Mineralocorticoid receptor antagonists in heart failure: Comparative Insights on Spironolactone and Finerenone across the Ejection Fraction Spectrum

 Corresponding author: Yan Wang Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. Mineralocorticoid receptor antagonists in heart failure: Comparative Insights on Spironolactone and Finerenone across the Ejection Fraction Spectrum Mahad Abdulkadir Ali 1, #, Yan Wang 2, 3, *, Xinbin Zhou 2, 3 and Tianjun Lian 2, 3 1 International Education College, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China. 2 The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), 310006 Hangzhou, Zhejiang, China. 3 Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), 310006 Hangzhou, Zhejiang, China. # Author contributed equally to the corresponding author. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 215-222 Publication history: Received on 01 April 2025; revised on 11 May 2025; accepted on 13 May 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.22.2.0500 Abstract This review critically examines the evolving roles of mineralocorticoid receptor antagonists (MRAs), specifically spironolactone and finerenone, across the heart failure (HF) spectrum, from reduced to preserved ejection fraction. Spironolactone, a steroidal MRA, has demonstrated robust mortality and hospitalization benefits in heart failure with reduced ejection fraction (HFrEF), as evidenced by landmark trials such as RALES and TOPCAT. However, its use is limited by endocrine side effects and hyperkalemia. In contrast, finerenone, a novel non-steroidal MRA, exhibits higher receptor selectivity, a favorable safety profile, and equal distribution to cardiac and renal tissues. Clinical evidence from FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF highlights its efficacy in reducing cardiovascular events and HF hospitalizations, particularly in patients with preserved ejection fraction and comorbid chronic kidney disease or diabetes. This review synthesizes mechanistic insights, pharmacologic distinctions, and clinical outcomes, underscoring finerenone’s role in addressing unmet needs in HFpEF and HFmrEF populations. Limitations of prior trials, such as regional inconsistencies and varying patient characteristics, are discussed, along with the safety concerns surrounding hyperkalemia and renal function decline. Despite the lack of head-to-head trials, finerenone appears to offer a viable alternative for patients intolerant to steroidal MRAs. The integration of MRAs into guideline-directed therapy remains pivotal, and ongoing research exploring combined regimens, such as with SGLT2 inhibitors, may further refine their clinical utility. Ultimately, MRAs remain a cornerstone of HF management, with finerenone expanding therapeutic opportunities across a broader range of patient profiles. Keywords: Heart failure; Mineralocorticoid receptor antagonists; MRA; Spironolactone; Finerenone; BAY 94-8862; 1999–2024 1. Introduction Heart failure (HF) remains a major global health burden, with millions affected worldwide and high rates of morbidity and mortality despite advances in pharmacologic therapies[1, 2]. Among the pharmacological cornerstones of HF management are mineralocorticoid receptor antagonists (MRAs), a class of agents that inhibit the deleterious effects of aldosterone, a hormone known to promote sodium retention, myocardial fibrosis, and vascular inflammation [3]. Initially introduced with the steroidal MRA spironolactone, clinical trials demonstrated a reduction in mortality and hospitalization among patients with heart failure with reduced ejection fraction (HFrEF). However, limitations World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 215-222 216 including endocrine side effects (e.g., gynecomastia) and hyperkalemia have prompted the development of newer agents [4]. Finerenone, a non-steroidal, selective MRA, has emerged as a novel alternative, demonstrating favorable cardiovascular and renal outcomes particularly in patients with heart failure with preserved ejection fraction (HFpEF) or comorbid chronic kidney disease (CKD) and diabetes [5] Steroidal and non-steroidal MRAs differ significantly in receptor selectivity, side effect profiles, and tissue distribution. While spironolactone binds multiple steroid hormone receptors leading to off-target effects, finerenone offers a more targeted approach with reduced risk of hyperkalemia and endocrine disruption, especially in high-risk populations[6]. The objective of this review is to examine and contrast the evolving roles of spironolactone and finerenone across the ejection fraction spectrum in heart failure, ranging from HFrEF to HFpEF. By comparing efficacy, safety, and patientspecific considerations, this discussion aims to provide an updated understanding of MRAs in contemporary heart failure management. 