Conduction System Pacing vs. Biventricular Pacing for Cardiac Resynchronization Therapy: An Updated Systematic Review and Meta‑Analysis

Technical Summary: Conduction System Pacing vs. Biventricular Pacing for Cardiac Resynchronization Therapy

Problem Statement
Cardiac Resynchronization Therapy (CRT) is a standard treatment for heart failure patients with ventricular electromechanical dyssynchrony. While traditional Biventricular Pacing (BiVP) has proven efficacy in reducing mortality and hospitalizations, it suffers from inherent limitations, including a clinical response rate of only ~70%, anatomical constraints of the coronary venous system, phrenic nerve stimulation, and non-physiological epicardial activation. Conduction System Pacing (CSP) has emerged as a more physiological alternative, encompassing techniques such as His Bundle Pacing (HBP) and Left Bundle Branch Pacing (LBBP). However, existing literature presents inconsistent results regarding the comparative efficacy and safety of CSP versus BiVP. Previous meta-analyses have often treated CSP as a monolithic entity, potentially obscuring critical differences between specific techniques (e.g., strict LBB capture vs. left ventricular septal pacing) and failing to account for operator experience and patient selection variables.

Methodology
This study is an updated systematic review and meta-analysis adhering to the PRISMA 2020 statement.

• Data Sources: A comprehensive search was conducted across PubMed, Embase, Cochrane Library, and Web of Science from inception to April 2026.
• Study Selection: The analysis included only Randomized Controlled Trials (RCTs) comparing any form of CSP (HBP, LBBP, LBBAP, or CSP with optimization) against BiVP in patients with symptomatic heart failure, LVEF ≤40%, and guideline-indicated CRT. Non-randomized studies and crossover trials without parallel periods were excluded.
• Subgroup Stratification: A key methodological feature was the pre-specified classification of CSP into four mutually exclusive subgroups based on technical characteristics and electrophysiological capture criteria:
  1. CSP with Optimization: Strategies allowing adjunctive coronary sinus (CS) lead placement if CSP alone was insufficient (e.g., LOT-CRT).
  2. Strict LBBP: Studies requiring electrophysiological confirmation of left bundle branch capture (e.g., specific stimulus-to-peak R-wave times or recording of LBB potentials).
  3. His-CRT: Pure His bundle pacing using a dedicated lead.
  4. LVSP-dominant: Left ventricular septal pacing without confirmed LBB capture.
• Outcomes: The primary outcome was the composite of all-cause death or heart failure hospitalization. Secondary outcomes included changes in LVEF and LVESV, echocardiographic response (structural and functional), QRS duration shortening, NYHA class improvement, and complication rates.
• Statistical Analysis: Random-effects meta-analysis (DerSimonian-Laird) was employed. Heterogeneity was assessed via $I^2$ and Cochran's Q. Meta-regression was used to explore sources of heterogeneity, including baseline QRS duration and CSP technique.

Key Contributions

1. Granular Technical Classification: Unlike previous meta-analyses that aggregated all CSP techniques, this study distinguishes between "strict" LBB capture, pure His pacing, and septal pacing. This approach reveals that efficacy and safety profiles are not uniform across the CSP spectrum.
2. Inclusion of Recent High-Impact RCTs: The analysis incorporates the most recent large multicenter trials (up to 2026), including the negative PhysioSync-HF trial and the long-term HeartSync-LBBP trial, providing a more current and comprehensive evidence base than prior reviews.
3. Differentiation of Hard vs. Surrogate Endpoints: The study rigorously separates hard clinical endpoints (death/hospitalization) from surrogate markers (LVEF, LVESV, QRS narrowing), highlighting that improvements in one domain do not always correlate linearly with the other.
4. Operator Experience Contextualization: By analyzing the PhysioSync-HF trial (conducted in centers with varying operator experience) alongside trials from high-volume expert centers, the study contextualizes the "learning curve" effect on CSP outcomes.

Results

• Primary Outcome: CSP significantly reduced the risk of all-cause death or heart failure hospitalization compared to BiVP (Risk Ratio [RR] 0.47, 95% CI 0.32–0.69, $P < 0.0001$). Subgroup analysis showed no significant interaction between subgroups for this outcome, though the His-CRT subgroup (driven by the Frandsen 2026 study) showed a strong trend toward benefit.
• LVEF and LVESV: Overall, there was no significant difference in LVEF change between CSP and BiVP (MD 2.03%, $P = 0.09$). However, significant heterogeneity existed ($I^2 = 80\%$). Subgroup analysis revealed that Strict LBBP (MD 5.55%) and His-CRT (MD 3.12%) significantly favored CSP, whereas CSP with optimization and LVSP-dominant strategies showed no difference. Similarly, Strict LBBP significantly reduced LVESV (MD –23.98 mL), while other subgroups did not.
• Functional and Structural Response: CSP favored functional response (LVEF increase ≥5%; RR 1.10, $P = 0.05$) but showed no difference in structural response (LVESV reduction ≥15%).
• Electrical Synchrony: CSP significantly shortened QRS duration overall (MD –8.88 ms, $P = 0.007$). The CSP-with-optimization subgroup showed the most consistent effect with no heterogeneity ($I^2 = 0\%$).
• NYHA Class: CSP significantly improved NYHA functional class compared to BiVP (MD –0.21, $P = 0.0007$).
• Safety: Overall complication rates did not differ significantly between groups. However, the His-CRT subgroup in the long-term Frandsen 2026 study reported a significantly higher risk of complications (RR 4.00), primarily driven by lead revisions and generator replacements due to threshold rises.
• Meta-Regression: Each 10 ms increase in baseline QRS duration was associated with a 4.09% reduction in the LVEF benefit of CSP over BiVP ($P = 0.04$). CSP technique was a significant moderator for both LVEF and LVESV outcomes.

Significance and Claims
The authors claim that this study provides the most complete picture to date regarding CSP for CRT, moving beyond the binary comparison of "CSP vs. BiVP" to a nuanced, technique-specific evaluation.

• Individualized Strategy: The findings support the conclusion that CSP techniques are not interchangeable. Strict LBBP appears to offer the most robust reverse remodeling (LVESV reduction) and stable parameters, making it a strong first-line CSP strategy. His-CRT may offer the greatest potential for hard clinical endpoints in well-selected patients but carries a higher long-term risk of device-related complications (lead revision/battery depletion), particularly in earlier adoption phases.
• Operator Dependency: The study emphasizes that the benefits of CSP are highly dependent on operator experience and strict adherence to capture confirmation criteria. The negative results of the PhysioSync-HF trial are interpreted not as a refutation of CSP, but as a caution that premature dissemination without structured training and quality assurance can lead to inferior outcomes.
• Clinical Implications: For experienced centers, CSP (specifically LBBP or His-CRT) is a viable, potentially superior alternative to BiVP. However, in centers without high CSP expertise, conventional BiVP remains the safer, effective first choice. The authors advocate for future large-scale RCTs that stratify operator experience and standardize LBB capture confirmation to definitively establish indications for each technique.