Download Should All Patients With Heart Block Receive Biventricular Pacing?

Controversies in
Arrhythmia and
Electrophysiology
Should All Patients With Heart Block
Receive Biventricular Pacing?
Routine Use of Biventricular Pacing Is Not Warranted for
Patients With Heart Block
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Ivan A. Arenas, MD, PhD; Jason Jacobson, MD; Gervasio A. Lamas, MD
V
between single and dual chamber pacing modes. In fact, by
2009, DDD pacemakers accounted for 82% of all implants
(VVI for only 14%).18 These statistics speak loudly about
the impact of technology on daily clinical practice. A similar quandary now exists with regards to biventricular pacing.
We suggest that the global utilization of biventricular pacing
for all bradycardia patients is not supported by existing data,
and that evidence-based application of technology is the best
choice for our patients.
entricular pacing can be lifesaving for patients with complete atrioventricular block (AVB). Since the introduction of permanent transvenous cardiac pacing >40 years ago,
the right ventricular (RV) apex has been the preferred site for
ventricular stimulation. This location provides good fixation
and low capture thresholds. However, RV apical pacing may
induce cardiac dyssynchrony. Hence, it has been suggested
that all patients with symptomatic AVB (regardless of current
indication for biventricular pacing), with anticipated high RV
pacing burden, should receive preventive biventricular pacing. In this article, we review the physiological effects of RV
pacing, data from observational studies (Table I in the Data
Supplement),1–6 and available randomized trials comparing
biventricular versus RV pacing (Table).7–16
Activation Pathways and Cardiac
Performance During RV Pacing
The sequence of electric activation of the heart is the physiological determinant of mechanical atrioventricular synchrony
and intra left ventricular (LV) synchrony; both of which are
independent and additive in contributing to normal cardiac
performance and to pacing hemodynamics.22,23 Studies in isolated human hearts24 showed that normal ventricular excitation
starts synchronously at 3 widely different endocardial locations in the LV, with RV activation to follow closely (5–10 ms
after LV activation). In contrast, RV-paced wavefronts propagate slowly from apex (or pacing site) to base.25 This slowing
is presumably because of predominant cell-to-cell propagation with limited or no engagement of the Purkinje conduction system. The effect of ventricular activation on cardiac
performance during pacing has been extensively investigated.
Boerth and Covell26 reported that during RV outflow-tract
Response by Fang et al on p 738
Since the initial report of the use of endocardial pacing to
treat complete AVB by Furman and Schwedel in 195917, pacemakers have evolved dramatically into complex devices with
the ability to sequentially pace the atrium and both ventricles.
Between 1993 and 2009, 2.9 million patients received a permanent pacemaker in the United States.18 During this time,
overall pacemaker use increased by 55.6%. However, although
the use of dual chamber (DDD) pacemakers increased by at
least 40%, the use of single-chamber ventricular (VVI) pacemakers decreased ≈50%,18 despite the evidence from large
pacing trials19–21 indicating no major differences in outcomes
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Department of Medicine, Division of Cardiology at Mount Sinai Medical Center, Columbia University, Miami Beach, FL.
The Data Supplement is available at http://circep.ahajournals.org/lookup/suppl/doi:10.1161/CIRCEP.114.000627/-/DC1.
Correspondence to Gervasio A. Lamas, MD, Mount Sinai Medical Center, 4300 Alton Rd, Suite 2070A, Miami Beach, FL 33140. E-mail gervasio.
[email protected]
(Circ Arrhythm Electrophysiol. 2015;8:730-738. DOI: 10.1161/CIRCEP.114.000627.)
