CLINICAL RESEARCH
Europace (2013) 15, 1412–1420
doi:10.1093/europace/eut239
Ablation for atrial fibrillation
Safety and efficacy of interrupted dabigatran
for peri-procedural anticoagulation in catheter
ablation of atrial fibrillation: a systematic review
and meta-analysis
Aref A. Bin Abdulhak 1, Abdur Rahman Khan 2, Imad M. Tleyjeh3,4, John A. Spertus 1,5,
Susan U. Sanders 6, Kristy E. Steigerwalt 6, Musa A. Garbati3, Reem A. Bahmaid 7,
and Alan P. Wimmer 1,5*
1
Department of Medicine, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64110, USA; 2Department of Medicine, University of Toledo Medical Center, Toledo,
OH 43606-3390, USA; 3Department of Internal Medicine, King Fahad Medical City, Riyadh11525, Saudi Arabia; 4Division of Epidemiology, Mayo Clinic, Rochester, MN 55902, USA;
5
Saint Luke’s Mid America Heart Institute, University of Missouri Kansas City, 4330 Wornall Road, Suite 2000, Kansas City, MO 64111, USA; 6Health Sciences Library, University of
Missouri-Kansas City, Kansas City, MO 64110, USA; and 7Department of Clinical Pharmacy, King Fahad Medical City, Riyadh 11525, Saudi Arabia
Received 25 May 2013; accepted after revision 8 July 2013; online publish-ahead-of-print 16 August 2013
Aims
To examine the safety (defined as bleeding risk) and efficacy (defined as prevention of thromboembolic events) of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation (CA) of atrial fibrillation (AF) in comparison
with warfarin.
.....................................................................................................................................................................................
Methods
Reviewers independently searched literature databases from January 2010 through April 2013 for studies comparing the
and results
safety and efficacy of dabigatran and warfarin in CA of AF and extracted pre-defined data. The Mantel –Haenszel method
was used to pool data of bleeding and thromboembolism outcomes into random and fixed effect model meta-analyses,
respectively. Odds ratios (ORs), and risk difference (RD) analysis when studies reported no events in either arm, were
used to generate an overall effect estimate of both outcomes. Publication bias and heterogeneity were assessed by
contour funnel plot and the I 2 test, respectively. Nine citations, including 3036 patients (1073 dabigatran), met the inclusion criteria. There was no significant difference between interrupted dabigatran and warfarin therapy in CA of AF in occurrence of bleeding [dabigatran 58 (5.4%), warfarin 103 (5.2%); OR 0.92 (95% confidence interval (CI) 0.55–1.45);
x 2 ¼ 13.03—P ¼ 0.11; I 2 ¼ 39%] or thromboembolism [dabigatran 5 (0.4%), warfarin 2 (0.1%); OR 2.15 (95%
CI—0.58 –7.98); x 2 ¼ 2.14, P ¼ 0.54; I 2 ¼ 0%; RD 0.00 (95% CI—0.00 to 0.01); x 2 ¼ 3.37, P ¼ 0.81; I 2 ¼ 0%].
Analysis of pre-defined subgroups (published articles vs. abstracts), sensitivity analyses (interrupted warfarin, USA
studies, and Japanese studies) and fixed effect model analyses showed similar results. Heterogeneity was mild in the bleeding outcome analysis and zero in thromboembolism. There was no evidence of publication bias in either meta-analysis.
.....................................................................................................................................................................................
Conclusion
Meta-analysis of currently available studies showed no significant difference in bleeding and thromboembolism between
interrupted dabigatran and warfarin therapy in CA of AF. Dabigatran appears to be safe and effective for peri-procedural
anticoagulation in CA of AF.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Dabigatran † Warfarin † Catheter ablation † Atrial fibrillation
Introduction
Catheter ablation (CA) for atrial fibrillation (AF) is an effective
rhythm-control strategy for selected patients. However, there is
risk of thromboembolism because the procedure involves ablation
in the systemic circulation and often conversion of AF to sinus
rhythm.1 The adoption of more aggressive peri-procedural anticoagulation has been associated with a decline in the rate of transient
* Corresponding author. Tel: +1 816 751 8487; fax: +1 816 756 364, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected].
1413
Interrupted dabigatran for peri-procedural anticoagulation in CA of AF
What’s new?
† Dabigatran is a novel oral anticoagulant approved for stroke
prevention in non-valvular atrial fibrillation (AF).
