Left vs Left Randomized Clinical Trial

Study Overview
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Brief Summary
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The investigators aim to prospectively test the comparative effectiveness of His or Left bundle branch pacing in relation to patient centered outcomes (quality of life, physical activity, heart failure hospitalization, mortality) and comparative safety in relation to device-related complications and re-interventions (e.g., lead dislodgement, infection) relative to standard of care biventricular pacing in patients with heart failure due to left ventricular systolic dysfunction (LVEF≤50%) and with either a wide QRS (≥130 ms) or with/anticipated >40% pacing who are already receiving current standard heart failure pharmacological therapy.

Detailed Description
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In this prospective, randomized, multi-center clinical trial, the investigators aim to prospectively evaluate the comparative effectiveness His or Left bundle branch pacing (His/LBBP) vs. biventricular pacing (BiVP) in patients with heart failure due to left ventricular systolic dysfunction (LVEF≤50%) and with either a wide QRS (≥130 ms) or with/anticipated >40% pacing who are already receiving current standard heart failure pharmacological therapy by assessing all cause death and heart failure hospitalization at the end of the study. Additional formal secondary objectives include evaluation disease-specific quality and psychological adjustment changes at 1 year after device implant and evaluation of a composite of death of any cause or heart failure hospitalization or more >15% increase in the left ventricular end-systolic volume index at the end of the study.

Official Title
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Cardiac Resynchronization Therapy Using His/Left Bundle Branch Pacing vs Biventricular Pacing With a Left Ventricular Epicardial Lead in Patients With Heart Failure (HF) With Left Ventricular Ejection Fraction (LVEF)≤50% and With Either a Wide QRS Complex (>130 ms) or With/Anticipated >40% Pacing Randomized Clinical Trial

Conditions
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Heart Failure, Heart Failure With Reduced Ejection Fraction, AV Block, LBBB, RBBB, Intraventricular Conduction Delay, Pacing-Induced Cardiomyopathy

Intervention / Treatment
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* Device: His/LBBP
* Device: BiVP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 18 years of age or older. A LVEF ≤ 50% within 6 months prior to enrollment. Resting QRS duration ≥130 ms as evidenced by a historical 12-lead ECG prior to enrollment OR anticipated right ventricular pacing >40% OR device in place with right ventricular pacing > 40%. Are optimized on HF guideline directed medical therapy according to current HF published guidelines. Exclusion Criteria: Women who are pregnant, lactating, or plan to become pregnant during the course of the trial. Participants with angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary, intervention in the next three (3) months. Enzyme-positive myocardial infarction within the past three (3) months prior to enrollment. Coronary artery bypass graft surgery or percutaneous coronary intervention (balloon and/or stent angioplasty) within the past three (3) months prior to enrollment. Reversible non-ischemic cardiomyopathy (e.g., acute viral myocarditis). Participants with Chagas disease, cardiac sarcoidosis or amyloidosis. Expected to receive left ventricular assist device or heart transplantation within 6 months. Participants with severe valvular disease (e.g., aortic stenosis). Have a life expectancy of less than 12 months. Participants with irreversible brain damage from preexisting cerebral disease. Participants with a contrast dye allergy unable or unwilling to undergo pretreatment with steroids and/or diphenhydramine. Participants participating in any other interventional cardiovascular clinical trial. Participants who would be unable to return for follow-up visits due to the distance from the clinic. Participants who do not anticipate being a resident of the area for the scheduled duration of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: His/Left Bundle Branch Pacing (His/LBBP)<br>Patients with LVEF≤35% at entry will receive a His/LBB defibrillator which includes implantation of three leads, an endocardial right atrial lead, an endocardial right ventricular ICD lead, and an endocardial His-bundle or left bundle branch pacing lead directly pacing the intrinsic conduction system. Patients with LVEF 36-50% at entry will receive His/LBB pacemaker which includes implantation of two leads, an endocardial right atrial lead, and an endocardial His-bundle or left bundle branch pacing lead directly pacing the intrinsic conduction system. | Device: His/LBBP<br>* Pacing at the level His-Bundle or left bundle branch is used to correct the underlying conduction abnormality, resulting in a faster and more homogeneous activation of the heart pacing directly via the intrinsic conduction system of the heart accompanied by a right atrial endocardial lead and a right ventricular defibrillator endocardial lead for LVEF≤35% and by a right atrial endocardial lead for LVEF 36-50%.<br>|
| Active Comparator: Biventricular Pacing (BiVP)<br>Patients with LVEF≤35% at entry will receive a BiV defibrillator which includes implantation of three leads, an endocardial right atrial lead, an endocardial right ventricular ICD lead, and and an epicardial left ventricular lead implanted in a branch of the coronary sinus. Patients with LVEF 36-50% at entry will receive BiV pacemaker which includes implantation of three leads, an endocardial right atrial lead, an endocardial right ventricular pacing lead, and and an epicardial left ventricular lead implanted in a branch of the coronary sinus. | Device: BiVP<br>* Biventricular pacing has been shown to improve outcomes by delivering synchronized electrical stimuli to the right and left ventricles utilizing an an endocardial right atrial lead, an endocardial right ventricular lead, and an epicardial left ventricular lead implanted in a branch of the coronary sinus. For LVEF≤35% a biventricular pacemaker-defibrillator will be implanted while for LVEF 36-50% a biventricular pacemaker will be implanted.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A combined clinical endpoint of all-cause mortality and hospitalization for heart failure | The primary efficacy outcome will be described using Kaplan-Meier freedom from event curves over time, with event-free survival compared between assigned treatment arms using a logrank test, stratified by levels of the two factors (LVEF (≤35% vs. 36 to 50%) and conduction abnormality (LBBB vs non-LBBB)) used for randomization. | 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess change in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at 12 months | Assess change in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) item score measured before and at 12 months after implant. | 12 months | 
| Change in composite endpoint comprised of death, first hospitalization for worsening HF and left ventricular end systolic volume index (LVESVi) at 5.5 years | Secondary endpoint measured from all cause death, first hospitalization for heart failure and echocardiography on left ventricular end-systolic volume index (LVESVi) in the His/LBBP vs. BIV-BiVP arm | 5.5 years | 
| Death from any cause at 5.5 years | Secondary endpoint measured from all cause death | 5.5 years | 
| Death from any cardiovascular cause at 5.5 years | Secondary endpoint measured from death due to cardiovascular causes | 5.5 years | 
| Hospitalization for heart failure at 5.5 years | Secondary endpoint measured from first hospitalization for heart failure | 5.5 years | 
| Cardiovascular hospitalization at 5.5 years | Secondary endpoint measured from first hospitalization for cardiovascular disease | 5.5 years | 
| Change in NYHA Classification at 12 months | Secondary endpoint measured from New York Heart Association class | 12 months | 
| Change in Six Minute Walk Test performance at 12 months | Secondary endpoint measured from Six Minute Walk Test | 12 months |