© 2015 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
730
DOI: 10.1161/CIRCEP.114.000627
Arenas et al Biventricular Pacing in Patients With Heart Block 731
Table. Randomized Controlled Studies Comparing Right Ventricular and Biventricular Pacing
Study/Reference
Year
n
Follow-Up (Mean)
Mean LVEF±SD (%)
Main Outcomes
Brignole et al,7 OPSITE study
2005
56
Crossover study;
3-mo treatment period
38±14
Quality-of-life and functional class were better in the
biventricular group (P<0.05). LVEF improved by 5% and
10% in the RV and biventricular groups (P<0.05)
Doshi et al,8 The Pave study
2005
184
6 mo
45±15
Biventricular group had greater improvement in 6-minute
walk distance. No differences in quality-of-life. LVEF was
higher (46±13) in the biventricular group compared with
RV pacing group (41±13) (P<0.05)
Orlov et al,9 AVAIL CLS/CRT
2010
108
6 mo
57±7
No differences in 6-minute walk, quality-of-life, or
mortality. LVEF did not change in the RV pacing group
but slightly improved in the biventricular group (from
56.1±9.4% to 59.3±7.7%; P<0.05)
Brignole et al10
2011
186
20 mo
37±14
Primary composite end point of death from HF, HFH, or
worsening HF occurred less in the biventricular vs RV
pacing (11% vs 26% respectively; P<0.01). No differences
in total mortality (P=0.37)
Kindermann et al,11 HOBIPACE study
2006
30
Crossover design;
3-mo treatment period
26±7
Biventricular pacing reduced LV volume (P<0.01), NTproBNP levels (P<0.01), and improved quality-of-life
(P=0.01). There was a 22% relative improvement in LVEF
(P<0.01) and functional parameters compared with RV
pacing
Yu et al,12 PACE study
2009
177
12 mo
61±6
LVEF was lower in RV pacing vs biventricular group
(54.8±9.1% vs 62.2±7.0%; P<0.05), and LV volume
higher (RV group: 35.7±16.3 mL; biventricular group:
27.6±10.4 mL; P<0.05). There were no differences in HFH
or mortality
Chan et al,13 PACE study
2011
177
2y
61±6
Compared with biventricular pacing, RV pacing was
associated with increased in LV end-systolic volume
(+13.0 mL; P<0.01) and decreased in LVEF (–9.9%;
P<0.01). There were no differences in quality-of-life,
6-minute hall-walk distance, and no differences in HFH or
mortality
Albertsen et al14
2008
55
12 mo
Median quartiles
59 (57–61)
LVEF was not different between groups after 12 mo.
NT-proBNP was unchanged in the DDD(R) group during
follow-up but decreased significantly in the biventricular
group (P=0.02)
Stockburger,15 PREVENT-HF
2011
108
12 mo
54±12
Intention-to-treat and on-treatment analyses revealed no
significant differences in outcomes. LVEF and HF events
did not differ between groups.
Curtis et al,16 BLOCK HF
2013
691
37 mo
40±8
Primary composite end point of death from any cause,
an urgent care visit for HF that required intravenous
therapy, or a 15% or more increase in left ventricular endsystolic volume index occurred least frequently in patients
assigned to biventricular pacing (hazard ratio, 0.74; 95%
CI, 0.6 to 0.9).
Patients after atrioventricular node ablation
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Patients with atrioventricular block
AVAIL CLS/CRT indicates the AV Node Ablation With CLS and CRT Pacing Therapies for Treatment of AF trial; BLOCK HF, the Biventricular Versus Right Ventricular
Pacing in Heart Failure Patients With Atrioventricular Block trial; CI, confidence interval; HF, heart failure; HFH, heart failure hospitalizations; HOBIPACE, Homburg
Biventricular Pacing Evaluation; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide; OPSITE, Optimal Pacing SITE; PACE, Pacing
to Avoid Cardiac Enlargement; PREVENT-HF, Preventing Ventricular Dysfunction in Pacemaker Patients Without Advanced Heart Failure; and RV, right ventricular.
stimulation the mechanical efficiency of the LV was decreased
without primary effects on cardiac contractility. Rosenqvist
et al27 reported that LV ejection fraction (LVEF) and cardiac
output were higher during single-chamber atrial than during
either DDD or VVI modes. The septum shows a paradoxical
pattern of movement during systole in most patients with VVI
or DDD pacing, which was associated with a 20% to 25%
impairment of the septal regional EF.
Other studies have shown that asynchronous ventricular
activation can increase, or even cause, mitral regurgitation,28
732 Circ Arrhythm Electrophysiol June 2015
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increase LV remodeling,29 change myocardial perfusion,30
and ventricular geometry.31 These unphysiological effects
have been attributed to an abnormal late activation of the
lateral wall of the LV, which results in a redistribution of
myocardial strain and work, with less effective contraction.32 Although RV apical pacing has some resemblance
in the surface ECG with a native left bundle branch block
(LBBB), the activation pathways, electromechanical delay,
and LV synchrony largely differ between both conditions.
Moreover, with RV pacing, the LV is activated more rapidly than with LBBB, even when a LBBB is present before
pacing.33 Therefore, it is not intellectually rigorous to fully
extrapolate the detrimental effects of LBBB and the benefits
of cardiac resynchronization therapy (CRT) to all patients
who need RV pacing.
But can the physiological findings attributed to RV pacing–induced cardiac dyssynchrony translate into meaningful
clinical outcomes such as heart failure hospitalizations (HFH)
and mortality? Can these outcomes be improved by preventive
biventricular pacing?
Lessons From Large Trials of Atrial Based
Versus Ventricular Pacing Modes
In 1994, the first randomized trial comparing single-chamber
atrial with VVI pacing in patients with normal AV conduction was reported.34 This relatively small trial included 225
patients (mean age of 76 years) with sinus node dysfunction
and normal QRS and reported no significant differences in
survival during the initial follow-up of 3.3 years. However,
longer follow-up to a mean of 5.5 years showed that cardiovascular death had occurred in more patients in the ventricular pacing group compared with the atrial pacing group
(P<0.01).35 Moreover, New York Heart Association (NYHA)
class was significantly lower in the atrial pacing group
(NYHA class I, 84%) compared with the ventricular pacing
group (NYHA class I, 65%). This study was relevant because
it was the first to suggest that the ventricular dyssynchrony
caused by RV pacing might have detectable clinical consequences. Yet, tempting as it may be, we cannot extrapolate
the benefit of avoidance of RV pacing a patient with a narrow
QRS to the conclusion that CRT is beneficial in all patients
with AVB.
