Effects of Mineralocorticoid Receptor Antagonists on Atrial Fibrillation Occurrence: A Systematic Review, Meta‐Analysis, and Meta‐Regression to Identify Modifying Factors

Abstract

BackgroundMineralocorticoid receptor antagonists (MRAs) have emerged as potential atrial fibrillation (AF) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRAs on AF occurrence and explore factors that could influence the magnitude of the effect size.Methods and ResultsPubMed, Embase, and Cochrane Central databases were used to search for randomized clinical trials and observational studies addressing the effect of MRAs on AF occurrence from database inception through April 03, 2018. We performed a systematic review and random effects meta‐analyses to compute odds ratios with 95% CIs. Meta‐regression was then applied to explore the sources of between‐study heterogeneity. We included 24 studies, 11 randomized clinical trials and 13 observational cohorts, representing a total number of 7914 patients (median age: 64.2 years; median left ventricular ejection fraction: 49.7%; median follow‐up: 12.0 months), 2843 (35.9%) of whom received MRA therapy. Meta‐analyses showed a significant overall reduction in AF occurrence in the MRA‐treated patients versus the control groups (15.0% versus 32.2%; odds ratio, 0.55; 95% CI, 0.44–0.70 [P<0.00001]), with the greatest benefit regarding recurrent AF episodes (odds ratio, 0.42; 95% CI, 0.31–0.59 [P<0.00001]) and with significant heterogeneity among the included studies (I 2=54%; P=0.0008). Meta‐regression analyses showed that effect size was significantly associated with older studies and higher AF occurrence rate in the control groups.Conclusions MRAs seem to be effective in AF prevention, especially regarding recurrent AF episodes.

Endothelial function and atrial fibrillation: A missing piece of the puzzle?

“…Although these approaches have largely focussed on targeting atrial fibrosis and inflammation, there is emerging evidence that endothelial dysfunction is a promising new addition to this list. Angiotensin-converting enzyme inhibitors (ACE inhibitors)/angiotensin receptor blockers (ARBs), 83 mineralocorticoid receptor antagonists (MRAs), 84 and antioxidants (such as N-acetylcysteine and ascorbic acid) 85 have all been shown to reduce the risk of new-onset AF and AF recurrence in large metaanalyses. Statins reduce all-cause and cardiovascular mortality in AF, 86 despite no consistent reduction in AF burden or recurrence.…”

Radiofrequency catheter ablation combined with spironolactone in the treatment of atrial fibrillation: A single‐center randomized controlled study

“…Neefs et al demonstrated that the mineralocorticoid receptor antagonists (MRA), spironolactone, and eplerenone significantly reduce new‐onset AF and recurrent AF; MRA treatment can be considered an additive therapeutic strategy for AF 9 . Alexandre et al showed a significant overall reduction in AF occurrence in patients treated with MRA versus the control groups (OR 0.55; 95% CI, 0.44–0.70, p < .00001), with the greatest benefit shown with regard to recurrent AF episodes (OR 0.42; 95% CI, 0.31–0.59, p < .00001) 10 . The renin–angiotensin system (RAS) is involved in the genesis of arrhythmia by the following two mechanisms: the induction of atrial fibrosis and structural remodeling by mitogen‐activated protein kinase (MAPK) expression and a reduction of collagenase activity, and the induction of electrical remodeling by a shortening of the atrial effective refractory period (AERP) and the action potential duration 11 …”

New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation

“… 227 A recent meta-analysis of 7914 patients showed that aldosterone pathway blockade with MR antagonists limited AF recurrence and, to a lesser extent, prevented the new onset of AF. 228 Since NPs counter-balance RAAS, recombinant human NPs (e.g. nesiritide—recombinant BNP) combined with neprilysin inhibitors (e.g.…”

“…sacubitril, enhancing NP signalling) and ARBs (e.g. valsartan), denoted ARNi (currently approved for the heart failure management) 228 or synthetic modified NPs designed to preferentially enhance signalling via specific NPRs, may also have potential benefits for AF management.…”