† Safety and efficacy of dabigatran in catheter ablation of AF is
still not yet defined.
† This first meta-analysis of the available observational studies
provides evidence that dabigatran is safe and effective in catheter ablation of AF.
ablation, cryoablation, electrocoagulation, dabigatran, and warfarin.
The search accounted for plurals and variations in spelling with the use
of appropriate wildcards. Non-English publications were excluded.
Meeting abstracts were searched in Embase. Efforts were made to identify research in progress, or in early stages, by examining clinical trial registries. The results were downloaded into EndNotew, a bibliographic
database manager, and duplicates were removed. Three reviewers
(A.A.B., S.U.S., and K.E.S.) independently extracted eligible studies from
the search results. Disagreement was resolved by consensus.
Study selection
2
ischaemic attack (TIA) and stroke. Although the use of intraprocedural heparin is the standard of care, several different
pre- and post-procedural anticoagulation strategies have been
used.3 Pre-ablation uninterrupted warfarin therapy has been
adopted by many institutions recently as it has proven safe and has
been associated with very low thromboembolic risk.4 – 9 However,
the international normalization ratio (INR) in as many as 50% or
more of patients on warfarin at the time of ablation may fall outside
the therapeutic range,10 with potential for increasing the risk of
bleeding or thromboembolic complications, or resulting in a delay
or cancellation of the procedure.
Until recently, warfarin was the only oral anticoagulant available for
thromboembolism prevention in AF. In 2010, the US Food and Drug
Administration approved the novel oral direct thrombin inhibitor
dabigatran for prevention of stroke in non-valvular AF, with a large
body of data demonstrating that the drug is as safe and at least as effective as warfarin in stroke prevention.11,12 Increasing numbers of
patients are on dabigatran at the time a decision to proceed with
CA of AF is made. How best to manage pre- and post-procedural
anticoagulation for these patients is unknown.
In the absence of a large randomized clinical trial comparing the
safety and efficacy of dabigatran for peri-procedural management
at the time of AF ablation, several observational studies have been
published with conflicting results.13 – 18 A multicentre study by
Lakkireddy et al.16 raised concern over the possibility of an increase
in both bleeding and thromboembolic complications with the use
of dabigatran. However, several recently published studies13 – 15,18
have shown no difference between dabigatran and warfarin in rates
of bleeding or thromboembolism.
Owing to the clinical importance of this issue for a widely performed therapeutic intervention, and the lack of definitive findings
from individual published reports, we sought to systematically
review the literature and perform a meta-analysis of the available
studies to examine the safety and efficacy of interrupted periprocedural dabigatran, as compared with warfarin, in CA of AF.
Methods
A systematic, pre-defined search strategy, study selection using specific
criteria, data identification and extraction, and quality assessment were
conducted according to the PRISMA19 and MOOSE20 guidelines for
reporting a systematic review and meta-analysis of observational studies.
Search strategy
Multiple databases, including Embase, Medline/PubMed, and Scopus from
January 2010 through April 2013, were queried. The following MeSH,
Emtree, and text word search terms were used: CA, radiofrequency
Any randomized control trial (RCT), case – control study, or cohort
study which examined the safety and or efficacy of peri-procedural
(pre- and post-procedural) dabigatran in comparison with warfarin in
CA of AF was considered for analysis. Owing to the perceived importance of minimizing the duration of interruption of anticoagulation and
in an effort to limit the degree of variation in the peri-procedural dabigatran regimen, the analysis was limited to studies in which dabigatran was
held beginning the evening before or morning of the procedure and
resumed on the same day as the procedure. Safety was assessed by occurrence of bleeding (defined as bleeding from any site), while efficacy was
assessed by prevention of thromboembolic events (defined as ischaemic
stroke, TIA, or systemic thromboembolism).
Data extraction and quality assessment
Two reviewers (A.A.B., A.R.K.) independently extracted data from eligible studies into a pre-defined data collection form. Data collected
included country of the study, year of publication, study design, sample
size, publication status, and bleeding and thromboembolic complications.
In addition, data on the dabigatran and warfarin regimens, type of bridging
therapy when used, duration of pre-procedural anticoagulation, ablation
strategy, use of transoesophageal echocardiography, and patient information, including age, gender, and type of AF when available, were also
recorded.
