Cardiovascular effects of mineralocorticoid receptor antagonists in acute coronary syndrome: an updated systematic review and meta-analysis of randomized clinical trials.

Background: Mineralocorticoid receptor antagonist (MRA) has a potential to improve clinical outcomes in heart failure with preserved ejection fraction (HFpEF), since MRA inhibits progression of myocardial hypertrophy and fibrosis. Soluble ST2 (sST2) is a novel biomarker reflecting myocardial stress and fibrosis. MRA plays a role in the interleukin-33/ST2 signaling modulation. Hypothesis: We hypothesized that the effect of MRA on clinical outcomes in HFpEF differed by sST2 level. This study aimed to evaluate the relationship between sST2 and clinical outcomes and to test for an interaction between the effect of MRA and sST2 level. Methods: 191 patients with acute decompensated HF and EF ≥50% were prospectively enrolled. The primary endpoint was major adverse cardiovascular events (MACE), which included death from cardiovascular disease, unplanned hospitalization for heart failure, acute coronary syndrome and stroke. Results: During follow-up (421±258days), 53 patients (27.7%) met endpoints. In a multivariable analysis, use of MRA and sST2 level were significantly associated with the endpoint (HR 0.48, 95%CI 0.26-0.86, P=0.01, HR 1.02, 1.01-1.03, P=0.01). Patients were divided into 4 groups according to use of MRA and a cutoff value of sST2 (18.5 ng/ml) determined by ROC analysis. Estimated event rate for MACE were significantly higher in patients without MRA compared with those in patients with MRA regardless of category of sST2 level. In a multivariable analysis, MRA was not a significant predictor of outcome in high sST2 group (HR 0.62, 0.28-1.30, P=0.21), whereas MRA was significantly associated with improved outcome in low sST2 group (HR 0.37, 0.13-0.91, P=0.03). Conclusion: The present study showed that higher sST2 level was associated with worse prognosis and predictive of less response to MRA treatment in patients with HFpEF, which suggests that sST2 may be used to predict response to MRA treatment.

Scarce data are available on the association of mineralocorticoid receptor antagonist (MRA) use with outcomes in acute decompensated heart failure (ADHF). To investigate the association of MRA use with all-cause mortality and hospital readmission in patients with ADHF. This cohort study examines participants enrolled in the Kyoto Congestive Heart Failure (KCHF) registry, a physician-initiated, prospective, multicenter cohort study of consecutive patients admitted for ADHF, between October 1, 2014, and March 31, 2016, into 1 of 19 secondary and tertiary hospitals throughout Japan. To balance the baseline characteristics associated with the selection of MRA use, a propensity score-matched cohort design was used, yielding 2068 patients. Data analysis was conducted from April to August 2018. Prescription of MRA at discharge from the index hospitalization. Composite of all-cause death or heart failure hospitalization after discharge. Among 3717 patients hospitalized for ADHF, 1678 patients (45.1%) had received MRA at discharge and 2039 (54.9%) did not. After propensity score matching, 2068 patients (with a median [interquartile range] age of 80 [72-86] years, and of whom 937 [45.3%] were women) were included. In the matched cohort (n = 1034 in each group), the cumulative 1-year incidence of the primary outcome was statistically significantly lower in the MRA use group than in the no MRA use group (28.4% vs 33.9%; hazard ratio [HR], 0.81; 95% CI, 0.70-0.93; P = .003). Of the components of the primary outcome, the cumulative 1-year incidence of heart failure hospitalization was significantly lower in the MRA use group than in the no MRA use group (18.7% vs 24.8%; HR, 0.70; 95% CI, 0.60-0.86; P < .001), whereas no difference in mortality was found between the 2 groups (15.6% vs 15.8%; HR, 0.98; 95% CI, 0.82-1.18; P = .85). No difference in all-cause hospitalization was observed between the 2 groups (35.3% vs 38.2%; HR, 0.88; 95% CI, 0.77-1.01; P = .07). In additional analyses that stratified by left ventricular ejection fraction, the association of MRA use with the primary outcome was statistically significant in patients with left ventricular ejection fraction of 40% or greater. Use of MRA at discharge from ADHF hospitalization did not appear to be associated with lower mortality but was associated with a lower risk of heart failure readmission. This finding suggests that MRA treatment at discharge may have minimal, if any, clinical advantages.

