Left Bundle Branch Pacing on Outcomes and Ventricular Remodeling in Biventricular CRT Nonresponders

NCT ID: NCT05760924

Last Updated: 2024-11-22

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-11-01
• Study Completion Date: 2028-09-01

Brief Summary

Heart failure (HF) is the most common nosology encountered in clinical practice. Its incidence and prevalence increase exponentially with increasing age and it is associated with the increased mortality, more frequent hospitalization and decreased quality of life. An initial approach to the treatment of HF patients with reduced left ventricular (LV) systolic function and left bundle branch block (LBBB) was implantation of device for cardiac resynchronization therapy using biventricular pacing. This has resulted in long-term clinical benefits such as improved quality of life, increased functional capacity, reduced HF hospitalizations and overall mortality. However, conventional cardiac resynchronization therapy (CRT) is effective in only 70% of patients. And the remaining 30% of patients are non-responders to conventional CRT. Cardiac conduction system pacing is currently a promising technique for these patients. Particularly, His bundle pacing (HBP) has been developed to achieve the same results. According to other studies HBP has shown greater improvement in hemodynamic parameters comparing with conventional biventricular CRT. But, nevertheless, there are significant clinical troubles with HBP, especially high pacing threshold. In this regard, in 2017, the left bundle branch pacing (LBBP) was developed, which demonstrated clinical advantages compared to conventional biventricular CRT. Also, since 2019, left bundle branch pacing-optimized CRT (LBBPO CRT) has been used in clinical practice. These methods have become an alternative to HBP due to the stimulation of LBB outside the blocking site, a stable pacing threshold and a narrow QRS complex duration on electrocardiogram. A series of case reports and observational studies have demonstrated the efficacy and safety of LBBP and LBBPO CRT in patients with CRT indications. However, it is not enough data about impact of CRT with LBBP and combined CRT with LBBP and LV pacing on myocardial remodeling, reducing mortality and complications. According to our hypothesis, CRT with LBBP and combined CRT with LBBP and LV pacing compared with conventional biventricular pacing will significantly improve the clinical outcomes and reverse myocardial remodeling in patients who are non-responders to biventricular CRT with HF, reduced LV ejection fraction and with indications to CRT devices with defibrillator function (CRT-D) or one of the CRT-D leads replacement.

Detailed Description

Recent advances in the cardiovascular pharmacological and cardiac device-based therapy have led to many benefits which improve the clinical condition, reduce morbidity, and increase survival in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) with biventricular pacing is a well-established method for the treatment of patients with the left bundle branch block (LBBB), cardiomyopathy of difference etiologies and HF with the reduced left ventricular ejection fraction (LVEF). Several prospective randomized trials have shown that biventricular CRT improves quality of life, improves exercise tolerance, reduces HF hospitalizations, and reduces all-cause mortality. The enthusiasm for this remarkable efficacy of CRT is limited by the fact that a proportion of patients have no benefits from this treatment. This category of patients is called nonresponder. These patients have no clinical and echocardiographic improvement with CRT. According to some studies, 30-50% of patients with biventricular CRT are non-responders.

The left bundle branch pacing (LBBP) was proposed in 2017 and demonstrated clinical benefits in patients with HF and LBBB, aiming to pace the proximal left bundle branch (LBB) along with LV myocardial capture. During selective pacing, only LBB is captured without the nearby myocardium, while with non-selective LBBP the septal myocardium is captured. LBBP with lead implanted slightly distal to the His bundle and screwed deep into the left ventricular (LV) septum is ideal for LBB capture. LBBP has emerged as an alternative to HBP due to pacing outside the blocking site, a stable pacing threshold, and a narrow QRS complex duration on electrocardiogram in patients with the bradycardia. In some clinical cases for the first time was demonstrated that LBBP could lead to complete correction of LBBB and improvement in cardiac function in patients with LBBB and HF. In another observational study it was shown that LBBP could be a new method of CRT. Subsequently, several case reports and observational studies have demonstrated the efficacy and safety of LBBP in patients with indications for CRT device implantation.