The Newcastle– Ottawa quality assessment scale (NOS) to evaluate
the quality of observational studies was used.21 Quality assessment was
limited to fully published articles. Newcastle– Ottawa quality assessment
scale rates observational studies based on three parameters: selection,
comparability between the exposed and non-exposed groups, and exposure/outcome assessment. It assigns a maximum of four stars for selection, two stars for comparability, and three stars for exposure/outcome
assessment. Studies with less than five stars were considered of low
quality, five to seven stars moderate quality, and more than seven stars
high quality. The Jadad scale22 was used for quality assessment of the
RCT which scores a maximum of two points for randomization, two
points for blinding, and one point for description of withdrawal and
drop out. Three reviewers independently (A.A.B., A.R.K., and M.G.)
assessed the quality of the eligible studies. Disagreement was resolved
by consensus.
Statistical analyses
We performed meta-analyses of bleeding and thromboembolism outcomes separately. Mantel – Haenszel method was used to pool data on
the bleeding outcome into random effect model meta-analysis. The
Mantel – Haenszel method with non-fixed zero cell correction was
used to pool thromboembolism outcome data into fixed effect model
meta-analysis. This method is recommended whenever sparse data are
pooled and the sizes of the study arms are unequal.23 An odds ratio
(OR), with its 95% confidence interval (CI), was used to calculate the
overall effect estimate of both outcomes. Owing to several studies
reporting no thromboembolic complications in either arm, a risk
1414
A.A. Bin Abdulhak et al.
difference (RD) was also calculated for the thromboembolism outcome.
Studies were analysed together as well as by subgroups according to the
publication status. Statistical heterogeneity among included studies was
assessed using x 2 and I 2. The I 2 statistic describes the proportion of variation in treatment estimate which is not related to sampling error.24 A
value of zero indicates no heterogeneity, 25 – 49% low, 50– 74% moderate, and .75% a high degree of heterogeneity. Publication bias was
assessed by generating a contour funnel plot. Sensitivity analyses were
carried out by repeating the meta-analysis on bleeding outcome using
fixed effect model meta-analysis, reporting outcomes for USA and Japanese studies separately because Japanese studies included lower dabigatran dosing (110 mg). The statistical software Review Manager 5.2
(RevMan, Version 5.2) was used for all analyses.
Results
Descriptive and qualitative review
The results of the search strategy are illustrated in Figure 1. A total of
290 citations were identified, with 9 citations, involving 3036 patients
(1073 dabigatran), meeting the inclusion criteria.13 – 18,25 – 27 One was
an RCT,27 one case –control,15 and the remaining were cohort
studies.13,14,16 – 18,25 – 27 All citations except one16 were single-centre
studies. Six citations were from the USA13,15 – 17,25,26 and three were
from Japan.14,18,27 All studies were fully published articles except
two which were in abstract form.25,26 All studies were published in
2012 –13. One study18 compared two different cohorts of patients
on warfarin therapy with dabigatran; the uninterrupted warfarin
group from this study was used in the primary analysis, and the interrupted warfarin group was used in the sensitivity analysis. All citations
scored high on the NOS and the RCT scored high on the Jadad scale.
Table 1 includes the baseline characteristics of the eligible
studies. The mean age of patients in both the dabigatran and warfarin
groups was 60, and the percentage of female patients ranged from
10 –39%. Paroxysmal AF was more common than persistent. There
Initial search: 290 citrations
261 citations excluded based on title and abstract review
29 citations considered for full review
2 dabigatran held
> 2 doses
7 no comparison arm
Excluded Excluded 2 editorials
2 dabigatran
uninterrupted
1 survey
5 dabigatran
resumed next day
after the procedure
1 not involving
catheter ablation
9 citations met inclusion criteria
Figure 1 Flow diagram of the included studies.
was no significant difference between the dabigatran and the warfarin
groups in mean age or gender within individual studies. The use of
pre-procedural transoesophageal echocardiogram (TEE) varied
among included studies; however, patients on dabigatran group
underwent TEE in most of the studies. Irrigated radiofrequency
CA was used in almost all the included studies. The target
intra-procedural activated clotting time (ACT) ranged between
300 and 450.
Konduru et al.2 observed that the time required to reach target
ACTs was prolonged and that target ACTs were often not reached
using a standard heparin dosing protocol when patients had been
on dabigatran prior to their procedure. In a larger cohort of patients,
Bassiouny et al.13 reported a similar observation, as well as improved
success in reaching target ACTs with adjustments to unfractionted
heparin (UFH) dosing.
