Heart Failure Reviews

https://doi.org/10.1007/s10741-018-9699-7

Clinical outcomes with biventricular versus right ventricular

pacing in patients with atrioventricular conduction defects
Dasheng Lu 1,2 & Hongxiang Zhang 1,2 & Chu Chen 3 & Kai Wang 4 & Qijun Shan 3

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
There have been increasing concerns about the unexpected effects of right ventricular (RV) pacing. We aimed to systematically evaluate
the effect of biventricular (BiV) versus RV pacing on clinical events in patients with impaired AV conduction. We searched PubMed,
EMBASE, and Cochrane Library for studies comparing BiV pacing with RV pacing in patients with AV block, through April 2017. We
selected randomized controlled trials (RCTs) reporting data on mortality, hospitalization for heart failure (HF), and/or 6-min walk distance
(6MWD). A total of 12 RCTs were finally included. Pooled analysis suggested that BiV pacing was associated with a significantly
reduced all-cause mortality in contrast to RV pacing (risk ratio (RR) = 0.77, 95% confidence interval (CI) 0.62 to 0.95, I2 = 9.6%). BiV
pacing, compared with RV pacing, significantly reduced the rate of HF hospitalization (RR = 0.74, 95% CI 0.59 to 0.93, I2 = 10.1%).
Sensitivity analyses by excluding studies with AV nodal ablation showed that BiV pacing still had a lower mortality and non-significant
reduced HF hospitalization. Patients in BiVand RV pacing mode had a similar 6WMD at follow-up (mean difference = 4.99 m, 95% CI
− 11.34 to 21.33 m, I2 = 0%). Meta-regression analysis showed that the effect size of all-cause mortality or HF hospitalization was not
significantly associated with mean LVEF value at baseline. In patients with impaired AV conduction that need frequent ventricular pacing,
BiV pacing was associated with reduced mortality and hospitalization for HF, compared with traditional RV pacing mode.

Keywords AV block . Heart failure . Heart block . Cardiac resynchronization therapy

Introduction patients with AVB. Right ventricular (RV) pacing is a tradi-

Atrioventricular (AV) block is an important cause of pacemak-
er implants [1]. Ventricular pacing (VP) is required in most
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s10741-018-9699-7) contains supplementary
material, which is available to authorized users.
* Dasheng Lu
ldslds@126.com
* Qijun Shan
qjshan@njmu.edu.cn
1
Department of Cardiology, The Second Affiliated Hospital of
Wannan Medical College, 123# Kangfu Road, Wuhu 241000, Anhui
Province, China
2 narrow QRS duration or preserved EF. Previous studies have
Vascular Diseases Research Center of Wannan Medical College,
Wuhu 241000, Anhui Province, China
3
Department of Cardiology, The First Affiliated Hospital of Nanjing
Medical University, 300# Guangzhou Road,
Nanjing 210029, Jiangsu Province, China
4
Department of Cardiology, The First Affiliated Hospital of Jiangsu
University, Zhenjiang, Jiangsu, China
tional pacing mode in this patient population. However, there
has been increasing concern about the unexpected effects of
RV pacing. It has been demonstrated that RV pacing accounts
for left ventricular (LV) mechanical dyssynchrony as well as
worsening heart failure (HF) [2, 3]. Although efforts have been
made to reduce unnecessary VP [4, 5], VP is unavoidable in
high-grade AV block. In clinical practice, patients with atrial
fibrillation undergoing AV junction (AVJ) ablation is another
condition in which great percentage of VP is needed. For HF
patients with poor LV ejection fraction (EF) and left bundle
branch block (LBBB), cardiac resynchronization therapy
(CRT), namely biventricular (BiV) pacing, has been shown
to improve LV function and reduce HF events [6, 7]. BiV
pacing, however, is not often recommended in patients with
compared BiV pacing with RV pacing in patients with high-
grade or AVJ ablation-induced AV block [8–11]. These indi-
vidual studies are limited by small sample size, and their results
regarding clinical events are controversial. In this case, we
sought to systematically evaluate the effect of BiV versus RV
pacing on HF events in patients with impaired AV conduction.

