Introduction
Right ventricular pacing (RVP) has been the standard-of-care therapy for patients with
bradycardia for sixty years. However, the selection of optimal pacing site is still
controversial. Right ventricular septal or outflow tract pacing has not resulted in
improved outcomes. RVP is considered to result in electrical and mechanical dyssynchrony
and an increased risk of pacing-induced cardiomyopathy (PICM), heart failure and
mortality. Biopace (Biventricular Pacing for Atrioventricular Block to Prevent Cardiac
Desynchronization) study is a randomized controlled trial with a large population
evaluating biventricular pacing versus RVP in patients with atrioventricular (AV) block.
But biventricular pacing was not shown superiority in clinical outcomes compared with
RVP. As biventricular pacing is delivered at two non-physiological sites, it actually
creates ventricular dyssynchrony in patients with narrow QRS durations. Thus, seeking for
the optimal pacing site has been the ultimate goal of doctors who specialize in cardiac
pacing.
His-bundle pacing (HBP) is thought to be the most physiological pacing modality, which
was initial applied by Deshmukh et al in 2000. HBP activates native His-Purkinje system
and produces favorable electrical and mechanical synchrony. Clinical observations have
shown HBP could reduce the incidence of PICM and improve combined clinical outcomes.
However, HBP is not widely applied because of challenging operating techniques, unstable
long-term pacing parameters and risk of loss of ventricular capture in a significant
number of patients.
Left bundle branch pacing (LBBP) was first introduced by Huang et al in 2017. Since then,
LBBP has been carried out boomingly in China. Similar with HBP, LBBP could activate left
bundle branch (LBB) fibers and provide narrower paced QRS duration and better left
ventricular (LV) mechanical synchrony than RVP. Animal studies also confirmed the
physiological characteristics and anatomical lead locations of LBBP. Several clinical
studies showed that LBBP could produce significantly narrower paced QRS duration and
better echocardiographic response than biventricular pacing in patients with heart
failure and LBB block. Furthermore, the implantation procedure appears easier and capture
threshold is lower when compared with HBP. LBBP has appeared to be a promising approach
in the clinical practice. However, no randomized controlled studies have been reported to
compare the efficacy of LBBP and other pacing modalities.
Objectives
The study aimed to demonstrate (1) the superiority of LBBP in preserving LV systolic
function over RVP and (2) the feasibility and long-term safety of LBBP in patients with
AV block.
Methods
Stratified randomization
A balanced randomization is applied according to the following stratifying criteria:
AF with slow ventricular rate: present or absent;
LVEF: ≤ 50% or > 50%.
Lead implantation of LBBP
The lead implantation of LBBP has been well described previously. The implantation was
performed using the Select Secure (3830) pacing lead delivered through a fixed-curve
sheath. The 3830 lead was introduced transvenously into the right ventricle and screwed
into the interventricular septum (IVS) until LV septum was reached, without protruding
into the LV cavity.
Venous access was obtained via the left axillary vein or subclavian vein. The 3830 lead
was inserted through the C315 HIS sheath. An intracardiac electrogram was recorded from
the lead tip using the electrophysiological recording system. His-bundle electrogram was
identified at the right anterior oblique 25° position and fluoroscopic image of the lead
position was recorded as a reference. The sheath and lead tip were first advanced to the
anterior lower site of the His-bundle position, and subsequently rotated in a
counterclockwise fashion to place the lead tip in a perpendicular orientation to the IVS.
A paced morphology of QS complex with a north in the nadir ("W"-shaped morphology) in
surface lead V1 was usually observed at this location. As the lead tip was gradually
screwed into the IVS, a rightward shift of the second notch in the "W"-shaped pacing
morphology can be observed. The lead tip was considered to be in the final position once
a paced morphology of right bundle branch delay (RBBD) in surface lead V1 was achieved.
Moreover, a discrete potential before the QRS complex could be often recorded from the
lead tip, and we defined this potential as the LBB potential. Left ventricular activation
time (LVAT) was measured from the intracardiac pacing spike to the R-wave peak of QRS
complex in lead V5 or V6. The penetration depth in the IVS was finally assessed by
injecting a small amount of contrast medium through the sheath in left anterior oblique
45°. Echocardiography was routinely performed to evaluate the lead depth in the IVS
before discharge.
Device programming
The devices are routinely programmed with a lower rate limit of 60 ppm. For DDD devices,
the paced and sensed AV intervals are set as 150 and 120 ms, respectively.
Study organization
Echocardiographic core lab Echocardiographic examinations are performed at each study
center before pacemaker implantation and at follow-up. All images are stored on DVD disks
and sent to the core lab (Zhongshan Hospital, Fudan University) for central analysis.
Study Steering Committee
The study steering committee is composed of three experts who are not the investigators
of this study. The committee is responsible for the academic issues including the
judgment of LBBP or LVSP.
Independent Data Monitoring Committee (iDMC)
The iDMC is composed of three experts including at least one statistical expert. The
committee is responsible for the data examination including mid-term evaluation during
the study and also the patient privacy protection.
Safety Review Committee
The safety review committee is composed of three experts who are not the investigators of
this study. In case of severe adverse events, including all-cause death, acute
cardiovascular or cerebrovascular events and other lethal or disabling diseases, the
committee will be responsible for the investigation of the events. The physicians should
report the events to the principal investigator of each center and the committee within 2
hours. The committee should report the events to the hospital ethics committee in 24
hours. The committee may recommend the early termination of the study if an excessive
rate of adverse events is suspected.
Statistical analysis
Intention-to-treat principle
Data analyses are performed according to the intention-to-treat principle. If LBBP or
LVSP fails, RVP will be performed and the patient will not be crossed over to the other
group. If LBBP fails but LVSP succeeds, the sub-group analysis for these patients with
LVSP will be done.
Sample size
According to previous publications of HBP and RVP, we supposed that the rate of 5-year
composite endpoints in RVP group was 25% and the rate in LBBP group was 15%. With a
recruitment period of 2 years and follow-up time of at least 3 years, at least 100 events
are required to achieve a power of 80%. With alpha as 0.05, rate of lost-of-follow-up
rate as 10%, the final sample size was estimated as 683 by using PASS Version 15.
Endpoint analysis
Kaplan-Meier analysis was used to compare the rate of endpoints between the two groups
over time. Cox proportional risk model will be applied to calculate the hazard ratio. A
p-value less than 0.05 was considered statistically significant.
Mid-term analysis
Mid-term analysis is performed by iDMC when the rate of events reaches 50% (at least 50
events of primary endpoint). If LBBP group exhibits statistically significant superiority
over RVP group with the significant level of 0.003, the study could be effectively early
terminated. Otherwise, the sample size will be re-evaluated. The iDMC may determine if
the study will continue according to the re-evaluation of the sample size. Eventually,
the data prior to and after the mid-term analysis are put together for final analysis
with the significant level of 0.047.
Statistical software
All statistical analyses were performed using SAS Version 9.4 or R Software Version 3.6.
Study timeframe
The study will start in October 2020 and the complete enrollment will be expected by the
end of 2022. At least 11 medical centers across China will participate in the study. With
a period of at least 3-year follow-up, the study is expected to finish at the end of
2025. The recruitment might be slower if the mid-term analysis does not reach the
statistical significance and a larger population is required.