Subsequently, larger pacing trials included in aggregate
>7000 bradycardia patients; the Pacemaker Selection in the
Elderly (PASE) trial,36 the Canadian Trial of Physiologic Pacing
(CTOPP),19 the United Kingdom Pacing and Cardiovascular
Events (UKPACE),21 and the Mode Selection Trial in Sinus
Node Dysfunction (MOST),20 investigated the outcomes of
physiological DDD pacemakers versus ventricular pacing.
Overall, these large pacing trials37 showed some benefit in
reducing atrial fibrillation (AF) rates (in MOST and CTOPP),
but only MOST showed slightly fewer HFH in the DDD pacing group (10.3%) than in the ventricular pacing group (12.3%;
P=0.02). However, no reduction in mortality was seen in any
individual trial. An individual patient data meta-analysis37
of these major pacing trials, including the trial by Andersen,
MOST, UKPACE, PASE, and CTOPP, investigated the aggregate effect of DDD versus ventricular pacing mode on mortality, stroke, heart failure (HF), or AF. There was no significant
reduction in mortality (hazard ratio [HR], 0.95; 95% confidence
interval [CI], 0.87–1.03; P=0.19) or HF (HR, 0.89; 95% CI,
0.77–1.03; P=0.15) with DDD pacing, only a reduction in AF
(HR, 0.80; 95% CI, 0.72–0.89; P<0.01) and borderline reduction in stroke (HR, 0.81; 95% CI, 0.67–0.99; P=0.03).37 Hence,
in aggregate, there were no major clinical benefits derived from
physiological pacing compared with ventricular pacing. These
findings contrasted sharply with the growing body of physiological data in favor of AV synchrony, puzzled the scientific
community, and were ignored by the practice community.
The modern impetus for understanding the consequences
of desynchronization by RV pacing was spearheaded by
Sweeney et al.38 In a retrospective analysis of MOST, a 6-year
trial comparing rate-modulated ventricular with DDD pacing (VVIR versus DDDR) in 2010, patients with sinus node
dysfunction, the authors found that the risk of HFH increased
with the cumulative percentage of RV pacing.38 Thus, in retrospect, it was thought that the benefits of AV synchrony in
these large trials could have been offset by LV dyssynchrony.
However, the association of RV pacing with HFH and AF seen
in MOST did not permit a conclusion, but rather posited a
hypothesis, which was subsequently tested in the Search AV
Extension and Managed Ventricular Pacing for Promoting
Atrioventricular Conduction trial (SAVE-PaCE).
The SAVE-PaCE study39 investigated the outcomes of
conventional DDD pacing compared with a pacing strategy to
reduce RV pacing. Thus, 1065 patients with sinus node disease,
intact atrioventricular conduction, and a normal QRS interval were randomized to either pacing strategy (535 versus 530
patients). The median burden of ventricular pacing was significantly less in the group assigned to DDD minimal RV pacing
than in the group assigned to conventional DDD pacing (9.1%
versus 99.0%, P<0.01), whereas the burden of atrial pacing was
similar between the groups. There was a 40% reduction in the
relative risk of persistent AF in patients with DDD minimal ventricular pacing when compared with those with conventional
DDD pacing, however, the mortality rate was not significantly
different between the 2 groups (4.9% for DDD minimal ventricular pacing versus 5.4% in the group receiving conventional
DDD pacing), and there were no differences in HFH.39 Thus,
for patients with sinus node dysfunction, it is best to avoid RV
pacing. Such avoidance reduces AF and may reduce HFH, but
there is no evidence that it reduces mortality. Although this strategy does not apply to patients with fixed complete heart block,
patients with first and second degree AVB and intermittent third
degree AVB might benefit from minimization of RV pacing.
Admittedly, the benefit of reducing ventricular pacing
for the most serious end points was modest. For instance,
in MOST, overall rates of HFH for patients with a ventricular pacing burden >90%, after a median follow-up of 33.1
months, were 12% and 16% in the DDDR and VVIR groups,
Arenas et al Biventricular Pacing in Patients With Heart Block 733
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respectively.38 Moreover, for the subset of patients with
normal LVEF, narrow baseline QRS, and no history of HF,
who were paced >80% or >40% of the time in the VVIR or
DDDR modes, the predicted 2-year probability of developing HF was <2%.40 In UKPACE, which randomized patients
with high degree AVB, the median percentage of ventricular
pacing was 94% in the single chamber and 99% in the DDD
group.21 The mean annual mortality rates were 7.2% in the
single-chamber group and 7.4% in the DDD group, and the
annual HFH rates were 3.2% and 3.3% respectively.21 Similar
mortality and HFH rates were seen in CTOPP.19 It is important
to note that the patients studied were bradycardia patients. As
a rule, they had a low background prevalence of HF, and when
LVEF was measured, the median was in the normal range.