Methods
Data sources and study selection
We searched PubMed, EMBASE, and Cochrane Library for
studies comparing BiV pacing with RV pacing in patients with
AV block (including AVJ ablation-induced AV block),
through April 2017. We also scanned references of retrieved
reports for additional potentially eligible studies. There was no
language restriction.
Only published data of randomized controlled trials (RCTs)
were included. We selected RCTs reporting data on mortality,
hospitalization for HF, and/or 6-min walk distance (6MWD).
Studies in which follow-up is less than 3 months or the pro-
portion of non-AV block patients is more than 50% were ex-
cluded from the analysis. Abstracts, letters, editorials, reviews,
and study protocols were also excluded.
Data extraction
Two reviewers independently extracted data on mortality, HF
hospitalization (primary endpoints), 6WMD (secondary end-
point), study population, and baseline characteristics. For re-
ports with different follow-up time points, we selected data
just from the longest time point of follow-up to analysis. All
disagreements were resolved by consensus. The quality of
included RCTs was assessed by means of Cochrane
Collaboration Risk of Bias Tool.
Statistical analysis
We calculated risk ratios (RR) with 95% confidence intervals
(CI) for primary endpoints (i.e., mortality and HF hospitaliza-
tion) in Comprehensive Meta-Analysis Version 2 (Biostat,
Fig. 1 Flow chart of literature
search and selection
Heart Fail Rev
Englewood, NJ), using the Mantel–Haenszel fixed-effects
model. Mean differences with 95% CI were calculated for
secondary outcome (i.e., 6MWD). I2 value was used to quan-
tify the between-study heterogeneity. When I2 value indicates
that heterogeneity was considerable (i.e., I2 > 50%), a random-
effects model was applied. Publication bias was estimated
visually by examining the asymmetry of funnel plots and by
the weighted regression test of Egger. To avoid the carryover
effect of crossover studies, we used data during the first period
only, if possible. Meta-regression analysis and subgroup anal-
ysis were performed in STATA version 12.0 (College Station,
TX) to estimate the relationship between primary outcomes
and mean baseline LVEF. A sensitivity analysis was conduct-
ed by assessing the pooled effect sizes after excluding studies
with AVJ ablation-induced AV block. Differences were con-
sidered statistically significant when P value < 0.05.
Results
Baseline characteristics
As shown in Fig. 1, a total of 12 RCTs were included in the
final analysis [9–20]. All trials featured a randomized design,
and most had a high quality (Supplementary Figure 1). Table 1
describes study population and leads implantation position.
Right ventricular (RV) apex was the most selected RV pacing
position. RV outflow tract was selected in only one trial [17].
The COMPACT trial chose the mid or lower portion of the
interventricular septal wall for RV pacing [16]. The postero-
lateral or lateral braches of coronary sinus were the most used
position where the left ventricular (LV) lead was placed. There
were four studies featuring a crossover design [12, 13, 15, 16].
The characteristics of included studies are summarized in
Heart Fail Rev

Table 1 Study population and leads implantation of included trials

Study Study population RV pacing position LV leads placement

HOBIPACE Patients with symptomatic bradycardia and 17 RV septum and 20 lateral, posterior, or posterolateral
AVB that required permanent VP; 13 RV apex position and 10 anterolateral
LVDD ≥ 60 mm and EF ≤ 40% position
Albertsen Patients with permanent or paroxysmal RV outflow tract Lateral or posterolateral branch
high-grade AVB of the coronary sinus tributary
PACE Patients with standard indications for pacing, RV apex Posterolateral or lateral venous
including sinus-node dysfunction and branches of the coronary sinus
bradycardia due to advanced AVB;
EF > 45%
COMBAT Patients with AVB, NYHA class II–IV, The mid or lower portion A branch of the coronary sinus over
and LVEF ≤ 40% of the interventricular the posterolateral or lateral LV wall
septal wall
PREVENT-HF Adults met class I or IIa implantation criteria RV apex LV lateral wall
for pacemaker stimulation and with a high
expected need for VP (at least 80%)
due to AVB
BLOCK HF Patients with a standard indication for VP NA NA
for AVB, EF ≤ 50%, and mild-to-moderate
heart failure
BIVPACE-AVB Patients with high-grade AVB, NYHA RV apex Preferentially lateral position
class I–III, and LVEF ≥ 35%
MUSTICa NYHA class III, LVEF < 35%, As far from the left Preferably mid-lateral
LVDD > 60 mm, and persistent AF needing as possible
permanent VP
OPSITEa Permanent AF needing AVJ ablation and RV apex Positioned via the coronary sinus
resistant HF needing CRT or epicardial
PAVEa Chronic AF needing AV nodal ablation, RV apex Via coronary sinus
6MWD < 450 m
AVAILa AF with indication for AV nodal ablation, NA NA
NYHA class II–III, age ≥ 18 years
APAFa Permanent AF with indications for AVJ RV apex Basal or mid-portion of the
ablation, permanent AF with drug-refractory postero-lateral free wall
needing CRT.

