- Email: [email protected]
Significant Benefit of Uninterrupted DOACs Versus VKA During Catheter Ablation of Atrial Fibrillation
JACC: CLINICAL ELECTROPHYSIOLOGY
VOL.
-, NO. -, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
Significant Benefit of Uninterrupted DOACs Versus VKA During Catheter Ablation of Atrial Fibrillation Jorge Romero, MD,a,* Roberto C. Cerrud-Rodriguez, MD,a,* Isabella Alviz, MD,a Juan Carlos Diaz, MD,a Daniel Rodriguez, MD,a Samiullah Arshad, MD,a Luis Cerna, MD,a Jose Taveras, MD,a Vito Grupposo, RT,a Andrea Natale, MD,b Mario Garcia, MD,a Luigi Di Biase, MD, PHDa
ABSTRACT OBJECTIVES This study assessed the incremental benefit of uninterrupted direct oral anticoagulants (DOACs) versus uninterrupted vitamin K antagonists (VKAs) for catheter ablation (CA) of nonvalvular atrial fibrillation (NVAF) on 3 primary outcomes: major bleeding events (MBEs), minor bleeding events, and thromboembolic events (TEs). The secondary outcome was post-procedural silent cerebral infarction (SCI) as detected by brain cardiac magnetic resonance. BACKGROUND As a class, evidence of the benefits of DOACs versus VKAs during CA of AF is scant. METHODS A systematic review of Medline, Cochrane, and Embase was done to find all randomized controlled trials in which uninterrupted DOACs were compared against uninterrupted VKAs for CA of NVAF. A fixed-effect model was used, except when I2 was $25, in which case, a random effects model was used. RESULTS The benefit of uninterrupted DOACs over VKAs was analyzed from 6 randomized control trials that enrolled a total of 2,256 patients (male: 72.7%) with NVAF, with significant benefit in MBEs (relative risk [RR]: 0.45; 95% confidence interval [CI]: 0.20 to 0.99; p ¼ 0.05). No significant differences were found in minor bleeding events (RR: 1.12; 95% CI: 0.87 to 1.43; p ¼ 0.39), TEs (RR: 0.75; 95% CI: 0.26 to 2.14; p ¼ 0.59), or post-procedural SCI (RR: 1.09; 95% CI: 0.80 to 1.49; p ¼ 0.58). CONCLUSIONS An uninterrupted DOACs strategy for CA of AF appears to be safer than uninterrupted VKAs with a decreased rate of minor bleeding events. There are no significant differences among the other outcomes. DOACs should be offered as a first-line therapy to patients undergoing CA of AF, due to their lower risk of minor bleeding events, ease of use, and fewer interactions. (J Am Coll Cardiol EP 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.
C
atheter ablation (CA) of atrial fibrillation
The COMPARE (Role of Coumadin in Preventing
(AF) is an effective therapeutic option in
Thromboembolism in Atrial Fibrillation (AF) Patients
symptomatic, drug-refractory AF (1). CA is a
Undergoing Catheter Ablation) study established un-
technically
difficult
procedure
with
potentially
interrupted warfarin as the standard of care for pa-
serious complications, such as stroke, transient
tients undergoing CA of AF (3). This randomized
ischemic attack, or systemic embolism, with reported
controlled trial (RCT) demonstrated that perfor-
incidence of adverse events as high as 4.6% (2).
ming
this
procedure
without
interrupting
oral
From the aMontefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and the bTexas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, Texas. *Drs. Romero and Cerrud-Rodriguez contributed equally to this work and are joint first authors. Dr. Di Biase has served as a consultant for Biosense Webster, Boston Scientific, Stereotaxis, and St. Jude Medical; and has received speaker honoraria/travel support from Biosense Webster, St. Jude Medical, Boston Scientific, Medtronic, Bristol-Myers Squibb, Pfizer, and Biotronik. Dr. A. Natale has served as a consultant for Baylis Medical, Boston Scientific, Biosense Webster, Bristol-Myers Squibb, St. Jude Medical, Biotronik, and Medtronic. Dr. Burkhardt has served as a consultant/speaker for Biosense-Webster and Stereotaxis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page. Manuscript received June 3, 2019; revised manuscript received July 23, 2019, accepted August 8, 2019.
ISSN 2405-500X/$36.00
https://doi.org/10.1016/j.jacep.2019.08.010
2
Romero et al.
-, NO. -, 2019
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
- 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
ABBREVIATIONS
anticoagulation with warfarin was associated
available evidence incorporated into the present
AND ACRONYMS
with a decreased risk of stroke and minor
analysis were also registered.
bleeding complications.
AF = atrial fibrillation
After the introduction of direct oral anti-
CA = catheter ablation
coagulants (DOACs), several studies tried to
CI = confidence interval
establish their noninferiority to vitamin K
CMR = cardiac magnetic
antagonists (VKAs) in CA of AF, including
resonance
some RCTs. The VENTURE-AF (Uninter-
DOAC = direct oral
rupted
anticoagulants
rivaroxaban
vs.
uninterrupted
vitamin K antagonists for catheter ablation in
DWI = diffusion weighted
non-valvular atrial fibrillation) was the first
imaging
MBE = major bleeding event
RCT that compared an uninterrupted DOAC (rivaroxaban) to an uninterrupted VKA (4).
MRI = magnetic resonance imaging
After this study, several others came out
NVAF = nonvalvular atrial
comparing outcomes between dabigatran
fibrillation
versus VKA and rivaroxaban versus VKA
RCT = randomized controlled
during CA of AF (5–10). Based on these
trial
studies, the Heart Rhythm Society/European
RR = risk ratio
Heart Rhythm Association published their
RRR = relative risk reduction
updated
SCI = silent cerebral infarction
regarding catheter and surgical ablation of AF
TE = thromboembolic event
in 2017 (1). The current standard of care in-
VKA = vitamin K antagonist
corporates the use of uninterrupted VKAs
expert
consensus
statement
(international normalized ratio goal: 2.0 to 3.0), uninterrupted dabigatran (evidence class IA), or uninterrupted rivaroxaban (class I-BR). Despite these studies providing evidence for individual DOACs, data regarding potential benefits of DOACs (as a class) over VKAs during CA of AF are scant. The present meta-analysis builds on the foundation laid by a previous meta-analysis by Romero et al. (11), which included RCTs only, and showed a trend toward fewer major bleeding events (MBEs) in the uninterrupted DOACs group during CA of AF. We thus decided to update our meta-analysis, with the data obtained by the ASCERTAIN (Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation) trial and the recently published ELIMINATE-AF (Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation) trial (12,13). Our goal was to determine the existence of any statistically significant benefit of uninterrupted DOACs over uninterrupted VKAs for CA of AF.