2. Methods This narrative review was conducted through a targeted search of the PubMed and MEDLINE databases for articles published between January 1999 and March 2024. Search terms included “mineralocorticoid receptor antagonists,” “spironolactone,” “finerenone,” “heart failure,” “HFrEF,” and “HFpEF.” Eligible studies included randomized controlled trials, meta-analyses, and high-quality reviews focusing on the efficacy, safety, and pharmacologic profiles of MRAs in heart failure. Key trials such as RALES, TOPCAT, EMPHASIS-HF, FIGARO-DKD, FIDELIO-DKD, and FINEARTS-HF were prioritized. Only English-language human studies were included. Data were extracted and thematically synthesized by mechanism of action, clinical outcomes, and safety considerations across different HF phenotypes. No formal metaanalysis was performed. 3. Mechanistic and Pharmacological Insights Aldosterone, synthesized by the zona glomerulosa cells of the adrenal cortex, plays a central role in the renin– angiotensin–aldosterone system by controlling salt and water balance through the mineralocorticoid receptor (MR) in kidney epithelial cells[7, 8]. It enhances sodium reabsorption and potassium excretion by stimulating the amiloridesensitive epithelial sodium channel[9]. MRAs play a pivotal mechanistic role in heart failure by counteracting aldosterone-driven sodium retention, myocardial fibrosis, and other maladaptive MR effects [10, 11]. Spironolactone, the initial MRA, which is also a steroidal MRA, improved survival in heart failure with reduced ejection fraction (HFrEF) [12, 13] as well as post-myocardial infarction LV dysfunction [14], establishing MR blockade as a key therapy[15]. Mechanistically, spironolactone is a competitive MR antagonist but is non-selective; it also binds androgen and progesterone receptors, leading to hormonal side effects like gynecomastia [16-18]. These adverse effects were lessened with the development of second-generation agents like eplerenone and newer nonsteroidal MRAs, including finerenone and esaxerenone[19]. It has even been described as a partial MR agonist, since it incompletely suppresses aldosteroneinduced gene expression [10, 20]. Finerenone, a novel non-steroidal MRA, is highly selective for MR and exhibits minimal binding to other steroid receptors[21, 22]. Unlike spironolactone, finerenone’s bulky structure induces an unstable MR– ligand complex that prevents coactivator recruitment, yielding more complete MR antagonism [6, 20]. This mechanism translates into anti-fibrotic and anti-remodeling effects on the myocardium. Finerenone also differs pharmacokinetically, with a shorter half-life and equal distribution to cardiac and renal tissue, whereas spironolactone’s active metabolite accumulates in the kidneys [6, 10]. Both MRAs mitigate deleterious cardiac remodeling across the ejection fraction spectrum, but finerenone’s greater receptor selectivity affords a more targeted profile with fewer endocrine side effects and a lower risk of severe hyperkalemia and kidney function deterioration[23] [24, 25]. MRAs show benefit not only in HFrEF but also in heart failure with preserved EF, as suggested by spironolactone in HFpEF trials and confirmed by finerenone’s positive results in HFpEF[5, 16, 26]. Table 1 Comparison of Spironolactone vs. Finerenone Feature Spironolactone Finerenone Type Steroidal MRA Non-steroidal MRA Receptor Selectivity Low (binds androgen, progesterone receptors) High (selective for MR only) World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 215-222 217 Mechanism Competitive antagonist, partial MR agonist Full MR antagonist, prevents coactivator recruitment Key Trials RALES, TOPCAT FIDELIO-DKD, FIGARO-DKD, FINEARTS-HF Major Benefits Reduced mortality in HFrEF Reduced HF hospitalizations in HFpEF Common Side Effects Gynecomastia, hyperkalemia