Clinical trial NCT05572957: LBBP as Initial Therapy in Patients With Non-ischemic Heart Failure and LBBB
Official title: Left Bundle Branch Pacing as Initial Therapy in Patients With Non-ischemic Heart Failure and Left Bundle Branch Block (LIT-HF Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Non-ischemic Cardiomyopathy
Heart Failure
Left Bundle-Branch Block
Keywords: Non-ischemic Cardiomyopathy
Heart Failure
Left Bundle-Branch Block
Guideline-Directed Medical Therapy
Left Bundle Branch Pacing
Implantable Cardioverter-Defibrillator
Cardiac Resynchronization Therapy
Lead sponsor: The First Affiliated Hospital with Nanjing Medical University
Sponsor class: OTHER
Collaborators: name: The First Affiliated Hospital of Dalian Medical University
name: West China Hospital
name: First Affiliated Hospital of Wenzhou Medical University
name: Fujian Medical University Union Hospital
name: Chinese Academy of Medical Sciences, Fuwai Hospital
First posted: 2022-10-10
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The present study will recruit 50 symptomatic non-ischemic cardiomyopathy (NICM) patients with left ventricular ejection fraction (LVEF) below 35% and complete left bundle branch block (CLBBB), who have not received complete guideline-directed medical therapy (GDMT). Each patient was randomized to 2 groups, GDMT or left bundle branch pacing combined with GDMT (LBBP+GDMT) as initial therapy and was followed up for 2 phases: 0-6 months (phase I), 7-18 months (phase II). The primary objective is to compare the LVEF change , syncope and malignant ventricular arrhythmias between GDMT group and LBBP+GDMT group, and to observe which strategy will significantly reduce the percentage of recommendations for an implantable cardioverter-defibrillator (ICD) during phase I study. The second outcome measures including health economics, echocardiography parameters\[left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV)\], N-terminal pro B-type natriuretic peptide (NT-proBNP) level, New York Heart Association (NYHA) class, 6-minute walking distance (6MWD), quality of life score(QOL) and incidence of clinical adverse events.

Detailed description: Therapies currently approved to treat heart failure with reduced ejection fraction (HFrEF) have generally shown significant benefit on morbidity and mortality, resulting in strong recommendations in treatment guidelines. Four standard drugs classes, composed of beta-blockers, angiotensin-converting enzyme-inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor (ACE-I/ARB/ARNI), mineralocorticoid receptor antagonist (MRA) and sodium-glucose co-transporter 2 inhibitor (SGLT2i), have already been standard background therapy in HFrEF. Cardiac resynchronization therapy with pacemaker/Cardiac resynchronization therapy with defibrillation (CRT-P/CRT-D) is an established treatment to HF patients, especially in LVEF ≤35%, sinus rhythm, CLBBB with a QRS duration (QRSd) ≥150 ms, and symptoms on 3-6 months of GDMT. Both the 2021 ESC and the 2022 AHA/ACC/HFSA guidelines for HF included LVEF≤35% after 3-6 months of GDMT as a strong indication for ICD implantation in non-ischemic heart disease.

The traditional biventricular pacing (BiVP) could correct the cardiac dyssynchrony to improve clinical symptoms and reduce all-cause mortality in HF. However, almost 30%-40% of patients with successful implantation show no response and BiVP just corrects the mechanical dyssynchrony caused by LBBB not corrects the LBBB. His Purkinje conduction system pacing (HPCSP) technology has made significant progress in recent five years. His bundle pacing (HBP) and left bundle branch pacing(LBBP) can correct LBBB and achieve physiological cardiac resynchronization only by ordinary single-chamber or dual-chamber pacemaker. LBBP has been reported to produce stable pacing thresholds, adequately sensed R-wave amplitude, and higher likelihood to correct LBBB by pacing more distal to the site of conduction block compared with HBP. The feasibility and efficacy of LBBP for CRT in HF patients with LBBB was demonstrated by previous observational studies showing that LBBP-CRT achieves a narrower QRSd, higher percentage of super responders, and lower pacing thresholds than BiVP-CRT. The LBBP-RESYNC study showed that LBBP-CRT demonstrated greater LVEF improvement than BiVP-CRT in HF patients with NICM and LBBB.

It remains unclear as to the following questions: 1. After 3-6 months of GDMT, what is the percentage of patients with LVEFs improvement from ≤35% to \>35% in HFrEF patients with NICM and CLBBB, and what are the absolute values of the increase in LVEFs; 2. How is the long-term prognosis of those patients with LVEF increased to \>35% after GDMT. Whether these patients still need an ICD/CRT-D since they do not fall within the recommendations for primary prevention of sudden cardiac death (SCD); 3. What are the differences of LVEFs changes if LBBP is added to the medical treatment at the beginning.

There are to date no randomized studies comparing GDMT and LBBP combined with GDMT (LBBP+GDMT) as the initial therapy in HFrEF patients with NICM and CLBBB. The purpose of this study is to compare the therapeutic effects of LBBP+GDMT and GDMT on LV function and clinical endpoints in such patients. The present study will randomize about 50 patients in multiple centres to LBBP+GDMT group or GDMT group.

