Download Biventricular Pacing in Patients with Bradycardia and Normal

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
original article
Biventricular Pacing in Patients with
Bradycardia and Normal Ejection Fraction
Cheuk-Man Yu, M.D., F.R.C.P., Joseph Yat-Sun Chan, F.H.K.A.M.,
Qing Zhang, M.M., Ph.D., Razali Omar, M.D.,
Gabriel Wai-Kwok Yip, M.D., F.A.C.C., Azlan Hussin, M.D., Fang Fang, Ph.D.,
Kai Huat Lam, M.B., B.S., Hamish Chi-Kin Chan, F.R.C.P.,
and Jeffrey Wing-Hong Fung, M.D., F.R.C.P.
A BS T R AC T
Background
Observational studies suggest that conventional right ventricular apical pacing may
have a deleterious effect on left ventricular function. In this study, we examined whether biventricular pacing is superior to right ventricular apical pacing in preventing
deterioration of left ventricular systolic function and cardiac remodeling in patients
with bradycardia and a normal ejection fraction.
Methods
In this prospective, double-blind, multicenter study, we randomly assigned 177 patients in whom a biventricular pacemaker had been successfully implanted to receive
biventricular pacing (89 patients) or right ventricular apical pacing (88 patients). The
primary end points were the left ventricular ejection fraction and left ventricular
end-systolic volume at 12 months.
Results
At 12 months, the mean left ventricular ejection fraction was significantly lower in
the right-ventricular-pacing group than in the biventricular-pacing group (54.8±9.1%
vs. 62.2±7.0%, P<0.001), with an absolute difference of 7.4 percentage points, whereas the left ventricular end-systolic volume was significantly higher in the rightventricular-pacing group than in the biventricular-pacing group (35.7±16.3 ml vs.
27.6±10.4 ml, P<0.001), with a relative difference between the groups in the change
from baseline of 25% (P<0.001). The deleterious effect of right ventricular apical
pacing occurred in prespecified subgroups, including patients with and patients
without preexisting left ventricular diastolic dysfunction. Eight patients in the rightventricular-pacing group (9%) and one in the biventricular-pacing group (1%) had
ejection fractions of less than 45% (P = 0.02). There was one death in the right-ventricular-pacing group, and six patients in the right-ventricular-pacing group and five in
the biventricular-pacing group were hospitalized for heart failure (P = 0.74).
From the Division of Cardiology, Department of Medicine and Therapeutics,
Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
(C.-M.Y., J.Y.-S.C., Q.Z., G.W.-K.Y., F.F.,
J.W.-H.F.); the Department of Cardiology,
West China Hospital, Sichuan University,
Chengdu, Sichuan, China (Q.Z.); the Department of Cardiology, National Heart
Institute, Kuala Lumpur, Malaysia (R.O.,
A.H., K.H.L.); the Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Tai Po, Hong Kong (H.C.-K.C.); and
the Department of Medicine, North District Hospital, Hong Kong (J.W.-H.F.).
Address reprint requests to Dr. Yu at the
Division of Cardiology, Department of
Medicine and Therapeutics, Prince of
Wales Hospital and Institute of Vascular
Medicine and Li Ka Shing Institute of
Health and Sciences, Chinese University
of Hong Kong, Hong Kong, or at cmyu@
cuhk.edu.hk.
This article (10.1056/NEJMoa0907555)
was published on November 15, 2009, at
NEJM.org.
N Engl J Med 2009;361.
Copyright © 2009 Massachusetts Medical Society.
Conclusions
In patients with normal systolic function, conventional right ventricular apical pacing resulted in adverse left ventricular remodeling and in a reduction in the left ventricular ejection fraction; these effects were prevented by biventricular pacing. (Centre for Clinical Trials number, CUHK_CCT00037.)
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
1
The
T
n e w e ng l a n d j o u r na l
he deleterious effect of nonphysiologic right ventricular apical pacing on
left ventricular systolic function has been
recognized since the 1920s.1 In the Dual Chamber and VVI Implantable Defibrillator (DAVID)
trial, the unexpected increased rates of death
and hospital admission for heart failure among
patients who were randomly assigned to the dualchamber, rate-adaptive (DDDR) mode were purportedly due to the adverse effect of right ventricular apical pacing on left ventricular structural
remodeling.2 Results of subsequent trials have supported the notion that right ventricular apical pacing might lead to adverse clinical outcomes in
patients with standard pacing indications.3-7 Nevertheless, right ventricular apical pacing continues to be practiced by many physicians because
of its easy accessibility and relative stability over
time; the optimal mode and site of pacing remain undefined.
Preclinical data suggested that biventricular
pacing might preserve myocardial performance
better than right ventricular apical pacing in patients with atrioventricular block and normal systolic function.8 The underlying mechanism may
be a reduction in left ventricular systolic dyssynchrony, as shown by advanced echocardiography.9
Furthermore, patients with preexisting left ventricular dysfunction and an indication for standard pacing have improved left ventricular systolic
function, exercise capacity, and quality of life after biventricular pacing as compared with right
ventricular apical pacing.10 This finding was corroborated in a study of acute hemodynamic responses in patients with a normal QRS complex
and a left ventricular ejection fraction of more than
40%, which showed that biventricular pacing, but
not right ventricular apical pacing, preserved left
ventricular systolic function.11 These results suggest that biventricular pacing may be a feasible
option for permanent pacing in the majority of
patients who have normal left ventricular systolic
function and that it may attenuate the adverse effect of conventional right ventricular apical pacing on left ventricular systolic function.
of
m e dic i n e
whether atrial-synchronized biventricular pacing
is superior to right ventricular apical pacing in
preserving left ventricular systolic function and
avoiding adverse left ventricular remodeling in patients with a normal left ventricular ejection fraction (45%) and standard indications for pacing.