Thus, the detrimental effects of ventricular desynchronization
were relatively minimal.
In contrast, the Dual Chamber and VVI Implantable
Defibrillator (DAVID) trial41 enrolled implantable cardioverter defibrillator (ICD) patients with significant LV dysfunction (mean LVEF of 27%), a population vulnerable to
any downward perturbation in LVEF and different from the
bradycardia patients discussed above. They found that when
compared with backup ventricular demand pacing at 40 beats
per minute (VVI-40), permanent DDDR pacing at 70 beats
per minute (DDDR-70) was associated with higher risk of
a combined outcome of death from any cause or HFH (relative hazard, 1.61; 95% CI, 1.06–2.44; P≤0.03). Although the
component end points did not reach statistical significance,
they did trend in favor of VVI-40 for reduction in events.
Rates of HFH at 1 year were 13.3% and 22.6% for VVI-40
and DDDR-70 groups (9.3% excess of HFH in the DDDR
group; P=0.07), whereas death rates were 6.5% and 10.1%,
respectively (P=0.15). Patients included in the DAVID trial
had normal AV conduction and no pacing needs, so that the
primary difference from a ventricular pacing perspective is
that because of traditional AV timing, the DDD-70 group
paced ventricle nearly 60% of all ventricular beats. The VVI40 group, not needing bradycardia pacing, had 1% ventricular pacing. Additional analyses of percentage of ventricular
pacing showed a breakpoint at 40% pacing, above which
adverse outcomes became more prevalent. Although these
observations cannot be extrapolated to patients with AVB
that require bradycardia pacing, they indicate that patients
with LV dysfunction sufficient to require ICD placement are
highly susceptible to ill effects from frequent ventricular pacing. Moreover, the data from MOST allow us to infer that
patients with severe baseline LV dysfunction are far more
vulnerable than are patients with preserved LV function.
This has been further explored in subanalyses of the Second
Multicenter Automated Defibrillator Implantation Trial
(MADIT II) and the Inhibition of Unnecessary RV Pacing
With AV Search Hysteresis in ICDs (INTRINSIC RV) that
included ICD patients programmed in the DDD mode. In
these trials, cumulative RV pacing was also associated with
higher rates of HF/mortality or VT-VF therapy.42,43
Clinical Outcomes of RV Pacing
in Observational Studies
Observational studies reporting effects from long-term RV
pacing are mostly retrospective in nature involve a small to
moderate sample size (n=55–304) and encompass a wide
range of follow-up (1–7.8 years; Table I in the Data Supplement).1–6 Most of these studies were conducted in patients
with AF and subsequent RV pacing after atrioventricular node
(AVN) ablation. Overall, they showed that for patients with
normal LV function preimplantation, there were no changes in
LVEF after 12 to 20 months of RV pacing.1,3 Moreover, 8% to
15% of patients experienced a decline in LVEF or developed
HF after 4 to 8 years of pacing.3,4 It is apparent from these
observations that most patients do not develop adverse clinical outcomes after prolonged RV pacing. Hence, it does not
seem appropriate to place preventive biventricular pacers in
all individuals that may require permanent ventricular pacing,
particularly when this minority of patients can often undergo
LV lead implantation should their clinical situation require it.
In fact, data from the European CRT survey comparing outcomes of nearly 2400 CRT implant procedures (≈30% CRT
upgrades), suggests no differences in clinical outcomes or
complication rates between upgrades and de novo CRT procedures.44 This survey showed that individuals undergoing CRT
upgrade are older have more ischemic pathogenesis of HF,
more prevalence of AF, wider QRS at the time of upgrade, but
similar functional class and slightly better LVEF compared
with patients having de novo CRT procedures.44
Randomized Clinical Trials Comparing
RV and Biventricular Pacing
Information from 9 trials comparing RV and biventricular
pacing including a total of 1595 patients is shown in Table.7–
16
Four studies7–10 (n=534) enrolled patients with AF after
AVN ablation, and 5 studies11–16 (n=1061) were conducted in
patients with AVB.