METHODS The present meta-analysis was performed according to Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements (14). This meta-analysis was
SEARCH STRATEGY. We searched PubMed, Embase,
and Cochrane Central Register of Clinical Trials (Cochrane Library, Issue 02, 2017) databases from January 2008 to April 2019 to identify RCTs that compared uninterrupted DOACs versus uninterrupted VKAs for CA of AF. We used the following terms: (“direct oral anticoagulants” OR DOAC OR dabigatran OR rivaroxaban OR apixaban) AND (warfarin OR “vitamin K antagonists” OR VKA) AND (“auricular fibrillation” OR “atrial fibrillation”) AND (ablation OR “catheter ablation”). No language restriction was applied. The reference lists of identified articles were also reviewed for additional sources. ELIGIBILITY CRITERIA. Studies with the following
characteristics
were
considered
eligible
to
be
included in this meta-analysis: 1) RCTs that compared uninterrupted DOACs versus uninterrupted VKAs for CA of AF; and 2) studies that compared the event rates of MBEs and/or minor bleeding and/or thromboembolic events (TEs) and/or incidence of silent cerebral
infarction
(SCI)
detected
by
diffusion-
weighted imaging (DWI) brain magnetic resonance imaging (MRI) between the 2 groups. Case reports, editorials, reviews, and expert opinions were excluded from our analysis. Abstracts presented at major international conferences that were not published as full papers were not considered in our analysis. PRIMARY AND SECONDARY OUTCOMES. The pri-
mary outcomes of this study were; 1) MBEs; 2) minor bleeding events; and 3) TEs. The secondary outcome was SCI as detected by post-procedural DWI brain MRI. MBEs were defined by using the Bleeding Academic Research Consortium (BARC) criteria, with a scale $2 being considered major bleeding (see Online Appendix: Material, Definition of Major Bleeding Events). In the case the reported events by the individual studies were reported using different criteria, these were reclassified using BARC, by consensus of the authors of this paper.” Minor bleeding events were all reported bleeding events that did not fulfil this criterion. TEs were defined as stroke, transient ischemic attack, systemic embolism,
or
development
of
an
intracardiac
thrombus post-procedure. Finally, SCI was defined as a clinically silent new brain lesion detected by DWI brain MRI post-procedurally.
registered in PROSPERO (International prospective
DATA EXTRACTIONS AND QUALITY APPRAISAL.
register of systematic reviews) with registration
Three investigators (J.R., R.C.R., and L.D.B.) inde-
number CRD42018089183. The updates to reflect new
pendently screened all titles and abstracts and
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
manually searched the full text versions of all relevant studies that fulfilled the inclusion criteria. Ref-
F I G U R E 1 Study Selection
erences of the retrieved articles were independently reviewed for further identification of potentially relevant studies. Disagreements were resolved by consensus after discussion (J.R. and R.C.R.). We extracted characteristics of each study, including methodology and baseline patient characteristics, MBEs, minor bleeding events, and TEs. SCI events were also extracted from the relevant studies. If the previously mentioned information was not readily available in the written article, the principal investigator of that particular study was contacted to supply pertinent information. QUALITY ASSESSMENT. The quality and reporting of
the included RCTs were assessed using the Cochrane Risk of Bias Tool (15). Six categories were included in the analysis: 1) selection bias: systematic differences between baseline characteristics of the groups that were compared; 2) performance bias: systematic differences between groups in the care that was provided, or in exposure to factors other than the interventions of interest. Blinding was not always possible, as was the case of the RCTs included in our study, because it would have been unethical not to monitor the international normalized ratio in the VKA arm; 3) detection bias: systematic differences between groups in how outcomes were determined. Blinding of outcome assessors might reduce the risk that knowledge of which intervention was received, rather than the intervention itself, because this affected outcome measure-
Study selection. DOAC ¼ direct oral anticoagulants; RCT ¼ randomized controlled trials.
ment; 4) attrition bias: systematic differences between groups due to withdrawals from a study. Withdrawals from the study led to incomplete outcome data; 5) reporting bias: systematic differences between reported and unreported findings; and 6) other biases: other sources of bias that were relevant only in certain circumstances. Quality of the included RCTs was summarized visually. STATISTICAL ANALYSIS. Descriptive statistics are
presented as number of cases (n) for dichotomous and categorical variables. Statistical analysis was performed in line with recommendations from the Cochrane Collaboration and PRISMA guidelines, using Review Manager (RevMan version 5.3, the Cochrane
Collaboration,
2014;
Oxford,
United
Kingdom) (14). Heterogeneity was assessed using the 2
I statistics, which is the proportion of total variation observed among the studies attributable to differences between studies, rather than a sampling error (chance). Data were summarized across groups using the Mantel-Haenszel risk ratio (RR) fixed-effect 2
2
was used if I 2 was $25%. Publication bias was estimated visually by funnel plots (17).
RESULTS A total of 741 studies were identified using the specified search criteria (Figure 1). After evaluation of these studies, based on titles and abstracts, 11 RCTs were further analyzed in their full-text versions, 5 of which were discarded, leaving another 6 RCTs that fulfilled the inclusion criteria. These 6 RCTs had a total of 2,256 participants (72.7% male; average age 61.3 2.6 years). Other RCTs were excluded due to a lack of information relevant to our study questions, because they did not follow an uninterrupted DOAC strategy, or their statistical power was poor due to the low number of enrolled patients (18). The summary of the primary and secondary outcomes can be found in the Central Illustration.
model if I was <25% (16). We considered I <25% as
CHARACTERISTICS
low and I 2 $75% as high. The random effects model
baseline characteristics of the included trials are
OF
INCLUDED
STUDIES. The
3
Romero et al.
4
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019 - 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
C E NT R A L IL L U ST R A T I O N Summary of Study Outcomes
B
14.0
13.9%
13.7%
DOACs
VKA
12.0 10.0 8.0 6.0 4.0 2.0 0.0
D
C
Thromboembolic Events (% of Patients)
RR 1.14 (95% CI 0.87-1.49) p = 0.35
Minor Bleeding Events (% of Patients)
RR 0.45 (95% CI 0.20-0.99) p = 0.05 10.0 RRR: 55% 9.0 8.0 7.0 6.0 5.2% 5.0 4.0 3.0 2.3% 2.0 1.0 0.0 DOACs VKA
RR 0.75 (95% CI 0.26-2.14) 1.0 p = 0.59 0.9 0.8 0.7 0.6 0.5 0.4% 0.4 0.3 0.2 0.1 0.0 DOACs
0.7%
SCI in Post-CA Brain MRI (% of Patients)
Major Bleeding Events (% of Patients)
A
VKA
RR 1.09 (95% CI 0.80-1.49) 20.0 p = 0.58 18.0 16.3% 15.4% 16.0 14.0 12.0 10.0 8.0 6.0 4.0 2.0 0.0 VKA DOACs
Romero, J. et al. J Am Coll Cardiol EP. 2019;-(-):-–-.