These indications included sinus-node dysfunction
and bradycardia due to advanced atrioventricular
block. Patients were excluded from the study if
they had persistent atrial fibrillation, unstable angina, or an acute coronary syndrome; if they had
undergone percutaneous coronary intervention or
coronary-artery bypass surgery within the previous 3 months; if they had a life expectancy of less
than 6 months; if they had received a heart transplant; or if they were pregnant.12 Patients who fulfilled the eligibility criteria but in whom implantation of a biventricular system was unsuccessful
were also excluded. Attending physicians were encouraged to maintain the same doses of medications, especially neurohormonal blockers and antiarrhythmic drugs, throughout the study period.
Study Design
Patients who were enrolled in the study received
an atrial-synchronized biventricular pacemaker capable of delivering right ventricular apical pacing
or biventricular pacing, depending on the programming of the device (InSync III, Medtronic).
In brief, the right atrial and right ventricular leads
were positioned at the right atrial appendage and
the right ventricular apex, respectively, through a
transvenous route. The left ventricular lead was
positioned preferentially at the posterolateral or
lateral venous branches of the coronary sinus. Two
days after successful implantation of the device,
patients were stratified according to the presence
of normal or abnormal left ventricular diastolic
function, as assessed by standardized criteria of
Doppler echocardiography (Fig. 1).13 Patients who
had a mechanical mitral valve or high-grade atrioventricular block and in whom left ventricular diastolic function could therefore not be determined
were counted as part of the group with abnormal
left ventricular diastolic function.
Patients in each of the groups that were stratified
according to left ventricular diastolic funcMe thods
tion were randomly assigned to receive biventricPatients
ular pacing or right ventricular apical pacing, and
The Pacing to Avoid Cardiac Enlargement (PACE) their pacemakers were programmed accordingly.
study was a prospective, double-blind, randomized, Patients were randomly assigned in a ratio of 1:1
multicenter clinical trial. It was designed to test by a computer-generated list at a central location.
2
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Biventricular vs. Right Ventricular Pacing
251 Patients were screened for
potential pacemaker therapy
7 Were excluded because of
inadequate image quality
6 Were excluded because of
ejection fraction <45%
238 Fulfilled the study inclusion
criteria
45 Declined participation
193 Underwent implantation of
the study device
16 Were excluded because of
procedure failure
177 Underwent randomization
67 Had normal diastolic function
33 Had RVA pacing
110 Had diastolic dysfunction
34 Had BiV pacing
55 Had RVA pacing
88 Received RVA pacing
55 Had BiV pacing
89 Received BiV pacing
1 Died
1 Declined follow-up
1 Declined follow-up
88 Completed 1-yr follow-up
(1 had inadequate image quality
for analysis)
86 Completed 1-yr follow-up
Figure 1. Screening, Enrollment, Random Assignment, and Follow-up.
BiV denotes biventricular, and AUTHOR:
RVA rightYu
ventricular apical.
RETAKE:
FIGURE: 1 of 4
1st
2nd
3rd
Revised
We used a permuted-block randomization
proce- mode, with a SIZE
lower rate of 60 beats per minute
ARTIST: MRL
dure, with each block containing
four
assignand
an
upper
tracking
rate of 140 beats per min6 col
TYPE: Line
Combo
4-C
H/T
ments, two for each pacing group. All the devices ute. For patients33p9
with heart block, the paced and
AUTHOR, PLEASE NOTE:
were programmed to an atrial-synchronized
DDDR
sensed
atrioventricular
intervals were programmed
Figure has been
redrawn and
type has
been reset.
Please check carefully.
JOB: 36122
ISSUE: 11-26-09
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
3
The
n e w e ng l a n d j o u r na l
to 130 msec and 100 msec, respectively. For patients with sinus-node dysfunction, the atrioventricular intervals were programmed to be 20 msec
shorter than the intrinsic atrioventricular interval.
The pacing settings were kept unchanged throughout the study period.
Baseline assessments included echocardiography, measurement of the distance covered on a
6-minute walk, quality-of-life assessment with the
use of the 36-Item Short-Form General Health
Survey (SF-36), and electrocardiography. All patients had follow-up visits at 1, 3, 6, 9, and 12
months, and the assessments were repeated at
those times. The echocardiographic images were
stored and sent to the core laboratory for analysis
by echocardiographic specialists who were unaware of the assigned treatment.
The study protocol was approved by the local
ethics committee at each participating institution
and complies with the provisions of the Declaration of Helsinki. Written informed consent was
obtained from all patients.
The study, which was sponsored by Medtronic,
was an investigator-initiated clinical trial, and the
protocol was designed and written by investigators
who were members of the steering committee (see
the Appendix). Data were gathered by the investigators. The publication committee consisted of
physicians on the steering committee and investigators from the top-enrolling centers. Data analy­
sis was performed by two of the investigators. The
manuscript was written by the principal investigator, and the accuracy of the data reported was
confirmed by the publication committee, whose
members had full access to the data; no restrictions or limitations were imposed by the sponsor.