Mineralocorticoid receptor antagonists in heart failure: they work better when patients use them.

Background The favourable effect of mineralocorticoid receptor antagonists (MRAs) on mortality was established in patients with stable heart failure (HF) with reduced ejection fraction (EF). However, its prognostic effect of MRAs in acute decompensated heart failure (ADHF) including HF with preserved EF (HFpEF) was unclear. Purpose This study sought to investigate the long-term impact of MRA on the post-discharge outcomes in patients with ADHF. Methods From the consecutive 3717 patients hospitalized for ADHF and discharged alive in the KCHF registry, we developed the propensity score (PS) for MRA use and constructed the PS-matched cohort. We compared the effect of MRA use on the primary outcome measure of all-cause death or HF hospitalization. Results A total of 1678 patients (45%) received MRA at discharge from the index hospitalization. Median follow-up was 470 days with 96% 1-year follow-up rate. In the PS-matched cohort (N=1034 in each group), the cumulative 1-year incidence of the primary outcome measure was significantly lower in the MRA group than in the no MRA group (28.4% vs. 33.9%, P=0.003) (Figure 1). The cumulative 1-year incidence of HF hospitalization was significantly lower in the MRA group than in the no MRA group (18.7% vs. 24.8%, P&lt;0.001), while there was no difference in mortality between the 2 groups (15.6% vs. 15.8%, P=0.85). There was no interaction between the effect of MRA and the 3 subgroups stratified by EF (EF &lt;40%, EF 40–49%, EF ≥50%) (interaction P=0.12). Figure 1 Conclusion The use of MRA was associated with lower risk for the primary composite outcome of all-cause death or HF hospitalization in patients hospitalized for ADHF including HFpEF, which was mainly driven by the lower risk for HF hospitalization.

To investigate the cardiovascular effects of sodium-glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF) and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2i vs. placebo. PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/post-hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Hazard ratios (HR)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. Five eligible studies were included, pooling data from 21 947 people with HF (type 2 diabetes mellitus, n = 10 805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs [HHF/CVD: hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.81 vs. HR 0.79; 95% CI 0.72-0.86; P-interaction = .43; HHF: HR 0.74; 95% CI 0.67-0.83 vs. HR 0.71; 95% CI 0.63-0.80; P-interaction = .53], with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR 0.81; 95% CI 0.72-0.91 vs. HR 0.98; 95% CI 0.86-1.13; P-interaction = .034). SGLT2i reduced all-cause mortality (P-interaction = .27) and adverse renal endpoints regardless of MRA use (P-interaction = .73) despite a higher risk of volume depletion with concomitant MRAs (P-interaction = .082). SGLT2i attenuated the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .051) associated with MRA use. MRAs did not influence SGLT2i effects on the composite of HHF/CVD, HHF or all-cause mortality; however, findings hinted at a more pronounced relative reduction in CVD in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA compared to those randomized to SGLT2i and not receiving MRAs. SGLT2i attenuated the risk of MRA-associated treatment-emergent hyperkalaemia. These findings warrant further validation in well-designed randomized controlled trials.

Background: The effects of Mineralocorticoid receptor antagonist (MRAs) on atrial fibrillation (AFib) outcomes following catheter ablation in patients with heart failure with preserved ejection fraction (HFpEF) is not well described. Objective: This study sought to assess the impact of MRAs on AFib catheter ablation outcomes among patients with HFpEF. Methods: We conducted a retrospective cohort study using the TriNetX research network, we identified, patients ≥18 years of age with HFpEF who had undergone AF ablation up to December 1, 2024 by means of CPT and ICD-10 codes. Patients were stratified based on the baseline MRAs use. Propensity score matching was performed to balance baseline characteristics between MRA users and non-users. The primary outcome was the risk of re-do AF ablation after a blanking period of the index ablation. Results: The study included 6,828 propensity-matched patients in each cohort. MRA use in patients with HFpEF undergoing AF ablation was associated with a non-significant trend toward a higher risk of redo AF ablation (OR: 1.11; 95% CI: 1.00–1.23; p = 0.05). This was accompanied by a modest yet statistically significant increase in rates of cardioversion (OR: 1.17; 95% CI: 1.07–1.27; p &lt; 0.001) and new antiarrhythmic drug use (OR: 1.15; 95% CI: 1.07–1.23; p &lt; 0.001). Additionally, MRA use in this group was not protective against acute HFpEF exacerbation and was linked to an increased odd of stroke. Conclusion: This retrospective analysis suggests that MRA use in patients with HFpEF undergoing AFib ablation may not be associated with a meaningful reduction in re-do ablation rates or improved event-free survival. Furthermore, MRA use was associated with a modestly higher burden of arrhythmia recurrence, as reflected by increased cardioversion rates and the need for new antiarrhythmic drug therapy. While our results suggest that MRAs may not confer a clear advantage in reducing arrhythmia recurrence or improving procedural outcomes, their clinical utility in this setting remains uncertain.