Dabigatran dosing was 150 mg twice daily for USA studies, with
what appears to be uncommon reported use of 75 mg twice daily
for patients with significant renal insufficiency. In contrast, dabigatran
110 mg twice daily was used exclusively in one Japanese study, and for
patients with renal dysfunction or advanced age in the other two
studies from Japan, with other patients receiving 150 mg twice daily
dosing.
Meta-analysis of bleeding
Interrupted peri-procedural dabigatran in CA of AF was as safe as warfarin with no difference between the anticoagulants in occurrence of
bleeding events [dabigatran 58 (5.4%), warfarin 103 (5.2%); OR 0.92
(95% CI 0.55–1.454); x 2 ¼ 13.03—P ¼ 0.11; I 2 ¼ 39%]. Subgroup
analyses had similar results, published articles [OR 0.92 (95% CI
0.54–1.71); x 2 ¼ 12.04—P ¼ 0.06; I 2 ¼ 50%] and abstracts [OR
0.49 (95% CI 0.09–2.78); x 2 ¼ 0.39—P ¼ 0.54; I 2 ¼ 0%], as
did fixed effect model analysis [OR 0.95 (95% CI 0.67–1.36); x 2 ¼
13.03—P ¼ 0.11; I 2 ¼ 39%]. There was mild heterogeneity, I 2 ¼
39% among the studies.
Sensitivity analysis showed no statistically significant difference
in bleeding events between dabigatran and warfarin therapy in
both Japan [OR 0.57 (95% CI 0.25– 1.33); x 2 ¼ 3.36—P ¼ 0.19;
I 2 ¼ 40%] and USA [OR 1.27 (95% CI 0.77–2.10); x 2 ¼ 5.43—
P ¼ 0.37; I 2 ¼ 8%] studies. Heterogeneity dropped to a negligible
level among USA studies, I 2 decreased from 39 to 8%, while it
remained around 40% in studies from Japan. Sensitivity analysis also
showed no significant difference between interrupted dabigatran
and interrupted warfarin therapy [OR 0.68 (95% CI 0.34– 1.37);
x 2 ¼ 5.04—P ¼ 0.17; I 2 ¼ 41%]. Figure 2 shows the total number
of patients, contribution of each study, results of the pooled analyses
by subgroups, and heterogeneity. Visual assessment of the contour
funnel plot (Figure 3) revealed no asymmetry, indicating absence of
publication bias.
Meta-analysis of thromboembolism
Meta-analysis of the thromboembolism outcome showed no significant difference between interrupted dabigatran as compared with
warfarin [dabigatran 5 (0.4%), warfarin 2 (0.1%); OR 2.15 (95% CI—
0.58–7.98); x 2 ¼ 2.14; P ¼ 0.54; I 2 ¼ 0%]. Only four studies were
included in the OR calculation as the remaining studies reported
zero events in both arms.15,17,18,25 Since multiple studies were necessarily excluded by this analytical method, an RD analysis was conducted
Study
Design
Sample
Size (D)
Country of
study
Mean age, F, % (D, PAF, %
year (D,
W)
(D, W)
W)
Duration AC TEE use
pre-ablation
Dabigatran
Dabigatran Warfarin
dose
ACT, second Ablation
catheter
Ablation
strategy
.............................................................................................................................................................................................................................................
