Safety and long-term outcomes of heart failure drug minimization in patients with improved ejection fraction: SLIM-HF study

Abstract Introduction Pharmacological drug therapy is the cornerstone of heart failure (HF) treatment, significantly improving symptoms, myocardial function and prognosis. However, for patients with improved ejection fraction (HFimpEF), the necessity of lifelong treatment and the burden of polypharmacy remain debated. Minimizing unnecessary medications can potentially enhance long-term adherence and reduce healthcare costs, benefiting both patients and healthcare systems. Purpose This observational study aimed to assess the safety and long-term outcomes of HFimpEF patients who minimized HF drugs and were enrolled in the prospective Rijnmond Heart Failure Registry at the Erasmus University Medical Center from 2014 to 2021. Methods HFimpEF patients were identified among HF patients with reduced ejection fraction, based on a follow-up left ventricular ejection fraction (LVEF) higher than 40%. Patients were subsequently divided into two groups. The minimization group included patients whose drug regimen was minimized to renin-angiotensin system inhibitors (RASi) and β-blockers, while the maintenance group included those who were either maintained mineralocorticoid receptor antagonists, loop diuretics, and/or digoxin during follow-up. The primary endpoint was defined as the first occurrence of HF-related hospitalization, heart transplantation, left ventricular assist device implantation, or death. The log-rank test was used to assess survival differences between groups. Cox regression analysis was employed to identify predictors for the primary endpoint, and the mixed-effects models were used to compare changes in key clinical parameters over time. Results From a total of 797 patients, 221 with HFimpEF were selected, all of whom consistently received a RASi and β-blockers. During a median follow-up of 6.0 years (IQR 3.1, 9.2), the primary endpoint occurred in 2 (3.4%) patients in the minimization group (n=58) and 37 (22.7%) patients in the maintenance group (n=163; HR: 9.36, 95% CI: 2.25-38.95, log-rank P0.001). Higher age (adjusted HR: 1.05, 95% CI: 1.01-1.08, P=0.004), history of cancer (adjusted HR: 3.71, 95% CI: 1.51-9.13, P=0.004), use of digoxin (adjusted HR: 3.16, 95% CI: 1.50-6.65, P=0.002), higher N-terminal pro-b-type natriuretic peptide (NT-proBNP)(adjusted HR: 1.01, 95% CI: 1.00-1.01, P0.001), and lower hemoglobin (adjusted HR: 0.65, 95% CI: 0.46-0.92, P=0.014) at baseline were identified as independent predictors for primary endpoint. Compared to the maintenance group, the minimization group exhibited stable LVEF (P0.001), NT-proBNP (P=0.008), and estimated glomerular filtration rate (P=0.012). Conclusion In this real-world registry, the long-term prognosis of HFimpEF patients who successfully minimized HF drugs to RASi and β-blockers was excellent. This suggests that HF drug minimization in this patient population is safe and achievable.Cumulative incidence of primary endpoint