The Left Bundle Cardiac Resynchronization Therapy Trial

A Non-inferiority Randomized Comparison Between LEFT BUNDLE Branch Area Pacing and Biventricular Pacing for Cardiac Resynchronization Therapy: The LEFT-BUNDLE-CRT Trial

Cardiac resynchronization therapy (CRT) via biventricular (BiV) pacing significantly reduces morbidity and mortality in patients with left bundle branch block (LBBB), impaired LV function and heart failure in spite of optimal medical treatment. CRT positive effects are based on the existence of an electromechanical dyssynchrony induced by the abnormal activation sequence associated with the presence of a left bundle branch block (LBBB), which is thought to be responsible for a negative LV remodeling leading to LVEF impairment and heart failure progression. However, one third of patients undergoing CRT are considered non responders due to different reasons. Recently, left bundle branch area pacing (LBBAP) has emerged as a novel physiological pacing modality aiming for conduction system recruitment in patients with normal or impaired atrioventricular conduction, including patients with LBBB. LBBAP achieves LBBB correction in up to 85% of the cases and thus could be a promising pacing modality for CRT candidates.

Medical device: Only CE-marked CRT-P or CRT-D Medtronic devices locally approved and commercially available (Medtronic 3830 Pacing Lead) shall be used in this protocol. Indication: Pacing and sensing in the right atrium or ventricle. It is also designed for pacing and sensing in the bundle as an alternative to pacing in the right ventricle in a single or dual chamber pacing system. Intended use: Patients with an indication for cardiac resynchronization therapy. Duration of the study: Approximate inclusion period of 18 months Follow-up: Patients will be followed for 12 months ± 4 weeks after implant Planned study period: The study is planned to start in Q1 2022 No. of sites: Approximately 11 sites in Spain. No. of subjects: 176 patients will be enrolled in the study Study type: Post-market study Study rationale: Previous studies show 85% implantation success, significant reduction in QRS duration, and significant improvement in NYHA functional class, LVEF, and LV end-diastolic diameter. Left bundle branch pacing could be an alternative to conventional biventricular pacing. Study design: Multicenter, prospective, randomized, non-inferiority, open. Objectives of the study: Primary objective: The primary objective of the study is to demonstrate that LBBAP is associated with a non-inferior percentage of CRT responders at 6 months follow-up than conventional BiV pacing using a conventional CS lead in patients with CRT indications according to current guidelines. Positive CRT response will be defined either by an improved Clinical Composite Score or ≥15% reduction in left ventricular end-systolic volume at 6 months follow-up Secondary objectives: To evaluate reverse ventricular remodeling response and dyssynchrony parameters based on echocardiographic data at 6 and 12 months follow-up. To asess clinical outcome using the Clinical Composite Score, 6 minute walking test, quality of life measurements (EuroQuol EQ 5-D) at 6 and 12 months follow-up. To evaluate HF related hospitalizations at 6 and 12 months follow-up. To evaluate mortality (global and cardiovascular) and need for cardiac transplantation at 6 and 12 month follow-up. To evaluate incidence of ventricular arrhythmias at 6 and 12 month follow-up. To evaluate differences in CRT response depending on the final LBBAP modality (LBBP vs deep septal pacing). To evaluate device related complications at 6 and 12 month follow-up. Primary Outcome Measures: Improved Clinical Composite Score or ≥15% reduction in left ventricular end-systolic volume at 6 months follow-up. Participating sites: Hospital Universitario y Politécnico La Fe, Valencia Hospital Clinic de Barcelona Hospital Virgen de las Nieves, Granada Hospital Virgen de la Arrixaca, Murcia Hospital Puerta de Hierro, Madrid Hospital General de Alicante Hospital Bellvitge, Barcelona Hospital 12 de Octubre, Madrid Hospital Universitario Lozano Blesa, Zaragoza Hospital Juan Ramón Jiménez, Huelva Hospital Universitario San Cecilio, Granada Study population: Subjects 18 years of age or older will be included in the study. Both sexes are eligible to participate. Subjects must present a left bundle branch block (according to Strauss criteria) with indication of CRT class I or IIa according to clinical practice guidelines. A selection of the subjects will be made before inclusion following the selection clinical investigation plan. After confirming that the subject meets the inclusion criteria and does not meet the exclusion criteria, they will be included in the clinical study. Study population criteria: Inclusion criteria: age > 18 years; Class I or IIa indication for CRT according to current ESC or ACC/AHA/HRS guidelines; left bundle branch block according to Strauss criteria; Signed and dated informed consent. Exclusion criteria: Pregnant woman; Permanent or long-lasting atrial fibrillation; Previous CRT device; Previous PM/ICD with ventricular pacing > 10%; Conventional pacemaker indication; Nonspecific IVCD (intraventricular conduction delay); Unstable angina, acute Myocardial Infarction (MI), Coronary Artery Bypass Graft (CABG), Percutaneous Coronary Angioplasty (PCI), valve repair or replacement within 90 days prior enrollment; Indication for valve repair or replacement; Already included in another clinical study that could confoud the results of the present study; Life expectancy < 12 months. Device Implantation Procedure: CRT obtained by biventricular pacing vs. CRT obtained by stimulating the left branch area. Follow-up: Follow-up should be carried out with pre-established periodic clinical appointments 3, 6, and 12 months after hospital discharge. In the follow-up, routine examinations such as vital signs, electrocardiogram and echocardiogram (6 and 12 months) are recorded to check the evaluation of the reverse ventricular remodeling response and asynchrony parameters based on echocardiographic data. Statistical considerations: Once patients have signed the informed consent at baseline visit, patients will be considered as "Enrolled population" in the statistical analysis. The sample size is based on the primary endpoint: Improved Clinical Composite Score or ≥15% reduction in left ventricular end-systolic volume at 6 months follow-up, showing that LBBAP is non-inferior to BiV-CRT. Accounting for a global attrition rate of 10% and considering the block size for randomization, 176 patients shall be enrolled.

