The goal of this clinical trial is to evaluate the safety and feasibility of withdrawing mineralocorticoid antagonists (MRA) in patients with stable heart failure with improved left ventricular ejection fraction (HFimpEF). The main questions it aims to answer are:

Does withdrawal of MRAs lead to a reduction in left ventricular ejection fraction greater than 10%, resulting in a final LVEF below 40%? Does withdrawal of MRAs cause a relative increase in NT-proBNP levels greater than 50% above age-adjusted thresholds? Researchers will compare MRAs withdrawal (placebo) with continuation of therapy to determine whether medication withdrawal can be performed safely without worsening heart failure status.

Participants will:

Attend scheduled clinical visits over a 24-week follow-up period; Undergo echocardiographic evaluation of left ventricular ejection fraction before study visits; Provide blood samples for NT-proBNP measurement at each visit; Provide one blood sample for genetic analysis of polymorphisms related to the renin-angiotensin-aldosterone system; Receive either continued MRA therapy or placebo as part of a double-blind randomized design; Be monitored for clinical stability, symptoms of heart failure, and potential adverse events during follow-up.

Heart failure (HF) is a major global health problem associated with high rates of hospitalization, mortality, and healthcare costs. Contemporary guideline-directed medical therapy has substantially improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Standard pharmacological management includes four major therapeutic pillars: beta-blockers, inhibitors of the renin-angiotensin system (ACE inhibitors, ARBs, or ARNI), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. These therapies improve survival and reduce hospitalizations.

A subset of patients with HFrEF experiences significant improvement in cardiac function after treatment and is now classified as having heart failure with improved ejection fraction (HFimpEF). These patients typically demonstrate recovery of left ventricular ejection fraction from previously reduced values to ≥40%. However, recovery of ejection fraction does not necessarily represent complete reversal of the underlying disease process, and structural or molecular abnormalities may persist. Current clinical guidelines generally recommend continuation of guideline-directed medical therapy even after improvement in ejection fraction due to concerns about relapse.

Despite the benefits of these therapies, patients with heart failure frequently require multiple medications to manage both their cardiac condition and associated comorbidities. Polypharmacy can increase the risk of adverse drug reactions, medication non-adherence, drug interactions, and treatment complexity. Simplification of pharmacological regimens may therefore represent an important strategy to improve adherence and reduce treatment burden in selected patients.

Previous studies investigating withdrawal of heart failure therapies have shown mixed results. In some populations, withdrawal of key disease-modifying medications resulted in relapse of cardiac dysfunction or worsening clinical status. However, there is limited evidence regarding selective withdrawal of specific medication classes in carefully selected patients who have achieved clinical stability and significant improvement in cardiac function.

Mineralocorticoid receptor antagonists, such as spironolactone, play an important role in the treatment of HFrEF by blocking the effects of aldosterone, thereby reducing myocardial fibrosis, neurohormonal activation, and ventricular remodeling. Although their benefits in patients with reduced ejection fraction are well established, the necessity of maintaining this therapy indefinitely in patients with stable HFimpEF remains uncertain.

The SIMPLIFY-HF study is designed to evaluate the safety and feasibility of discontinuing MRAs in clinically stable patients with HFimpEF. This study will be a multicenter, randomized, double-blind clinical trial comparing withdrawal of MRAs (with placebo substitution) versus continuation of therapy. Eligible participants will have a history of heart failure with previously reduced ejection fraction that improved to ≥40%, stable clinical status, optimized background therapy, and no recent hospitalizations or signs of decompensation.

Participants will be followed for 24 weeks with scheduled clinical visits, echocardiographic evaluation of left ventricular function, and measurement of NT-proBNP levels as a biomarker of cardiac stress. Safety monitoring will be performed throughout the study to detect any signs of worsening heart failure, including deterioration in functional status, reduction in ejection fraction, or significant increases in natriuretic peptide levels.

The results of this study may provide important evidence regarding whether selected patients with stable HFimpEF can safely undergo simplification of pharmacological therapy through withdrawal of MRAs, potentially reducing treatment burden while maintaining clinical stability.

Inclusion Criteria:

• Diagnosis of heart failure (HF) and use of MRAs and an ACE inhibitor/ARB/ARNI for at least 12 months
• Left ventricular ejection fraction (LVEF) ≥40%, improved from a prior value ≤35%, with a sustained absolute increase >10%
• Left ventricular end-diastolic diameter within normal limits according to predefined criteria (≤59 mm for men and ≤53 mm for women)
• NYHA functional class I or II
• BNP levels <100 pg/mL, or NT-proBNP levels within age-adjusted thresholds: ≥450 pg/mL for individuals <50 years, ≥900 pg/mL for those 50-75 years, and ≥1800 pg/mL for individuals >75 years
• In cases of atrial fibrillation, NT-proBNP thresholds should be doubled
• Clinical stability defined as no hospitalizations or need for increased diuretic therapy due to congestion within the previous 12 months
• Optimized heart failure medications with no modifications for at least 3 months
• Maximum allowed dose of furosemide of 80 mg/day
• Acceptable etiologies: HF following cardiac resynchronization therapy (CRT); non-ischemic HF after myocarditis; non-ischemic HF due to tachycardiomyopathy; non-ischemic HF due to alcoholic cardiomyopathy; non-ischemic HF due to cardiotoxicity; non-ischemic HF due to peripartum cardiomyopathy; non-ischemic HF after correction or intervention for valvular disease; ischemic HF after revascularization

Exclusion Criteria:

• Acute coronary syndrome within the past 12 months
• Arrhythmia requiring therapy within the past 12 months
• Syncope or appropriate device therapy (if ICD present) within the past 12 months
• Uncorrected moderate to severe valvular disease
• Severe unrevascularized coronary artery disease, defined as >50% stenosis of the left main coronary artery (LMCA) or >70% stenosis of the left anterior descending artery (LAD), circumflex artery (LCx), or right coronary artery (RCA)