Article Abstract

Differential efficacy profile of aldosterone receptor antagonists, depending on the type of chronic heart failure, whether with reduced or preserved left ventricular ejection fraction—results of a meta-analysis of randomized controlled trials

Authors: Renato De Vecchis, Carmelina Ariano


Background: Because of renin-angiotensin-aldosterone system (RAAS) activation, the patients with chronic heart failure (CHF) manifest increased ventricular stress, with impaired left ventricular function, and a slowing down in systemic venous drainage. More importantly, a reduction of the patient's life expectancy has been proven in the case of RAAS overstimulation. For these reasons, huge efforts have been made to obtain molecules able to efficaciously antagonize the RAAS overstimulation, such as aldosterone receptor antagonists (ARAs). These drugs have been shown to improve clinical outcomes in patients with heart failure with reduced left ventricular ejection fraction (HFREF), but not in those with preserved left ventricular ejection fraction (HFpEF). In order to study this topic more deeply, we carried out a meta-analysis of selective and nonselective ARAs in HFREF and HFpEF.
Methods: Only randomized controlled trials (RCTs) were incorporated in our meta-analysis. Studies were included if they satisfied 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.
Results: Overall, 15 RCTs including a total of 15,671 patients were eligible for inclusion in the metaanalysis. 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 [odds ratio (OR) =0.79; 95% CI: 0.73–0.87]. Subgroup analysis based on the heart failure (HF) type revealed a statistically significant benefit as regards all- cause death for patients with HFREF (OR =0.77; 95% confidence interval (CI): 0.69–0.84), but not for those with HFpEF (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. Besides, ARA use was shown to be associated with the occurrence of gynecomastia. In particular, selective ARAs didn’t induce 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).
Conclusions: Based on this meta-analysis, ARAs should be systematically used in patients with HFREF, in whom these drugs proved to reduce all-cause mortality and hospitalizations from cardiac cause. Conversely, ARA usage in HFpEF patients is questionable since in this CHF setting no significant improvement in clinical endpoints has been demonstrated so far. New selective ARAs are devoid of the risk of gynecomastia, while are similar to nonselective ARAs with regard to the efficacy profile as well as to the risk of eliciting hyperkalemia.