Hyperkalemia (lower gynecomastia risk) Tissue Distribution Renal > Cardiac Cardiac ≈ Renal 4. Clinical Evidence 4.1. Spironolactone: Insights from RALES and TOPCAT • HFrEF (RALES): The landmark RALES trial tested spironolactone (25 mg daily) in 1,663 patients with severe HFrEF (NYHA class III–IV, LVEF ≤35%) on standard therapy. Spironolactone reduced all-cause mortality by 30% (35% vs 46% mortality over 24 months; P<0.001) and HF hospitalisation by 35%. This marked improvement in survival established MRAs as a foundational therapy in HFrEF. Notably, gynecomastia or breast pain occurred in 10% of men on spironolactone vs 1% on placebo[12], reflecting spironolactone’s anti-androgenic activity. Hyperkalemia incidence in RALES was low due to careful patient selection (baseline K<5.0) and monitoring. However, the rapid uptake of spironolactone after RALES was later linked to increased hyperkalemia-related hospitalizations in clinical practice[27], underscoring the need for monitoring. • HFpEF (TOPCAT): The TOPCAT trial evaluated spironolactone in 3,445 patients with HFpEF (EF ≥45%) Over ~3 years, the primary composite outcome (CV death, aborted cardiac arrest, or HF hospitalization) occurred in 18.6% on spironolactone vs 20.4% on placebo (HR 0.89, P=0.14), a nonsignificant 11% relative risk reduction. Although overall neutral, spironolactone did reduce HF hospitalizations (12.0% vs 14.2%; P=0.04). No improvement in mortality was seen. Hyperkalemia was twice as frequent with spironolactone (18.7% vs 9.1%) [16], consistent with the need for caution in HFpEF patients (often older with comorbid kidney disease). Importantly, a post-hoc regional analysis revealed marked heterogeneity: patients enrolled in Russia/Georgia had unusually low event rates and no detectable treatment benefit, whereas those in the Americas showed significant reductions in HF outcomes with spironolactone[28]. This suggests that trial conduct and patient characteristics influenced TOPCAT’s neutral result. Nonetheless, TOPCAT provided a signal that selected HFpEF patients might benefit from MRAs by reducing HF hospitalizations, and guidelines have since given a cautious endorsement (class IIb) for spironolactone in HFpEF when renal function and potassium allow[29]. 4.2. Eplerenone: Evidence from EPHESUS and EMPHASIS-HF Eplerenone is a selective MRA designed to minimize sex-hormone side effects. It was first proven effective in postmyocardial infarction HF (the EPHESUS trial showed reduced mortality[14] and later in chronic HFrEF. The EMPHASISHF trial studied eplerenone in 2,737 patients with mild HFrEF (NYHA II, LVEF ≤35%) on background ACE inhibitors/βblockers [13]. The trial was stopped early at 21 months due to clear efficacy: eplerenone reduced the composite of CV death or HF hospitalization by 37% (18.3% vs 25.9%; HR 0.63, P<0.001)[13]. All-cause mortality was significantly lower (12.5% vs 15.5%; HR ~0.76)[13]. Eplerenone also cut arrhythmic deaths and improved outcomes across risk subgroups [13]. Hyperkalemia (>5.5 mmol/L) occurred in 11.8% on eplerenone vs 7.2% on placebo, indicating an elevated but manageable risk. Notably, eplerenone’s selectivity translated to a lower incidence of gynecomastia than seen with spironolactone (in EPHESUS, gynecomastia was ~1% with eplerenone, similar to placebo). Overall, EMPHASIS-HF confirmed that adding an MRA (eplerenone) improves survival even in mild HFrEF[13], cementing MRAs as standard therapy across the HFrEF spectrum. 4.3. Finerenone: Findings from FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF Finerenone is a non-steroidal MRA with high receptor selectivity. It has a shorter half-life and different tissue distribution than spironolactone, potentially reducing off-target effects. Finerenone has been tested extensively in patients with diabetic kidney disease, who are at high risk for HF. In the FIDELIO-DKD trial[21], 5,734 patients with type 2 diabetes and moderate-to-advanced CKD (eGFR 25–<60) were randomized to finerenone or placebo on top of ACEi/ARB therapy. Over 2.6 years, finerenone significantly reduced the primary composite renal outcome (kidney failure, sustained ≥40% eGFR decline, or renal death; HR 0.82, P=0.001) and also reduced the key secondary outcome of CV death, nonfatal MI, nonfatal stroke, or HF hospitalization (HR 0.86, P=0.03)[21]. The subsequent