(A) Incidence of major bleeding events. (B) Incidence of minor bleeding events. (C) Incidence of thromboembolic events. (D) Incidence of silent cerebral infarction (SCI) in post-catheter ablation diffusion weighted imaging (DWI) brain magnetic resonance imaging (MRI). CA ¼ Catheter ablation; CI ¼ confidence interval; DOACs ¼ direct oral anticoagulants; RR ¼ risk ratio; RRR ¼ relative risk reduction; VKA ¼ Vitamin K antagonist.
summarized in Table 1. Uninterrupted dabigatran
QUALITY ASSESSMENT AND PUBLICATION BIAS.
was used in 317 (14.1%) patients (8), rivaroxaban in
Funnel plots did not suggest publication bias for the
187 (8.3%) patients (4,13), apixaban in 418 (18.5%)
selected outcomes of minor bleeding events, TE, and
patients (19,20), and edoxaban in 316 (14.0%) pa-
SCI (Figure 2). All the RCTs included in this meta-
tients (12). The remaining patients (n ¼ 1,018; 45.1%)
analysis had good methodological quality that indi-
were on uninterrupted VKA. For detailed informa-
cated a low risk of bias (Figure 3).
tion regarding duration
oral anticoagulation
IMPACT ON MBEs. We found a statistically significant
before CA and the follow-up periods for each study,
reduction in MBEs in the uninterrupted DOAC strat-
of
please refer to Online Table 1. The target interna-
egy (RR: 0.45; 95% confidence interval [CI]: 0.20 to
tional normalized ratio for patients receiving VKA
0.99; p ¼ 0.05), with a relative risk reduction (RRR) of
was between 2.0 and 3.0.
55%. The incidence of MBEs in the uninterrupted
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
5
Benefit of DOACs Versus VKA During CA of AF
T A B L E 1 Baseline Characteristics of Included RCTs
Type of Study
n
ASCERTAIN
RCT
127
AXAFA
RCT
633 424
ELIMINATEAF
RCT
417
Kuwahara 2016
RCT
200 147
Study
Mean Male Age
106
DOAC Used in the Study
No. of No. of Patients on Patients DOACs on VKA
Paroxysmal AF
Vascular Mean Prior Disease CHA2DS2Stroke/ (CAD, PAD, Persistent Long-Standing Vasc TIA/ Carotid Mean AF Persistent AF Score CHF HTN DM Embolism Disease) BMI
60
Rivaroxaban
64
63
82
28
17
NP
63
13
NP
NP
24.1
127
63.4
Apixaban
318
315
367
NP
NP
2.4
212 571
76
47
83
29
335
60
Edoxaban
316
101
292
103
22
2.1
68 239 47
19
86
28.3
177
65.5
Apixaban
100
100
119
NP
NP
2.2
NP
NP
NP
NP
NP
NP
200
311
7
DWI Brain MRI
RE-CIRCUIT
RCT
635 475
59.2
Dabigatran
317
318
432
167
36
2.1
65
343 64
19
105
28.7
NA
VENTUREAF
RCT
244
59.6 Rivaroxaban
123
121
182
NP
NP
1.6
21
116
3
47
29.4
NA
176
22
CHA2DS2-Vasc score ¼ age 65 to 74 years (þ1) or $75 (þ2), female (þ1), congestive heart failure history (þ1), hypertension history (þ1), stroke/transient ischemic attack/thromboembolism history (þ2), vascular disease history (þ1). AF ¼ atrial fibrillation; ASCERTAIN ¼ Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation; AXAFA ¼ Apixaban During Atrial Fibrillation Catheter Ablation; BMI ¼ body mass index; CAD ¼ coronary artery disease; CHF ¼ congestive heart failure; DM ¼ diabetes mellitus; DOAC ¼ direct oral anticoagulant; DWI ¼ diffusion-weighted imaging; ELIMINATE-AF ¼ Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation; HTN ¼ hypertension; MI ¼ myocardial infarction; MRI ¼ magnetic resonance imaging; NSAIDs ¼ nonsteroidal anti-inflammatory drugs; PAD ¼ peripheral artery disease; RCT ¼ randomized controlled trials; RE-CIRCUIT ¼ Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation; TIA ¼ transient ischemic attack; VENTURE-AF ¼ Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
DOAC strategy was 2.3%, and the incidence of MBEs
The use of uninterrupted DOACs during CA of AF
in the uninterrupted VKA strategy was 5.2%. (Central
has been steadily increasing, mainly due to the pub-
Illustration and Figure 4).
lished data showing that DOACs have a favorable
IMPACT ON MINOR BLEEDING EVENTS. The minor
bleeding rates in the DOAC and VKA groups were 13.9% and 13.7%, respectively. There were no significant differences between groups (RR: 1.12; 95% CI: 0.87 to 1.43; p ¼ 0.39) (Central Illustration and Figure 5).
safety and efficacy profile (5,6). A meta-analysis by Zhao et al. (22), which used observational data in >7,900 patients, showed no difference between groups in preventing TEs; DOAC use was associated with a lower risk of bleeding. The concern of not having readily available reversal agents in case of life-
IMPACT ON TEs. There were no significant differ-
threatening bleeding (e.g., a pericardial tamponade)
ences between groups regarding TEs. The stroke rates
may be allayed by the Food and Drug Administration
in the DOAC and VKA groups were 0.4% and 0.7%,
approval of andexanet alfa as a reversal agent for
respectively (RR: 0.75; 95% CI: 0.26 to 2.14; p ¼ 0.59) (Central Illustration and Figure 5). IMPACT
ON
SCI. Four
rivaroxaban and apixaban, as well as idarucizumab for dabigatran (23,24).
of the 6 included RCTs
Our meta-analysis used all published RCT data that
included a component to assess for post-CA SCI using
compared the outcomes of uninterrupted DOACs
DWI brain MRI (12,13,19,20). In our analysis, we could
versus uninterrupted VKAs on MBEs, minor bleeding
not find any statistically significant difference be-
events, TEs, and SCI. We included a total of 2,256
tween the uninterrupted DOAC group (16.3%) and the
participants who underwent CA of AF. The pertinent
uninterrupted VKA group (15.4%) regarding SCI as
findings of this study were the following:
detected by brain MRI (RR: 1.09; 95% CI: 0.80 to 1.49; p ¼ 0.56) (Central Illustration and Figure 6).
DISCUSSION CA of AF is an important rhythm control strategy for improvement of quality of life in patients with AF. A recent meta-analysis by Turagam et al. (21) showed a mortality benefit of CA of AF in patients with congestive heart failure. Although this procedure carries the risk of embolization, an uninterrupted
1. Uninterrupted
DOACs
provided
a
significant
benefit toward fewer MBEs (RRR of 45% and adjusted RR of 2.9%; p ¼ 0.05) compared with uninterrupted VKAs. 2. There were no statistically significant differences between groups in the outcomes of minor bleeding events and TEs, or in post-CA SCI. Our study was not specifically powered to detect TEs, and the overall event rate was low. This, in turn, increased the risk of a type II error.