Bassiouny
et al. 13
Cohort
967 (344)
USA
59, 63
25, 28
57, 50
NR
Some patients 1–2 doses held
150 mg
before
procedure;
resumed at
conclusion of the
procedure
Imamura
et al. 14
Cohort
227 (101)
Japan
61, 62
25, 29
56, 49
At least 4
weeks
All patients
Khan et al. 25
(Abstract)
Cohort
116 (50)
USA
56, NR
39, NR
NR
NR
NR
Kim et al. 15
Case –
control
763 (191)
USA
61, 61
20, 26
53, 48
Lakkireddy
et al. 16
Cohort
290 (145)
USA
60, 60
21, 21
Mendoza
et al. 26
(Abstract)
Cohort
118 (60)
USA
63, 64
Nin et al. 27
RCT
90 (45)
Japan
Snipelisky
et al. 17
Cohort
225 (31)
309 (106)A
300
(106)B
Yamaji et al. 18 Cohort
Uninterrupted
350 –450
Irrigated RF
PVI
Held 12 –24 h
110 –150 mg Interrupted;
before
+bridging
procedure;
heparin
resumed 3 h after
ablation
.300
Irrigated RF
PVI + focal/
linear
ablation
Held 24 h before the 150 mg
procedure;
resumed 6 h after
the procedure
Uninterrupted;
+LMWH
bridging
NR
RF; cryoablation NR
At least 4
weeks
All Dab
PM and AM held;
150 mg
patients;
resumed 4 h after
some War
sheath removal
patients
Uninterrupted
300 –350
Irrigated RF
PVI + focal/
linear
ablation
57, 57
30 days
All Dab
patients
AM dose held;
resumed 3 h
post-procedure
150 mg
Uninterrupted
300 –400
Irrigated RF
PVI + focal/
linear
ablation
10, 12
NR
NR
NR
AM dose held;
Resumed after
sheath removal
150 mg
Uninterrupted
300 –350
NR
PVI
61, 61
26, 20
76, 71
At least 3
weeks
All patients
AM dose held;
resumed 4 h
post-procedure
110 mg
Interrupted
300 –400
Irrigated RF
PVI + focal/
linear
ablation
USA
61, 65
19, 26
68, 47
NR
NR
AM dose held;
resumed at PM
150 mg
Interrupted
At least 350
RFCA
NR
Japan
60, 62
60, 61
25, 25
25,
23
65, 61
65, 63
At least 30 days All patients
AM dose held;
resumed 3 h
post-procedure
+ IV heparin
used
110 –150 mg Group A:
uninterrupted
Group B:
interrupted
300 –350
Irrigated RF
VI + focal/
linear
ablation
Interrupted dabigatran for peri-procedural anticoagulation in CA of AF
Table 1 Characteristics of the included studies
ACT, activated clotting time; D, Dabigatran; F, female; LMWH, low molecular weight heparin; NR, not reported; PAF, paroxysmal atrial fibrillation; PVI, pulmonary vein isolation; RCT, randomized control trial; RFCA, radiofrequency catheter
ablation; RF, radiofrequency; TEE, transoesophageal echocardiogram; W, Warfarin.
1415
1416
A.A. Bin Abdulhak et al.
Dabigatran
Study or subgroup
Warfarin
Events Total
Events Total Weight
Odds ratio
Odds ratio
M-H, random, 95% Cl
M-H, random, 95% Cl
1.1.1 Abstract
Khan
1
50
4
66
4.6%
0.32 [0.03, 2.92]
Mendoza et al. 2012
Subtotal (95% Cl)
1
60
110
1
58
124
3.1%
7.7%
0.97 [0.06, 15.82]
0.49 [0.09, 2.78]
Total events
2
1.81 [0.11, 29.08]
5
Heterogeneity: τ2 = 0.00; χ2 = 0.38, df = 1 (P = 0.54); I 2 = 0%
Test for overall effect: Z = 0.81 (P = 0.42)
1.1.2 Published
Bassiouny
1
344
1
623
3.1%
Imamura et al. 2013
8
101
9
126
14.7%
1.12 [0.42, 3.01]
Kim et al. 2012
9
191
31
572
18.8%
0.86 [0.40, 1.85]
21
145
9
145
17.7%
2.56 [1.13, 5.80]
0.31 [0.12, 0.80]
Lakkireddy et al. 2012
Nin et al. 2012
9
45
20
45
15.6%
Snipelisky et al. 2012
6
31
21
125
14.4%
1.19 [0.43, 3.25]
Yamaji 2013 A
Subtotal (95% Cl)
2
106
963
7
203
1839
7.9%
92.3%
0.54 [0.11, 2.64]
0.96 [0.54, 1.71]
Total events
56
98
Heterogeneity: τ2 = 0.28; χ2 = 12.04, df = 6 (P = 0.06); I 2 = 50%
Test for overall effect: Z = 0.13 (P = 0.90)
Total (95% Cl)
1073
Total events
1963 100.0%
58
0.92 [0.55, 1.54]
103
Heterogeneity: τ2 = 0.22; χ2 = 13.03, df = 8 (P = 0.11); I 2 = 39%
0.01
Test for overall effect: Z = 0.32 (P = 0.75)
Test for subgroup differences: τ2 = 0.53, df = 1 (P = 0.47); I 2 = 0%
0.1
1
10
Dabigatran
Warfarin
100
Figure 2 Random effect model meta-analysis of bleeding risk in the dabigatran group compared with warfarin in CA of AF. Error bars indicate the
CI.