The sponsor had no involvement in the design of
the study, the analysis of the data, or the preparation or editing of the manuscript.
of
m e dic i n e
Echocardiographic Assessments
Standard echocardiography (with the Vivid 7 system, General Electric) was performed to assess left
ventricular function. To assess left ventricular volume and ejection fraction, real-time three-dimensional echocardiography (with the iE33 system,
Philips) was preferred and was used in 90% of the
patients, whereas the biplane Simpson’s method
was used in the other 10%. For three-dimensional
echocardiography, optimized images of full left
ventricular volume were obtained in the apical
four-chamber view with the use of a matrix-array
transducer (X3-1, 1.9/3.8 MHz; Philips), while the
patient held his or her breath. Image optimization and quality requirements have been described
previously.14 The images were stored digitally and
transferred to the work station for blinded offline
analysis.
Echocardiographic images were analyzed off­
line for the treatment effect in the echocardiography core laboratory with the use of dedicated
software (QLAB 7.0, Philips). Images from different time points were arranged in random order
and were then analyzed by experienced readers in
a blinded fashion. An automatic left ventricular
border detection algorithm was used, and a virtual
left ventricular cast was constructed that measured left ventricular volume, ejection fraction, and
systolic dyssynchrony.14,15 Interobserver and intraobserver variability for the measurement of left
ventricular ejection fraction, left ventricular volume, and dyssynchrony index (the standard deviation of the time to minimal systolic volume among
the 16 left ventricular segments) were assessed in
30 randomly selected patients; the rates of interobserver and intraobserver variability were 3.9%
and 4.2%, respectively, for measurement of left
ventricular ejection, 6.7% and 6.5% for measurement of left ventricular volume, and 8.8% and
7.4% for dyssynchrony index.
Study End Points
The two primary end points were the left ventricular ejection fraction (as an assessment of left
ventricular systolic function) and left ventricular
end-systolic volume (as an assessment of left ventricular remodeling) at 12 months. They were evaluated primarily with the use of real-time threedimensional echocardiography. The secondary end
points included the distance covered in a 6-minute walk, quality of life as assessed with the use
of the SF-36, and hospitalization for heart failure.
4
Statistical Analysis
The sample size was estimated on the basis of
the postulated difference in left ventricular ejection fraction of 5 percentage points between the
two pacing groups at 12 months (PASS 2000 software, NCSS). We estimated that with 85 patients
in each group, the study would have 90% power
to detect a difference of 5 percentage points between the null hypothesis that both groups would
have a mean ejection fraction of 60% and the al-
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Biventricular vs. Right Ventricular Pacing
ternative hypothesis that the mean ejection fraction in the right-ventricular-pacing group would
be 55%, with a standard deviation of 10% and a
two-sided 5% type 1 error. Thus, the estimated
sample size for the study was 170 patients. With
this sample size, we estimated that the study would
also have at least 90% power to detect a difference
of 5 ml in left ventricular end-systolic volume.
The primary analysis was performed on the
basis of the intention-to-treat principle, and patients with a minimum of 3 months of follow-up
were included. An analysis was also performed on
the basis of final pacing sites. A two-sided Student’s t-test was used to test for a difference in
prespecified end points between the right-ventricular-pacing group and the biventricular-pacing
group at baseline and at the 12-month visit. In the
analysis, when the assumption of normality was
violated, a nonparametric test (Mann–Whitney test
or Wilcoxon signed-rank test) was performed.
A subgroup analysis was performed with the use
of a general linear model to look for potential
interactions between clinical factors and primary
end points. Prespecified subgroups were defined
according to the presence or absence of preexisting
left ventricular diastolic dysfunction, age (<70 or
≥70 years), sex, indication for pacing (sinus-node
dysfunction or heart block), and presence or absence of diabetes mellitus, hypertension, and coronary heart disease. A subgroup analysis that was
not prespecified was performed for QRS duration
(<110 or ≥110 msec). All reported P values are twosided and have not been adjusted for multiple
analyses.
R e sult s
Patients
From March 2005 through July 2008, a total of
251 patients were screened at four centers (Fig. 1).
Fifty-eight patients were excluded from the study
because of echocardiographic images that were of
poor quality (7 patients), ejection fractions that
were less than 45% (6), or the patients’ refusal to
join the study (45). Among 193 patients who underwent implantation of the study device, 14 had a
high left ventricular lead pacing threshold (>5 V)
and 2 had dissection of the coronary sinus without clinical complications. These 16 patients received conventional dual-chamber pacing and did
not undergo randomization. The remaining 177
patients were randomly assigned to biventricular
pacing (89) or right ventricular apical pacing (88).
The majority of the left ventricular leads (95%) were
placed in a lateral or posterolateral position, with
33% at the posterolateral vein, 31% at the lateral
vein, and 31% at the posterior vein. At 12 months,
the average percentage of ventricular pacing was
98% in the biventricular-pacing group and 97% in
the right-ventricular-pacing group (P = 0.95). The
baseline clinical characteristics were similar between the two treatment groups, and medications
were similar at 12 months (Table 1).
