Key result
MRA alone linked to ~34% higher 30-day readmissions vs ARNI combination therapy in HFrEF.
Why the study?
The benefits of sacubitril/valsartan in HFmrEF and HFpEF are less clear than in HFrEF, and direct comparisons between sacubitril/valsartan and MRAs across HF subtypes, especially HFmrEF, are limited.
Does sacubitril/valsartan-based therapy or ARNI plus MRA combination therapy reduce 7-, 15-, and 30-day all-cause readmissions compared with MRA-based therapy in adults aged 30 to 60 years with newly diagnosed HFrEF, HFmrEF, and HFpEF?
Cohort (n=23,649)
Yes
Does sacubitril/valsartan-based therapy or ARNI plus MRA combination therapy reduce 7-, 15-, and 30-day all-cause readmissions compared with MRA-based therapy in adults aged 30 to 60 years with newly diagnosed HFrEF, HFmrEF, and HFpEF?
Answers are grounded in this paper and cite their sources.
In a large cohort of younger adults (aged 30-60) with newly diagnosed heart failure, combined ARNI plus MRA therapy was associated with lower short-term readmission odds in HFrEF compared with MRA-based therapy alone, whereas ARNI-based therapy without MRA had higher 30-day readmission odds than MRA-based therapy in both HFrEF and HFpEF.
Abstract Background: Heart failure (HF) is classified as HFrEF, HFmrEF, and HFpEF. Sacubitril/valsartan improves outcomes in HFrEF, but benefits in HFmrEF and HFpEF are less clear. MRAs reduce mortality in HFrEF and hospitalizations in HFpEF. Direct comparisons across HF subtypes, especially HFmrEF, are limited. Goal: To compare sacubitril/valsartan (ARNI) based therapy, MRA based therapy, and ARNI plus MRA combination therapy in HFrEF, HFmrEF, and HFpEF, specifically evaluating their association with short term all cause readmission at 7, 15, and 30 days after discharge. This analysis was designed to assess readmission risk alone and does not evaluate mortality or symptom based outcomes. Because all patients also received background therapy with an ACE inhibitor, angiotensin receptor blocker, or beta blocker, the ARNI and MRA groups are best understood as ARNI based and MRA based regimens rather than true monotherapy. Methods: Retrospective analysis of 23,649 adults with newly diagnosed HF from the HCA Healthcare national database (190 hospitals, ~2,400 ambulatory sites). Patients were aged 30 to 60 years, representing a comparatively younger heart failure population than most national registries, in which average age at hospitalization exceeds 70 years. Patients were stratified by EF phenotype and grouped as MRA only, ARNI only, or combination therapy; prior outpatient use was exclusionary. Readmission risks were analyzed at 7, 15, and 30 days, accounting for race and comorbidities. Baseline Characteristics: The cohort was 70.1% male, 54.2% White, 33.0% Black. Comorbidities included hypertension (65.2%), diabetes (26.3%), and CKD (17.7%). Most had HFrEF (68.3%), followed by HFmrEF (17.4%) and HFpEF (14.4%). MRA monotherapy was most frequent (64.1%). Among patients, 4,164 received ARNI, 15,162 MRA, and 4,323 combination therapy. Results: In HFrEF, MRA based therapy increased readmission odds compared with combination therapy at 7 days (OR 1.24), 15 days (OR 1.25), and 30 days (OR 1.34). ARNI based therapy increased 30-day readmissions compared with MRA based therapy in HFrEF (OR 1.19) and HFpEF (OR 1.60). CKD increased 15- and 30-day readmissions in HFrEF. In HFpEF, African American race was linked to lower 15- and 30-day readmissions, a finding discussed further in the Discussion as a possible reflection of differential outcome ascertainment rather than a true protective effect. Keywords: Abbreviations: HF – Heart Failure; HFrEF – Heart Failure with Reduced Ejection Fraction; HFmrEF – Heart Failure with Mildly Reduced Ejection Fraction; HFpEF – Heart Failure with Preserved Ejection Fraction; ARNI – Angiotensin Receptor-Neprilysin Inhibitor; MRA – Mineralocorticoid Receptor Antagonist; Keywords: GDMT – Guideline-Directed Medical Therapy; EF – Ejection Fraction; LVEF – Left Ventricular Ejection Fraction; ACEi – Angiotensin-Converting Enzyme Inhibitor; ARB – Angiotensin Keywords: Receptor Blocker; BB – Beta-Blocker; CKD – Chronic Kidney Keywords: Disease; HTN – Hypertension; DM – Diabetes Mellitus; SGLT2 – Sodium-Glucose Cotransporter-2; NYHA – New York Heart Association; RCT – Randomized Controlled Trial; OR – Odds Ratio; CI – Confidence Interval ; HR – Hazard Ratio; eGFR – Estimated Glomerular Filtration Rate; RASI – Renin-Angiotensin System Inhibitor ; ESC – European Society of Cardiology; AHA – American Heart Association; ACC – American College of Cardiology; HFSA – Heart Failure Society of America; KDIGO – Kidney Disease: Improving Global Outcomes; PPCM – Peripartum Cardiomyopathy; ECHO – Echocardiogram; HER2 – Human Epidermal Growth Factor Receptor 2; Rehospitalization – used synonymously with Readmission throughout the manuscript.
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A et al. (2026) conducted a cohort in Newly diagnosed heart failure across all EF subtypes (HFrEF, HFmrEF, HFpEF) (n=23,649). Sacubitril/valsartan (ARNI) based therapy and ARNI plus MRA combination therapy vs. Mineralocorticoid receptor antagonist (MRA) based therapy was evaluated on Short-term all-cause readmission at 7, 15, and 30 days after discharge (OR 1.34). ARNI-based therapy increased 30-day readmissions vs MRA-based therapy in HFrEF (OR 1.19) and HFpEF (OR 1.60), while MRA alone increased 30-day readmissions vs combination therapy in HFrEF (OR 1.34).
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