However, proximal LBBP is inherently limited in its ability to restore the physiological activation of LV lateral wall in patients with the conduction delay in the distal segment of LBB, Purkinje fibers or LV myocardium. Moreover, it is possible that in many patients with LBBP, only LV septal myocardial capture has been obtained, resulting in a small but potentially important non-physiological delay in LV lateral wall activation.

Conventional biventricular CRT based on right ventricular (RV) and LV pacing is also limited in its ability to fully restore physiological LV activation. Limitations of biventricular CRT may also include the potential desynchronizing effect of RV pacing , non-physiological epicardial LV pacing, latency and suboptimal position of LV lead (paraseptal or apical) due to anatomical features of the target vein, and the presence of LV myocardial scar. The inability of biventricular CRT to restore physiological activation may be expressed in QRS complex widening, rather than in its narrowing. That is observed in a third of patients with biventricular CRT and associated with a poor prognosis.

The combination of LBB and LV pacing may overcome some of the aforementioned limitations of both methods, providing a narrower QRS complex and more effective CRT, especially in difficult cases and in patients with more severe HF. Several studies have shown that combined CRT with LBB and LV pacing is feasible and safe and provides greater electrical resynchronization compared to biventricular CRT.

The above studies demonstrate that LBBP is clinically feasible in patients with HF and LBBB. However, there are still few data about CRT using LBBP in patients with HF and reduced LVEF. There are also only few studies on direct comparison of changes in clinical, speckle tracking echocardiography and other laboratory and instrumental parameters between patients with conventional biventricular CRT and CRT with LBBP.

CRT induces reverse remodeling of the affected heart, improves LV systolic and diastolic function and left heart filling pressure. The measurement of fibrosis and remodeling biomarkers representing the pattern of active processes in HF may be useful.

The relationship between changes in the biomarkers level and reverse remodeling process in patients with LBBP is currently poorly understood. And there are no publications regarding the correlation of the level of such biomarkers as mid-regional pro atrial natriuretic peptide (MR-proANP), growth differentiation factor (GDF)-15, galectin-3, suppression of tumorigenicity 2 (ST2), mid-regional pro adrenomedullin (MR-proADM) and aminoterminal propeptide of type I procollagen (PINP) with clinical and instrumental indicators of patients with LBBP in the available literature. This creates all the prerequisites for studying the association of the above biomarkers with the reverse remodeling process in patients with CRT using LBBP.

Conditions

Heart Failure; Left Bundle-Branch Block; Ischemic Cardiomyopathy; Non-ischemic Dilated Cardiomyopathy; Left Ventricular Dysfunction; Left Ventricle Remodeling

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cardiac Resynchronization Therapy with Biventricular Pacing

Patients who are non-responders to biventricular cardiac resynchronization therapy (CRT) with indications to CRT devices with defibrillator function (CRT-D) or CRT-D leads replacement. CRT-D or CRT-D leads replacement will be performed in this group of patients.

Group Type: ACTIVE_COMPARATOR

Cardiac Resynchronization Therapy Devices with Defibrillator Function (CRT-D) or CRT-D Leads Replacement

Intervention Type: DEVICE

The local anesthesia will be performed on the left/right subclavian area after prepping the skin. The device pocket will be opened, the old CRT-D will be removed and disconnected from the leads. The pacing threshold, intracardiac signal amplitude and impedance (pacing and shock) on the atrial, defibrillation and left ventricular leads will be performed. If there is a lead dysfunction, the new lead will be implanted. The new CRT-D will be connected with leads and placed back into the pocket. The pocket will be closed by separate stitches (2-4 suffice) using the resorbable braided suture.

Cardiac Resynchronization Therapy with Left Bundle Branch Pacing

Patients who are non-responders to biventricular cardiac resynchronization therapy (CRT) with indications to CRT devices with defibrillator function (CRT-D) or CRT-D leads replacement. CRT-D or CRT-D leads replacement with the new lead implantation to the left bundle branch and inactivation of conventional right and left ventricular pacing will be performed in this group of patients.