Compliance with Therapy
At 12 months, data from 87 patients in the biventricular-pacing group and 86 patients in the rightventricular-pacing group were available for analyses of the primary end point. Four patients who
had undergone randomization were not included
in the analysis: two patients declined the 12-month
visit (one from each group, both of whom remained
well clinically at 12 months), one patient died,
and the echocardiographic images for one patient
were of inadequate quality for analysis. Diaphragmatic stimulation occurred in two patients in the
biventricular-pacing group, and the two patients
were crossed over to the right-ventricular-pacing
group (one at 1 month and one at 7 months); the
analyses were performed according to the intention-to-treat principle. There was no crossover
from right ventricular apical pacing to biventricular pacing.
Assessment of the Primary End Points
At 12 months, the right-ventricular-pacing group
had a significantly lower mean left ventricular
ejection fraction than did the biventricular-pacing group (54.8±9.1% vs. 62.2±7.0%, P<0.001),
with an absolute difference of 7.4 percentage
points (P<0.001) (Table 2 and Fig. 2A). The absolute reduction in the ejection fraction from baseline to 12 months in the right-ventricular-pacing
group was 6.7 percentage points, but there was
no change in the ejection fraction in the biventricular-pacing group.
The left ventricular end-systolic volume was
significantly larger at 12 months in the rightventricular-pacing group than in the biventricular-pacing group (P<0.001), with an absolute difference of 8.1 ml (a relative difference between
the groups in the change from baseline of 25%,
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
5
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Table 1. Characteristics of Patients in the Right-Ventricular-Pacing and Biventricular-Pacing Groups.*
Right
Ventricular
Apical Pacing
(N = 88)
Variable
Biventricular
Pacing
(N = 89)
P Value
0.76
Age — yr
68±11
69±11
Male sex — no. (%)
49 (56)
47 (53)
0.70
24±4
25±6
0.49
Systolic
143±22
148±24
0.14
Diastolic
69±12
73±12
0.01
59±18
59±17
0.98
Body-mass index at baseline†
Blood pressure at baseline — mm Hg
Heart rate at baseline — beats/min
QRS duration at baseline — msec
107±30
107±27
0.98
Left ventricular ejection fraction at baseline — %
61.5±6.6
61.9±6.7
0.86
Dyssynchrony index at baseline — msec‡
12.4±8.1
14.0±10.6
0.43
Advanced atrioventricular block
55 (62)
49 (55)
Sinus-node dysfunction
33 (38)
40 (45)
Indication for pacing — no. (%)
0.24
Medical history — no. (%)
Hypertension
55 (62)
62 (70)
Diabetes mellitus
26 (30)
23 (26)
0.70
Coronary heart disease
20 (23)
19 (21)
0.71
Heart failure
12 (14)
10 (11)
0.63
4 (5)
2 (2)
0.44
Diuretics
14 (16)
20 (22)
0.27
Beta-blockers
15 (17)
16 (18)
0.87
ACE inhibitors or ARBs
26 (30)
29 (33)
0.55
Calcium-channel blockers
28 (32)
34 (38)
0.46
Chronic renal failure
0.24
Medications at baseline — no. (%)
Alpha-blockers
11 (12)
12 (13)
0.85
Antiplatelet agents or warfarin
39 (44)
35 (39)
0.79
Statins
18 (20)
17 (19)
0.82
Antiarrhythmic agents
14 (16)
18 (20)
0.46
Nitrates
19 (22)
12 (13)
0.26
Medications at 12 mo — no. (%)
Diuretics
13 (15)
17 (19)
0.47
Beta-blockers
27 (31)
22 (25)
0.45
ACE inhibitors or ARBs
28 (32)
32 (36)
0.53
Calcium-channel blockers
25 (28)
37 (42)
0.07
Alpha-blockers
11 (12)
15 (17)
0.30
Antiplatelet agents or warfarin
44 (50)
42 (47)
0.80
Statins
27 (31)
18 (20)
0.09
Antiarrhythmic agents
33 (38)
27 (30)
0.35
Nitrates
16 (18)
7 (8)
0.14
*Plus–minus values are means ±SD. ACE denotes angiotensin-converting enzyme, and ARB angiotensin-receptor blocker.
†The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡The dyssynchrony index is the standard deviation of the time to minimal systolic volume among the 16 left ventricular
segments.
6
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Biventricular vs. Right Ventricular Pacing
Table 2. End-Point Measures According to Treatment Group.*
End Point
Right
Ventricular
Apical Pacing
(N = 86)
Biventricular
Pacing
(N = 87)
P Value
Primary
Left ventricular ejection fraction (%)
Baseline
61.5±6.6
61.9±6.7
0.86
12 mo
54.8±9.1
62.2±7.0
<0.001
Baseline
28.6±10.7
28.6±9.4
0.71
12 mo
35.7±16.3
27.6±10.4
<0.001
Left ventricular end-systolic volume (ml)
Other
Distance in 6-min walk (m)
Baseline
335±98
345±105
0.88
12 mo
374±112
380±110
0.81
Baseline
73.3±19.8
74.3±17.5
0.61
12 mo
76.7±22.5
71.5±17.8
0.25
Baseline
65±30
68±25
0.63
12 mo
71±23
70±28
0.75
Baseline
38±45
42±45
0.74
12 mo
61±43
72±40
0.14
Baseline
68±30
78±28
0.04
12 mo
72±26
77±26
0.21
Baseline
42±23
50±24
0.05
12 mo
45±28
53±24
0.05
Baseline
72±22
77±20
0.13
12 mo
77±18
78±20
0.31
Baseline
62±42
69±42
0.22
12 mo
67±42
73±38
0.39
Baseline
49±17
49±13
0.88
12 mo
49±6
50±9
0.27
Baseline
56±25
64±23
0.06
12 mo
66±21
64±24
0.67
Left ventricular end-diastolic volume (ml)
SF-36 score†
Physical functioning
Role — physical
Bodily pain
General health
Mental health
Role — emotional
Social functioning
Vitality
*Plus–minus values are means ±SD.