VKA strategy has been shown to decrease this risk
Given our findings, we believe it is reasonable and
to <1% with no associated increase in the rate of
beneficial to offer patients who need to undergo CA of
bleeding complications (3).
AF uninterrupted anticoagulation with DOACs as
6
Romero et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
Benefit of DOACs Versus VKA During CA of AF
-, NO. -, 2019 - 2019:-–-
F I G U R E 2 Funnel Plots
(A) Minor bleeding events. (B) Thromboembolic events. (C) Silent cerebral infarction as demonstrated by post-catheter ablation diffusionweighted imaging brain magnetic resonance imaging RR ¼ risk ratio.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
F I G U R E 3 Risk of Bias Summary
Benefit of DOACs Versus VKA During CA of AF
CA of NVAF. A previous study by our research group failed to reach statistical significance, which was likely due to a lack of statistical power because of its smaller sample size (11). This lack of power was solved with the inclusion of the data published by both the ASCERTAIN and the ELIMINATE-AF trials (12,13). Two previous meta-analysis found results similar to ours using different methodologies. A metaanalysis by Zhao et al. (25), which analyzed 6 RCTs, found a significantly decreased risk of MBEs with DOACs. However, 1 of the included papers, by Zhu et al. (18), whose main goal was to analyze the metabolic effects of rivaroxaban (measuring outcomes such as serum total protein, albumin, and globulin levels), had poor statistical power due to the extremely small number of enrolled patients (30 patients each in the rivaroxaban and the VKA arms). Zhao et al. also used inaccurate MBE rates in their analysis when referring to the ASCERTAIN trial, because they used preliminary data published in the Circulation Supplement for Abstracts presented at the American Heart Association 2016 meeting. The final, definitive data of the ASCERTAIN trial were published as a full paper in JACC: Clinical Electrophysiology in December 2018 (26). A second meta-analysis by Cardoso et al. (27) found significantly decreased MBEs using uninterrupted DOACs. The authors included a total of 12 studies in its analysis, 3 of which were RCTs (4,8,19). The
investigators
found
significantly
decreased
Risk of bias summary: review authors’ judgements about each risk
MBEs in a dedicated quantitative synthesis of
of bias item for each included study. ASCERTAIN ¼ Asymptom-
studies with a lower risk of selection bias, which
atic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation; AXAFA ¼ Apixaban During Atrial Fibrillation Catheter
included the previously mentioned 3 RCTs and 3
Ablation; ELIMINATE-AF ¼ Uninterrupted edoxaban vs. vitamin K
additional studies: a multicenter prospective registry
antagonists for ablation of atrial fibrillation; RE-CIRCUIT ¼
that assessed uninterrupted apixaban versus unin-
Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial
terrupted VKAs by Di Biase et al (28); a study by
Fibrillation; VENTURE-AF ¼ Uninterrupted rivaroxaban vs.
Dillier et al. (10) that matched patients in the inter-
uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
vention
arm
(uninterrupted
rivaroxaban)
with
control subjects (uninterrupted VKA) by age, sex, and type of AF (10); and a multicenter prospective registry that matched patients on uninterrupted
first-line therapy. These conclusions fall in line with
rivaraxoban with patients on uninterrupted VKAs by
the recent consensus statement on the use of unin-
Lakireddy et al. (9).
terrupted DOACs for CA of AF that gave a class I
We want to highlight that our meta-analysis was
recommendation for the use of uninterrupted dabi-
the only one to include only RCTs in its analysis and
gatran or rivaroxaban (1). DOACs are more convenient
to include all DOACs currently on the market, and to
for both the patient and the physician, have fewer
reclassify
interactions with medications and food, and do not
classification.”
all
bleeding
events
using
the
BARC
require frequent blood testing to monitor the inter-
STUDY LIMITATIONS. Our meta-analysis had some
national normalized ratio.
limitations. Most of the RCTs included in our meta-
The results of our meta-analysis proved that there
analysis were exploratory trials with administra-
was a significant decrease in the risk of MBEs between
tively determined trial sizes, because the sample
uninterrupted DOACs and uninterrupted VKAs during
required to provide sufficient power to establish
7
8
Romero et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019 - 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
F I G U R E 4 Forest Plot for Major Bleeding Events
The diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% confidence interval [CI]); width of the shaded square is the size of the population. The random effects model was used in the major bleeding events outcome as I2 >25%, the fixed-effect model was used in all other outcomes. DOAC ¼ direct oral anticoagulant; MH ¼ Mantel–Haenszel; VKA ¼ vitamin K antagonists.
formal noninferiority would have made them unfea-
Another limitation of our study was that the event
sible. The AXAFA (Apixaban) trial was the exception,
frequency of TEs was quite low; it was not specifically
because it was designed from the beginning to accu-
powered to measure this outcome, which might pre-
mulate sufficient events for a formal noninferiority
dispose to a type II error.
analysis by selecting patients with at least 1 risk factor for stroke (20).
The results of our study should generate interest in the design of larger, well-designed RCTs comparing
F I G U R E 5 Forest Plot of Minor Bleeding Events and Thromboembolic Events
(A) Minor bleeding events. (B) Thromboembolic events. The diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% CI); width of the shaded square is the size of the population. Fixed-effect model model was used as I2 #25%. Abbreviations as in Figure 4.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
F I G U R E 6 Forest Plot of Silent Cerebral Infarction
Silent cerebral infarction as demonstrated by post-catheter ablation diffusion-weighted imaging brain magnetic resonance imaging. The diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% CI); width of the shaded square is the size of the population. Fixed-Effect model model was used as I2 #25%. Abbreviations as in Figure 4.
the safety and efficacy, not only of uninterrupted DOACs versus uninterrupted VKAs in CA of AF, but
ADDRESS FOR CORRESPONDENCE: Dr. Luigi Di
also compare the differences in outcomes when using
Biase, Montefiore-Einstein Center for Heart and
the different DOACs now available in the market. As
Vascular Care, Montefiore Medical Center, Albert
in our previous study, we believe the number of pa-
Einstein College of Medicine, 111 East 210th Street,
tients assessed for SCI was still insufficient to deter-
Bronx, New York 10467. E-mail: [email protected].
mine if there was a difference between uninterrupted DOACs and uninterrupted VKAs. Finally, we believe
PERSPECTIVES
that the main limitation of our analysis lies in the low COMPETENCY IN MEDICAL KNOWLEDGE: As a group,
number of events.