The study is divided into two phases:

Phase I (0-6 months) : Patients are randomly assigned to either the drug therapy group (GDMT group) or the experimental group (LBBP+GDMT group). In GDMT group at 3-month follow-up, CRT-P/CRT-D will be implanted if LVEF is still ≤35% with absolute increase \<5% from baseline or ventricular tachycardia/ventricular fibrillation (VT/VF) events are recorded; otherwise, GDMT will be continued when LVEF \>35% or LVEF≤35% but absolute increase \>5% from baseline and no VT/VF event is observed. Patients in LBBP+GDMT group are directly treated with LBBP and GDMT after enrollment. The proportions of patients with LVEF ≤35% or VT/VF events in LBBP+GDMT group are assessed at 3-month and 6-month. The percentages of patients with LVEF ≤35% or VT/VF events in GDMT group are also assessed after 3 and 6 months as well.

Phase II (7-18 months): Patients in each group are followed up regularly (every 3-6 months, with mandatory at 12 and 18 months, with additional as appropriate) to assess the need for CRT-P/CRT-D/ICD when EF decreasing to ≤35%, syncope, or VT/VF events occurred.

Eligibility criteria: Inclusion Criteria:

1. Non-ischemic cardiomyopathy with LVEF≤35% as assessed by echocardiography, NYHA class II-III, and less than 3 months of optimized (complete) GDMT\*;
2. Sinus rhythm (paroxysmal atrial fibrillation may be present) with complete left bundle branch block meeting STRAUSS's criteria;
3. Between the ages of 18 and 80;
4. With informed consent signed.

Exclusion Criteria:

1. After mechanical tricuspid valve replacement;
2. Ischemic cardiomyopathy;
3. Persistent AF without AV node ablation;
4. History of unexplained syncope or indications for pacemaker implantation;
5. Indications for ICD implantation such as a history of sustained ventricular tachycardia or sudden cardiac arrest;
6. Unstable angina, acute MI, CABG or PCI within the past 3 months;
7. Enrollment in any other study；
8. A life expectancy of less than 12 months;
9. Pregnant or with child-bearing potential;
10. History of heart transplantation.

Primary outcomes:
measure: Proportion of patients requiring ICD implantation for prevention of sudden cardiac death(SCD)
timeFrame: 6-month follow-up
Secondary outcomes:
measure: Health economics
timeFrame: 3-month, 6-month, 12-month, and 18-month follow-up
measure: Changes in LVEF
timeFrame: Baseline; 3-month, 6-month, 12-month, and 18-month follow-up
measure: Changes in LVESV
timeFrame: Baseline; 3-month, 6-month, 12-month, and 18-month follow-up
measure: Changes in LVEDV
timeFrame: Baseline; 3-month, 6-month, 12-month, and 18-month follow-up
measure: Changes in concentration of NT-proBNP in blood between baseline and follow-up
timeFrame: Baseline; 3-month, 6-month, 12-month, and 18-month follow-up
measure: Changes in New York Heart Association Heart Function Classification between baseline and follow-up
timeFrame: Baseline; 3-month, 6-month, 12-month, and 18-month follow-up
measure: Change in Quality Of Life Questionnaire score between baseline and follow-up
timeFrame: Baseline; 3-month, 6-month, 12-month, and 18-month follow-up
measure: Incidence of clinical adverse events
timeFrame: Baseline; 3-month, 6-month, 12-month, and 18-month follow-up
Other outcomes:
Locations:
city: Beijing
country: China
facility: Fuwai Hospital, Chinese Academy of Medical Sciences
state: Beijing
city: Fuzhou
country: China
facility: Fujian Medical University Union Hospital
state: Fujian
city: Nanjing
country: China
facility: The First Affiliated Hospital with Nanjing Medical University
state: Jiangsu
city: Dalian
country: China
facility: The First Affiliated Hospital of Dalian Medical University
state: Liaoning
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
Study officials:
affiliation: First Affiliated Hospital, Nanjing Medical University
name: Jiangang Zou, MD,Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: First Affiliated Hospital, Nanjing Medical University
name: Xiaofeng Hou, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Dalian Medical University
name: Yunlong Xia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The First Affiliated Hospital of Dalian Medical University
name: Yingxue Dong, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Wang Y, Zhu H, Hou X, Wang Z, Zou F, Qian Z, Wei Y, Wang X, Zhang L, Li X, Liu Z, Xue S, Qin C, Zeng J, Li H, Wu H, Ma H, Ellenbogen KA, Gold MR, Fan X, Zou J; LBBP-RESYNC Investigators. Randomized Trial of Left Bundle Branch vs Biventricular Pacing for Cardiac Resynchronization Therapy. J Am Coll Cardiol. 2022 Sep 27;80(13):1205-1216. doi: 10.1016/j.jacc.2022.07.019.
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citation: Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW; ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 3;145(18):e895-e1032. doi: 10.1161/CIR.0000000000001063. Epub 2022 Apr 1.