FIGARO-DKD trial focused on CV outcomes in a slightly earlier-stage CKD cohort. In FIGARO-DKD, finerenone reduced the incidence of the World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 215-222 218 primary composite of CV death, MI, stroke, or HF hospitalization by 13% (12.4% vs 14.2%; HR 0.87, P=0.03), driven mainly by a 29% reduction in HF hospitalizations (HR ~0.71)[22]. These outcomes highlight finerenone’s cardioprotective benefit, particularly in preventing HF exacerbations, in diabetics with CKD[22]. Finerenone was well tolerated apart from hyperkalemia: in FIDELIO-DKD, potassium-related drug discontinuation was 2.3% vs 0.9%[21], and in FIGARO-DKD serious hyperkalemia was similarly infrequent (1.2% vs 0.4%)[22] Encouraged by these results, investigators studied finerenone in HF patients with HFmrEF/HFpEF in the FINEARTS-HF trial. FINEARTS-HF enrolled 6,000 patients with symptomatic HF and LVEF ≥40% (mean ~53%), all with elevated natriuretic peptides. Finerenone significantly lowered the composite endpoint of total HF hospitalizations plus CV death: there were 1,083 events in the finerenone group vs 1,283 in placebo, a 16% rate-based reduction (rate ratio 0.84, P=0.007)[26]. This was primarily due to fewer HF hospitalizations; total HF events fell by 18% with finerenone (RR 0.82, P=0.006)[26]. CV mortality was not significantly different (8.1% vs 8.7%; HR 0.93, 95% CI 0.78–1.11), consistent with prior HFpEF trials. Finerenone improved patients’ quality of life (KCCQ clinical summary scores) but did not change NYHA class[26]. Hyperkalemia >5.5 mmol/L occurred in about 14% on finerenone versus 7% on placebo[26], higher than in spironolactone’s HFpEF trial, which may reflect the inclusion of many CKD patients. Importantly, FINEARTS-HF is the first positive trial of an MRA in HFmrEF/HFpEF, demonstrating a benefit in reducing HF events in this population[30]. It indicates that finerenone can fill an unmet need in HFpEF, especially in patients with co-existing kidney disease or diabetes[31] , who were well represented in the trial. Table 2 Major Clinical Trials of MRAs Trial Population Outcome Key Results RALES HFrEF (NYHA III–IV, LVEF ≤35%) All-cause mortality ↓ mortality by 30% TOPCAT HFpEF (EF ≥45%) Composite CV death/HF hospitalization Neutral overall; ↓ HF hospitalizations EMPHASISHF Mild HFrEF (NYHA II, LVEF ≤35%) CV death or HF hospitalization ↓ by 37% FIDELIO-DKD Diabetic CKD patients Renal and CV outcomes ↓ renal events, ↓ CV events FIGARO-DKD Early CKD and diabetes CV outcomes ↓ HF hospitalizations FINEARTSHF HFmrEF/HFpEF (LVEF ≥40%) HF hospitalizations + CV death ↓ HF events by 16% 4.4. Interpretation and Limitations 4.4.1. Efficacy Across HF Spectrum MRAs are now proven to improve outcomes across the spectrum of HF. In HFrEF, multiple trials (RALES, EPHESUS, EMPHASIS-HF) consistently show reduced mortality and hospitalizations with MRAs [12, 13]. In HFmrEF and HFpEF, MRAs primarily reduce HF hospitalization risk without a clear mortality benefit to date. A 2024 meta-analysis pooling RALES, EMPHASIS-HF, TOPCAT, and FINEARTS-HF confirmed that MRAs significantly reduce the combined risk of HF hospitalization or CV death overall (HR ~0.77), with a larger effect in HFrEF (HR ~0.66) than in HFpEF (HR ~0.87) [5]. Total HF hospitalizations are reduced in both HFrEF and HFpEF groups (meta-analytic HR 0.63 and 0.82, respectively) [5], but only HFrEF trials showed significant reductions in CV and all-cause mortality[5]. These findings reinforce current guideline recommendations: MRAs are a Class I therapy in HFrEF and provide morbidity benefit in HFpEF[15]. 4.4.2. Safety and Tolerability A key limitation of MRAs is hyperkalemia. All MRA trials excluded patients with advanced renal dysfunction or high baseline K+, yet even with careful monitoring an uptick in potassium-related adverse events was observed (e.g. doubling of hyperkalemia in TOPCAT[16] and >2-fold increase in serious hyperkalemia in pooled data[5]. In routine practice, MRAs are underutilized partly due to concerns about hyperkalemia and renal impairment. Real-world data after RALES showed increased hospital admissions for hyperkalemia associated with spironolactone use in susceptible patients[27]. Thus, careful patient selection (avoiding MRAs if eGFR <30 ml/min or K>5.0) and monitoring of serum potassium is essential. The development of potassium binders may help broaden safe MRA use in the future by mitigating hyperkalemia risk. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 215-222 219 While steroidal MRAs were associated with reductions in eGFR, their mortality benefit in heart failure patients remained substantial. Spironolactone demonstrated the highest absolute benefit among patients with reduced eGFR[32], even though worsening renal function (WRF) is linked to unfavorable outcomes, as its mortality benefit persisted . Similarly, the addition of eplerenone to optimal treatment raised the risks of WRF and hyperkalemia (HK), yet these adverse effects did not lessen its positive impact on survival[33] 4.4.3. Biomarkers & NT-proBNP NT-proBNP a crucial biomarker for assessing both treatment effectiveness and prognosis in heart failure, with a reduction greater than 30% often reflecting successful therapy[34, 35]. Comparisons between finerenone and steroidal MRAs such as spironolactone or eplerenone (25–50 mg/day) revealed no significant differences in NT-proBNP reduction at any finerenone dose (P > .05), indicating comparable efficacy. Nonetheless, combined findings from two randomized controlled trials by [36] and Sato et al [37] demonstrated a dose-dependent tendency toward greater NTproBNP improvement with higher finerenone doses. At 10 and 15 mg/day, finerenone was found to be equally or slightly more effective than eplerenone, though the differences lacked statistical significance. Furthermore, additional data from Pitt et al [24], not incorporated into the meta-analysis, also indicated a favorable trend in NT-proBNP reduction with finerenone 10 mg/day compared to spironolactone. Several studies have indicated that finerenone at a 10 mg/day dosage is associated with significantly fewer treatment-emergent adverse events (TEAEs) compared to spironolactone or eplerenone [24, 37]. The incidence of serious adverse events, such as hyperkalemia and treatment discontinuation due to side effects, was also lower with finerenone. In addition, a separate study [38] involving patients with diabetic nephropathy found no significant differences in adverse or serious adverse events between the finerenone and placebo groups, and higher doses of finerenone (>10 mg/day) were not linked to an increased occurrence of drug-related serious events. Finerenone has shown superior efficacy in reducing cardiovascular and renal events compared to placebo, with a lower risk of serious adverse events. This makes it a safer alternative for patients who are intolerant to the side effects of steroidal MRAs[39, 40] 4.4.4. Trial Limitations Differences in trial populations and execution have influenced outcomes. RALES and EMPHASIS-HF were placebocontrolled trials in well-defined HFrEF cohorts and yielded unequivocal benefits[12]. By contrast, TOPCAT’s neutral overall result is partly attributed to enrolling a low-event-rate population in certain regions, which diluted the treatment effect[28]. Post-hoc analyses suggest spironolactone was effective in the higher-risk HFpEF subset (Americas) [28], implying that patient selection (e.g. requiring elevated natriuretic peptides, as done in FINEARTS-HF) is critical in HFpEF trials. Finerenone’s success in FINEARTS-HF likely reflects an enriched study population and possibly pharmacologic differences, but head-to-head data against spironolactone are lacking. Another limitation is that MRAs have not improved survival in HFpEF; the benefit in that group is limited to reducing hospitalizations and improving symptoms. HFpEF is a heterogeneous syndrome, and MRAs address only one pathway (aldosterone), which might explain the lack of mortality impact. 4.4.5. Clinical Use Despite limitations, MRAs remain a cornerstone in HFrEF therapy, producing substantial survival gains when added to other guideline-directed treatments (β-blockers, ACEi/ARNI, etc.)