DOACs can be safely used as first-line anticoagulation therapy in patients undergoing CA of NVAF, because they are significantly
CONCLUSIONS
less likely to cause a major bleeding event than VKAs. There is no
An uninterrupted DOACs strategy for CA of NVAF carries a lower risk of MBEs compared with uninterrupted VKAs. There were no significant differences among the other outcomes (minor bleeding events, TE, SCI) between groups. We thus believe DOACs should be considered a first option to offer to patients
difference between groups in minor bleeding events or TEs. TRANSLATIONAL OUTLOOK: Additional research is necessary to determine if post-ablation SCI can be prevented with oral anticoagulation and, if so, which kind would offer the best protectiondDOACs or VKAs.
undergoing CA of AF, over traditional VKAs.
REFERENCES 1. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Europace 2018;20:e1–160. 2. Chen J, Dagres N, Hocini M, et al. Catheter ablation for atrial fibrillation: results from the first European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA) Part II. Europace 2015;17:1727–32.
(COMPARE) randomized trial. Circulation 2014; 129:2638–44.
atrial fibrillation. J Interv Card Electrophysiol 2013;37:233–9.
4. Cappato R, Marchlinski FE, Hohnloser SH, et al.
7. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter pro-
Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015;36:1805–11. 5. Kaiser DW, Streur MM, Nagarakanti R, Whalen SP, Ellis CR. Continuous warfarin versus periprocedural dabigatran to reduce stroke and systemic embolism in patients undergoing cath-
spective registry. J Am Coll Cardiol 2012;59: 1168–74.
3. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation man-
eter ablation for atrial fibrillation or left atrial flutter. J Interv Card Electrophysiol 2013;37:241–7.
tran versus warfarin for ablation in atrial fibrillation. N Engl J Med 2017;377:495–6.
agement: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation
6. Haines DE, Mead-Salley M, Salazar M, et al. Dabigatran versus warfarin anticoagulation before and after catheter ablation for the treatment of
9. Lakkireddy D, Reddy YM, Di Biase L, et al.
8. Calkins H, Nordaby M. Uninterrupted dabiga-
Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients
9
10
Romero et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019 - 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014;63:982–8.
17. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.
24. Pollack CV Jr., Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017;377:431–41.
10. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhyth Electrophysiol 2014;7:576–82.
18. Zhu J, Gao RJ, Liu Q, et al. Metabolic benefits of rivaroxaban in non-valvular atrial fibrillation patients after radiofrequency catheter ablation. J Zhejiang Univ Sci B 2017;18:946–54.
25. Zhao Y, Lu Y, Qin Y. A meta-analysis of randomized controlled trials of uninterrupted periprocedural anticoagulation strategy in patients
11. Romero J, Cerrud-Rodriguez RC, Diaz JC, et al. Uninterrupted direct oral anticoagulants vs. uninterrupted vitamin K antagonists during catheter ablation of non-valvular atrial fibrillation: a systematic review and meta-analysis of randomized controlled trials. Europace 2018;20:1612–20.
19. Kuwahara T, Abe M, Yamaki M, et al. Apixaban versus warfarin for the prevention of periprocedural cerebral thromboembolism in atrial fibrillation ablation: multicenter prospective randomized study. J Cardiovasc Electrophysiol 2016;27: 549–54.
12. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019 April 11 [E-pub ahead of print].
20. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J 2018;39: 2942–55.
13. Kimura T, Kashimura S, Nishiyama T, et al. Asymptomatic cerebral infarction during catheter ablation for atrial fibrillation: comparing uninterrupted rivaroxaban and warfarin (ASCERTAIN). J Am Coll Cardiol EP 2018;4:1598–609.
21. Turagam MK, Garg J, Whang W, et al. Catheter ablation of atrial fibrillation in patients with heart failure: a meta-analysis of randomized controlled trials. Ann Intern Med 2019;170:41–50.
14. Knobloch K, Yoon U, Vogt PM. Preferred reporting items for systematic reviews and metaanalyses (PRISMA) statement and publication bias. J Craniomaxillofac Surg 2011;39:91–2. 15. Cochrane Methods Bias. Assessing risk of bias in included studies. . Available at: http://methods. cochrane.org/bias/assessing-risk-bias-includedstudies. Accessed February 24, 2018. 16. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88.
22. Zhao Y, Yang Y, Tang X, Yu X, Zhang L, Xiao H. New oral anticoagulants compared to warfarin for perioperative anticoagulation in patients undergoing atrial fibrillation catheter ablation: a metaanalysis of continuous or interrupted new oral anticoagulants during ablation compared to interrupted or continuous warfarin. J Interv Card Electrophysiol 2017;48:267–82.
undergoing atrial fibrillation catheter ablation. Int J Cardiol 2018;270:167–71. 26. Takatsuki S, Kimura T, Nakajima K, et al. Abstract 23233: Asymptomatic cerebral infarction during catheter ablation of atrial fibrillation comparing uninterrupted rivaroxaban and warfarin (ASCERTAIN Study). Circulation 2016;134:A23233. 27. Cardoso R, Knijnik L, Bhonsale A, et al. An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted anticoagulation in atrial fibrillation catheter ablation. Heart Rhythm 2018;15:107–15. 28. Di Biase L, Lakkireddy D, Trivedi C, et al. Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: results from a multicenter study. Heart Rhythm 2015;12:1162–8.
KEY WORDS atrial fibrillation, catheter ablation, direct oral anticoagulants, randomized controlled trials, vitamin K antagonists, warfarin
23. Heo YA. Andexanet alfa in the treatment of acute major bleeding related to apixaban and rivaroxaban: a profile of its use in the USA. Drugs Ther Perspect 2018;34:507–12.
A PPE NDI X For an expanded Methods section and the supplemental table, please see the online version of this paper.
VOL.
-, NO. -, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
Significant Benefit of Uninterrupted DOACs Versus VKA During Catheter Ablation of Atrial Fibrillation Jorge Romero, MD,a,* Roberto C. Cerrud-Rodriguez, MD,a,* Isabella Alviz, MD,a Juan Carlos Diaz, MD,a Daniel Rodriguez, MD,a Samiullah Arshad, MD,a Luis Cerna, MD,a Jose Taveras, MD,a Vito Grupposo, RT,a Andrea Natale, MD,b Mario Garcia, MD,a Luigi Di Biase, MD, PHDa
ABSTRACT OBJECTIVES This study assessed the incremental benefit of uninterrupted direct oral anticoagulants (DOACs) versus uninterrupted vitamin K antagonists (VKAs) for catheter ablation (CA) of nonvalvular atrial fibrillation (NVAF) on 3 primary outcomes: major bleeding events (MBEs), minor bleeding events, and thromboembolic events (TEs). The secondary outcome was post-procedural silent cerebral infarction (SCI) as detected by brain cardiac magnetic resonance. BACKGROUND As a class, evidence of the benefits of DOACs versus VKAs during CA of AF is scant. METHODS A systematic review of Medline, Cochrane, and Embase was done to find all randomized controlled trials in which uninterrupted DOACs were compared against uninterrupted VKAs for CA of NVAF. A fixed-effect model was used, except when I2 was $25, in which case, a random effects model was used. RESULTS The benefit of uninterrupted DOACs over VKAs was analyzed from 6 randomized control trials that enrolled a total of 2,256 patients (male: 72.7%) with NVAF, with significant benefit in MBEs (relative risk [RR]: 0.45; 95% confidence interval [CI]: 0.20 to 0.99; p ¼ 0.05). No significant differences were found in minor bleeding events (RR: 1.12; 95% CI: 0.87 to 1.43; p ¼ 0.39), TEs (RR: 0.75; 95% CI: 0.26 to 2.14; p ¼ 0.59), or post-procedural SCI (RR: 1.09; 95% CI: 0.80 to 1.49; p ¼ 0.58). CONCLUSIONS An uninterrupted DOACs strategy for CA of AF appears to be safer than uninterrupted VKAs with a decreased rate of minor bleeding events. There are no significant differences among the other outcomes. DOACs should be offered as a first-line therapy to patients undergoing CA of AF, due to their lower risk of minor bleeding events, ease of use, and fewer interactions. (J Am Coll Cardiol EP 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.