RV Versus Biventricular Pacing in Patients With AF
After AVN Ablation
The sample size of these studies ranged from 56 to 186 patients
with a maximal follow-up duration of 20 months. The studies
by Brignole et al,7 Doshi et al,8 and Orlov et al9 conducted in
patients with relatively preserved LVEF (38% to 55%) found
that patients who received biventricular pacers had a modest
improvement in LVEF (2% to 5% absolute EF increase), and
some improvement in quality of life scores7,8 or walking distance compared with patients receiving RV pacing.9 The Ablate
and Pace in Atrial Fibrillation (APAF) published in 201110 was
the only trial showing benefits in terms of HFH. However, this
study enrolled 186 patients who were in drug-refractory HF
with depressed LV function and wide QRS complexes and
in whom a clinical decision had been made to undertake AV
nodal ablation and biventricular pacing. Indeed, nearly 50% of
patients had LVEF≤35% and ≈40% required ICD placement
at the time of enrollment, resembling more the population of
734 Circ Arrhythm Electrophysiol June 2015
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the DAVID trial. In these patients, the primary composite end
point of death from HF, HFH, or worsening HF occurred less
often in the biventricular group (11%) compared with the RV
group (26%). However, there were no differences in mortality. As expected, the greatest benefit was seen in patients who
already met CRT requirements, but there was only a borderline significant reduction in the risk of HF, HR (0.41; 95% CI,
0.17–0.99; P=0.05), when the analysis was confined to individuals with LVEF>35% (n=140).10 The authors did not report
the baseline characteristics of this subgroup. A meta-analysis45
including the APAF trial10 as well as of the trials by Brignole
et al,7 Doshi et al,8 and Orlov et al9 with a total of 534 patients
found that compared with RV pacing, biventricular pacing was
associated with an absolute increase in LVEF (2.6%; 95% CI,
1.69–3.44), improvement in quality of life, but no significant
improvement in 6-minute walk distance and no significant
reduction in mortality.45 Therefore, in patients with refractory
AF that undergo AVN ablation, biventricular pacing may provide clinical benefit only in patients who have LV dysfunction,
whereas for those with normal or near normal LVEF, there is
no apparent clinical benefit. Thus, the modest differences in
LVEF between RV and biventricular pacing are likely to be
clinically relevant only in patients with symptomatic HF and
reduced ventricular function.
RV Versus Biventricular Pacing in Patients With AVB
Two trials enrolled patients with reduced LVEF11,16 and 3 trials
randomized patients with normal or nearly normal LVEF12–15
(Table).
The Homburg Biventricular Pacing Evaluation
(HOBIPACE) trial reported in 200611 was a prospective, randomized crossover study that compared 3 months of RV pacing
with 3 months of biventricular pacing in 30 patients with LVEF
<40% (with most participants having LVEF<30%). The average participant of this study was in HF (NYHA functional class
3.0±0.6) had low LVEF ≈26% and a long QRS (≈174 ms) with
a LBBB (63% of participants had complete LBBB); hence most
participants were already eligible for ICD and CRT. Both RV
and biventricular pacing were associated with improvement in
LVEF and reduced LV end-diastolic and end-systolic volumes.
However, biventricular pacing resulted in a 6.3% absolute
increase in LVEF compared with RV pacing (34.8±8.9 versus
28.5±11.2; P<0.01; relative increase of 22%, P<0.01), reduced
LV end-systolic volume by 17% (P<0.01), and peak oxygen
consumption by 12% (P<0.01). In RV-paced patients, benefits
were mostly seen in those who received septal RV leads. Of
note, similar to other trials, the physiological response to biventricular pacing showed a wide range from absent to large.11 In
contrast, the studies by Albertsen et al14 and Stockburger et al15
included patients with normal LVEF and borderline QRS duration (117 and 123 ms). The average follow-up was 12 months
in both studies. In these trials, there were no differences in outcomes, which included LVEF changes and HFH rates.14,15
Similarly, The Pacing to Avoid Cardiac Enlargement
(PACE) trial12 found that in individuals with normal LVEF
randomized to RV or biventricular pacing, there were no differences in functional class, HFH, or mortality after 12 months
of follow-up. However, after 1 year of follow-up, patients in
the RV group had a reduction in LVEF (from 61.5±6.6% to
54.8±9.2%; P<0.01), whereas the LVEF in the biventricular pacing group remained unchanged (from 61.8±6.7% to
62.2±7%). LV end-systolic volume increased in the RV pacing
group (from 28.4±10.7 to 35.7±16.2 mL; P<0.01) but did not
significantly change in the biventricular group (from 28.2±9.4
to 27.6±10.2 mL). Chan et al13 reported a 2-year follow-up of
the PACE trial. There was a small additional mean absolute
reduction in LVEF of 1.8% compared with LVEF at 1 year
(P<0.05) and an absolute mean increase in LV end-systolic
volume of 2.6 mL in the RV group (P<0.05), whereas for the
average biventricular patient, LVEF and LV size remained
stable. However, after 2 years of follow-up, there were no
differences in quality-of-life assessment, 6-minute hall-walk
distance, or clinical outcomes (HFH or mortality).13 Overall,
these trials found biventricular pacing to have a modest impact
on LVEF and LV volume compared with RV pacing but no
differences in HFH or mortality.