RV right ventricular, LV left ventricular, AVB atrioventricular block, NYHA New York Heart Association, LVDD LV end-diastolic diameter, EF ejection
fraction, AVJ atrioventricular junction, CRT cardiac resynchronization therapy, AF atrial fibrillation
a
Studies with AF patients undergoing AVJ ablation

Table 2, the year of publication ranged from 2002 to 2016, and
mean baseline LVEF varied from 26 to 61.9%. There were
five studies with AF patients undergoing AVJ ablation [9, 10,
12–14]; thus, they featured almost permanent ventricular pac-
ing. While the majority of the remaining seven trials were with
intrinsic AV block, and the percentages of ventricular pacing
were great too (ranged from 80 to 100%). Mean ages of all
studies exceeded 65 years old, with an exception of the
COMBAT trial (mean age 58.3 years).
Mortality
All 12 trials report deaths in each group. Totally, the all-
cause mortality was 11.9% (128 out of 1072) in BiV pac-
ing group, and 16.2% (151 out of 933) in RV pacing group.
Mean follow-up duration ranged from 3 months to
4.8 years. Pooled analysis suggested that BiV pacing mode
was associated with a significantly reduced all-cause
mortality in contrast to RV pacing (RR = 0.77, 95% CI
0.62 to 0.95) (Fig. 2a), with a low between-study hetero-
geneity (I2 = 9.6%). A sensitivity analysis by excluding
studies with AF patients undergoing AVJ ablation showed
that BiV pacing still had a lower all-cause mortality (RR =
0.77, 95% CI 0.61 to 0.98, I2 = 6.4%) (Fig. 2b). Funnel plot
and Egger test indicated no significant publication bias
(P = 0.62) (Supplementary Figure 2A).
Hospitalization for heart failure
Six studies reported HF hospitalization [10–12, 16, 19,
20], which was approximately 15.1% in BiV pacing (102
out of 677) and 20.5% in RV pacing group (134 out of
654). Pooled estimate showed that BiV pacing, in compar-
ison to RV pacing, significantly reduced the rate of hospi-
talization for HF (RR = 0.74, 95% CI 0.59 to 0.93) (Fig.
3a), and heterogeneity was low (I 2 = 10.1%). No
 Heart Fail Rev

Table 2 Baseline characteristics of included studies

Study (first author) Year Group VP rate (%) No. Age (years) Male (%) Baseline BP (mmHg) Baseline LVEF (%)

Cross-over RCTs
MUSTIC (Leclercq)a 2002 RVP → BiVP Permanent 43 65 81.4 NA 26 ± 10
HOBIPACE (Kindermann) 2006 RVP → BiVP Permanent 30 69.6 77 NA 26.1 ± 7.8
COMBAT (Martinelli) 2010 RVP NA 31 57.4 67.7 NA 29.2 ± 7.4
BiVP NA 29 59.3 62.1 NA 30.1 ± 9.2
OPSITE (Brignole)a 2005 RVP → BiVP Permanent 56 70 61 NA 38.0 ± 14.0
Parallel RCTs
PAVE (Doshi)a 2005 RVP Permanent 106 67 64 NA 45.0 ± 15.0
BiVP Permanent 146 70 63 NA 47.0 ± 16.0
Albertsen 2008 RVP 100 25 76 68 155/83 59.7 (57–61)
BiVP 100 25 76 68 146/79 58.9 (47–62)
PACE (Yu, C) 2009 RVP 97 88 68 56 143/69 61.5 ± 6.6
BiVP 98 89 69 53 148/73 61.9 ± 6.7
a
APAF (Brignole) 2011 RVP Permanent 89 72 73 NA 37 ± 14
BiVP Permanent 97 72 67 NA 38 ± 14
AVAIL (Orlov)a 2010 RVP 97 20 70.1 65 NA 57.2 ± 7.5
BiVP 98 88 73.0 40 NA 56.1 ± 9.4
PREVENT-HF (Stockburger) 2011 RVP ≥ 80 58 69.5 76 141.7 54.9 + 12.9
BiVP ≥ 80 50 71.6 68 139.1 57.5 + 11.8
BLOCK HF (Curtis) 2013 RVP ≥ 97 342 73 72.8 NA 39.6 ± 8.3
BiVP ≥ 97 349 73.7 76.8 NA 40.3 ± 8.4
BIVPACE-AVB (Zhang) 2016 RVP 95.47 57 66 70.2 126.1/74.4 60.6 ± 9.5
BiVP 96.32 57 67.1 71.9 125.9/76.4 59.4 ± 10.2