C
atheter ablation (CA) of atrial fibrillation
The COMPARE (Role of Coumadin in Preventing
(AF) is an effective therapeutic option in
Thromboembolism in Atrial Fibrillation (AF) Patients
symptomatic, drug-refractory AF (1). CA is a
Undergoing Catheter Ablation) study established un-
technically
difficult
procedure
with
potentially
interrupted warfarin as the standard of care for pa-
serious complications, such as stroke, transient
tients undergoing CA of AF (3). This randomized
ischemic attack, or systemic embolism, with reported
controlled trial (RCT) demonstrated that perfor-
incidence of adverse events as high as 4.6% (2).
ming
this
procedure
without
interrupting
oral
From the aMontefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and the bTexas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, Texas. *Drs. Romero and Cerrud-Rodriguez contributed equally to this work and are joint first authors. Dr. Di Biase has served as a consultant for Biosense Webster, Boston Scientific, Stereotaxis, and St. Jude Medical; and has received speaker honoraria/travel support from Biosense Webster, St. Jude Medical, Boston Scientific, Medtronic, Bristol-Myers Squibb, Pfizer, and Biotronik. Dr. A. Natale has served as a consultant for Baylis Medical, Boston Scientific, Biosense Webster, Bristol-Myers Squibb, St. Jude Medical, Biotronik, and Medtronic. Dr. Burkhardt has served as a consultant/speaker for Biosense-Webster and Stereotaxis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page. Manuscript received June 3, 2019; revised manuscript received July 23, 2019, accepted August 8, 2019.
ISSN 2405-500X/$36.00
https://doi.org/10.1016/j.jacep.2019.08.010
2
Romero et al.
-, NO. -, 2019
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
- 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
ABBREVIATIONS
anticoagulation with warfarin was associated
available evidence incorporated into the present
AND ACRONYMS
with a decreased risk of stroke and minor
analysis were also registered.
bleeding complications.
AF = atrial fibrillation
After the introduction of direct oral anti-
CA = catheter ablation
coagulants (DOACs), several studies tried to
CI = confidence interval
establish their noninferiority to vitamin K
CMR = cardiac magnetic
antagonists (VKAs) in CA of AF, including
resonance
some RCTs. The VENTURE-AF (Uninter-
DOAC = direct oral
rupted
anticoagulants
rivaroxaban
vs.
uninterrupted
vitamin K antagonists for catheter ablation in
DWI = diffusion weighted
non-valvular atrial fibrillation) was the first
imaging
MBE = major bleeding event
RCT that compared an uninterrupted DOAC (rivaroxaban) to an uninterrupted VKA (4).
MRI = magnetic resonance imaging
After this study, several others came out
NVAF = nonvalvular atrial
comparing outcomes between dabigatran
fibrillation
versus VKA and rivaroxaban versus VKA
RCT = randomized controlled
during CA of AF (5–10). Based on these
trial
studies, the Heart Rhythm Society/European
RR = risk ratio
Heart Rhythm Association published their
RRR = relative risk reduction
updated
SCI = silent cerebral infarction
regarding catheter and surgical ablation of AF
TE = thromboembolic event
in 2017 (1). The current standard of care in-
VKA = vitamin K antagonist
corporates the use of uninterrupted VKAs
expert
consensus
statement
(international normalized ratio goal: 2.0 to 3.0), uninterrupted dabigatran (evidence class IA), or uninterrupted rivaroxaban (class I-BR). Despite these studies providing evidence for individual DOACs, data regarding potential benefits of DOACs (as a class) over VKAs during CA of AF are scant. The present meta-analysis builds on the foundation laid by a previous meta-analysis by Romero et al. (11), which included RCTs only, and showed a trend toward fewer major bleeding events (MBEs) in the uninterrupted DOACs group during CA of AF. We thus decided to update our meta-analysis, with the data obtained by the ASCERTAIN (Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation) trial and the recently published ELIMINATE-AF (Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation) trial (12,13). Our goal was to determine the existence of any statistically significant benefit of uninterrupted DOACs over uninterrupted VKAs for CA of AF.
METHODS The present meta-analysis was performed according to Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements (14). This meta-analysis was
SEARCH STRATEGY. We searched PubMed, Embase,
and Cochrane Central Register of Clinical Trials (Cochrane Library, Issue 02, 2017) databases from January 2008 to April 2019 to identify RCTs that compared uninterrupted DOACs versus uninterrupted VKAs for CA of AF. We used the following terms: (“direct oral anticoagulants” OR DOAC OR dabigatran OR rivaroxaban OR apixaban) AND (warfarin OR “vitamin K antagonists” OR VKA) AND (“auricular fibrillation” OR “atrial fibrillation”) AND (ablation OR “catheter ablation”). No language restriction was applied. The reference lists of identified articles were also reviewed for additional sources. ELIGIBILITY CRITERIA. Studies with the following
characteristics
were
considered
eligible
to
be
included in this meta-analysis: 1) RCTs that compared uninterrupted DOACs versus uninterrupted VKAs for CA of AF; and 2) studies that compared the event rates of MBEs and/or minor bleeding and/or thromboembolic events (TEs) and/or incidence of silent cerebral
infarction
(SCI)
detected
by
diffusion-
weighted imaging (DWI) brain magnetic resonance imaging (MRI) between the 2 groups. Case reports, editorials, reviews, and expert opinions were excluded from our analysis. Abstracts presented at major international conferences that were not published as full papers were not considered in our analysis. PRIMARY AND SECONDARY OUTCOMES. The pri-
mary outcomes of this study were; 1) MBEs; 2) minor bleeding events; and 3) TEs. The secondary outcome was SCI as detected by post-procedural DWI brain MRI. MBEs were defined by using the Bleeding Academic Research Consortium (BARC) criteria, with a scale $2 being considered major bleeding (see Online Appendix: Material, Definition of Major Bleeding Events). In the case the reported events by the individual studies were reported using different criteria, these were reclassified using BARC, by consensus of the authors of this paper.” Minor bleeding events were all reported bleeding events that did not fulfil this criterion. TEs were defined as stroke, transient ischemic attack, systemic embolism,
or
development
of
an
intracardiac
thrombus post-procedure. Finally, SCI was defined as a clinically silent new brain lesion detected by DWI brain MRI post-procedurally.