Group Type: EXPERIMENTAL

CRT-D or CRT-D Leads Replacement with New Lead Implantation to Left Bundle Branch and Inactivation of Conventional Right and Left Ventricular Pacing

Intervention Type: DEVICE

The local anesthesia will be performed on the left/right subclavian area after prepping the skin. The device pocket will be opened, the old CRT-D will be removed and disconnected from the leads. The pacing threshold, intracardiac signal amplitude and impedance (pacing and shock) on the atrial, defibrillation and left ventricular leads will be performed. If there is a lead dysfunction, the new lead will be implanted. The lead implantation to the left bundle branch (LBB) will be performed by transvenous approach and special delivery system. The new CRT-D will be connected with the leads (LBB pacing lead will be connected to defibrillation lead (DL) IS-1 connector of CRT-D and IS-1 tip of DL will be capped) and placed back into pocket. The pocket will be closed by separate stitches (2-4 suffice) using the resorbable braided suture. RV and LV pacing will be inactivated and only LBB pacing will be switched on.

Cardiac Resynchronization Therapy with Combined Left Bundle Branch and Left Ventricular Pacing

Patients who are non-responders to biventricular cardiac resynchronization therapy (CRT) with indications to CRT devices with defibrillator function (CRT-D) or CRT-D leads replacement. CRT-D or CRT-D leads replacement with the new lead implantation to the left bundle branch and inactivation of conventional right ventricular pacing will be performed in this group of patients.

Group Type: EXPERIMENTAL

CRT-D or CRT-D Leads Replacement with New Lead Implantation to Left Bundle Branch and Inactivation of Conventional Right Ventricular Pacing

Intervention Type: DEVICE

The local anesthesia will be performed on the left/right subclavian area after prepping the skin. The device pocket will be opened, the old CRT-D will be removed and disconnected from the leads. The pacing threshold, intracardiac signal amplitude and impedance (pacing and shock) on the atrial, defibrillation and left ventricular leads will be performed. If there is a lead dysfunction, the new lead will be implanted. The lead implantation to the left bundle branch (LBB) will be performed by transvenous approach and special delivery system. The new CRT-D will be connected with the leads (LBB pacing lead will be connected to defibrillation lead (DL) IS-1 connector of CRT-D and IS-1 tip of DL will be capped) and placed back into pocket. The pocket will be closed by separate stitches (2-4 suffice) using the resorbable braided suture. LBB and LV pacing will be switched on.

Interventions

Cardiac Resynchronization Therapy Devices with Defibrillator Function (CRT-D) or CRT-D Leads Replacement

The local anesthesia will be performed on the left/right subclavian area after prepping the skin. The device pocket will be opened, the old CRT-D will be removed and disconnected from the leads. The pacing threshold, intracardiac signal amplitude and impedance (pacing and shock) on the atrial, defibrillation and left ventricular leads will be performed. If there is a lead dysfunction, the new lead will be implanted. The new CRT-D will be connected with leads and placed back into the pocket. The pocket will be closed by separate stitches (2-4 suffice) using the resorbable braided suture.

Intervention Type: DEVICE

CRT-D or CRT-D Leads Replacement with New Lead Implantation to Left Bundle Branch and Inactivation of Conventional Right and Left Ventricular Pacing

The local anesthesia will be performed on the left/right subclavian area after prepping the skin. The device pocket will be opened, the old CRT-D will be removed and disconnected from the leads. The pacing threshold, intracardiac signal amplitude and impedance (pacing and shock) on the atrial, defibrillation and left ventricular leads will be performed. If there is a lead dysfunction, the new lead will be implanted. The lead implantation to the left bundle branch (LBB) will be performed by transvenous approach and special delivery system. The new CRT-D will be connected with the leads (LBB pacing lead will be connected to defibrillation lead (DL) IS-1 connector of CRT-D and IS-1 tip of DL will be capped) and placed back into pocket. The pocket will be closed by separate stitches (2-4 suffice) using the resorbable braided suture. RV and LV pacing will be inactivated and only LBB pacing will be switched on.

Intervention Type: DEVICE

CRT-D or CRT-D Leads Replacement with New Lead Implantation to Left Bundle Branch and Inactivation of Conventional Right Ventricular Pacing

The local anesthesia will be performed on the left/right subclavian area after prepping the skin. The device pocket will be opened, the old CRT-D will be removed and disconnected from the leads. The pacing threshold, intracardiac signal amplitude and impedance (pacing and shock) on the atrial, defibrillation and left ventricular leads will be performed. If there is a lead dysfunction, the new lead will be implanted. The lead implantation to the left bundle branch (LBB) will be performed by transvenous approach and special delivery system. The new CRT-D will be connected with the leads (LBB pacing lead will be connected to defibrillation lead (DL) IS-1 connector of CRT-D and IS-1 tip of DL will be capped) and placed back into pocket. The pocket will be closed by separate stitches (2-4 suffice) using the resorbable braided suture. LBB and LV pacing will be switched on.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

1. The patient is willing and able to comply with the protocol and has provided written informed consent;

2. Male or female patients aged 18 to 80 years;

3. Patients with ischemic or non-ischemic cardiomyopathy;

4. Symptomatic HF for at least 3 months prior to enrollment in the study;

5. New York Heart Association (NYHA) functional class HF ≥ II;

6. Patients who are non-responders to biventricular CRT with HF, reduced LVEF and CRT-D replacement or one of the CRT-D leads replacement indications (without LVEF increase ≥ 5% and/or without a left ventricle end-systolic volume decrease ≥ 15% after CRT-D implantation at least 1 year old);

7. Optimal HF medical therapy.

Exclusion Criteria

1. Coronary artery (CA) bypass grafting, balloon dilatation or CA stenting within 3 months prior to enrollment;

2. Acute myocardial infarction within 3 months prior to enrollment;

3. Acute coronary syndrome;

4. Patients with planned cardiovascular intervention (CA bypass grafting, balloon dilatation or CA stenting);

5. Patients listed for heart transplant;

6. Patients with implanted cardiac assist device;

7. Acute myocarditis;

8. Infiltrative myocardial disease;

9. Hypertrophic cardiomyopathy;

10. Severe primary stenosis or regurgitation of the mitral, tricuspid and aortic valves;

11. Woman currently pregnant or breastfeeding or not using reliable contraceptive measures during fertility age;

12. Mental or physical inability to participate in the study;

13. Patients unable or unwilling to cooperate within the study protocol;

14. Patients with rheumatic heart disease;

15. Mechanic tricuspid valve patients;

16. Patients with any serious medical condition that could interfere with this study;

17. Enrollment in another investigational drug or device study;

18. Patients not available for follow-up;

19. Patients with severe chronic kidney disease (estimated glomerular filtration rate ˂ 30 ml/min/1.73 m2);

20. Life expectancy ≤ 12 months;

21. Participation in another telemonitoring concept.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tomsk National Research Medical Center of the Russian Academy of Sciences

OTHER

Sponsor Role: lead

Responsible Party

Tariel A. Atabekov

Medical Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tariel A Atabekov, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences

Roman E Batalov, M.D.

Role: STUDY_DIRECTOR

Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences

Locations

Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences

Tomsk, , Russia

Site Status: RECRUITING

Countries

Russia

Central Contacts

Tariel A Atabekov, Ph.D.

Role: CONTACT

kgma1011@mail.ru

+79528002625

Facility Contacts

Tariel A Atabekov, Ph.D.

Role: primary

kgma1011@mail.ru

+79528002625

Other Identifiers

RESCUE

Identifier Type: -

Identifier Source: org_study_id