Mineralocorticoid receptor antagonists (MRAs) have been shown to provide survival benefits in patients with heart failure; however, MRA use in patients with chronic kidney disease has been limited by safety concerns. The effects of MRAs on outcomes in patients with end-stage renal disease (ESRD) and heart failure remain unknown. The aim of this study was to evaluate the effects of MRAs on cardiovascular outcomes in patients with heart failure under maintenance dialysis in a real-world setting. A retrospective cohort study was conducted by collecting data from the Taiwan National Health Insurance Research Database (NHIRD). Patients diagnosed with heart failure and ESRD and who started maintenance dialysis between 1 January 2001 and 31 December 2013 were identified. Patients were grouped according to MRA prescription. The outcomes of interest included cardiovascular (CV) death, hospitalization for heart failure (HHF), all-cause mortality, acute myocardial infarction (AMI), ischaemic stroke, any coronary revascularization procedures, and new-onset hyperkalaemia. Propensity score matching was performed at a 1:3 ratio between MRA users and non-users to minimize selection bias. A total of 50 872 patients who satisfied our inclusion and exclusion criteria were identified. After 1:3 matching, 2176 patients were included in the MRA group, and 6528 patients were included in the non-MRA group. The risk of CV death was significantly lower among patients who received MRAs than those who did not (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.80-0.95), as was the risk of all-cause mortality (HR 0.88, 95% CI 0.83-0.94). Reductions in the risks of CV death and all-cause mortality were more prominent among patients undergoing haemodialysis and those with coronary artery disease. In patients undergoing regular dialysis who are diagnosed with heart failure, the use of MRAs is associated with lower risks of all-cause mortality and CV death. The benefits of MRA treatment in heart failure may persist in patients with ESRD. Further investigations through randomized controlled trials are needed to assess the efficacy and safety of MRAs in this high-risk population.

BackgroundPostoperative atrial fibrillation occurs in ~40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We evaluated the association of preoperative MRA use with postoperative atrial fibrillation and investigated atrial cell types modulated by MRAs during cold preservation.MethodsWe studied 19 042 cardiac surgery patients at Mayo Clinic. Propensity 1:3 matching identified 298 MRA users and 894 non‐users. A subgroup analysis of patients on any preoperative diuretic was performed to isolate cardiac‐specific effects of MRAs, matching 298 MRA users to 894 non‐MRA diuretic users. AF recurrence was assessed for up to 6‐years. Single‐nucleus RNA sequencing (snRNA‐seq) was performed on human donor atria exposed to canrenone (a water‐soluble MRA) during cold preservation with ex‐vivo reperfusion, and expression profiles were compared with atria from patients with AF.ResultsAfter matching, preoperative MRA use was associated with a lower incidence of postoperative atrial fibrillation (19.8% versus 31.8%, P<0.001). In the diuretic‐only subgroup, MRA users also had lower postoperative atrial fibrillation (19.8% versus 33.2%, P<0.001). MRA use was associated with a reduced incidence of paroxysmal and chronic AF at 6‐years. snRNA‐seq identified a cardiomyocyte subpopulation, CM2, with high mineralocorticoid receptor expression where canrenone suppressed cold preservation‐induced mineralocorticoid receptor target gene expression, which was conversely elevated in chronic AF. Canrenone also attenuated stress‐response in atrial macrophages and pericytes.ConclusionsPreoperative MRAs were associated with reduced postoperative and long‐term AF after cardiac surgery. Mechanistically, our ex‐vivo human atrial model revealed that MRAs suppress mineralocorticoid receptor ‐driven atrial stress responses, particularly in conduction‐relevant cardiomyocytes.