The CRT-P/CRT-D device and leads should be implanted according to the physician's standard practice. Only locally approved Medtronic CRT-P/CRT-D generators will be used during the study. It is strongly encouraged the designation of a single and experienced implanting physician at each center for the LBBAP implant procedures. During the implant procedure lead impedances, pacing and sensing parameters will be measured using a pacing system analyzer (PSA). For LBBAP, the Medtronic 3830 lead will be used. Acceptable LBBAP threshold should be <2,5V@0,5ms.

The CRT-P/CRT-D device and leads should be implanted according to the physician's manual provided with the devices. Only locally approved Medtronic CRT-P/CRT-D generators will be used during the study. Investigators may use any market approved right atrial (RA) pace/sense lead, right ventricular (RV) pacing/defibrillator lead with pace/sense capabilities and any market approved unipolar/bipolar/quadripolar LV pacing lead. During the implant procedure lead impedances, pacing and sensing parameters will be measured using a pacing system analyzer (PSA). The LV lead should be implanted at a lateral or posterolateral CS branch in a basal or mid ventricular position confirmed by ortogonal fluoroscopic views (RAO and LAO 40º). Acceptable LV pacing threshold should be <3V@0,5ms and phrenic nerve stimulation (PNS) margin should be >1V with respect to the pacing threshold

Standard BiV-CRT The CRT-P/CRT-D device and leads should be implanted according to the physician's manual provided with the devices. Only locally approved Medtronic CRT-P/CRT-D generators will be used during the study. The LV lead should be implanted at a lateral or posterolateral CS branch in a basal or mid ventricular position confirmed by ortogonal fluoroscopic views (RAO and LAO 40º). Acceptable LV pacing threshold should be <3V@0,5ms and phrenic nerve stimulation (PNS) margin should be >1V with respect to the pacing threshold. LBBAP-CRT The CRT-P/CRT-D device and leads should be implanted according to the physician's standard practice. Only locally approved Medtronic CRT-P/CRT-D generators will be used during the study. During the implant procedure lead impedances, pacing and sensing parameters will be measured using a pacing system analyzer (PSA). For LBBAP, the Medtronic 3830 lead will be used. Acceptable LBBAP threshold should be <2,5V@0,5ms

Positive CRT response will be defined either by an improved Clinical Composite Score or ≥15% reduction in left ventricular end-systolic volume

Assessed by the EuroQuol EQ-5D questionary evaluates the 5 different dimensions of quality of life (mobility, personal care, daily activities, pain/discomfort, and anxiety/depression)

Inclusion Criteria: age > 18 years Class I or IIa indication for CRT according to current ESC or ACC/AHA/HRS guidelines left bundle branch block according to Strauss criteria Signed and dated informed consent Exclusion Criteria: Pregnant woman Permanent or long-lasting atrial fibrillation Previous CRT device Previous PM/ICD with ventricular pacing > 10% Conventional pacemaker indication Nonspecific IVCD (intraventricular conduction delay) Unstable angina, acute Myocardial Infarction (MI), Coronary Artery Bypass Graft (CABG), Percutaneous Coronary Angioplasty (PCI), valve repair or replacement within 90 days prior enrollment Indication for valve repair or replacement Already included in another clinical study that could confoud the results of the present study Life expectancy < 12 months