registered in PROSPERO (International prospective
DATA EXTRACTIONS AND QUALITY APPRAISAL.
register of systematic reviews) with registration
Three investigators (J.R., R.C.R., and L.D.B.) inde-
number CRD42018089183. The updates to reflect new
pendently screened all titles and abstracts and
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
manually searched the full text versions of all relevant studies that fulfilled the inclusion criteria. Ref-
F I G U R E 1 Study Selection
erences of the retrieved articles were independently reviewed for further identification of potentially relevant studies. Disagreements were resolved by consensus after discussion (J.R. and R.C.R.). We extracted characteristics of each study, including methodology and baseline patient characteristics, MBEs, minor bleeding events, and TEs. SCI events were also extracted from the relevant studies. If the previously mentioned information was not readily available in the written article, the principal investigator of that particular study was contacted to supply pertinent information. QUALITY ASSESSMENT. The quality and reporting of
the included RCTs were assessed using the Cochrane Risk of Bias Tool (15). Six categories were included in the analysis: 1) selection bias: systematic differences between baseline characteristics of the groups that were compared; 2) performance bias: systematic differences between groups in the care that was provided, or in exposure to factors other than the interventions of interest. Blinding was not always possible, as was the case of the RCTs included in our study, because it would have been unethical not to monitor the international normalized ratio in the VKA arm; 3) detection bias: systematic differences between groups in how outcomes were determined. Blinding of outcome assessors might reduce the risk that knowledge of which intervention was received, rather than the intervention itself, because this affected outcome measure-
Study selection. DOAC ¼ direct oral anticoagulants; RCT ¼ randomized controlled trials.
ment; 4) attrition bias: systematic differences between groups due to withdrawals from a study. Withdrawals from the study led to incomplete outcome data; 5) reporting bias: systematic differences between reported and unreported findings; and 6) other biases: other sources of bias that were relevant only in certain circumstances. Quality of the included RCTs was summarized visually. STATISTICAL ANALYSIS. Descriptive statistics are
presented as number of cases (n) for dichotomous and categorical variables. Statistical analysis was performed in line with recommendations from the Cochrane Collaboration and PRISMA guidelines, using Review Manager (RevMan version 5.3, the Cochrane
Collaboration,
2014;
Oxford,
United
Kingdom) (14). Heterogeneity was assessed using the 2
I statistics, which is the proportion of total variation observed among the studies attributable to differences between studies, rather than a sampling error (chance). Data were summarized across groups using the Mantel-Haenszel risk ratio (RR) fixed-effect 2
2
was used if I 2 was $25%. Publication bias was estimated visually by funnel plots (17).
RESULTS A total of 741 studies were identified using the specified search criteria (Figure 1). After evaluation of these studies, based on titles and abstracts, 11 RCTs were further analyzed in their full-text versions, 5 of which were discarded, leaving another 6 RCTs that fulfilled the inclusion criteria. These 6 RCTs had a total of 2,256 participants (72.7% male; average age 61.3 2.6 years). Other RCTs were excluded due to a lack of information relevant to our study questions, because they did not follow an uninterrupted DOAC strategy, or their statistical power was poor due to the low number of enrolled patients (18). The summary of the primary and secondary outcomes can be found in the Central Illustration.
model if I was <25% (16). We considered I <25% as
CHARACTERISTICS
low and I 2 $75% as high. The random effects model
baseline characteristics of the included trials are
OF
INCLUDED
STUDIES. The
3
Romero et al.
4
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019 - 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
C E NT R A L IL L U ST R A T I O N Summary of Study Outcomes
B
14.0
13.9%
13.7%
DOACs
VKA
12.0 10.0 8.0 6.0 4.0 2.0 0.0
D
C
Thromboembolic Events (% of Patients)
RR 1.14 (95% CI 0.87-1.49) p = 0.35
Minor Bleeding Events (% of Patients)
RR 0.45 (95% CI 0.20-0.99) p = 0.05 10.0 RRR: 55% 9.0 8.0 7.0 6.0 5.2% 5.0 4.0 3.0 2.3% 2.0 1.0 0.0 DOACs VKA
RR 0.75 (95% CI 0.26-2.14) 1.0 p = 0.59 0.9 0.8 0.7 0.6 0.5 0.4% 0.4 0.3 0.2 0.1 0.0 DOACs
0.7%
SCI in Post-CA Brain MRI (% of Patients)
Major Bleeding Events (% of Patients)
A
VKA
RR 1.09 (95% CI 0.80-1.49) 20.0 p = 0.58 18.0 16.3% 15.4% 16.0 14.0 12.0 10.0 8.0 6.0 4.0 2.0 0.0 VKA DOACs
Romero, J. et al. J Am Coll Cardiol EP. 2019;-(-):-–-.
(A) Incidence of major bleeding events. (B) Incidence of minor bleeding events. (C) Incidence of thromboembolic events. (D) Incidence of silent cerebral infarction (SCI) in post-catheter ablation diffusion weighted imaging (DWI) brain magnetic resonance imaging (MRI). CA ¼ Catheter ablation; CI ¼ confidence interval; DOACs ¼ direct oral anticoagulants; RR ¼ risk ratio; RRR ¼ relative risk reduction; VKA ¼ Vitamin K antagonist.
summarized in Table 1. Uninterrupted dabigatran
QUALITY ASSESSMENT AND PUBLICATION BIAS.
was used in 317 (14.1%) patients (8), rivaroxaban in
Funnel plots did not suggest publication bias for the
187 (8.3%) patients (4,13), apixaban in 418 (18.5%)
selected outcomes of minor bleeding events, TE, and
patients (19,20), and edoxaban in 316 (14.0%) pa-
SCI (Figure 2). All the RCTs included in this meta-
tients (12). The remaining patients (n ¼ 1,018; 45.1%)
analysis had good methodological quality that indi-
were on uninterrupted VKA. For detailed informa-
cated a low risk of bias (Figure 3).
tion regarding duration
oral anticoagulation
IMPACT ON MBEs. We found a statistically significant
before CA and the follow-up periods for each study,
reduction in MBEs in the uninterrupted DOAC strat-
of
please refer to Online Table 1. The target interna-
egy (RR: 0.45; 95% confidence interval [CI]: 0.20 to
tional normalized ratio for patients receiving VKA
0.99; p ¼ 0.05), with a relative risk reduction (RRR) of
was between 2.0 and 3.0.
