Impact of Late ARNI Initiation on Quality of Life and Functional Capacity in CRT-Treated HFrEF Patients: A Single-Centre Cohort Study

<b>Background/Objectives:</b> Cardiac resynchronization therapy (CRT) is a cornerstone treatment for heart failure with reduced ejection fraction (HFrEF), yet many patients remain symptomatic despite long-term electrical optimization. Although sacubitril/valsartan (ARNI) is central to guideline-directed medical therapy (GDMT), data on its late initiation in patients with chronic CRT are scarce. This study evaluated the impact of delayed ARNI initiation on clinical status, functional capacity, and cardiac remodelling in a real-world CRT population. <b>Methods:</b> We performed a single-centre, retrospective observational study including 76 HFrEF patients with chronic CRT who started ARNI between 2022 and late 2024. Patients underwent standardized assessment at baseline (T0) and after 12 ± 3 months (T1), including clinical evaluation, 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), symptom-limited bicycle exercise testing, and comprehensive echocardiography. The primary endpoint was change in quality of life (QoL). Secondary endpoints included exercise capacity, echocardiographic reverse remodelling, NYHA class, loop diuretic dose, and device-detected arrhythmias. Dose-response and multidimensional response patterns were explored. <b>Results:</b> KCCQ-12 increased from 52.96 ± 16.33 to 75.55 ± 18.12 (Δ +22.59 ± 13.22, <i>p</i> < 0.001), with 89.5% achieving a clinically meaningful improvement. Exercise duration and peak workload improved significantly. LVEF increased from 35.08 ± 6.96% to 43.18 ± 8.42% (Δ +8.11%, <i>p</i> < 0.001), with reductions in left ventricular and atrial volumes. Loop diuretic dose decreased (median -10 mg/day furosemide equivalent, <i>p</i> < 0.001), and 26.3% discontinued diuretics. A lower prevalence of device-detected arrhythmias was observed at follow-up, from 34.2% to 6.6% (<i>p</i> < 0.001). Higher ARNI doses were associated with greater likelihood of clinical, functional, and structural response. Longer CRT duration reduced the probability of structural remodelling but not symptomatic or functional benefit. <b>Conclusions:</b> In patients with long-standing CRT, delayed ARNI initiation was associated with improvements in QoL, exercise capacity, cardiac remodelling, congestion status, and electrical stability. These findings suggest that CRT is not a therapeutic ceiling and that late ARNI initiation remains a valuable component of comprehensive GDMT.