The Biventricular Versus Right Ventricular Pacing in Heart
Failure Patients With Atrioventricular Block (BLOCK HF)
trial16 is the most recent and largest trial comparing RV and
biventricular pacing modes in patients with indication for pacing and evidence that they would require frequent ventricular
pacing (2nd and 3rd degree AVB or first degree AVB with a PR
interval of at least 300 ms when paced at 100 beats per minute)
and a LVEF of ≤50%. BLOCK HF enrolled 691 patients with
LV dysfunction (average LVEF 40%), 30% had LVEF<35%
and near a third of participants (n=207) had an ICD placed at
the time of pacemaker insertion. Participants were in NYHA
class I, II, or III and not meeting current indications for CRT
to receive DDDR or BIV-DDDR pacing. The median percentage of ventricular pacing during follow-up was >97% for both
pacing groups, and the mean follow-up was 37 months. The
combined primary end point was unusual in that it combined
morphological and clinical variables (increase in left ventricular end-systolic volume index >15% or urgent care visit for HF
or death). Such end points are even harder to interpret than the
usual combined clinical end points. Regardless, the primary
end point occurred more often in the RV pacing group with
a 26% relative reduction in the biventricular group, largely
driven by change in LV end-systolic volume which occurred
in 160 patients in the biventricular group compared with 190
patients in the RV group. Urgent care visits for HF occurred
in 56 and 61 patients and death occurred in 17 and 14 patients
in the biventricular and RV groups, respectively, a small clinical difference. In this trial, a Bayesian analysis was utilized
and its comparability to traditional analyses is unclear. HFH
occurred in 21% and 26% of the biventricular and RV groups,
respectively, which represents a 5% absolute risk reduction
(n=14 events). Although this study would seem to suggest that
biventricular pacing might be the mode of choice for patients
with AVB, patient selection again weakens the assertion. The
Arenas et al Biventricular Pacing in Patients With Heart Block 735
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study was heavily seeded with low EF, HF patients: 30% of
the participants of this study had LVEF<35% and a third of
individuals were NHYA class III patients who already might
benefit from a biventricular ICD. Furthermore, nearly 50% of
participants in this study were not in complete heart block and
could benefit from atrial-based minimal ventricular pacing.
Thus, BLOCK HF suggests that there is at least a group of
patients with LV dysfunction requiring bradycardia pacing, in
whom biventricular pacing will possibly yield at least modest
clinical benefit, so long as baseline LV function is known. It is
not clear, however, whether the benefit is isolated to patients
who should be receiving an ICD anyways. Moreover, the 5%
absolute risk reduction by biventricular pacing in this population could be offset by the higher rate of complications related
to this procedure (10.3% in BLOCK HF).
Available trial data suggest that for individuals with normal LVEF, the use of preventive biventricular pacing has no
clinical benefits in terms of HFH or mortality. In those with
moderate to severe LV dysfunction (LVEF<35%), biventricular pacing improves functional capacity and reduces HFH.
However, for patients with LVEF between 35% and 50%, the
benefit of preventive biventricular pacing is unclear, and predicting deterioration of LV function after prolonged RV pacing in this population is clinically relevant. Hence, long-term
follow-up studies investigating the role of biventricular pacing
in AVB patients with mildly reduced LV function are needed.
BLOCK HF provided the longest follow-up of the available
trials comparing RV and biventricular pacing (mean followup, 3.7 years; Table). However, BLOCK HF also included
high-risk patients with low LVEF.
Prior HFH, coronary artery disease, male sex, and wider
paced QRS duration after implantation may predict worse outcomes after prolonged RV pacing.5,6 In MOST, NYHA class
at the time of pacemaker implantation, history of myocardial
infarction, low baseline LVEF, and prolonged QRS duration
(spontaneously or with RV pacing) predicted HFH.40 Still,
there is a lack of validated predictors to guide on the table
decisions to find the RV location that best suits a particular
patient or to decide if a particular patient will benefit most
for biventricular pacing. Indeed, the best strategy seems to be
to know the patients’ LVEF and their functional class before
pacemaker implantation, data obtainable with a bedside echo
and a short conversation rather than the shotgun overuse of
technology in every case. Of note, other RV pacing locations
have been associated with less cardiac dyssynchrony when
compared with RV apical pacing. These include para-Hisian
pacing, RV septum, right ventricular outflow tract in the septal
region, and the pulmonary infundibulum. Pacing from the RV
septum results in a shorter QRS compared with pacing from
other RV sites.46 Pacing failure in this setting occurs more
often in patients with AF, RV dilatation, or high-grade tricuspid insufficiency.47 However, a meta-analysis by Shimony et
al,48 including a total of 754 patients from 14 studies, found
no significant differences in terms of quality of life, functional
tests (walking test, maximum oxygen consumption), and
morbidity/mortality. A favorable effect on LVEF was demonstrated for follow-up periods of >12 months and for patients
with LVEF ≤45%. Current large randomized studies are comparing right ventricular outflow tract and RV septum with RV
apical pacing.49
So ultimately, we are left with the question of what patient
who does not concurrently require a biventricular ICD requires
biventricular bradycardia pacing alone? Biventricular bradycardia pacemakers account for <10% of implants in the United
States.18 Biventricular pacers are more expensive and associated with more complications. These may lead to hospitalizations and reoperations in 10% to 15% of patients.8,11,13 In the
BLOCK HF trial,16 10.3% of patients had events related to the
procedure or device. LV lead–related complications occurred
in 6.4% of patients (dislodgement 3%). Moreover, 4.9% had
serious adverse events related to CRT within 6 months (eg,
lead damage, pacing failure, and diaphragmatic pacing). The
rate of complications may be at least as high in clinical practice. Furthermore, biventricular implantation is more technically complex with a success rate ≈90% (when compared
with a success rate of ≈98% using single ventricular leads).
