His-SYNC: His Bundle Pacing Versus Coronary Sinus Pacing for Cardiac Resynchronization Therapy

• Sponsor: University of Chicago (Other)
• Overall Status: Completed
• CT.gov ID: NCT02700425
• Collaborator: University of California, Los Angeles (Other), Northwestern University (Other), Rush University Medical Center (Other), Geisinger Clinic (Other), Indiana University (Other), Edward Hospital (Other), Baptist Health, Louisville (Other)
• Enrollment: 41
• Locations: 8
• Arms: 2
• Actual Duration (Months): 50.5
• Patients Per Site: 5.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The goal of this study is to compare the effectiveness of pacing from a physiologic His bundle (HB) lead position versus with the standard coronary sinus (CS) lead position in subjects with heart failure undergoing cardiac resynchronization therapy (CRT). While placement of left ventricular leads via the coronary sinus has anatomic limitations, we hypothesis that the achievement of QRS narrowing with His bundle capture will be superior for improving systolic function by echocardiographic indices (ejection fraction and strain) and quality of life and decreased rehospitalization and mortality.

Condition or Disease	Intervention/Treatment	Phase
Congestive Heart Failure	Device: CRT Pacemaker	N/A

Detailed Description

This is a randomized, single-blinded study of 40 patients to a strategy of HB pacing versus CS pacing, and remain blinded to their treatment allocation. Both treatment options use standard-of-care, FDA-approved devices. The distinction is only in the allocation toward HB pacing and CS pacing. Treating physicians will be aware of assignment in order to facilitate routine device follow-up. Echocardiographic and electrocardiographic evaluation will also be performed in a blinded manner.

Cross-over is permitted between treatment group allocation if:

• CS lead cannot be placed due to difficult cannulation of the CS, limited branches at the posterolateral or lateral wall, or phrenic nerve capture. These subjects may then cross-over to HB pacing.

• HB pacing subjects may cross-over if HB lead cannot be positioned with adequate stability and reasonable pacing output, or if QRS width does not narrow by at least 20% or to a QRS width of ≤ 130 msec.

Implant procedure will be per routine percutaneous access, as is standard for pacemaker and ICDs. All subjects will receive an FDA-approved cardiac resynchronization therapy pacemaker or defibrillator device, as per standard of care outlined for the subject. In order to facilitate optimal lead placement, arterial access for levo-phase CS angiography and/or LV septal mapping to characterize site of bundle-branch block may also be performed, at the discretion of the implanting physician per his/her standard practice.

Follow-up will be performed at 2 weeks post-implant for incision check and device interrogation as is standard of care. In addition, routine device and clinical follow-up will be scheduled at 1, 3, 6, and 12 months. Electrocardiography (ECG) will be performed pre-implant, prior to hospital discharge, at 3 months, 6 months, and 12 months. Echocardiography will be performed pre-implant and 6 months to evaluate for change in LVEF, chamber dimension, and wall motion with strain imaging as is standard of care in the treatment of patients with advanced heart failure. NYHA functional class and quality of life (utilizing the Kansas City Cardiomyopathy Questionnaire) will be assessed pre-implant and at 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: His Bundle Pacing Versus Coronary Sinus Pacing for Cardiac Resynchronization Therapy
• Actual Study Start Date: May 17, 2016
• Actual Primary Completion Date: Jul 31, 2020
• Actual Study Completion Date: Jul 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: His Bundle Pacing Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing.	Device: CRT Pacemaker; Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Active Comparator: Coronary Sinus Pacing Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical.	Device: CRT Pacemaker; Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.

Outcome Measures

Primary Outcome Measures

1. Change in Left Ventricular Ejection Fraction (LVEF) [baseline and 6 months]

   Change in left ventricular ejection fraction (LVEF) as measured by echocardiography in a blinded core lab.