†The scores on the 36-Item Short-Form General Health Survey (SF-36) range from 0 to 100, with higher scores indicating better health status.
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
7
The
A
n e w e ng l a n d j o u r na l
BiV pacing
RVA pacing
LV Ejection Fraction (%)
P<0.001 vs.
RVA pacing
60
55
50
0
B
P<0.001
Baseline
1 yr
BiV pacing
RVA pacing
P<0.001
LV End-Systolic Volume (ml)
40
30
P<0.001 vs.
RVA pacing
25
P=0.42
20
Baseline
1 yr
Figure 2. Comparison of Primary End Points at 12
1st
Yu
AUTHOR:
Months between
Patients Who Received RETAKE:
Biventricular
2nd
Pacing
and Those Who Received Right Ventricular ApiFIGURE: 2 of 4
3rd
cal Pacing.
Revised
ARTIST:
MRL
The
values
shown are means. Among patientsSIZE
who re3 col was
ceived
rightLine
ventricular
apical4-C
(RVA)H/T
pacing, there
Combo
TYPE:
16p6
a significant decrease in the left ventricular ejection
AUTHOR,
PLEASE
NOTE:
fraction (Panel A), whereas the left ventricular endFigure has been redrawn and type has been reset.
systolic volume was
increased
(Panel B). I bars indicate
Please
check carefully.
95% confidence intervals. BiV denotes biventricular,
JOB: LV
36122
ISSUE: 11-26-09
and
left ventricular.
P<0.001) (Table 2 and Fig. 2B). The left ventricular end-systolic volume increased by 7.1 ml (a relative increase of 26%) from baseline to 12 months
in the right-ventricular-pacing group but remained
unchanged in the biventricular-pacing group. At
12 months, eight patients in the right-ventricularpacing group (9%) and one patient in the biventricular-pacing group (1%) had a left ventricular
ejection fraction that had decreased to less than
45% (P = 0.02).
8
In the assessment of distance covered in a 6-minute walk, although both pacing groups had an
increase of more than 30 m at 12 months, there
was no significant difference between the groups
(Table 2). In the assessment of quality of life,
the domain of physical role was improved at 12
months in both pacing groups, although there was
no significant difference between the groups in
any of the domains (Table 2). There was no significant difference between the two groups in
the rate of hospitalization for heart failure.
For the subgroups shown in Figures 3 and 4,
no significant interaction was seen between biventricular pacing and left ventricular ejection fraction or left ventricular end-systolic volume at 12
months.
Events and Adverse Events
35
0
m e dic i n e
Assessment of Secondary End Points
and Subgroup Analyses
P=0.76
65
of
There were no periprocedural deaths. One patient
in the right-ventricular-pacing group died before
the 12-month visit as a result of a urinary tract
infection and septicemia. Of the 177 patients who
underwent randomization, 11 were hospitalized
for heart failure (6%): 6 in the right-ventricularpacing group (7%) and 5 in the biventricular-pacing group (6%) (P = 0.74). Among these 11 patients,
only 2, both of whom were in the right-ventricular-pacing group, had a left ventricular ejection
fraction of less than 45% at 12 months. Furthermore, three patients in the right-ventricular-pacing group (3%) were hospitalized for an acute
coronary syndrome, and two in the biventricularpacing group (2%) were hospitalized for stroke.
Seven patients in the biventricular-pacing group
had diaphragmatic pacing. In the case of five of
these patients, the condition was managed by reprogramming of the device, and there were no
further problems; the other two patients crossed
over to the right-ventricular-pacing group.
Discussion
This study shows that right ventricular apical pacing has a detrimental effect on left ventricular systolic function in patients with a normal ejection
fraction and indications for pacing owing to bradycardia. The adverse cardiac remodeling can be
prevented by biventricular pacing.
Despite the use of right ventricular apical pac-
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Biventricular vs. Right Ventricular Pacing
No. of
Patients
Subgroup
Diastolic dysfunction
No
Yes
Pacing indication
Heart block
Sinus-node dysfunction
Age
<70 yr
≥70 yr
Sex
Male
Female
Hypertension
No
Yes
Diabetes
No
Yes
Coronary heart disease
No
Yes
QRS duration
<110 msec
≥110 msec
All patients
LV Ejection Fraction (%)
RVA
BiV
Difference (percentage points)
P Value for
Interaction
0.46
66
107
54.4
55.0
63.1
61.6
102
71
54.5
55.3
62.6
61.7
86
87
54.8
54.8
60.4
63.9
95
78
53.2
57.0
61.1
63.5
60
113
56.1
54.0
62.3
62.1
125
48
56.3
51.2
62.5
61.0
135
38
55.4
53.1
62.6
60.6
113
60
173
56.2
52.2
54.8
62.5
61.8
62.2
0.53
0.20
0.62
0.53
0.67
0.93
0.24
−5.0
0.0
5.0
RVA Pacing Better
10.0
15.0
BiV Pacing Better
Figure 3. Subgroup Analyses of the Primary End Point of Left Ventricular Ejection Fraction at 12 Months.