Data were mean ± SD or median (25th, 75th)

RCTs randomized controlled trials, RVP right ventricular pacing, BiVP biventricular pacing, FU follow-up, VP ventricular pacing, No. number of
patients, BP blood pressure, LVEF left ventricular ejection fraction, NA not available
a
Studies in which patients underwent atrioventricular junction or His bundle ablation

significant publication bias was detected (Supplementary
Figure 2B, P = 0.3). A sensitivity analysis after removal of
studies focusing on AVJ ablation-induced AV block
showed that BiV pacing was associated with a non-
significant reduced HF hospitalization (RR = 0.80, 95%
CI 0.63 to 1.02, I2 = 0%) (Fig. 3b).
Six-minute walk distance
Pooled analysis based on eight studies showed that patients in
BiV pacing and RV pacing mode had a similar 6WMD at
follow-up (mean difference = 4.99 m, 95% CI − 11.34 to
21.33 m, I2 = 0%) (Fig. 4a). After removing studies involving
AVJ ablation for AF, the result remained unchanged (mean
difference = − 4.35 m, 95% CI − 26.83 to 18.14 m, I2 = 0%)
(Fig. 4b).
(P = 0.68, Fig. 5b) was not significantly associated with base-
line mean LVEF value.
Subgroup analysis
We divided included studies into two groups: (i) studies with
baseline mean LVEF < 50% and (ii) those with mean LVEF >
50% at baseline. We found that both mortality (RR = 0.75,
95% CI 0.58 to 0.96) and hospitalization for HF (RR = 0.74,
95% CI 0.59 to 0.93) were significantly reduced with BiV
pacing compared with RV pacing mode in studies with mean
LVEF < 50% (Fig. 5c, d). These differences became non-
significant in studies with mean LVEF > 50% (RR = 0.72,
95% CI 0.42 to 1.25 for HF hospitalization and RR = 0.98,
95% CI 0.56 to 1.71 for mortality) (Fig. 5c, d).

Meta-regression analysis Discussion

Our meta-regression analysis showed that the effect size of all- Our pooled estimates showed that BiV pacing reduced all-
cause mortality (P = 0.48, Fig. 5a) or hospitalization for HF cause mortality and hospitalization for HF by 23 and 26% in
Heart Fail Rev
Fig. 2 Forest plot of all-cause
mortality with biventricular
versus right ventricular pacing. a
Pooled analysis of all included
studies. b Pooled analysis after
removing studies with AV nodal
ablation
patients with impaired AV conduction, compared with RV
pacing. Although the analyses included both patients with
intrinsic AV block and those with AVJ ablation-induced AV
block, these two groups of patients all required permanent or
intermittent ventricular pacing (as shown in Table 2, they all
featured a high percentage of ventricular pacing), and thus met
our inclusion criteria. The small I2 values also indicated low
clinical heterogeneity. Besides, after removing reports with
AVJ ablation-induced AV block, namely, including only stud-
ies with intrinsic AV block, our pooled estimates still sug-
gested that BiV pacing significantly reduced mortality by
23%. Also, the RR for HF hospitalization showed a non-
significant trend towards a reduction with BiV (RR = 0.80,
95% CI 0.63 to 1.02), indicating that our results regarding
primary outcomes were stable. Of note, 6MWD was not
significantly increased with BiV pacing compared with RV
pacing, both in individual studies and pooled estimate. One
reason is that the small sample size might result in limited
power of the pooled analysis to detect the difference.
Another explanation is that 6WMD, as a subjective indicator,
might not be an eligible surrogate for clinical events in this
patient population.
BiV pacing has the ability to correct ventricular
dyssynchrony in patients with intraventricular conduction
delay and was widely adopted in those with poor LVEF (<
35%) and LBBB to reduce HF symptoms and death rate [6,
21]. And studies have suggested that BiV pacing was su-
perior to RV pacing in preserving LV systolic function,
even for patients with normal QRS complex and LVEF
[8]. Previous studies regarding CRT usually excluded

Fig. 3 Forest plot of
hospitalization for heart failure
with biventricular versus right
ventricular pacing. a Pooled
analysis of all included studies. b
Pooled analysis after removing
studies with AV nodal ablation
patients with AV block [11]. Recently, several studies have
compared BiV pacing with RV pacing in patients with im-
paired AV conduction. These individual studies had con-
troversial results and various study population (some with
normal LVEF, some with reduced LVEF), and were subject
to limited sample size. Besides, they mainly evaluated LV
reversal remodeling or excise capacity with BiV versus RV
pacing. There was a lack of a comprehensive evaluation on
clinical events with BiV versus RV pacing in patients with
impaired AV conduction.
Baseline LVEF might exert an impact on the prognoses
of patients receiving ventricular pacing, as indicated by
previous studies. The detrimental effects of RV pacing ap-
pear more evident in patients with poor LVEF [3]. Using a
Heart Fail Rev
method of meta-regression analysis, we observed no sig-
nificant relationship between baseline mean LVEF and the
effect size of mortality or HF hospitalization, indicating
that BiV pacing was superior to RV pacing, regardless of
the mean LVEF value. However, subgroup analysis found
that BiV pacing significantly reduced mortality and HF
hospitalization in studies with reduced LVEF (< 50%) but
not in those with preserved LVEF (> 50%), compared with
RV pacing. This is not surprising as RV (particularly api-
cal) pacing is really only bad for the vulnerable left ventri-
cle as shown in the DAVID trial [3]. Notably, the number
of studies in each group became smaller after grouping,
which may weaken the power of pooled statistical analy-
ses. In addition, pooled estimate of studies with preserved
Heart Fail Rev
Fig. 4 Forest plot of 6-min walk
distance (6MWD) with
biventricular versus right
ventricular pacing. a Pooled
analysis of all included studies. b
Pooled analysis after removing
studies with AV nodal ablation
LVEF also showed a reduced trend (despite non-significant
differences) towards primary endpoints with BiV pacing
compared with pacing, which was somehow consistent
with the finding from the meta-regression analysis.
RV pacing location may also influence the effect of RVP on
LV remodeling and function. Whether RVoutflow tract pacing
is superior to RV apical pacing remains controversial [22–25].
The optimal RV pacing site has not been determined [11, 26].
Our sensitivity analysis by removing studies not using RV
apical pacing showed that the superiority of BiVP over RVP
had not been changed.
Clinical implications
The indications for CRT are mainly for patients with an EF
of < 35%, LBBB, or widened QRS duration of > 150 s [27,
28]. Although the guidelines also do mention regarding the
use of CRT in patients with anticipated VP > 40% [29],
CRT is still reserved for patients with narrow QRS com-
plexes or normal LVEF. This study further confirms that
we may choose CRT in those with anticipated high burdens
of ventricular pacing.
Study limitations
This study was a meta-analysis based on available data in
published articles rather than on individual patient data,
which is an inherent limitation of this kind of study.
Another concern is that most studies were based on elderly
people (mean ages in 11 out of 12 trials more than
65 years). The between-group difference in mortality
might be blurred due to the high aging-related death rate.
However, it might be inevitable as AV block is a disease of
elderly people unless it is congenital. Besides, although
the majority of included patients were with advanced or
complete AV block, sinus node dysfunction was not

Fig. 5 Meta-regression between mean baseline LVEF and log risk ratio (logRR) of a mortality (P = 0.48) or b heart failure hospitalization (P = 0.68).
Subgroup analyses of c mortality and d hospitalization for heart failure, stratified by the presence of reduced LVEF (< 50%)
excluded in one trial (accounts for 47%) [8], and moderate
AV conduction defects (e.g., first-degree AV block) were
not separated in the BLOCK-HF study [11]. However, the
average ventricular pacing percentages in all studies were
great enough (ranged from 80 to 100%) to produce pacing-
included effects. Therefore, this may be unlikely to have
significantly influenced our results. Future studies should
investigate whether BiV pacing is also feasible in patients
with moderate AV block. BioPace study is an unpublished
large, randomized trial, which has enrolled various types
of AV block [30], and we expect the publication of the
main results of this important study to provide further
insights.
Conclusion
In patients with impaired AV conduction that need frequent
ventricular pacing, BiV pacing was associated with reduced
Heart Fail Rev
mortality and hospitalization for HF, compared with tradition-
al RV pacing mode.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
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