Aldosterone receptor antagonists decrease mortality and cardiovascular hospitalizations in chronic heart failure with reduced left ventricular ejection fraction, but not in chronic heart failure with preserved left ventricular ejection fraction: a meta-analysis of randomized controlled trials.

Abstract

Aldosterone receptor antagonists (ARAs) were introduced in the treatment of chronic heart failure (CHF), as a result of the demonstration of their protective effect on the failing heart. However, important questions remain unanswered regarding the clinical efficacy of the ARAs on the clinical and echocardiographic phenotype of heart failure, called heart failure with preserved left ventricular ejection fraction (HFpEF). The aim of the present meta-analysis was to verify the impact of the ARAs on some hard endpoints, such as all-cause death and hospitalizations from cardiovascular cause, making a comparative evaluation of these outcomes in CHF patients with reduced left ventricular ejection fraction (HFREF) and in those with HFpEF, respectively. Only randomized controlled trials (RCTs) were incorporated in our meta-analysis. The studies were included if they met the following criteria: experimental groups included patients with CHF treated with ARAs in addition to the conventional therapy; control groups included patients with CHF receiving conventional therapy without ARAs. Outcomes of interest were all-cause mortality, cardiovascular hospitalizations, hyperkalemia, or gynecomastia. Overall, 15 RCTs comprising a total of 15671 patients were eligible for inclusion in the meta-analysis. ARA use in patients with heart failure was associated with a significant reduction in adverse outcomes. Indeed, a significant reduced odds of all-cause death among CHF patients treated with ARAs compared to controls was found (OR=0.79; 95% CI: 0.73-0.87). Subgroup analysis based on the HF type revealed a statistically significant benefit as regards all-cause death for patients with HFREF (OR=0.77; 95% CI: 0.69-0.84), whereas a protective effect against the all-cause death was not attained by ARAs in the HFpEF subset (OR=0.91; 95% CI: 0.76-1.1). Furthermore reduced odds of CV hospitalizations was detected in the entire group of CHF patients under treatment with ARAs (OR=0.73; 95% CI: 0.61-0.89) as well as among HFREF patients treated with ARAs, compared to controls (OR=0.66; 95% CI: 0.51-0.85). Hyperkalemia was significantly more frequent with ARA use. In addition, subgroup analysis by ARA type documented that both nonselective and selective ARAs were similarly associated with increased odds of episodes of hyperkalemia compared to controls. Besides, ARA use was shown to be associated with the occurrence of gynecomastia. In particular, selective ARAs proved not to produce significant amounts of gynecomastia compared to controls (OR=0.74; 95% CI: 0.43-1.27), while nonselective ARAs did (OR 8.22; 95% CI: 4.9-13.81. Our meta-analysis provides further evidence that ARAs should be systematically used in patients with HFREF, in whom these drugs improve some hard clinical endpoints, such as all-cause mortality and hospitalizations from cardiac cause. Conversely, based on the present meta-analysis, ARA usage in HFpEF patients is questionable since in this CHF setting no significant improvement in clinical endpoints has been demonstrated so far, in the face of the well-known risks of hyperkalemia and/or gynecomastia that chronic ARA therapy entails. Furthermore, new selective ARAs are not burdened by significant risk of gynecomastia, while are similar to nonselective ARAs with regard to the efficacy profile as well as to the risk of eliciting hyperkalemia.