Reverse Remodeling Following Sacubitril/Valsartan Initiation in CRT-Treated HFrEF Patients: Insights from a...

Background: Sacubitril/valsartan is a cornerstone of guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF), yet data regarding reverse remodeling after ARNI initiation in patients previously treated with cardiac resynchronization therapy (CRT) remain limited. This study evaluated echocardiographic reverse remodeling following sacubitril/valsartan initiation in a real-world cohort of CRT-treated patients and explored the association between treatment timing and remodeling response. Methods: This single-center retrospective pilot study included 188 patients with HFrEF treated with CRT who subsequently initiated sacubitril/valsartan. Patients were categorized into early (≤12 months after CRT, n = 112) and late (>12 months, n = 76) initiation groups. Echocardiographic parameters and functional status were assessed at baseline and at approximately 12 months. Reverse remodeling was evaluated using changes in left ventricular ejection fraction (LVEF), ventricular volumes, and clinical status. Multivariable logistic regression was used to explore factors associated with reverse remodeling (ΔLVEF ≥ 10%). Results: Sacubitril/valsartan therapy was associated with significant improvements in LVEF, left ventricular end-diastolic volume, left atrial volume, and NYHA functional class in both groups. The magnitude of improvement in echocardiographic parameters was similar between early and late initiation groups. In exploratory multivariable analyses, earlier ARNI initiation was associated with clinically meaningful reverse remodeling (ΔLVEF ≥ 10%) (OR 6.36, 95% CI 1.59-25.50, p = 0.009). SGLT2 inhibitor therapy was also associated with reverse remodeling (OR 5.76, 95% CI 1.86-17.87, p = 0.002), while a longer CRT-to-ARNI interval was associated with lower odds of response (OR 0.77 per year, 95% CI 0.62-0.96, p = 0.018). Analysis of CRT-to-ARNI interval as a continuous variable showed only a weak association with reverse remodeling, while receiver operating characteristic analysis did not identify a meaningful temporal threshold (AUC 0.497). Conclusions: Sacubitril/valsartan initiation after CRT was associated with significant reverse remodeling, including in patients who initiated therapy several years after CRT implantation, although the late-initiation subgroup was of limited size, and treatment intervals beyond the interquartile range (4.0-7.0 years) were sparsely represented. Absolute echocardiographic improvements were broadly similar between groups, and receiver operating characteristic analysis did not identify a discriminative temporal threshold (AUC 0.497), indicating no discriminative ability beyond chance. Exploratory multivariable analysis identified an association between earlier initiation and clinically meaningful reverse remodeling, but this finding was not supported by a clinically meaningful temporal threshold.