[15, 41]. For HFpEF, spironolactone has been used offlabel in those with higher BNP or prior HF hospitalization, and now finerenone offers a new option with proven efficacy in reducing HF events. Clinicians must weigh the benefits against risks: in patients with HF (reduced or preserved EF) who have acceptable renal function, MRAs can significantly reduce HF morbidity. Endocrine side effects (e.g. gynecomastia) with spironolactone may necessitate switching to eplerenone or finerenone for better tolerability. The OPRA-HF trial suggests that optimizing MRA therapy with sodium zirconium cyclosilicate (SZC) can help manage hyperkalemia, allowing for higher MRA doses and potentially improving outcomes in HFrEF patients[42]. Cost is another consideration; spironolactone is inexpensive, whereas finerenone is a newer agent that may be cost-prohibitive for some patients until further guideline endorsement and insurance coverage. Eplerenone has been identified as a favorable option in the Brazilian healthcare context, offering a balance between efficacy and cost[43]. 4.4.6. Future Perspectives The therapeutic landscape of heart failure continues to evolve, and finerenone represents a promising advance in expanding MRA utility beyond HFrEF. Its high receptor selectivity and favorable safety profile make it particularly suitable for patients with HFpEF or those intolerant to steroidal MRAs. Importantly, three major ongoing trials may further establish its role across diverse heart failure populations. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 215-222 220 • REDEFINE-HF (NCT06008197) is evaluating the efficacy and safety of finerenone versus placebo, added to standard care, in more than 5,200 patients with HFmrEF or HFpEF (EF >40%) who were recently hospitalized or discharged. The primary outcome includes total HF events and cardiovascular death. • FINALITY-HF (NCT06033950) is enrolling over 2,600 patients with HFrEF (EF <40%) who are either ineligible for or intolerant to steroidal MRAs. The trial is assessing the effect of finerenone on cardiovascular death or HF events, addressing a key unmet need in this subgroup. • CONFIRMATION-HF (NCT06024746) is a phase III, open-label study investigating the combination of finerenone with an SGLT2 inhibitor versus standard care in approximately 1,500 hospitalized HF patients, irrespective of EF. Its hierarchical composite outcome includes all-cause mortality, time to first HF event, and total HF event frequency over six months. These trials are expected to provide critical data on the real-world applicability of finerenone, including its role in polytherapy and among patients not traditionally eligible for MRAs. As the treatment paradigm shifts toward phenotype-specific and combination therapies, finerenone may emerge as a central agent in the individualized management of HF across the ejection fraction spectrum. 5. Conclusion Spironolactone and finerenone represent two distinct but complementary MRAs in the management of heart failure. Steroidal MRAs like spironolactone and eplerenone have consistently improved survival in HFrEF, while finerenone has expanded the therapeutic horizon by demonstrating efficacy in patients with HFmrEF, HFpEF, and those with concurrent CKD or diabetes. Finerenone’s improved receptor selectivity and safety profile offer an alternative for patients intolerant to steroidal agents, especially those at risk for endocrine side effects or hyperkalemia. In clinical practice, MRAs should be considered integral to guideline-directed HF therapy, with careful attention to renal function and potassium levels. The availability of finerenone may increase the proportion of patients eligible for MRA therapy, particularly in populations previously underserved. Future studies, including ongoing randomized trials exploring finerenone’s role in combination therapies and across various EF phenotypes will further clarify its place in treatment algorithms. MRAs continue to play a central role in heart failure care, with emerging agents like finerenone paving the way for more personalized and tolerable approaches across the ejection fraction spectrum. Compliance with ethical standards Disclosure of conflict of interest The authors declare no conflicts of interest in this work. Funding The author declared that this study has received no financial support. References [1] Akinterinwa, O.E., et al., A Need to Preserve Ejection Fraction during Heart Failure. Int J Mol Sci, 2024. 25(16). [2] Udelson, J.E. and L.W. Stevenson, The Future of Heart Failure Diagnosis, Therapy, and Management. Circulation, 2016. 133(25): p. 2671-86. [3] Ferreira, J.P., B. Pitt, and F. Zannad, Mineralocorticoid Receptor Antagonists in Heart Failure: An Update. 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