Download Should All Patients With Heart Block Receive Biventricular Pacing?

Controversies in
Arrhythmia and
Electrophysiology
Should All Patients With Heart Block
Receive Biventricular Pacing?
All Heart Block Patients With a Pacemaker Indication Should
Receive Biventricular Pacing
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One Move, Double the Gains?
Fang Fang, MB, PhD; John E. Sanderson, MD; Cheuk-man Yu, MD
C
onventional right ventricular (RV) pacing can cause
left ventricular (LV) dysfunction and even heart failure (HF) particularly if ventricular pacing is frequent.1 New
onset HF has been observed in approximately one third of
patients receiving RV pacing for acquired second- or thirddegree atrioventricular block (AVB) after a median follow-up
of nearly 8 years.2 An elegant study has shown recently that
apparent pacing induced cardiomyopathy could occur even
if the accumulative pacing percentage was <40%.1 Although
there has been rapid progress in medication and device therapy for HF, it is still a burden on the public health systems
and better prevention remains important.3 Avoiding the use of
a potentially harmful device when a good alternative is available is a matter of serious consideration.
require pacing but do not have a conventional indication for
biventricular pacing.6,7 Biventricular pacing is emerging as a
realistic treatment option to prevent RV pacing induced LV
dysfunction for symptomatic patients with advanced AVB.
Prevalence and Indications for Pacing
in AVB—The Size of the Problem
Despite the lack of accurate epidemiology data for AVB, it is
clear that it is not uncommon in both apparently healthy populations and those with overt heart disease. Approximately 1% to
2% of normal subjects have first-degree AVB which increases
to 5% in men over the age of 60 with cardiac diseases.8–10 The
prevalence of second-degree AVB for Mobitz II block is estimated to be 3% in patients with HF, and it is estimated that
5% to 10% of people will develop a third-degree heart block
in those >70 years old and having a history of heart disease.8
In clinical practice, decisions for pacemaker implantation are
determined by symptoms and pacing indications as in the
guidelines which are based on expert opinion from experience
because there is no other effective treatment for bradycardia and
no major randomized trials.11 According to the updated ACC/
AHA/HRS Guidelines for Device-Based Therapy11 and European Society of Cardiology guidelines on cardiac pacing and
Response by Arenas et al on p 729
Single- or dual-chamber pacemakers with RV pacing are
undoubtedly the main therapy for symptomatic AVB. With
increasing evidence of potential adverse effects of permanent
RV pacing mainly because of systolic dyssynchrony,4,5 other
pacing modalities or pacing modes are being considered.
Biventricular pacing is one of the options and has been shown
to be potentially superior to RV pacing even for those who
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Institute of Innovative Medicine, Heart
Education and Research Training (HEART) Center, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong
Kong, Hong Kong, China.
Correspondence to Cheuk-man Yu, MD, Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Institute of
Innovative Medicine, Heart Education and Research Training (HEART) Center, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The
Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. E-mail [email protected]
(Circ Arrhythm Electrophysiol. 2015;8:722-729. DOI: 10.1161/CIRCEP.114.000626.)
© 2015 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
722
DOI: 10.1161/CIRCEP.114.000626
Fang et al Heart Block and Biventricular Pacing 723
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cardiac resynchronization therapy (CRT),12 RV pacing is indicated for third-degree block and advanced second-degree AVB
with symptoms, ventricular arrhythmias, operation-induced or
advanced AVB caused by ablation of atrial fibrillation, medical
conditions requiring drug therapy that may exacerbate the bradycardia, atrial fibrillation with long pauses.
The majority of patients with Mobitz type I second-degree
AVB do not require a permanent pacemaker, but it should
be considered for persistent and symptomatic Mobitz type I
second-degree AVB, which also might be associated with an
increased risk of HF.11,12 Although first-degree AVB is traditionally considered to be a benign condition, it was found
recently to be associated with an increased risk of atrial fibrillation and all-cause mortality in community populations, and to
be related to HF and mortality in patients with stable coronary
artery disease.9 Hence, first-degree AVB is likely to be an electric marker of more severe underlying disease.13 In summary,
the various forms of AVB are common and a substantial number of patients will receive a pacemaker, and therefore identification of the best pacing mode will have a widespread impact.
