to be tested rigorously in large randomized clinical trials, if ever a change in clinical practice is to be achieved. An example of such an ongoing trial is the BETAMI study, aiming at providing exactly this clinical scientific clarification [5]. Details on the trial configuration and real-time study progress are visible from the study-design article [5] and from www.betami.org.

References:

1. Chen ZM, Pan HC, Chen YP et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1622–1632.
2. Freemantle N, Cleland J, Young P, Mason J, Harrison J: Beta-blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999 Jun 26;318(7200):1730-7.
3. Bangalore S, Makani H, Radford M, et al. Clinical outcomes with beta-blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med. 2014;127(10):939-953.
4. Dahl Aarvik M, Sandven I, Dondo TB, Gale CP, Ruddox V, Munkhaugen J, Atar D, Otterstad JE: Effect of oral β-blocker treatment on mortality in contemporary post-myocardial infarction patients: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2019 Jan 1;5(1):12-20
5. Munkhaugen J, Ruddox V, Halvorsen S, Dammen T, Fagerland MW, Hernæs KH, Vethe NT, Prescott E, Jensen SE, Rødevand O, Jortveit J, Bendz B, Schirmer H, Køber L, Bøtker HE, Larsen AI, Vikenes K, Steigen T, Wiseth R, Pedersen T, Edvardsen T, Otterstad JE, Atar D: 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.