Long-term beta-blocker treatment in stable patients after myocardial infarction: a potential impact due to changes in the diagnosis of myocardial infarction?

This commentary refers to the article ‘Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study’, by A. Holt et al., doi:10.1093/eurheartj/ehaa1058 and the discussion piece ‘Temporal changes in myocardial infarction diagnostic criteria do not account for lack of long-term beta-blocker effect on cardiovascular prognosis’, by A. Holt et al., doi:10.1093/eurheartj/ehab260. We would like to congratulate Holt et al.1 for their important study regarding the possible clinical benefit of beta-blocker treatment in the reperfusion era. We are concerned that unaddressed confounders may have impacted on their findings. May we ask the authors to provide more details helping clinicians to better put these findings into perspective. First, the absolute number of patients included in this study per year increased substantially from 4697 patients (2003–05) to 8183 patients (2015–18) during the study period. In parallel, despite increased availability of 24 h/7 day invasive treatment options for acute myocardial infarction (AMI), the proportion of patients not receiving coronary revascularization and the proportion not receiving beta-blockers increased. We hypothesize that this major change in treatment was driven by a change in the underlying pathology. In their analysis, the authors assume that AMI remained a homogenous disease throughout the study period. Providing additional data will help to test this assumption. May we ask the authors to report the peak cardiac troponin (cTn) concentration of the AMIs included per year and to add peak cTn to their multivariate models. High-sensitivity cTn (hs-cTn) assays were clinically introduced in 2009/10 and increasingly replaced less sensitive contemporary cTn assays in the following years. This innovation enabled clinicians to also reliably diagnose patients with small AMIs with mild cTn elevations,2 thereby increased the incidence of AMI by about 20%.2–5 The inclusion of a large proportion of smaller AMIs in the later years of the study, in which a larger proportion was not treated with beta-blockers, confounded the association of beta-blocker therapy and outcome. May we ask the authors to perform a sensitivity analysis restricted to the period time prior to hs-cTn use (e.g. 2003–09). Second, the use of hs-cTn also increased the detection AMI without significant coronary artery disease (CAD), and of type 2 AMI, not related to atherothrombosis, but due to supply-demand mismatch, e.g. due to hypotension or anaemia.2–4 Both phenotypes have been found to have a lower risk of death vs. traditional type 1 AMI, again confounding the association of beta-blockers and outcome.5 The difference in coronary angiographies without percutaneous coronary intervention in patients without beta-blocker therapy (26%) compared with those with beta-blocker therapy (14%) might be a reflection of this phenomenon. Please report a sensitivity analysis restricted to patients with type 1 AMI with significant CAD (e.g. defined as requiring coronary revascularization). Third, another potential confounder that should be assessed to appropriate inform clinicians is the prescription of beta-blockers due to supraventricular and ventricular tachyarrhythmias. These arrhythmias are per se associated with a higher risk of death and my again have confounded the association between beta-blockers and outcome. May we ask the authors to add supraventricular and ventricular tachyarrhythmias to their multivariate model and a sensitivity analysis restricted to patients without supraventricular and ventricular tachyarrhythmias. Providing these additional analyses will help address the confounding introduced by AMI size, underlying AMI pathophysiology, and beta-blocker indication and provide more reliable estimates for clinicians. Conflict of interest: J.G.v.d.S. received a research grant from the Goldschmidt-Jacobson Stiftung from the University of Basel. J.B. received research grants from the University of Basel, the University Hospital of Basel and the Division of Internal Medicine, the Swiss Academy of Medical Sciences, the Gottfried, and Julia Bangerter-Rhyner-Foundation, and speaker honoraria/consulting honoraria from Siemens, Roche Diagnostics, Ortho Clinical Diagnostics, and Quidel Corporation, outside of the submitted work.