Mid-Term and Long-Term Clinical Events with Conduction System Pacing Versus Biventricular Pacing in HFrEF with Wide QRS: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis

Background/Objectives: Conduction system pacing (CSP) has emerged as a more physiological alternative to biventricular pacing (BiVP) in heart failure with reduced ejection fraction (HFrEF) and wide QRS, but recent randomized controlled trials (RCTs) have yielded discordant results. This meta-analysis aimed to compare CSP with BiVP for clinical events and functional recovery in HFrEF. Methods: MEDLINE, Embase, and Cochrane Library were searched for RCTs through 15 April 2026. Primary outcomes were all-cause mortality (ACM) and heart failure hospitalization (HFH) at mid-term (6–12 months) and long-term (>12 months) follow-up. Random-effects meta-analyses and Trial Sequential Analysis (TSA) were performed. Results: Eleven RCTs comprising 12 reports and 1073 patients were included. CSP showed no significant difference in mid-term ACM (RR 0.72; 95% CI 0.21 to 2.49; p = 0.605) or HFH (RR 0.97; 95% CI 0.52 to 1.81; p = 0.918). At long-term follow-up (three RCTs; n = 312), CSP showed a non-significant trend toward ACM reduction (RR 0.34; 95% CI 0.11 to 1.06; p = 0.063; low-certainty evidence) and a significant, TSA-supported reduction in HFH (RR 0.30; 95% CI 0.16 to 0.58; p < 0.001; moderate-certainty evidence). At 6 months, CSP improved LVEF (MD 2.84%; 95% CI 0.74 to 4.93; p = 0.008) and reduced QRS duration (MD −9.97 ms; 95% CI −18.57 to −1.37; p = 0.023), with NYHA improvement at 12 months (MD −0.31; 95% CI −0.50 to −0.11; p = 0.002). Conclusions: In this meta-analysis of RCTs predominantly evaluating left bundle branch area pacing, CSP was associated with a lower risk of long-term HFH compared with BiVP in HFrEF with a wide QRS, although the evidence remains limited by the small number of available trials. The observed trend toward lower long-term ACM should be considered hypothesis-generating. Larger, adequately powered RCTs with longer follow-up are needed to confirm these findings and determine whether CSP provides sustained clinical benefit over BiVP.