It requires longer fluoroscopic times and usually requires the
use of contrast agents to define the coronary venous anatomy.
Although the reported incidence of severe immediate reactions to contrast material is low (0.1–0.4%), contrast-induced
nephropathy can occur in 8% of all patients and ≤12% of
patients requiring >95 cm3 of contrast for LV lead placement.50
Patients with chronic kidney disease and HF are particularly
susceptible. AV conduction defects may account for ≈50% to
55% of pacemaker implants, and one-third of patients who
need a pacemaker have LV systolic impairment.51,52 In addition, only 50% to 70% of patients with a clear indication will
benefit from CRT therapy.53 Thus, the widespread use of biventricular pacemakers in patients with AVB would invariably
result in a higher number of complications in the community,
without clearly defined benefit for a small number of patients.
Although biventricular pacing coupled with ICD therapy
reduces HF and mortality in patients with low LVEF, LBBB,
and HF symptoms, the data supporting the widespread application of biventricular bradycardia pacing to all patients with
heart block is insufficient. Although changes in LVEF and
LV volumes are often cited as evidence of benefit, pacemaker
therapies must be calibrated to reduce hard clinical end
points, such as HF and mortality. Patient selection for biventricular ICDs can be as simple as an echo and a short conversation about symptoms and length of time since the last
myocardial infarction or revascularization. Still, the answer
may be more nuanced, as alternative RV pacing sites may
minimize the ill effects of apical RV pacing. For patients with
AVB that have some intrinsic conduction, atrial-based minimal ventricular pacing mode in DDD devices may help to
reduce unnecessary RV pacing.54 Overall, however, the one
size fits all approach to ventricular pacing in this population
is not supported by available trial data, which does not support universal biventricular pacing.
736 Circ Arrhythm Electrophysiol June 2015
Disclosures
None.
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Key Words: biventricular pacing ◼ cardiac resynchronization therapy
◼ heart block ◼ pacemaker, artificial
738 Circ Arrhythm Electrophysiol June 2015
Response to Ivan A. Arenas, MD, PhD, Jason Jacobson, MD, Gervasio A. Lamas, MD
Fang Fang, MB, PhD, John E. Sanderson, MD, FRCP, Cheuk-man Yu, MD, FACC, FRCP
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
Arenas et al have nicely summarized much of the information we have on dual chamber (DDD) and biventricular pacing.
They have concluded that the available trial data do not support universal biventricular pacing for heart block. But in our
view, the data do support wider use than currently. We would like to make the following comments:
The authors make a comparison with the now historical debate on whether DDD pacing is superior to ventricular pacing
only to illustrate how at that time there was a disconnect between clinical trials (no difference in mortality) and clinical practice (large increase in DDD pacemaker implantations) and to suggest this should be avoided now with biventricular pacing.
However, clinicians favoring DDD pacing based on their opinion that the atria are present for a purpose were subsequently
proven right. Meta-analyses found significant beneficial effects with DDD pacing for prevention of atrial fibrillation and
pacemaker syndrome and providing better exercise capacity.1,2 Prevention of atrial fibrillation and pacemaker syndrome may
even be more important to an elderly patient than a few months of extra life. Furthermore, nearly all the trials, Arenas et al
quote relate to patients with sick sinus syndrome. Patients with chronic atrioventricular block are a different population; for
example, sick sinus syndrome is more common in women, atrioventricular block is more prevalent in men, and the associated risk factors are different. Therefore, the relevance of the data from this earlier debate about pacing is questionable.