Comparison of RV and Biventricular
Pacing for AVB Patients
Dual-chamber pacing with leads fixed in the RV and right atrium
has been the main therapy for AVB and restoration of AV synchrony is relatively easy to implement. However, detrimental
effects attributed to long-term RV pacing, including LV adverse
remodeling, cardiac dysfunction, and the occurrence of HF,
have been consistently reported14–21 (Figure 1). Those receiving the most pacing are likely at greatest risk.15,16,22 Attempts
to reduce the negative effects are mainly focused on minimizing ventricular pacing in sinus node disease, optimizing pacemaker settings, and seeking better pacing sites. An alternative
approach is to use a site other than the RV apex in an attempt
to reduce pacing-induced ventricular dyssynchrony.5,23,24 Other
pacing sites include the RV mid or low septum, the RV inflow
tract, the RV outflow tract, and the His bundle region. However,
Figure 1. Pathophysiological mechanism of right ventricular
pacing–induced electric dyssynchrony on left ventricular (LV)
adverse remodeling.
true RV septal pacing and His bundle pacing are limited by the
difficulty of achieving stable lead positions.25,26 The most commonly used alternative site is the RV outflow tract, but there is
as yet no randomized trial evidence that supports the superiority
of this pacing site compared with RV apical pacing.27
Biventricular pacing is a well-established therapy for HF
patients with LV ejection fraction (LVEF) <35% and wide QRS
complex duration. It has also been shown to produce improvement on LV function and reverse LV remodeling when upgrading RV pacing to biventricular pacing in those who develop
LV systolic dysfunction.28 The recognition that intraventricular
systolic incoordination (dyssynchrony) can be corrected with
biventricular pacing is an important reason that promotes indications for biventricular pacing to evolve.12 Intriguingly, 8% to
15% of patients with advanced HF have symptomatic bradycardia which necessitates pacemaker therapy and, conversely, it
is estimated that up to 40% of patients with permanent pacemakers have HF or LV systolic dysfunction because of frequent
RV pacing and their underlying cardiac disease.29 In addition,
many patients with HF and preserved LVEF have an evidence of
ventricular dyssynchrony at rest and on exercise which may be
worsened by RV apical pacing.30 Biventricular pacing has been
promising in recent randomized controlled clinical trials comparing biventricular and RV pacing irrespective of baseline LV
systolic function (Table).6,7,31,32
Evidence for Biventricular Pacing for
Heart Block With Depressed EF
In a randomize trial conducted in patients with AV node ablation
for atrial fibrillation, biventricular pacing was first proven to be
superior to RV pacing, achieving better exercise capacity and
LVEF, especially for those with pre-existing HF.35 These benefits
were also confirmed in a later meta-analysis.36 Because the pathophysiology of complete AVB and AV node ablation are similar,
this adds support to the notion that biventricular pacing should be
used routinely in patients with LV dysfunction and conventional
indications for pacing. A direct comparison between biventricular pacing and RV pacing in patients with AVB was performed
in the Homburg Biventricular Pacing Evaluation (HOBIPACE)
randomized study. Although the sample size was small (n=30),
biventricular pacing was superior to conventional RV pacing in
reduction of LV volumes, and improvement of LVEF, quality
of life, maximal and submaximal exercise capacity.33 A similar
effect was also found in the Conventional Versus Multisite Pacing for Brady Arrhythmia Therapy (COMBAT) study.34 More
evidence came from the randomized Biventricular Versus Right
Ventricular Pacing in Heart Failure Patients With Atrioventricular Block (BLOCK HF) study, which had a much larger sample
size (n=691; 134 with first degree, 227 with second degree, and
329 patients with third-degree AVB).6 Patients were randomized
