Effect of sacubitril/valsartan and SGLT2 inhibitors on echocardiographic response and clinical outcomes after cardiac resynchronization therapy: insights from a real-world cohort

Introduction Cardiac resynchronization therapy (CRT) is recommended for symptomatic heart failure (HF) patients with QRS duration ≥150ms, left bundle branch block morphology, and left ventricular ejection fraction (LVEF) ≤35%, despite guideline-directed medical therapy (GDMT), to improve symptoms and reduce morbidity and mortality. However, pivotal trials supporting CRT were conducted before the widespread use of angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose co-transporter-2 inhibitors (SGLT2i), and it remains unknown whether CRT retains its benefit with contemporary HF therapy. Purpose To assess whether ARNI and/or SGLT2i therapy is associated with differences in echocardiographic response to CRT and clinical outcomes in a real-world cohort. Methods We performed a single-center retrospective study of consecutive patients undergoing CRT between January 2017 and April 2024. Patients were classified by baseline use of ARNI and/or SGLT2i versus neither. Echocardiographic assessments were performed at baseline and 6-12 months post-CRT. CRT response was defined as ≥15% reduction in LV end-systolic volume or absolute increase in LVEF ≥10%. The primary endpoint was major adverse cardiac events (MACE), including all-cause mortality or HF hospitalisation. Secondary endpoints included cardiovascular mortality, heart-failure hospitalization, requirement for IV diuretics and NYHA class improvement. Time-to-event analyses were performed using Kaplan–Meier methods. Results A total of 206 patients were included (median age 74 [IQR 66-79] years, 68.4% male, 67.5% non-ischemic, mean follow-up time 35±24 months), of whom 105 (51%) received ARNI/SGLT2i. Baseline clinical characteristics were comparable between groups, although beta-blocker (81.0% vs 66.3%, p=0.017) and mineralocorticoid receptor antagonist use (65.7% vs 46.5%, p=0.006) were more frequent in the ARNI/SGLT2i group. CRT response (81.1% vs 82.9%, p=0.782) and NYHA class improvement (64.9% vs 70.9%, p=0.388) were similar. MACE events were significantly lower in ARNI/SGLT2i patients (18.3% vs 46%, p<0.001), as were all-cause mortality (14.4% vs 35%, p<0.001), HF hospitalisation (12.5% vs 26.0%, p=0.014) and requirement for IV diuretics (16.3% vs 33.0%, p=0.006). Kaplan–Meier analysis suggested a non-significant trend toward lower event rates in ARNI/SGLT2i patients (log-rank p=0.199). Conclusion In this real-world cohort, CRT remained associated with high rates of echocardiographic and functional response, and contemporary HF therapy with ARNI and/or SGLT2i was associated with a trend toward improved event-free survival, suggesting that the clinical benefit of CRT is maintained in the era of modern guideline-directed therapy.Cumulative MACE-free survival