In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. To study the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751). In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, HF events, and a ≥5 point difference in KCCQ-TSS at 90 days, assessed using the win ratio (WR). First HF hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRA at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR=1.46, 95%CI=1.08-1.97 and WR=1.27, 95%CI=0.93-1.73 in MRA users and non-users, respectively; interactionP=0.52). The effect of empagliflozin on first HF hospitalization or cardiovascular death was not modified by MRA use (HR=0.58, 95%CI=0.30-1.11 and HR=0.85, 95%CI=0.47-1.52 in MRA users and non-users, respectively; interactionP=0.39). Investigator-reported and severe hyperkalemia events were infrequent (<6%) irrespective of MRA use. In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF. This article is protected by copyright. All rights reserved.

Patients with kidney failure have a high risk of cardiovascular disease due to cardiac remodeling, left ventricular fibrosis, and hyperaldosteronism, all of which can be potentially mitigated by mineralocorticoid receptor antagonists. However, because of the fear of hyperkalemia, the use of mineralocorticoid receptor antagonists in patients with kidney failure is limited in current clinical practice, and few studies have investigated the efficacy and safety. Thus, we aimed to determine the benefits and side effects of mineralocorticoid receptor antagonists in patients with kidney failure treated with dialysis. This is a systematic review and meta-analysis of randomized controlled trials published from 2005 to 2020 that compared the effect of mineralocorticoid receptor antagonists with either placebo or no treatment in patients with kidney failure. Two reviewers independently searched the PubMed, EMBASE, and Cochrane databases for all published studies, extracted data, assessed the risk of bias, and rated the quality of evidence. A meta-analysis was conducted on 14 eligible randomized controlled trials, and a total of 1309 patients were included. High-quality evidence suggested that mineralocorticoid receptor antagonists are associated with lower cardiovascular mortality (relative risk, 0.41; 95% confidence interval, 0.24 to 0.70; P=0.001) and all-cause mortality (relative risk, 0.44; 95% confidence interval, 0.30 to 0.66; P<0.001), and the risk of hyperkalemia was comparable with that of control group (relative risk, 1.12; 95% confidence interval, 0.91 to 1.36; P=0.29). However, no significant decrease in nonfatal cardiovascular events and stroke was observed, and there was no significant improvement in BP or cardiac performance parameters, including left ventricular ejection fraction and left ventricular mass index. Our meta-analysis suggests that mineralocorticoid receptor antagonists might improve clinical outcomes of patients with kidney failure without significant increase in the risk of hyperkalemia.

Background Heart failure (HF) is a clinical syndrome characterized by high mortality and morbidity. In 2016, Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was recommended as a new treatment option for HF in patients with HFrEF. In the 2021 European Society of Cardiology guidelines for treatment of HFrEF patients Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were introduced because they demonstrated significantly reduced HF events or cardiovascular (CV) mortality. Since ARNI and SGLT2i were introduced to treat HF, its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). Purpose This study is aimed to compare effectiveness of modern therapy including ARNI and SGLT2i with conventional heart failure treatment. Conventional HF treatment includes (BB, ACEi/ARB, with or without MRA) and modern heart failure treatment (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i) in real-world. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n=20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n=709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality compared to conventional HF treatment (adjusted HR [aHR]: 0.72 (95% CI 0.54 - 0.96), p=0.024), and had 33% reduced all-cause mortality (aHR: 0.67 (95% CI 0.48 - 0.94), p=0.019) within 2 years of index registration. Similarly, modern HF therapy was associated with a significant 62% reduction in CV mortality compared to conventional HF treatment (aHR: 0.38 (95% CI 0.21 - 0.68), p=0.0013). In addition, we found a 58% reduced CV mortality (aHR 0.42 (95% CI 0.22 - 0.79), p=0.0067) within 2 years of index registration. In the propensity score 1:1 matched cohort in which ARNI was included in the matching procedure, i.e., no ARNI was used in any of the two treatment groups and the effect of SGLT2i was the target assessment. The results were associated with a statistically significant risk reduction of 42% in all-cause mortality in the modern HF treatment group compared to the conventional treatment group (aHR: 0.58 (95% CI 0.36 - 0.94), p=0.028), and a 49% (aHR: 0.51 (95% CI 0.29 - 0.89), p=0.018) risk reduction within 2 years of index registration. Conclusion This study demonstrates that modern HF therapy in a real-world Swedish HF population is associated with a statistically significant risk reduction in all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF compared to conventional HF therapy.Central Illustration

