Mineralocorticoid receptor antagonists for heart failure: systematic review and meta-analysis

Nicolas M. Berbenetz, Marko Mrkobrada

Mineralocorticoid receptor antagonists (MRAs) have been associated with improved patient outcomes in patients with heart failure with reduced ejection fraction (HFrEF) but not preserved ejection fraction (HFpEF). We conducted a systematic review and meta-analysis of selective and nonselective MRAs in HFrEF and HFpEF. We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE. We included randomized controlled trials (RCT) of MRAs in adults with HFpEF or HFrEF if they reported data on major adverse cardiac events or drug safety. We identified 15 studies representing 16321 patients. MRAs were associated with a reduced risk of cardiovascular death (RR 0.81 [0.75-0.87], I(2) 0%), all-cause mortality (RR 0.83 [0.77-0.88], I(2) 0%), and cardiac hospitalizations (RR 0.80 [0.70-0.92], I(2) 58.4%). However, an a-priori specified subgroup analysis demonstrated that these benefits were limited to HFrEF (cardiovascular death RR 0.79 [0.73-0.86], I(2) 0%; all-cause mortality RR 0.81 [0.75-0.87], I(2) 0%; cardiac hospitalizations RR 0.76 [0.64-0.90], I(2) 68%), but not HFpEF (all-cause mortality RR 0.92 [0.79-1.08], I(2) 0%; cardiac hospitalizations RR 0.91 [0.67-1.24], I(2) 17%). MRAs increased the risk of hyperkalemia (RR 2.03 [1.78-2.31], I(2) 0%). Nonselective MRAs, but not selective MRAs increased the risk of gynecomastia (RR 7.37 [4.42-12.30], I(2) 0% vs. RR 0.74 [0.43-1.27], I(2) 0%). Evidence was of moderate quality for cardiovascular death, all-cause mortality and cardiovascular hospitalizations; and high-quality for hyperkalemia and gynecomastia. MRAs reduce the risk of adverse cardiac events in HFrEF but not HFpEF. MRA use in HFpEF increases the risk of harm from hyperkalemia and gynecomastia. Selective MRAs are equally effective as nonselective MRAs, without a risk of gynecomastia.