Differences in the left ventricular
(LV) ejection
fraction between patients
who received
RETAKE:
1st biventricular (BiV) pacing
AUTHOR:
Yu
and those who received right ventricular apical (RVA) pacing are shown for each subgroup.
P values for interaction
2nd
FIGURE:
3 of 4 intervals.
3rd
are shown. The bars indicate 95%
confidence
Revised
ARTIST: MRL
SIZE
6 col
4-C
H/T
27-29
pacing in patients
33p9with sinus-node dysfunction.
AUTHOR,
NOTE: even a relatively low cumulative percentand even death has
beenPLEASE
However,
Figure has been redrawn and type has been reset.
past 7 years with the
pubage
of right ventricular apical pacing may result
Please check carefully.
Line
associationTYPE:
with the
Combo
develop-
ing for decades, its
ment of heart failure
recognized only in the
lication of the results of various large-scale trials
JOB: 36122
of pacemakers and implantable cardioverter–defi2,3,16,17
brillators.
The adverse clinical events seem
to be related to a high cumulative percentage of
right ventricular apical pacing.2-7 Such pacing
causes an abnormal left ventricular electrical-activation sequence, which is manifested on an electrocardiogram as left bundle-branch block18,19;
this abnormal sequence leads to an electro­
mechanical delay in contraction (or systolic dyssynchrony) and, subsequently, to asymmetric hypertrophy, increased mitral regurgitation, and a
decreased ejection fraction.4,20-26 Several pacing
algorithms have been developed in an attempt to
reduce the percentage of right ventricular apical
in impaired cardiac function, especially in elderly
ISSUE: 11-26-09
patients with underlying risk factors for heart
16
failure.
The PACE study showed that the mean (±SD)
left ventricular ejection fraction declined by almost
7 percentage points (from 61.5±6.6 to 54.8±9.1)
in the first year of right ventricular apical pacing
in patients with a normal ejection fraction. A previous observational study involving patients with
mildly reduced systolic function who received right
ventricular apical pacing suggested that the left
ventricular ejection fraction was reduced by 5 percentage points after a follow-up period of 3 years.30
Since three-dimensional echocardiography has
been shown to be highly accurate in measuring
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
9
The
Subgroup
Diastolic dysfunction
No
Yes
Pacing indication
Heart block
Sinus-node dysfunction
Age
<70 yr
≥70 yr
Sex
Male
Female
Hypertension
No
Yes
Diabetes
No
Yes
Coronary heart disease
No
Yes
QRS duration
<110 msec
≥110 msec
All patients
No. of
Patients
n e w e ng l a n d j o u r na l
of
m e dic i n e
LV End-Systolic Volume (ml)
RVA
BiV
P Value for
Interaction
Difference (ml)
0.39
66
107
36.9
34.9
26.4
28.4
102
71
38.6
31.2
28.0
27.1
86
87
37.4
33.8
31.8
23.4
95
78
39.4
30.6
31.1
23.3
60
113
32.2
37.7
29.4
26.8
125
48
33.5
40.8
26.6
30.6
135
38
34.0
40.1
27.0
29.6
113
60
173
34.3
38.1
35.7
25.9
29.2
27.6
0.16
0.17
0.83
0.10
0.53
0.52
0.94
−25.0
−20.0
−15.0
−10.0
BiV Pacing Better
−5.0
0.0
5.0
RVA Pacing Better
Figure 4. Subgroup Analyses of the Primary End Point of Left Ventricular End-Systolic Volume at 12 Months.
Differences in left ventricular (LV)
end-systolic
volume between patients
who received
RETAKE:
1st biventricular (BiV) pacing
AUTHOR:
Yu
and those who received right ventricular apical (RVA) pacing are shown for each subgroup.
P values for interaction
2nd
FIGURE:
4 of 4 intervals.
3rd
are shown. The bars indicate 95%
confidence
Revised
ARTIST: MRL
TYPE:
ejection
4-C
efit
H/T
even
SIZE
6 col
more 33p9
from
left ventricular volume and
biventricular pacing. Patients
AUTHOR,
NOTE:
validated against cardiac magnetic resonance
im-PLEASE
with
normal left ventricular diastolic function and
Figure has been redrawn and type has been reset.
aging and computed tomography,31 our Please
results
with abnormal left ventricular diastolic funccheckthose
carefully.
suggest that adverse left ventricular remodeling tion benefited from biventricular pacing. Since
JOB: 36122
ISSUE: 11-26-09
caused by right ventricular apical pacing might systolic and diastolic function are closely cou32
have developed more rapidly than previously an- pled, the randomization scheme of the PACE
ticipated. The results of our study suggest that in study should have avoided any confounding effect
patients who require a high percentage of ventricu- of preexisting left ventricular diastolic dysfunction
lar pacing — especially patients with atrioventricu- on the ejection fraction. Furthermore, the supelar block — a biventricular-pacing strategy is riority of biventricular pacing over right ventricpreferable to right ventricular apical pacing.
ular apical pacing was consistently observed in all
One relevant observation in the PACE study was the prespecified subgroups.
that of the nine patients in whom the left venWe did not observe any significant difference
tricular ejection fraction decreased to less than between the two pacing groups in the results of
45% at 12 months, eight (89%) were in the right- the 6-minute walk test or the quality of life assessventricular-pacing group. This suggests that the ment at the 12-month visit. Symptoms related to
ejection fraction could decrease rapidly in vulner- chronotropic incompetence might have been alleable patients and that these patients might ben- viated by the rate-responsive support afforded by
10
Line
Combo
fraction
when
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Biventricular vs. Right Ventricular Pacing
the devices in both groups. Also, a difference in
these end points may be detected with extended
follow-up if more heart-failure events occur.