0
SE (log[OR])
0.5
1
1.5
OR
2
0.01
0.1
1
10
Subgroups
Abstract
Published
Figure 3 Contour funnel plot of bleeding outcome.
100
and showed no difference between the dabigatran and the warfarin
groups [RD 0.00 (95% CI—20.00 to 0.01); x 2 ¼ 3.37; P ¼ 0.81;
I 2 ¼ 0%] in prevention of thromboembolism. Heterogeneity was
zero in both analyses as shown in Figures 4 and 5. A contour funnel
plot (Figure 6) revealed no visual evidence of asymmetry.
The thromboembolic manifestations in the dabigatran group consisted of one pulmonary embolism,13 one case of medial longitudinal
fasciculus syndrome [magnetic resonance imaging (MRI) showed multiple cerebral infarcts] which resolved completely the next day,14 and
three patients who developed unspecified neurological symptoms
recovered completely at 3 months follow-up.16 In the warfarin
group, there was one patient with right-sided weakness and expressive aphasia (MRI showed small left middle cerebral artery stroke)
which resulted in minimal deficit at 3 months follow-up,13 and one unspecified cerebrovascular accident.26
Discussion
In this first systematic review and meta-analysis assessing the safety
and efficacy of dabigatran vs. warfarin for peri-procedural
1417
Interrupted dabigatran for peri-procedural anticoagulation in CA of AF
Dabigatran
Study or subgroup
Events
Warfarin
Total Events
Total
Odds ratio
Odds ratio
Weight
M-H, Fixed, 95% Cl
M-H, Fixed, 95% Cl
1.3.1 Abstract
Khan
0
50
0
66
Mendoza et al. 2012
Subtotal (95% Cl)
0
60
110
1
58
124
47.4%
47.4%
0.32 [0.01,7.94]
0.32 [0.01, 7.94]
Total events
0
Not estimable
1
Heterogeneity: Not applicable
Test for overall effect: Z = 0.70 (P = 0.48)
1.3.2 Published
Bassiouny
1
376
1
623
23.5%
1.66 [0.10, 26.60]
Imamura et al. 2013
1
101
0
126
13.8%
3.78 [0.15, 93.69]
Kim et al. 2012
0
191
0
572
Lakkireddy et al. 2012
3
145
0
145
15.3%
7.15 [0.37, 139.62]
Snipelisky et al. 2012
0
31
0
125
Yamaji 2013 A
Subtotal (95% Cl)
0
106
950
0
203
1794
52.6%
Not estimable
3.81 [0.74, 19.64]
Total events
5
1918
100.0%
2.15 [0.58, 7.98]
Heterogeneity:
χ2
Not estimable
Not estimable
1
= 0.52, df = 2 (P = 0.77);
I2
= 0%
Test for overall effect: Z = 1.60 (P = 0.11)
Total (95% Cl)
Total events
1060
5
2
Heterogeneity: χ2 = 2.14, df = 3 (P = 0.54); I 2 = 0%
Test for overall effect: Z = 1.15 (P = 0.25)
Test for subgroup differences: χ2 = 1.82, df = 1 (P = 0.18); I 2 = 45.0%
0.01
0.1
1
10
Dabigatran Warfarin
100
Figure 4 Fixed effect model meta-analysis of thromboembolic risk in the dabigatran group compared with warfarin in CA of AF with OR as
measure of overall effect estimate. Error bars indicate the CI.
anticoagulation in CA of AF, we found that interrupted dabigatran did
not significantly differ from warfarin. This may have important implications for management of patients undergoing this procedure, especially considering the increasing number of patients with AF on
chronic dabigatran therapy. However, this evidence is largely based
on meta-analysis of observational studies that are limited by inherent
biases, difference in the study designs, and use of unadjusted data.