to CRT-Pacemaker, CRT-Defibrillator , or RV apical pacing. At
a mean follow-up of 37 months and median ventricular pacing
burden of >97%, patients receiving biventricular pacing had a
significant 26% reduction in the combined end point (all-cause
mortality, urgent care for HF or increase in LV end-systolic
724 Circ Arrhythm Electrophysiol June 2015
Table. Major Clinical Trials That Compared the Use of RV Pacing Versus Biventricular Pacing in Patients With Bradycardia
Indications
Study
Number Inclusion Criteria
Numbers with
Atrioventricular
Block
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Treatment
Follow-Up Time
30
After run-in
phase, patients
randomized to
2 pacing mode:
RV (3 mo)–
biventricular
(3 mo) and
biventricular
(3 mo)–RV (3 mo)
Follow-up
performed for 2
to 3-mo study
periods with
crossover to the
complementary
pacing mode
LV end-systolic
volume, LV ejection
fraction, and peak
oxygen consumption
More improvement of LV
function, QoL, and maximal
as well as submaximal
exercise capacity with
biventricular pacing than
with RV pacing
Complete: 30
Type II: 19
Advance: 11
Group A:
RV pacing–
biventricular
Pacing and
crossed back to
RV pacing
Group B:
biventricular
Pacing–RV
pacing–
biventricular
pacing
Each mode
lasting at least
3 mo
QoL and NYHA Class
Significant improvements
in QoL, NYHA, LVEF, and
LV end-systolic volume
with biventricular pacing
compared with RV pacing
and death occurred more
frequently with RV pacing
104 AV block
patients
Biventricular
pacing (n=89)
and RV pacing
(n=88) at 1 y
biventricular
pacing (n=82)
and RV pacing
(n=81)
1 y and
extended to 2 y
LVESV and LVEF
LVEF and LVESV
deteriorated at 1 y in RV
pacing group but remained
unchanged in biventricular
group. This effect
sustained at 2-y follow-up
Biventricular
pacing (n=50)
RV pacing
(n=58)
12 mo
Primary end point: LV
end-diastolic volume
Secondary end
points: LVESV, LVEF,
and a combination
of HF events and
cardiovascular
hospitalizations, mitral
regurgitation
No differences between 2
pacing groups
BLOCK HF6
691 AV block with NYHA First-degree: 134 Biventricular
I–III and LVEF≤50% Second-degree: 227 group (n=349)
Third-degree: 329 and RV group
(n=342)
37 mo
Death from any
cause, an urgent care
visit for HF requiring
intravenous therapy,
or an increase in the
LVESV index of 15%
Biventricular pacing
resulted in a 26%
significant reduction in the
combined end point
BioPACE trial43
1810 Indication for implantation of a ventricular pacemaker
according to guideline or anticipated
need for frequent
ventricular pacing
5.6 y
Combination of
time-to-death or
first hospitalization
because of HF
The composite primary end
point is similar between 2
pacing modes
HOBIPACE33
30
Patients with
permanent
ventricular pacing
indication and
LV end-diastolic
diameter ≥60 mm
and LVEF≤40%
COMBAT34
68
AVB with pacemaker
indications and
NYHA Class II–IV,
and LVEF ≤40%
PACE and
extended
follow-up7,31
177 Bradycardia and
LVEF≥45%
PREVENT-HF32
108 Patients with an
108 with AV block
expected ventricular
pacing percentage
≥80%
N/A
Biventricular
group (n=902)
and RV group
(n=908)
End Point
Results
AVB indicates atrioventricular block; BIOPACE, Atrioventricular Block to Prevent Cardiac Desynchronization; BLOCK HF, Biventricular Versus Right Ventricular Pacing in
Heart Failure Patients With Atrioventricular Block; HF, heart failure; HOBIPACE, Homburg Biventricular Pacing Evaluation; LVEF, left ventricular ejection fraction; LVESV,
left ventricular end-systolic volume; NYHA, new York heart association; PACE, Pacing to Avoid Cardiac Enlargement; QoL, quality of life; and RV, right ventricular.
Fang et al Heart Block and Biventricular Pacing 725
volume index >15%) when compared with RV pacing. The benefits were similar in the CRT-Pacemaker and CRT-Defibrillator
groups. The superiority of biventricular pacing to RV pacing for
the secondary end points (death or hospitalization for HF) was
also established with posterior probability of a combined hazard
ratio >0.9775.
This landmark trial provided promising evidence that
biventricular pacing is able to prevent LV remodeling, HF
events, and mortality caused by conventional RV pacing in
patients with mild or modest systolic dysfunction. With these
results, the Food and Drug Administration (FDA) approved
the use of biventricular pacing in those with AVB associated
with high ventricular pacing percentage, mild to moderate HF
symptoms, and LVEF≤50%.37
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Evidence of Biventricular Pacing for
Advanced AVB Patients With Normal LVEF
Patients with normal LVEF seem more resistant to the adverse
effects of RV pacing,4,5,23 but LV dysfunction is still commonly
observed especially in those with frequent and long-term ventricular pacing.38 However, the depression of LV systolic function can become manifest at an early stage and may persist after
the cessation of pacing.39,40 Biventricular pacing may avoid this
negative impact. This hypothesis was tested in the Pacing to
Avoid Cardiac Enlargement (PACE) trial, which was the first
randomized, controlled, multicenter study that compared biventricular pacing with RV pacing in bradycardia patients with a
pacing indication and normal LVEF.7 At 1-year follow-up, RV
pacing resulted in a significant reduction of LVEF and enlargement of LV end-systolic volume which were prevented by biventricular pacing (Figure 2). Benefit was shown in the subgroup
of patients with AVB. Extended 2-year follow-up demonstrated
further deterioration of LVEF and LV end-systolic volume in
the RV pacing group, but no deterioration in the biventricular
pacing group.31 Long-term follow-up of this trial confirmed the
same pattern and also that HF hospitalizations were less frequent in the biventricular pacing arm.41 Further analysis showed
that the development of pacing-induced systolic dyssynchrony
was associated with LVEF reduction and LV adverse remodeling.5 This trial provided good evidence for a progression of LV
remodeling and eventually HF caused by RV pacing which was
prevented by biventricular pacing in patients with bradycardia
and normal LVEF. Moreover, the potential mechanism of the
benefit of biventricular pacing appeared to be related to the correction of systolic dyssynchrony.
Despite these encouraging studies, the evidence is not
yet sufficiently strong to support widespread adoption of
biventricular pacing in patients with normal LVEF because
of conflicting results from other trials. The Progressive
Ventricular Dysfunction Prevention in Pacemaker Patients
(PREVENT-HF) trial found little difference in LV volumes,
LVEF, mitral regurgitation, or the combination of HF events
and cardiovascular hospitalization at 1-year follow-up between
biventricular and RV pacing groups.36 The main criticism of
this trial was small sample size (n=108 with ventricular pacing
percentages ≥80%) and high crossover rate from biventricular
to RV pacing.42 The preliminary results of the larger (n=1,810)
Biventricular pacing for Atrioventricular Block to Prevent
Cardiac Desynchronization (BIOPACE) study43 were released
at the annual meeting of the European Society of Cardiology
in 2014. The composite end point of death or first HF hospitalization was similar between biventricular and RV pacing
Figure 2. Three-dimensional echocardiography demonstrated that left ventricular end-systolic volume (LVESV) and ejection fraction (EF)
deteriorated after right ventricular pacing (A) but remained unchanged during biventricular pacing (B).
726 Circ Arrhythm Electrophysiol June 2015
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groups although there was a nonsignificant trend for superiority of biventricular pacing (P=0.08). More details are necessary
to decipher which subgroups really benefit from biventricular
pacing. This neutral result might be related to the high rate of
implantation failure for biventricular pacing (14.1%). Other
details, such as biventricular pacing percentage and the battery
longevity in the biventricular pacing arm, which could have an
impact, were not reported.
Currently, any benefit of prophylactic biventricular pacing in patients with bradycardia and normal LVEF seems marginal. Given the fact that nearly 30% of all CRT implants were
upgraded from RV pacing in a registry,28 and that the pacing
population is commonly elderly and vulnerable to developing HF because of age-related increase in chamber stiffness,
hypertension, LV hypertrophy, diabetes mellitus, and coronary artery disease, some feel that the de novo use of biventricular pacing should not be criticized in AVB patients when
the aim is to prevent LV remodeling.44 The identification of
patients at high risk to develop LV dysfunction or HF from RV
pacing would be useful, but at the moment there is not even
consensus on a definition of frequent ventricular pacing that
increases this risk.
Biventricular Pacing in First-Degree AVB
Although first-degree AVB usually causes no symptoms and
does not require any special treatment, it is an independent
predictor of all-cause mortality in the general population and
is independently associated with HF hospitalization, mortality, and the combined end point of HF hospitalization or cardiovascular mortality in coronary artery disease patients.45,46
Irrespective of baseline LV function, dual-chamber pacemakers can improve the symptoms in those with a P-R interval
≥0.30 s.47 Around half of patients with biventricular pacing for
standard HF indications have first-degree AVB,48 but the value
of biventricular pacing in these patients is not clear.49,50 In the
Comparison of Medical Therapy, Pacing and Defibrillation in
Heart Failure (COMPANION) trial, CRT was associated with
a reduction in the all-cause, cardiac, and HF hospitalization
rates. First-degree AVB was present in 52% of the subjects
and reduction in relative risk (CRT versus optimal medical
therapy) was 29% for those with normal P-R intervals but was
46% (P<0.01) for those with P-R prolongation. The authors
concluded that P-R prolongation may affect mortality and HF
hospitalizations in patients with systolic dysfunction, HF, and
a wide QRS complex, and that the effect of P-R prolongation
may be attenuated by CRT.48
Practical Issues of Biventricular Pacing for
Heart Block Patients in Real-World Practice
At present, however, there is no evidence for a reduction of
mortality with biventricular pacing when compared with RV
pacing, which might be ascribed to the relatively short duration of follow-up in patients studied.51 For those patients with
normal LVEF, mortality and HF hospitalizations are much less
frequent with RV pacing than in patients with reduced LVEF.
The main challenge in these patients is to detect the vulnerable
group before implantation to avoid closing the door after the
horse has bolted. Despite the lack of a consensus on the risk
factors for developing LV dysfunction, a wider QRS in combination with underlying heart diseases have been suggested
as potential predictors.2,52 However, it must be acknowledged
in the elderly in whom pacing is being undertaken primarily
to prevent syncope and who have a relatively short-life expectancy, it is obviously reasonable to implant a standard RV
pacemaker, particularly in view of the increased complexity
and expense of biventricular pacing.
The implantation of biventricular pacemakers requires
extra skill in placing the LV lead into the coronary sinus
and its branches. Although this can be a technical challenge
in the markedly enlarged LV in HF subjects, it seems to be
technically much easier in the normal or near normal sized
heart. Furthermore, technological advances have significantly improved the ability to access to the coronary sinus
and increased the success rate of LV lead implantation with
fewer complications.53 The expanding application of biventricular pacing in AVB patients will be challenged because of
higher cost. Data to compare the cost-effectiveness between
RV pacing and biventricular pacing are scanty,54 but the cost of
implantation may be outweighed by the clinical improvement
and savings from reduced hospital admissions in those with
AVB and reduced LVEF.52
In patients who are receiving RV pacing, many centers
do not routinely perform echocardiography to evaluate ventricular function, and signs of HF might be missed until more
serious symptoms or a HF hospitalization occur.55 Therefore,
it is recommended to monitor cardiac function on a regular
basis so that upgrading to biventricular pacing can be implemented without delay if evidence of LV adverse remodeling
and reduced LVEF is present.
Conclusions
Biventricular pacing reverses LV remodeling and reduces HF
hospitalization and mortality in patients with established HF,
low LVEF, and wide QRS. It is also beneficial in patients with
mild HF who require frequent ventricular pacing, in whom
biventricular pacing could be remarkably more beneficial than
routine RV pacing. Apart from these established roles, biventricular pacing is evolved to be an appropriate consideration for
the broader pacing population. Although it holds promise, a preventive role of biventricular pacing avoiding HF in subjects with
normal LVEF remains controversial. Although guidelines do not
currently recommend routine biventricular pacing for all patients
with heart block, with the increasingly recognized potential for
harmful effects of RV pacing and accumulating evidence of
the benefits of biventricular pacing, the “one move, double the
gains” strategy deserves more attention and discussion.
Disclosures
None.
Fang et al Heart Block and Biventricular Pacing 727
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Key Words: atrioventricular block ◼ bradycardia ◼ cardiac resynchronization
therapy
Fang et al Heart Block and Biventricular Pacing 729
Response to Fang Fang, MB, PhD, John E. Sanderson, MD, Cheuk-man Yu, MD
Ivan A. Arenas, MD, PhD, Jason Jacobson, MD, Gervasio A. Lamas, MD
Downloaded from http://circep.ahajournals.org/ by guest on May 12, 2017
Fang et al in the counterpart review for this debate have for the most part agreed that the evidence for the “one move, double
the gains” strategy to support the widespread use of biventricular pacing in all patients with heart block is not robust. Fang
et al agreed with our view that current data do not support the use of biventricular pacing in patients with preserved left
ventricular (LV) ejection fraction. Still, they failed to conclude that the supporting evidence for patients with mild LV dysfunction is at most, observational. In fact, they did not comment on important details of BLOCK HF1; this trial did not show
any effect on mortality. Moreover, the decreased event rate of the combined primary endpoint was driven mostly by changes
in LV geometry and heart failure (HF) hospitalizations. Importantly, the trial randomized patients with mild to severe LV
dysfunction, and approximately one third of participants were in NYHA class 3, but the effect of prepacing LV ejection
fraction/functional class on outcomes was not reported. We agree the available evidence favors the use of biventricular pacing in patients with moderate to severe LV dysfunction with concurrent advanced atrioventricular block and expected high
percentage of ventricular pacing. However, for patients with mild LV dysfunction with frequent right ventricular (RV) pacing, it remains unclear if biventricular pacing is better than a watchful approach (eg, RV pacing and biventricular pacing if
needed). Based on the results of BLOCK HF, the Food and Drug Administration (FDA) approved the use of biventricular
pacing for patients with atrioventricular block with NYHA class 1 to 3 and LV ejection fraction ≤50% who are expected
to have frequent ventricular pacing.2 This may lead to unnecessary biventricular pacing placements without certainty about
costs/benefits. Furthermore, it is about that this approval may decrease the interest of the scientific community to further
investigate predictors of LV dysfunction after right ventricular pacing, and may shut the funding from industry to support a
well-powered trial to answer the unresolved questions. At this juncture, patient history and a baseline echocardiogram are
likely our best shot to better assist patients with heart block when considering pacemaker options. We are left with the message that not all patients who require permanent right ventricular pacing will develop clinical HF or worsening LV function.
For those patients who may develop HF/LV dysfunction, there is a time frame that could be of months to years depending
on prepacing LV function and history of HF (and other unknown factors). Recommending biventricular pacing for all heart
block patients may be equivalent to recommend biventricular pacing to all patients with pre-existent LBBB. Upgrading to
biventricular pacing once a patient develops a clinical indication (eg, unexplained drop in LV ejection fraction) is feasible
and it is not associated with higher complication rates compared with an upfront biventricular pacing approach.
References
1. Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, Sherfesee L, Shinn T, Sutton MS. Biventricular versus Right Ventricular Pacing in Heart Failure
Patients with Atrioventricular Block (BLOCK HF) Trial Investigators. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J
Med. 2013;368:1585–1593.
2. www.fda.gov. Press Release April, 2014.
Should All Patients With Heart Block Receive Biventricular Pacing?: All Heart Block
Patients With a Pacemaker Indication Should Receive Biventricular Pacing: One Move,
Double the Gains?
Fang Fang, John E. Sanderson and Cheuk-man Yu
Downloaded from http://circep.ahajournals.org/ by guest on May 12, 2017
Circ Arrhythm Electrophysiol. 2015;8:722-729
doi: 10.1161/CIRCEP.114.000626
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