Direct His/LBB pacing as an alternative to biventricular pacing in patients with HFrEF and a typical LBBB: Design and rationale for the His-Alternative II trial

Background Cardiac resynchronization therapy (CRT) using biventricular pacing (BiV-CRT) is an established treatment for patients with symptomatic heart failure, reduced left ventricular ejection fraction, and left bundle branch block (LBBB), leading to improvements in symptoms, ventricular function, exercise capacity and survival. Despite these benefits, up to one third of patients fail to respond optimally with no clinical improvement despite meeting current criteria for implantation. Conduction system pacing (CSP), delivered via His bundle pacing or left bundle branch area pacing, has emerged as an appealing alternative by directly engaging the native His–Purkinje system. However, randomized data directly comparing CSP-based CRT with conventional BiV-CRT remain limited. Study design His-Alternative II is an investigator-initiated, multicenter, randomized non-inferiority trial designed to evaluate whether CRT delivered via CSP is non-inferior to conventional biventricular pacing with respect to left ventricular reverse remodeling. The study enrolls patients with symptomatic heart failure (New York Heart Association class II to III), left ventricular ejection fraction ≤35%, strict LBBB by electrocardiographic criteria, and optimal medical therapy. A total of 150 patients were randomized with a 1:2 randomization ratio to receive BiV-CRT or CSP-based CRT (His bundle pacing or left bundle branch pacing) and followed for 6 months. The primary endpoint is change in left ventricular end-systolic volume assessed by echocardiography; a surrogate endpoint consistently associated with long-term outcomes in CRT populations. Secondary endpoints include functional capacity, symptomatic status, quality of life, electrical resynchronization, and device-related complications. Conclusions His-Alternative II is designed to determine whether CSP-based CRT can achieve left ventricular reverse remodeling comparable to that obtained with conventional BiV-CRT. The study will provide randomized evidence to inform the role of physiologic pacing strategies in contemporary CRT practice. ClinicalTrials.gov identifier NCT04409119.