The Effect of Mineralocorticoid Receptor Antagonists on Heart Failure with Nonreduced Ejection Fraction: A Systematic Review and Meta-Analysis

PD4-4 - Interaction Between Mineralocorticoid Receptor Antagonist and Soluble ST2 in Heart Failure with Preserved Ejection Fraction

BackgroundThe role of mineralocorticoid receptor antagonists (MRAs) in acute myocardial infarction (MI) remains controversial, with conflicting evidence from landmark trials. We aimed to assess the impact of MRAs on mortality and cardiovascular outcomes post-acute MI.MethodsWe systematically searched PubMed, Embase and Cochrane CENTRAL databases up to February 2025 for randomised controlled trials comparing MRAs with placebo or standard care in adults experiencing acute MI. Primary outcome was all-cause mortality; secondary outcomes included cardiovascular mortality, heart failure, recurrent MI and ventricular arrhythmia. Data were pooled using random-effects models, with heterogeneity explored via subgroup analyses and meta-regression.Results15 trials (n=18 471) were included. MRA therapy demonstrated non-significant reductions in all-cause mortality (OR 0.80, 95% CI 0.55 to 1.18), cardiovascular mortality (OR 0.84, 95% CI 0.59 to 1.18), heart failure (OR 0.76, 95% CI 0.52 to 1.12), recurrent MI (OR 0.92, 95% CI 0.67 to 1.27) and ventricular arrhythmia (OR 0.83, 95% CI 0.47 to 1.47). Subgroup analyses revealed that trials with >6 months follow-up demonstrated modest cardiovascular mortality reduction (OR 0.86, 95% CI 0.75 to 0.99). Effects were consistent across MRA types, left ventricular ejection fraction categories and initiation timing. Meta-regression showed no significant effect modifiers among baseline characteristics or concomitant therapies.ConclusionsIn MI populations, MRA therapy did not significantly improve mortality or cardiovascular outcomes in the short term. However, a significant reduction in cardiovascular mortality emerged after 6 months, alongside a non-significant trend towards less heart failure, indicating potential benefits for high-risk patients with longer-term treatment rather than routine use in all acute MI cases.

&lt;p dir="ltr"&gt;Objective: In FLOW, semaglutide reduced the risk of major kidney and cardiovascular (CV) outcomes and all-cause mortality in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). This prespecified analysis assessed the effects of semaglutide on kidney, CV and mortality outcomes by baseline mineralocorticoid receptor antagonist (MRA) use.&lt;/p&gt;&lt;p dir="ltr"&gt;Research Design and Methods: Participants were randomized to once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary kidney outcome was a composite of time to first persistent ≥50% eGFR reduction from baseline, kidney failure, or death due to kidney/CV causes. Baseline MRA was predominantly spironolactone, finerenone was only available after recruitment ended.&lt;/p&gt;&lt;p dir="ltr"&gt;Results: Effects were analyzed by baseline MRA use (n=257 [136/121 semaglutide/placebo]) and non-use (n=3,276 [1631/1645]). Semaglutide reduced the risk of the primary kidney outcome by 49% (59 events, hazard ratio [HR] 0.51; 95% CI 0.30, 0.86) and 21% (682 events, HR 0.79; 0.68, 0.92; P-interaction=0.12) versus placebo in MRA and non-MRA subgroups, respectively. There was no heterogeneity, favoring the effects of semaglutide on major adverse CV events (MACE) and all-cause mortality in both MRA subgroups (P-interaction &gt;0.7). Albuminuria at 104 weeks was reduced from baseline with semaglutide by 15% (95% CI −41, 31) in MRA users and 33% (26, 39) in non-users versus placebo (P-interaction=0.22). eGFR decline was similarly reduced with semaglutide (P-interaction=0.71). The safety profile of semaglutide was comparable between subgroups. &lt;/p&gt;&lt;p dir="ltr"&gt;Conclusions: In participants with T2D and CKD, consistent benefits of semaglutide on major kidney outcomes, MACE, and all-cause mortality were observed regardless of baseline MRA use.&lt;/p&gt;