The likelihood of peri-procedural TIA or stroke in CA for AF has
declined as anticoagulation strategies have evolved. Historically,
with interrupted warfarin without bridging therapy and insufficient
intra-procedural anticoagulation, thromboembolic event rates as
high as 5% were reported.28 Subsequent strategies, as reflected in
the first worldwide survey of CA of AF, were associated with lower
thromboembolic event rates.29 The stroke/TIA rate in the survey was
0.76%30 and in a subsequent report from an experienced centre was
1%.30 More recent series including .3000 patients where warfarin
was not interrupted for the procedure [and higher ACTs (.350 s)
were targeted], report very low cerebral thromboembolic event
rates (0–0.098%) while maintaining relatively low bleeding rates.4,6
Dabigatran, in contrast, because of the lack of a well-studied,
readily available antidote, has generally been held before CA of AF,
raising questions regarding the safety of the procedure given prior
experience with interrupted anticoagulation without bridging.28
A report of initial experience with dabigatran in CA for AF by Lakkireddy et al.16 supported this concern, finding higher rates of thromboembolic as well as bleeding complications in comparison with
warfarin. However, the medication, which is a renally cleared, reversible, direct thrombin inhibitor, has potential advantages over warfarin, including a rapid onset of therapeutic anticoagulation, a
relatively abbreviated time to reversal of anticoagulation after the
medication is held, and a predictable anticoagulant effect.31 – 33 In addition, as many as 50% or more of patients on uninterrupted warfarin
present for CA of AF with an INR outside the therapeutic range.9
These factors underlie the idea that dabigatran could be used periprocedurally with a minimized window off of fully therapeutic anticoagulation with results similar to those achieved with uninterrupted
but often sub- or supra-therapeutic warfarin.
Similar thromboembolism and bleeding rates for dabigatran and
warfarin were reported in three recently published larger studies;
two comparing interrupted dabigatran to uninterrupted warfarin,13,15 and one comparing interrupted dabigatran with interrupted warfarin with UFH bridging.14 These findings are supported
1418
A.A. Bin Abdulhak et al.
Dabigatran
Study or subgroup
Events
Warfarin
Total Events
Total
Weight
Risk difference
Risk difference
M-H, Fixed, 95% Cl
M-H, Fixed, 95% Cl
1.3.1 Abstract
Khan
0
50
0
66
4.3%
0.00 [–0.03, 0.03]
Mendoza et al. 2012
0
60
1
58
4.5%
–0.02 [–0.06, 0.03]
124
8.8%
–0.01 [–0.04, 0.02]
110
Subtotal (95% Cl)
1
0
Total events
Heterogeneity: χ2 = 0.39, df = 1 (P = 0.53); I 2 = 0%
Test for overall effect: Z = 0.70 (P = 0.58)
1.3.2 Published
Bassiouny
1
376
1
623
35.6%
0.00 [–0.01, 0.01]
Imamura et al. 2013
1
101
0
126
8.5%
0.01 [–0.02, 0.04]
Kim et al. 2012
0
191
0
572
21.7%
0.00 [–0.01, 0.01]
Lakkireddy et al. 2012
3
145
0
145
11.0%
0.02 [–0.01, 0.05]
Snipelisky et al. 2012
0
31
0
125
3.8%
0.00 [–0.04, 0.04]
Yamaji 2013 A
0
106
0
203
10.6%
0.00 [–0.01, 0.01]
1794
91.2%
0.00 [–0.00, 0.01]
1918 100.0%
0.00 [–0.00, 0.01]
950
Subtotal (95% Cl)
Total events
Heterogeneity:
1
5
χ2
= 3.83, df = 5 (P = 0.57);
I2
= 0%
Test for overall effect: Z = 1.33 (P = 0.18)
Total (95% Cl)
1060
Total events
2
5
Heterogeneity: χ2 = 3.73, df = 7 (P = 0.81); I 2 = 0%
–1
Test for overall effect: Z = 0.93 (P = 0.35)
Test for subgroup differences: χ2 = 0.69, df = 1 (P = 0.41); I 2 = 0%
–0.5
Dabigatran
0
0.5
Warfarin
1
Figure 5 Fixed effect model meta-analysis of thromboembolic risk in the dabigatran group compared with warfarin in CA of AF with RD measure
of overall effect estimate. Error bars indicate the CI.
by the present meta-analysis which showed no difference in bleeding
or thromboembolism risk for those treated with interrupted dabigatran in comparison with warfarin. Similar results were observed in
secondary analyses comparing interrupted dabigatran with interrupted warfarin combined with bridging anticoagulation [either intravenous UFH or subcutaneous low molecular weight heparin
(LMWH)]. The lack of difference between dabigatran and warfarin
was consistent in all subgroup and sensitivity analyses.
0 SE (log[OR])
0.5
1
Clinical implications
1.5
2
0.01
OR
0.1
1
10
100
Subgroups
Abstract
Published
Figure 6 Contour funnel plot of thromboembolic outcome.