There are several limitations of this study. The
sample was small, and the study was not powered
to detect significant differences in clinical events.
However, the study was designed with adequate
power to test for the expected differences between
the two pacing groups with respect to left ventricular systolic function and left ventricular volume. The success rate for implantation of the
biventricular-pacing system was 92%, which is
lower than that for conventional dual-chamber
pacing but similar to that for pacemakers that are
implanted in patients with heart failure. Advances
in the techniques used to implant left ventricular
leads would be expected to improve the success
rate even further and reduce device-related complications. The increased cost and complications
associated with biventricular pacemakers are potential concerns. Randomized trials with longer
follow-up periods, larger samples, and sufficient power to evaluate clinical outcomes between
these two pacing strategies are warranted.
Supported by Medtronic.
Dr. Yu reports receiving consulting fees from Philips, lecture
fees from GE, St. Jude Medical, Philips, Medtronic, and Boston
Scientific, and research grants from Sanofi-Aventis Hong Kong
and Philips; and Drs. Omar, Yip, and Hussin, receiving lecture
fees from Medtronic. No other potential conflict of interest relevant to this article was reported.
APPENDIX
Steering Committee: C.-M. Yu, G.W.-K. Yip, Q. Zhang, J.Y.-S. Chan, Chinese University of Hong Kong; J.W.-H. Fung, North District
Hospital; O. Razali, H. Azlan; National Heart Institute. Echocardiographic Core Laboratory: G.W.-K. Yip, C.-M. Yu, Q. Zhang, F. Fang,
Chinese University of Hong Kong. Clinical Event Committee: W. Chan, A. Chan, Chinese University of Hong Kong; W.L Chan, Alice Ho
Miu Ling Nethersole Hospital. Publication Committee: C.-M. Yu, J.W.-H. Fung, G.W.-K. Yip, Q. Zhang, J.Y.-S. Chan, Chinese University of Hong Kong; O. Razali, H. Azlan, National Heart Institute. Other investigators and institutions that participated in the PACE study:
Alice Ho Miu Ling Nethersole Hospital, Hong Kong — H.C.-K. Chan, W.L. Chan; Prince of Wales Hospital, Chinese University of Hong
Kong — J.Y.-S. Chan, C.-M. Yu, G.W.-K. Yip, A.K.Y. Chan; G.C.P. Chan; National Heart Institute, Kuala Lumpur — O. Razali, H. Azlan,
K.H. Lam; North District Hospital, Hong Kong — J.W.-H. Fung, K.H. Yiu.
References
1. Wiggers CJ. The muscular reactions of
mammalian ventricles to artificial surface
stimuli. Am J Physiol 1925;73:346-78.
2. Wilkoff BL, Cook JR, Epstein AE, et al.
Dual-chamber pacing or ventricular backup pacing in patients with an implantable
defibrillator: the Dual Chamber and VVI
Implantable Defibrillator (DAVID) Trial.
JAMA 2002;288:3115-23.
3. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular
pacing on heart failure and atrial fibrillation among patients with normal baseline
QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932-7.
4. Thambo JB, Bordachar P, Garrigue S,
et al. Detrimental ventricular remodeling
in patients with congenital complete heart
block and chronic right ventricular apical
pacing. Circulation 2004;110:3766-72.
5. Tse HF, Yu C, Wong KK, et al. Functional abnormalities in patients with permanent right ventricular pacing: the effect of sites of electrical stimulation. J Am
Coll Cardiol 2002;40:1451-8.
6. O’Keefe JH Jr, Abuissa H, Jones PG, et
al. Effect of chronic right ventricular apical pacing on left ventricular function.
Am J Cardiol 2005;95:771-3.
7. Thackray SD, Witte KK, Nikitin NP,
Clark AL, Kaye GC, Cleland JG. The prevalence of heart failure and asymptomatic
left ventricular systolic dysfunction in a
typical regional pacemaker population.
Eur Heart J 2003;24:1143-52.
8. Frias PA, Corvera JS, Schmarkey L,
Strieper M, Campbell RM, Vinten-Johansen
J. Evaluation of myocardial performance
with conventional single-site ventricular
pacing and biventricular pacing in a canine model of atrioventricular block. J Cardiovasc Electrophysiol 2003;14:996-1000.
9. Cojoc A, Reeves JG, Schmarkey L, et
al. Effects of single-site versus biventricular epicardial pacing on myocardial performance in an immature animal model
of atrioventricular block. J Cardiovasc Electrophysiol 2006;17:884-9.
10. Kindermann M, Hennen B, Jung J,
Geisel J, Böhm M, Fröhlig G. Biventricular
versus conventional right ventricular stimulation for patients with standard pacing
indication and left ventricular dysfunction: the Homburg Biventricular Pacing
Evaluation (HOBIPACE). J Am Coll Cardiol
2006;47:1927-37.