2. Change in QRS Duration [baseline and 12 months]

   Change in QRS duration as measured by electrocardiography

3. Time to First Cardiovascular Hospitalization or Death [Through study completion, an average of 12 months.]

   Time to first cardiovascular hospitalization or death in months

Secondary Outcome Measures

1. New York Heart Association (NYHA) Functional Class Change [baseline, 6 months, and 12 months]

   New York Heart Association (NYHA) functional class change for baseline, 6 months, and 12 months. NYHA class determines the functional status of the patient. There are classes I-IV. Class I is no symptoms or limitation of physical activity, II is slight limitation of physical activity but comfortable at rest, III marked limitation of physical activity, and IV is unable to carry any physical activity without discomfort, heart failure symptoms at rest, and discomfort increases with any physical activity as described the American Heart Association (AHA).

2. Quality of Life Change by Kansas City Questionnaire (KCCQ) [baseline and 12 months]

   Quality of life change as measured by Kansas City Questionnaire (KCCQ) is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from minimum of 0-100 (maximum); higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.

3. Time to First Cardiovascular Rehospitalization [Through study completion, an average of 12 months]

   Time to first cardiovascular rehospitalization in 12 months

4. Time to First Treated Ventricular Arrhythmia/Ventricular Tachycardia (VT/VF) [Through study completion, an average of 12 months]

   Time to first treated ventricular arrhythmia/ventricular tachycardia (VT/VF) in 12 months

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients at least 18 years of age

• LV systolic dysfunction with LVEF ≤ 35%

• Evidence of intraventricular conduction delay with QRS duration > 120 msec

• NYHA Class II, III, and ambulatory Class IV heart failure with either ischemic or nonischemic cardiomyopathy and patients with NYHA Class I symptoms and ischemic cardiomyopathy

• Left ventricular ejection fraction (LVEF) ≤ 35%, sinus rhythm (SR), left bundle-branch block (LBBB) morphology, and QRS duration ≥ 150 msec, and NYHA Class II, III, or ambulatory Class IV patients on goal-directed medical therapy (GDMT) [Class I]

• LVEF ≤ 35%, SR with LBBB with QRS 120-149 msec on GDMT [Class IIa]

• LVEF ≤ 35%, SR with non-LBBB with QRS ≥ 150 msec on GDMT [Class IIa]

• LVEF ≤ 35%, in AF if medication or AV nodal ablation will allow near 100% pacing [Class IIa]

• LVEF ≤ 35% undergoing new or replacement device with anticipated >40% ventricular pacing on GDMT [Class IIa]

• LVEF ≤ 30%, ischemic etiology of HF, SR with LBBB ≥ 150 msec and NYHA Class I symptoms on GDMT [Class IIb]

• LVEF ≤ 35%, SR with non-LBBB with QRS 120-149 msec, NYHA Class III/ambulatory Class IV HF on GDMT [Class IIb] LVEF ≤ 35%, SR with non-LBBB with QRS ≥ 150 msec, NYHA Class II HF on GDMT [Class IIb]

Exclusion Criteria:

• Existing CRT device

• Inability of patient capacity to provide consent for themselves either due to medical or psychiatric comorbidity

• Pregnancy

• Participation in other trials

• Difficulty with follow-up

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of California, Los Angeles	Los Angeles	California	United States	90095
2	Northwestern University	Chicago	Illinois	United States	60611
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	The University of Chicago	Chicago	Illinois	United States	60637
5	Edward Hospital	Naperville	Illinois	United States	60540
6	Indiana University	Indianapolis	Indiana	United States	46202
7	Baptist Health Louisville	Louisville	Kentucky	United States	40207
8	Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711

Sponsors and Collaborators

• University of Chicago
• University of California, Los Angeles
• Northwestern University
• Rush University Medical Center
• Geisinger Clinic
• Indiana University
• Edward Hospital
• Baptist Health, Louisville

Investigators

• Principal Investigator: Roderick Tung, MD, University of Chicago
• Principal Investigator: Gaurav A. Upadhyay, MD, University of Chicago

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 9, 2019

More Information

Publications

None provided.

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT02700425
• Other Study ID Numbers: IRB15-1728
• First Posted: Mar 7, 2016
• Last Update Posted: Sep 5, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Keywords provided by University of Chicago: Wide QRS; Ventricular Dyssynchrony
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Period Title: Overall Study
STARTED	21	20
COMPLETED	21	19
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing	Total
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Total of all reporting groups
Overall Participants	21	19	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (11.4)	63.8 (14.1)	64.6 (12.6)
Sex: Female, Male (Count of Participants)
Female	7 33.3%	8 42.1%	15 37.5%
Male	14 66.7%	11 57.9%	25 62.5%
Race/Ethnicity, Customized (Count of Participants)
White	13 61.9%	12 63.2%	25 62.5%
African-American	7 33.3%	5 26.3%	12 30%
Hispanic	1 4.8%	1 5.3%	2 5%
Other	0 0%	1 5.3%	1 2.5%
Region of Enrollment (participants) [Number]
United States	21 100%	19 100%	40 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.4 (9.6)	166.5 (13.3)	169.6 (11.7)
Weight (kg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg]	88.0	78.0	83.5
Body Mass Index (BMI) (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	29.4	29.4	29.4
Hypertension (HTN) (Count of Participants)
Hypertension	16 76.2%	14 73.7%	30 75%
No Hypertension	5 23.8%	5 26.3%	10 25%
Coronary Artery Disease (CAD) (Count of Participants)
CAD	13 61.9%	13 68.4%	26 65%
No CAD	8 38.1%	6 31.6%	14 35%
History of Coronary-Artery Bypass Graft (CABG) (Count of Participants)
CABG	5 23.8%	2 10.5%	7 17.5%
No CABG	16 76.2%	17 89.5%	33 82.5%
History of Atrial Fibrillation (AF) (Count of Participants)
AF	8 38.1%	5 26.3%	13 32.5%
No AF	13 61.9%	14 73.7%	27 67.5%
Chronic Obstructive Pulmonary Disease (COPD) (Count of Participants)
COPD	4 19%	6 31.6%	10 25%
No COPD	17 81%	13 68.4%	30 75%
Diabetes Mellitus Type 2 (DM2) (Count of Participants)
DM	11 52.4%	8 42.1%	19 47.5%
No DM	10 47.6%	11 57.9%	21 52.5%
Chronic Kidney Disease (CKD) (Count of Participants)
CKD	10 47.6%	9 47.4%	19 47.5%
No CKD	11 52.4%	10 52.6%	21 52.5%
End-Stage Renal Disease (ESRD) (Count of Participants)
ESRD	1 4.8%	2 10.5%	3 7.5%
No ESRD	19 90.5%	17 89.5%	36 90%
Unknown	1 4.8%	0 0%	1 2.5%
New York Heart Association (NYHA) Class (stages) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [stages]	3.0	2.5	3.0
Beta-blocker (BB) (Count of Participants)
BB	21 100%	18 94.7%	39 97.5%
No BB	0 0%	1 5.3%	1 2.5%
Angiotensin-converting enzyme inhibitor (ACE-I) (Count of Participants)
ACE-I	5 23.8%	6 31.6%	11 27.5%
No ACE-I	16 76.2%	13 68.4%	29 72.5%
Angiotensin II Receptor Blocker (ARB) (Count of Participants)
ARB	5 23.8%	5 26.3%	10 25%
No ARB	16 76.2%	14 73.7%	30 75%
Angiotensin II Recptor Blocker (ARB)/neprilysin inhibitor (Count of Participants)
ARB/neprilysin inhibitor	5 23.8%	4 21.1%	9 22.5%
No ARB/neprilysin inhibitor	16 76.2%	15 78.9%	31 77.5%
Amiodarone (Count of Participants)
Amiodarone	4 19%	4 21.1%	8 20%
No Amiodarone	17 81%	15 78.9%	32 80%
Digoxin (Count of Participants)
Digoxin	2 9.5%	4 21.1%	6 15%
No Digoxin	19 90.5%	15 78.9%	34 85%
Spironolactone (Count of Participants)
Spironolactone	7 33.3%	7 36.8%	14 35%
No Spironolactone	14 66.7%	12 63.2%	26 65%
PR interval (PR) (ms) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ms]	186	184	186
QRS interval (QRS) (seconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [seconds]	172 (16)	165 (18)	168 (18)
QTc (ms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ms]	484 (48)	478 (35)	481 (42)
Left Ventricular end-diastolic volume (LVEDV) (mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL]	220	190	201
Left Ventricular End-Systolic Volume (LVESV) (mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL]	165	126	148
Left Ventricular Ejection Fraction (LVEF) (percent of ejection fraction) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percent of ejection fraction]	26.3	30.5	27.8

Outcome Measures

1. Primary Outcome

Title	Change in Left Ventricular Ejection Fraction (LVEF)
Description	Change in left ventricular ejection fraction (LVEF) as measured by echocardiography in a blinded core lab.
Time Frame	baseline and 6 months

Outcome Measure Data

Analysis Population Description

All analyses shown are intention-to-treat. Of note, 5 patients from Coronary Sinus Pacing crossed over to His Bundle Pacing, but were analyzed Coronary Sinus Pacing. Likewise, 10 patients from His Bundle Pacing crossed over to the Coronary Sinus Pacing, but they were analyzed as His Bundle Pacing under intention-to-treat analysis.

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Measure Participants	21	19
Baseline	26.3	30.5
6-months	31.9	34.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Coronary Sinus Pacing
	Comments	The sample size was estimated based on the primary endpoint of echocardiographic response to test the hypothesis that an absolute 10% greater improvement in LVEF would be observed with His Bundle Pacing compared to Coronary Sinus Pacing, with a significance level of 0.05 and a power of 0.80. Primary outcome was presented at baseline and 6-months as median (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with the Wilcoxon signed rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value was not adjusted for multiple comparisons. Test was two-tailed, considered statistically significant with a p-value <0.05, and conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC) and STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments	Wilcoxon signed rank test

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	His Bundle Pacing
	Comments	The sample size was estimated based on the primary endpoint of echocardiographic response to test the hypothesis that an absolute 10% greater improvement in LVEF would be observed with His Bundle Pacing compared to Coronary Sinus Pacing, with a significance level of 0.05 and a power of 0.80. Primary outcome was presented at baseline and 6-months as median (interquartile range) based upon the Shapiro-Wilks test of normality, and then analyzed with the Wilcoxon signed rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value was not adjusted for multiple comparisons. Test was two-tailed, considered statistically significant with a p-value <0.05, and conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC) and STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments	Wilcoxon signed rank test

2. Primary Outcome

Title	Change in QRS Duration
Description	Change in QRS duration as measured by electrocardiography
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

All analyses shown are intention-to-treat. Of note, 5 patients from Coronary Sinus Pacing crossed over to His Bundle Pacing, but were analyzed Coronary Sinus Pacing. Likewise, 10 patients from His Bundle Pacing crossed over to the Coronary Sinus Pacing, but they were analyzed as His Bundle Pacing under intention-to-treat analysis.

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Measure Participants	21	19
Baseline	172 (16)	165 (19)
1-year	144 (30)	152 (30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Coronary Sinus Pacing
	Comments	Primary outcome was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments	paired t-test
Statistical Test of Hypothesis	p-Value	0.002
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	His Bundle Pacing
	Comments	Primary outcome of His Bundle Pacing was presented at baseline and 1-year as means +/- standard deviations based upon the Shapiro-Wilks test of normality, and then analyzed with paired t-tests.
	Type of Statistical Test	Other
	Comments	paired t-test
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	t-test, 2 sided
	Comments

3. Primary Outcome

Title	Time to First Cardiovascular Hospitalization or Death
Description	Time to first cardiovascular hospitalization or death in months
Time Frame	Through study completion, an average of 12 months.

Outcome Measure Data

Analysis Population Description

All analyses shown are intention-to-treat. Of note, 5 patients from Coronary Sinus Pacing crossed over to His Bundle Pacing, but were analyzed Coronary Sinus Pacing. Likewise, 10 patients from His Bundle Pacing crossed over to the Coronary Sinus Pacing, but they were analyzed as His Bundle Pacing under intention-to-treat analysis.

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Measure Participants	21	19
Median (Inter-Quartile Range) [months]	10.63	11.58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	His Bundle Pacing, Coronary Sinus Pacing
	Comments	Primary outcome of time to first cardiovascular hospitalization or death by His Bundle Pacing compared to Coronary Sinus Pacing presented median and interquartile range in years based upon the Shapiro-Wilks test of normality, and then analyzed with a log rank test.
	Type of Statistical Test	Other
	Comments	Log rank test of a survival analysis
Statistical Test of Hypothesis	p-Value	0.62
	Comments	P-value did not need to be adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	New York Heart Association (NYHA) Functional Class Change
Description	New York Heart Association (NYHA) functional class change for baseline, 6 months, and 12 months. NYHA class determines the functional status of the patient. There are classes I-IV. Class I is no symptoms or limitation of physical activity, II is slight limitation of physical activity but comfortable at rest, III marked limitation of physical activity, and IV is unable to carry any physical activity without discomfort, heart failure symptoms at rest, and discomfort increases with any physical activity as described the American Heart Association (AHA).
Time Frame	baseline, 6 months, and 12 months

Outcome Measure Data

Analysis Population Description

All analyses shown are intention-to-treat. Of note, 5 patients from Coronary Sinus Pacing crossed over to His Bundle Pacing, but were analyzed Coronary Sinus Pacing. Likewise, 10 patients from His Bundle Pacing crossed over to the Coronary Sinus Pacing, but they were analyzed as His Bundle Pacing under intention-to-treat analysis. NYHA class determines the functional status of the patient. There are classes I-IV. Class I is no symptoms and IV is symptoms at rest.

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Measure Participants	21	19
Baseline	3.0	2.5
6-Months	2.0	2.0
1-Year	3.0	2.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Coronary Sinus Pacing
	Comments	NYHA functional class of Coronary Sinus Pacing arm was presented at baseline as medians (interquartile ranges) based upon the Shapiro-Wilks test of normality, and then analyzed with a Wilcoxon sign rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments	Wilcoxon sign rank test

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	His Bundle Pacing
	Comments	NYHA functional class of the His Bundle Pacing arm was presented at baseline and 12 months as medians (interquartile ranges) based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon sign rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments	Wilcoxon sign rank test

5. Secondary Outcome

Title	Quality of Life Change by Kansas City Questionnaire (KCCQ)
Description	Quality of life change as measured by Kansas City Questionnaire (KCCQ) is a 23-item instrument that is self-administered. KCCQ measures physical function, symptoms (specifically frequency, severity, and recent change), social function, self-efficacy and knowledge, and quality of life. Subscales and Total Score range from minimum of 0-100 (maximum); higher scores show better health status. Developed and validated by Dr. John Spertus,MD of University of Missouri-Kansas City.
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

All analyses shown are intention-to-treat. Of note, 5 patients from Coronary Sinus Pacing crossed over to His Bundle Pacing, but were analyzed Coronary Sinus Pacing. Likewise, 10 patients from His Bundle Pacing crossed over to the Coronary Sinus Pacing, but they were analyzed as His Bundle Pacing under intention-to-treat analysis.

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Measure Participants	21	19
Baseline	65	70
1-Year	44	85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	His Bundle Pacing
	Comments	Quality of Life was presented at baseline and 1-year as medians (interquartile range) for patients with His Bundle Pacing based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Coronary Sinus Pacing
	Comments	Quality of Life was presented at baseline and 1-year as medians (interquartile range) for patients with Coronary Sinus Pacing based upon the Shapiro-Wilks test of normality, and then analyzed with Wilcoxon signed-rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments	P-values are not adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Sign test
	Comments

6. Secondary Outcome

Title	Time to First Cardiovascular Rehospitalization
Description	Time to first cardiovascular rehospitalization in 12 months
Time Frame	Through study completion, an average of 12 months

Outcome Measure Data

Analysis Population Description

All analyses shown are intention-to-treat. Of note, 5 patients from Coronary Sinus Pacing crossed over to His Bundle Pacing, but were analyzed Coronary Sinus Pacing. Likewise, 10 patients from His Bundle Pacing crossed over to the Coronary Sinus Pacing, but they were analyzed as His Bundle Pacing under intention-to-treat analysis.

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Measure Participants	21	19
Median (Inter-Quartile Range) [months]	10.63	11.58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	His Bundle Pacing, Coronary Sinus Pacing
	Comments	Primary outcome of time to first cardiovascular rehospitalization by His Bundle Pacing compared to Coronary Sinus Pacing presented median and interquartile range in years based upon the Shapiro-Wilks test of normality, and then analyzed with a log rank test.
	Type of Statistical Test	Other
	Comments	Log rank test of a survival analysis
Statistical Test of Hypothesis	p-Value	0.14
	Comments	P-value did not need to be adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Log Rank
	Comments

7. Secondary Outcome

Title	Time to First Treated Ventricular Arrhythmia/Ventricular Tachycardia (VT/VF)
Description	Time to first treated ventricular arrhythmia/ventricular tachycardia (VT/VF) in 12 months
Time Frame	Through study completion, an average of 12 months

Outcome Measure Data

Analysis Population Description

All analyses shown are intention-to-treat. Of note, 5 patients from Coronary Sinus Pacing crossed over to His Bundle Pacing, but were analyzed Coronary Sinus Pacing. Likewise, 10 patients from His Bundle Pacing crossed over to the Coronary Sinus Pacing, but they were analyzed as His Bundle Pacing under intention-to-treat analysis.

Arm/Group Title	His Bundle Pacing	Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.	Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
Measure Participants	21	19
Median (Inter-Quartile Range) [months]	10.63	11.58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	His Bundle Pacing, Coronary Sinus Pacing
	Comments	Primary outcome of time to first treated VT/VF by His Bundle Pacing compared to Coronary Sinus Pacing presented median and interquartile range in years based upon the Shapiro-Wilks test of normality, and then analyzed with a log rank test.
	Type of Statistical Test	Other
	Comments	Log rank test of a survival analysis
Statistical Test of Hypothesis	p-Value	0.14
	Comments	P-value did not need to be adjusted for multiple comparisons. Tests were two-tailed, considered statistically significant with a p-value <0.05, and conducted using STATA MP version 15 (College Station, TX).
	Method	Log Rank
	Comments

Adverse Events

Time Frame	Adverse event data were collected over 1 year.
Adverse Event Reporting Description	Adverse events were required to be systematically reported into REDCap at time of procedure.
Arm/Group Title	His Bundle Pacing		Coronary Sinus Pacing
Arm/Group Description	Subjects will be randomized to the HB lead position with their cardiac resynchronization therapy (CRT) pacemaker. HB lead pacing will be performed with the Medtronic SelectSecure™, Model 3830 lead. Delivery of the lead utilizes a deflectable sheath, the Medtronic SelectSite™, Model C304. Both devices are FDA approved for the purpose of HB pacing. It is the only device available which is presently FDA approved for selective HB pacing. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.		Subjects will be randomized to the CS lead position with their cardiac resynchronization therapy (CRT) pacemaker. CS lead and CRT device generator selected for implant will be left to the discretion of the operator. Only FDA approved CS leads and CRT generators will be utilized in the study. There are five present manufacturers of CS leads and CRT generators: Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. CRT Pacemaker: Cardiac Resynchronization Therapy (CRT) is the use of a pacemaker with two endocardial leads placed in the right atrium (RA) and right ventricle (RV). The third lead is traditionally placed in a tributary of the coronary sinus (CS) overlying the epicardial surface of the left ventricle (LV). Alternatively, the third lead may be positioned based on mapping of the common His bundle and actively fixed to achieve QRS normalization via direct His bundle capture.
All Cause Mortality
	His Bundle Pacing		Coronary Sinus Pacing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		1/19 (5.3%)
Serious Adverse Events
	His Bundle Pacing		Coronary Sinus Pacing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	His Bundle Pacing		Coronary Sinus Pacing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		3/19 (15.8%)
Nervous system disorders
Transient ischemic attack with aphasia	0/21 (0%)	0	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders
hematoma	1/21 (4.8%)	1	0/19 (0%)	0
Surgical and medical procedures
atrial lead microdislodgment	0/21 (0%)	0	2/19 (10.5%)	2

Limitations/Caveats

This pilot study was underpowered to detect differences less than 10% between groups.The criteria for LBBB definitions impact the outcomes of CRT studies. More precise electrophysiologic definitions are necessary to refine patient selection for His bundle pacing. Longer helices, deflectable sheaths with septal orientation and variable curves may further improve His correction rates and stability of thresholds.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.