Presently available data, including recent larger than previously
reported individual studies, and the present meta-analysis, support
the use of interrupted dabigatran as an alternative to warfarin for
peri-procedural anticoagulation for CA for AF. Holding dabigatran
for 1– 2 doses before the procedure with resumption after the procedure on the same day has shown similar safety and efficacy as uninterrupted warfarin or interrupted warfarin with bridging
anticoagulation with UFH or LMWH. A longer hold for dabigatran
for patients with renal dysfunction is advisable, although supporting
1419
Interrupted dabigatran for peri-procedural anticoagulation in CA of AF
data in CA of AF are lacking. With anticoagulation being interrupted
and the majority of studies using pre-procedural TEE for patients on
dabigatran, routine use of pre-procedural TEE for patients on dabigatran may be warranted.
Particular attention to intra-procedural anticoagulation with UFH
may be advised as larger doses of UFH appear to be necessary to
achieve target ACTs for patients treated with dabigatran, although
a mechanism for this difference has not been identified and its clinical
significance is not currently known.
Strengths
An extensive search strategy was conducted to help ensure representation of all currently available data from studies meeting the predefined inclusion criteria. The findings were robust and consistent
among different subgroup and sensitivity analyses. There was no significant in between studies heterogeneity and no evidence of publication bias.
Limitations
The study has several limitations. It involves meta-analysis of unadjusted data from mainly observational studies with all the inherent
biases of such study design. Our meta-analysis could not control for
variation of practices among different centres. Although no study
reported dabigatran outcomes in comparison with historical warfarin
use, it is possible that dabigatran use was concentrated in more recent
cases and may have been favourably affected by safer procedural
practices and greater clinical experience. The availability of data on
the use of dabigatran during CA for AF is limited, as the drug was
only recently approved and marketed, and while our efforts captured
all the available studies as of 2013, ongoing studies will further
improve the ability to estimate the risks and benefits of dabigatran
as compared with warfarin.
Although the results of the meta-analyses are consistent, there is
variability among individual study results. Different results may be attributable to differences in patient risk profiles (CHADS2 score), ablation strategies, ablation catheter, ACT ranges, TEE practices,
physician experience, target INRs, and dabigatran dosing. Transoesophageal echocardiogram practices not only differed among centres,
but often differed for dabigatran in contrast to warfarin patients at
the same centre. How often intracardiac thrombus was identified
during pre-procedural TEE and the ablation procedure postponed
was not reported. Thrombembolic events were not analysed based
on whether patients were in sinus rhythm or required cardioversion
at the time of the ablation procedure, which may have differed among
centres and between warfarin and dabigatran groups.
Conclusion
Meta-analysis of currently available studies shows no significant difference in bleeding or thromboembolism between interrupted dabigatran and warfarin therapy in CA of AF. Dabigatran appears to be
safe and effective for peri-procedural anticoagulation in CA of AF, although small differences in comparison with warfarin cannot be
excluded. Given limitations to the available studies, additional data
from a large multicentre randomized study are needed.
Conflict of interest: none declared.
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IMAGES IN ELECTROPHYSIOLOGY
doi:10.1093/europace/eut137
Online publish-ahead-of-print 22 May 2013
.............................................................................................................................................................................
Adjusting treatment to pulmonary vein rare anatomic variants: a box lesion
for the ablation of atrial fibrillation in a patient with an atypical common
inferior trunk
Rui Providência*, Stéphane Combes, and Jean-Paul Albenque
Département de Rythmologie, Clinique Pasteur, 45 avenue de Lombez, BP 27617, 31076 Toulouse Cedex 3, France
* Corresponding author. Tel: +33 5 62 21 16 45; fax: +33 5 62 21 16 41. Email: [email protected]
The presence of a common inferior trunk of
pulmonary veins (PVs) is a rare anatomical variant
that may pose difficulties in catheter ablation of
atrial fibrillation.
Panels A– D are computed tomography scan
images edited on a CARTO-3w console illustrating
the presence of a common inferior PV arising on the
posterior wall and a novel treatment approach: a
box lesion encircling the four PVs. The SmartTouchw catheter was used (contact force levels
.10 g can be seen all along the radiofrequency
line). Isolation of the four PVs was possible
without the need of complementary radiofrequency applications and the patient remains asymptomatic 3 months later.
Conflict of interest: J.P.A. is a consultant for
St Jude Medical.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected].