Mineralocorticoid receptor antagonists for atrial fibrillation prevention: effective solution or empty promise?

This commentary refers to ‘Mineralocorticoid receptor antagonists and atrial fibrillation: a meta-analysis of clinical trials’, by A. Oraii et al., https://doi.org/10.1093/eurheartj/ehad811 and the discussion piece ‘Utility of mineralocorticoid receptor antagonists in reducing burden of atrial fibrillation’, by T. S. Rodrigues et al., https://doi.org/10.1093/eurheartj/ehae686. We thank Rodrigues et al. for their interest in our study,1 and raising two important discussion points regarding the utility of mineralocorticoid receptor antagonists (MRAs) for reducing the risk of atrial fibrillation (AF). First, the authors argue that patients with heart failure (HF)/left ventricular (LV) dysfunction receive a larger risk reduction than those without HF/LV dysfunction. Second, the authors mention the side effects associated with MRAs and their impact on decision-making. In this forum, we would like to elaborate on these arguments and their implications for future research. In our meta-analysis of randomized trials, the pooled estimate for the efficacy of MRAs in reducing AF events is mainly driven by the large landmark trials that used opportunistic rhythm monitoring strategies and considered AF as an adverse event or a secondary endpoint. Inclusion or exclusion of a single study assessing postoperative AF during a short follow-up period, with <10% weight in the pooled effect estimate, does not change any of the inferences.2 However, limitations of the original trial designs for ascertaining AF events are far more important for determining the certainty of the evidence. Of note, opportunistic AF ascertainment is of a greater concern in patients with HF/LV dysfunction considering that MRAs significantly reduced HF-related hospitalizations. As a result, the likelihood of detecting AF episodes may have been further diminished in the intervention arm of HF trials due to their decreased healthcare encounters compared with the control group. This can potentially overestimate the relative risk reduction with MRAs in patients with HF/LV dysfunction. Subgroup analysis of the included studies found no statistical evidence of differential efficacy in the relative treatment effect between patients with or without HF/LV dysfunction (interaction P-value = .48). Yet, the number needed to treat may be lower in patients with HF/LV dysfunction because of their higher baseline absolute risk of AF compared with those with other comorbidities (e.g. myocardial infarction or diabetes mellitus). Most importantly, the efficacy of MRAs for AF prevention is retained in patients without HF/LV dysfunction. This finding opens new opportunities to broaden the indications for MRAs, extending their use beyond HF treatment. A similar concept applies to sodium-glucose cotransporter 2 inhibitors, another pillar HF medication, that result in a similar relative reduction in AF events in patients with and without HF/LV dysfunction.3,4 However, Rodrigues et al. raise an important point that the benefits of therapy could be offset by medication side effects.5 These adverse effects can be mitigated by using more selective formulations or non-steroidal alternatives. Moreover, identifying patients at higher risk for AF who would achieve a greater absolute risk reduction can further guide treatment decisions. Although patients with established AF diagnosis are at higher risk of recurrence, it is yet unclear whether having AF on its own in the absence of HF/LV dysfunction is high risk enough to justify MRA therapy. Until future randomized trials, an individualized approach is needed in patients who do not meet the current indications and are at risk of developing AF. J.S.H. is supported by the Population Health Research Institute Stuart Connolly Chair in Cardiology Research at McMaster University; has received research grants from St. Jude Medical, Boehringer Ingelheim, Medtronic, Bristol-Myers Squibb/Pfizer, and Boston Scientific; and speaking fees from St. Jude Medical, Boston Scientific, and Medtronic, all outside of the current work. W.F.M. has received consulting fees from Trimedics and Atricture, as well as speaker fees from Servier, Bayer, and Eli Lilly, all outside of the current work. A.O. has no disclosures to report.

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