11. Lieberman R, Padeletti L, Schreuder J,
et al. Ventricular pacing lead location alters systemic hemodynamics and left ventricular function in patients with and without reduced ejection fraction. J Am Coll
Cardiol 2006;48:1634-41.
12. Fung JW, Chan JY, Omar R, et al. The
Pacing to Avoid Cardiac Enlargement
(PACE) trial: clinical background, ratio-
nale, design, and implementation. J Cardiovasc Electrophysiol 2007;18:735-9.
13. Oh JK, Seward JB, Tajik AJ. The echo
manual. 3rd ed. Philadelphia: Lippincott
Williams & Wilkins, 2006.
14. Zhang Q, Yu CM, Fung JW, et al. Assessment of the effect of cardiac resynchronization therapy on intraventricular mechanical
synchronicity by regional volumetric changes. Am J Cardiol 2005;95:126-9.
15. Kapetanakis S, Kearney MT, Siva A,
Gall N, Cooklin M, Monaghan MJ. Realtime three-dimensional echocardiography: a novel technique to quantify global
left ventricular mechanical dyssynchrony.
Circulation 2005;112:992-1000.
16. Sweeney MO, Hellkamp AS. Heart
failure during cardiac pacing. Circulation
2006;113:2082-8.
17. Steinberg JS, Fischer A, Wang P, et al.
The clinical implications of cumulative
right ventricular pacing in the Multicenter
Automatic Defibrillator Trial II. J Cardiovasc Electrophysiol 2005;16:359-65.
18. Tops LF, Schalij MJ, Holman ER, van
Erven L, van der Wall EE, Bax JJ. Right
ventricular pacing can induce ventricular
dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol 2006;48:1642-8.
19. Vassallo JA, Cassidy DM, Miller JM,
Buxton AE, Marchlinski FE, Josephson
ME. Left ventricular endocardial activa-
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
11
Biventricular vs. Right Ventricular Pacing
tion during right ventricular pacing: effect of underlying heart disease. J Am Coll
Cardiol 1986;7:1228-33.
20. Prinzen FW, Augustijn CH, Arts T, Allessie MA, Reneman RS. Redistribution of
myocardial fiber strain and blood flow by
asynchronous activation. Am J Physiol 1990;
259:H300-H308.
21. Kanzaki H, Bazaz R, Schwartzman D,
Dohi K, Sade LE, Gorcsan J III. A mechanism for immediate reduction in mitral
regurgitation after cardiac resynchronization therapy: insights from mechanical
activation strain mapping. J Am Coll Cardiol 2004;44:1619-25.
22. Maurer G, Torres MA, Corday E,
Haendchen RV, Meerbaum S. Two-dimensional echocardiographic contrast assessment of pacing-induced mitral regurgitation: relation to altered regional left
ventricular function. J Am Coll Cardiol
1984;3:986-91.
23. Vanderheyden M, Goethals M,
Anguera I, et al. Hemodynamic deterioration following radiofrequency ablation of
the atrioventricular conduction system.
Pacing Clin Electrophysiol 1997;20:2422-8.
12
24. Nielsen JC, Kristensen L, Andersen
HR, Mortensen PT, Pedersen OL, Pedersen
AK. A randomized comparison of atrial
and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome:
echocardiographic and clinical outcome.
J Am Coll Cardiol 2003;42:614-23.
25. Nielsen JC, Andersen HR, Thomsen
PE, et al. Heart failure and echocardiographic changes during long-term followup of patients with sick sinus syndrome
randomized to single-chamber atrial or
ventricular pacing. Circulation 1998;97:
987-95.
26. Nahlawi M, Waligora M, Spies SM,
Bonow RO, Kadish AH, Goldberger JJ.
Left ventricular function during and after
right ventricular pacing. J Am Coll Cardiol
2004;44:1883-8.
27. Gillis AM, Pürerfellner H, Israel CW,
et al. Reducing unnecessary right ventricular pacing with the managed ventricular
pacing mode in patients with sinus node
disease and AV block. Pacing Clin Electrophysiol 2006;29:697-705.
28. Olshansky B, Day J, McGuire M, Hahn
S, Brown S, Lerew DR. Reduction of right
ventricular pacing in patients with dualchamber ICDs. Pacing Clin Electrophysiol
2006;29:237-43.
29. Sweeney MO, Bank AJ, Nsah E, et al.
Minimizing ventricular pacing to reduce
atrial fibrillation in sinus-node disease.
N Engl J Med 2007;357:1000-8.
30. Glotzer TV, Hellkamp AS, Zimmerman J, et al. Atrial high rate episodes detected by pacemaker diagnostics predict
death and stroke: report of the Atrial Diagnostics Ancillary Study of the MOde
Selection Trial (MOST). Circulation 2003;
107:1614-9.
31. Sugeng L, Mor-Avi V, Weinert L, et al.
Quantitative assessment of left ventricular size and function: side-by-side comparison of real-time three-dimensional
echocardiography and computed tomography with magnetic resonance reference.
Circulation 2006;114:654-61.
32. Yip GW, Zhang Y, Tan PY, et al. Left
ventricular long-axis changes in early diastole and systole: impact of systolic function on diastole. Clin Sci (Lond) 2002;
102:515-22.
Copyright © 2009 Massachusetts Medical Society.
10.1056/nejmoa0907555 nejm.org
Downloaded from www.nejm.org on November 15, 2009 . For personal use only. No other uses without permission.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.