Heart failure (HF) constitutes a major public health concern [1], associated with increased morbidity and mortality, reduced life quality and an adverse economic footprint [2,3]. Contemporary HF classification is based upon the values of left ventricular ejection fraction (LVEF) as a surrogate marker of myocardial systolic performance. Currently, the most widely accepted HF categorization scheme is HF with reduced (≤40%), mildly reduced (41-49%) and preserved (≥50%) LVEF, named as HFrEF, HFmrEF and HFpEF respectively [4, 5, 6]. According to these categories, various pharmacological therapies have been endorsed by international guidelines [4,5,7] to improve clinical outcomes in these patients.

Mineralocorticoid receptor antagonists (MRAs) constitute a principal pharmacological treatment for HF management, strongly indicated in HFrEF, less so in HFmrEF. Spironolactone's introduction in clinical practice was pivotal for HFrEF management ensuing its demonstrated efficacy in the large Randomized Aldactone Study (RALES) study [8]. Nevertheless, spironolactone's use was also associated with certain side effects [9], including gynecomastia and hyperkalemia which led to considerable discontinuation rates [8]. To tackle these issues, several randomized clinical trials (RCTs) have been performed to evaluate the efficacy and safety of other steroidal and non-steroidal MRAs [10]. Eplerenone is a steroidal MRA introduced shortly after spironolactone [11,12]. Finerenone is a non-steroidal MRA recently licensed for the treatment of chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) [13,14], while canrenone is an active spironolactone metabolite [15].

Hitherto, various systematic reviews (SRs) have been conducted to pool RCT data on the efficacy and safety of MRAs [16]. Nonetheless, new evidence continuously emerge creating the need for an updated analysis on the comparative efficacy and safety of MRAs. Considering the above, the primary objectives of the present SR and NMA were to assess the comparative efficacy and safety of different MRAs in patients with HFrEF and a LVEF of no more than 45%.