There is considerable information demonstrating that RV apical pacing has acute adverse consequences on left ventricular
(LV) function (albeit differing from left bundle branch block). It is hard not to conclude that asynchronous contraction will
have deleterious long-term consequences on LV function and that biventricular pacing should be preferable. As noted, there
is conclusive evidence that biventricular pacing definitely improves LV function, reduces mortality, and improves quality of
life in those with damaged LVs. The question is whether this benefit can be realized in those with apparently more normal
LV function and prevents further deterioration. We accept that although at present the data from the clinical trials in terms of
mortality are conflicting, it is not clear if other benefits, such as quality of life, which is equally important, may be improved.
Although Arenas et al state “....changes in LV ejection fraction and LV volumes are often cited as evidence of benefit,
pacemaker therapies must be calibrated to reduce hard clinical endpoints, such as HF and mortality,” this is not the whole
story. Quality of life may be more important is this elderly group of patients. Arenas et al conclude that “Overall, however,
the ‘one size fits all’ approach to ventricular pacing in this population is not supported by available trial data, which does
not support universal biventricular pacing.” But they are also guilty of another “one size fits all” mentality when they, and
frequently trialists, assert dogmatically that the results of large clinical trials are definitive and apply to all subjects; and that
if mortality is not reduced the therapy is not worth considering further. This outlook inhibits the development of more tailored and individually directed therapy which is increasingly common in other branches of medicine, such as oncology. We
need to develop better criteria to identify those patients who may benefit substantially in terms of quality, as well as quantity
of life, from new therapies. This group of patients may be obscured or lost in large clinical trials using only a mortality end
point. Our article is designed to stimulate debate and further research to focus on these issues and to promote the best pacing
therapy for each individual patient. In this regard much remains to be done.
References
1. Dretzke J, Toff WD, Lip GYH, Raftery J, Fry-Smith A, Taylor RS. Dual chamber versus single chamber ventricular pacemakers for sick sinus syndrome
and atrioventricular block. Cochrane Database Syst Rev. 2004; Issue 2. CD003710.
2. Healey JS, Toff WD, Lamas GA, Andersen HR, Thorpe KE, Ellenbogen KA, Lee KL, Skene AM, Schron EB, Skehan JD, Goldman L, Roberts RS,
Camm AJ, Yusuf S, Connolly SJ. Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation. 2006;114:11–17.
Routine Use of Biventricular Pacing Is Not Warranted for Patients With Heart Block
Ivan A. Arenas, Jason Jacobson and Gervasio A. Lamas
Downloaded from http://circep.ahajournals.org/ by guest on November 1, 2016
Circ Arrhythm Electrophysiol. 2015;8:730-738
doi: 10.1161/CIRCEP.114.000627
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SUPPLEMENTAL MATERIAL
Supplemental table 1. Clinical outcomes after right ventricular pacing in observational studies
Study/reference
Kay GN et al (1). The
Ablate and Pace trial.
Year
Type of study/population
n
1998
Prospective study, AF patients with
AVN ablation.
Tops LF et al (2)
2006
Retrospective study, AF patients with
AVN ablation.
55
Chen L et al (3)
2008
Retrospective study, AF patients with
AVN ablation.
286
Poçi D et al (4)
Tan ES et al (5)
Zhang XH et al (6 )
2009
Retrospective study, AF patients with
AVN ablation.
2008
Retrospective study, AF patients with
AVN ablation.
2008
Retrospective study, patients with
acquired AVB that received RV pacing
(81.9% DDD; 18.1% VVI)
156
213
121
304
Follow up
(mean)
Mean
LVEF±SD
(%)
Main outcomes
50±20
LVEF improved (from 31% to 41%; p<0.01) in
patients with reduced LVEF pre-pacing. There were
no significant changes in functional capacity
evaluated by duration in a treadmill or VO2max.
3.8 years
48±7
LVEF decreased (from 48 ± 7% to 43 ± 7%; p <
0.05), LV end-diastolic volume increased (from 116
± 39 ml to 130 ± 52 ml; p < 0.05) and HF worsen
but only in patients with LV dyssynchrony.
20 months
48±18
No change in LVEF overall.13% LVEF improved
>10%, 15% of patients LVEF decreased >15% and
72% had no change in LVEF.
6 years
55±12
13% developed HF or LVEF < 45%; New HF
happened after an average time of 44 months
following AVN ablation. For those with history of
HF, 26% developed aggravation of HF during
follow-up.
4.3 years
Mean
fractional
shortening
28%±10
12 months
7.8 years
65±10
HFH occurred in 20% patients, predominantly in
patients with history of HF. LV end systolic diameter
decreased and fractional shortening improved.
26% developed new-onset HF; those with paced
QRS>165 ms had higher incidence of HF
(sensitivity/specificity: 58/64%; p<0.01). The mean
duration of pacing from pacemaker implantation to
onset of HF was 6.5 ± 5.7 years (range 0.2–27.7
years).
AF: Atrial fibrillation; AVN: atrioventricular node ablation; AVB: Atrioventricular block; LVEF: left ventricular ejection fraction; HFH: Heart failure Hospitalization.