55%. The incidence of MBEs in the uninterrupted
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
5
Benefit of DOACs Versus VKA During CA of AF
T A B L E 1 Baseline Characteristics of Included RCTs
Type of Study
n
ASCERTAIN
RCT
127
AXAFA
RCT
633 424
ELIMINATEAF
RCT
417
Kuwahara 2016
RCT
200 147
Study
Mean Male Age
106
DOAC Used in the Study
No. of No. of Patients on Patients DOACs on VKA
Paroxysmal AF
Vascular Mean Prior Disease CHA2DS2Stroke/ (CAD, PAD, Persistent Long-Standing Vasc TIA/ Carotid Mean AF Persistent AF Score CHF HTN DM Embolism Disease) BMI
60
Rivaroxaban
64
63
82
28
17
NP
63
13
NP
NP
24.1
127
63.4
Apixaban
318
315
367
NP
NP
2.4
212 571
76
47
83
29
335
60
Edoxaban
316
101
292
103
22
2.1
68 239 47
19
86
28.3
177
65.5
Apixaban
100
100
119
NP
NP
2.2
NP
NP
NP
NP
NP
NP
200
311
7
DWI Brain MRI
RE-CIRCUIT
RCT
635 475
59.2
Dabigatran
317
318
432
167
36
2.1
65
343 64
19
105
28.7
NA
VENTUREAF
RCT
244
59.6 Rivaroxaban
123
121
182
NP
NP
1.6
21
116
3
47
29.4
NA
176
22
CHA2DS2-Vasc score ¼ age 65 to 74 years (þ1) or $75 (þ2), female (þ1), congestive heart failure history (þ1), hypertension history (þ1), stroke/transient ischemic attack/thromboembolism history (þ2), vascular disease history (þ1). AF ¼ atrial fibrillation; ASCERTAIN ¼ Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation; AXAFA ¼ Apixaban During Atrial Fibrillation Catheter Ablation; BMI ¼ body mass index; CAD ¼ coronary artery disease; CHF ¼ congestive heart failure; DM ¼ diabetes mellitus; DOAC ¼ direct oral anticoagulant; DWI ¼ diffusion-weighted imaging; ELIMINATE-AF ¼ Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation; HTN ¼ hypertension; MI ¼ myocardial infarction; MRI ¼ magnetic resonance imaging; NSAIDs ¼ nonsteroidal anti-inflammatory drugs; PAD ¼ peripheral artery disease; RCT ¼ randomized controlled trials; RE-CIRCUIT ¼ Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation; TIA ¼ transient ischemic attack; VENTURE-AF ¼ Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
DOAC strategy was 2.3%, and the incidence of MBEs
The use of uninterrupted DOACs during CA of AF
in the uninterrupted VKA strategy was 5.2%. (Central
has been steadily increasing, mainly due to the pub-
Illustration and Figure 4).
lished data showing that DOACs have a favorable
IMPACT ON MINOR BLEEDING EVENTS. The minor
bleeding rates in the DOAC and VKA groups were 13.9% and 13.7%, respectively. There were no significant differences between groups (RR: 1.12; 95% CI: 0.87 to 1.43; p ¼ 0.39) (Central Illustration and Figure 5).
safety and efficacy profile (5,6). A meta-analysis by Zhao et al. (22), which used observational data in >7,900 patients, showed no difference between groups in preventing TEs; DOAC use was associated with a lower risk of bleeding. The concern of not having readily available reversal agents in case of life-
IMPACT ON TEs. There were no significant differ-
threatening bleeding (e.g., a pericardial tamponade)
ences between groups regarding TEs. The stroke rates
may be allayed by the Food and Drug Administration
in the DOAC and VKA groups were 0.4% and 0.7%,
approval of andexanet alfa as a reversal agent for
respectively (RR: 0.75; 95% CI: 0.26 to 2.14; p ¼ 0.59) (Central Illustration and Figure 5). IMPACT
ON
SCI. Four
rivaroxaban and apixaban, as well as idarucizumab for dabigatran (23,24).
of the 6 included RCTs
Our meta-analysis used all published RCT data that
included a component to assess for post-CA SCI using
compared the outcomes of uninterrupted DOACs
DWI brain MRI (12,13,19,20). In our analysis, we could
versus uninterrupted VKAs on MBEs, minor bleeding
not find any statistically significant difference be-
events, TEs, and SCI. We included a total of 2,256
tween the uninterrupted DOAC group (16.3%) and the
participants who underwent CA of AF. The pertinent
uninterrupted VKA group (15.4%) regarding SCI as
findings of this study were the following:
detected by brain MRI (RR: 1.09; 95% CI: 0.80 to 1.49; p ¼ 0.56) (Central Illustration and Figure 6).
DISCUSSION CA of AF is an important rhythm control strategy for improvement of quality of life in patients with AF. A recent meta-analysis by Turagam et al. (21) showed a mortality benefit of CA of AF in patients with congestive heart failure. Although this procedure carries the risk of embolization, an uninterrupted
1. Uninterrupted
DOACs
provided
a
significant
benefit toward fewer MBEs (RRR of 45% and adjusted RR of 2.9%; p ¼ 0.05) compared with uninterrupted VKAs. 2. There were no statistically significant differences between groups in the outcomes of minor bleeding events and TEs, or in post-CA SCI. Our study was not specifically powered to detect TEs, and the overall event rate was low. This, in turn, increased the risk of a type II error.
VKA strategy has been shown to decrease this risk
Given our findings, we believe it is reasonable and
to <1% with no associated increase in the rate of
beneficial to offer patients who need to undergo CA of
bleeding complications (3).
AF uninterrupted anticoagulation with DOACs as
6
Romero et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
Benefit of DOACs Versus VKA During CA of AF
-, NO. -, 2019 - 2019:-–-
F I G U R E 2 Funnel Plots
(A) Minor bleeding events. (B) Thromboembolic events. (C) Silent cerebral infarction as demonstrated by post-catheter ablation diffusionweighted imaging brain magnetic resonance imaging RR ¼ risk ratio.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
F I G U R E 3 Risk of Bias Summary
Benefit of DOACs Versus VKA During CA of AF
CA of NVAF. A previous study by our research group failed to reach statistical significance, which was likely due to a lack of statistical power because of its smaller sample size (11). This lack of power was solved with the inclusion of the data published by both the ASCERTAIN and the ELIMINATE-AF trials (12,13). Two previous meta-analysis found results similar to ours using different methodologies. A metaanalysis by Zhao et al. (25), which analyzed 6 RCTs, found a significantly decreased risk of MBEs with DOACs. However, 1 of the included papers, by Zhu et al. (18), whose main goal was to analyze the metabolic effects of rivaroxaban (measuring outcomes such as serum total protein, albumin, and globulin levels), had poor statistical power due to the extremely small number of enrolled patients (30 patients each in the rivaroxaban and the VKA arms). Zhao et al. also used inaccurate MBE rates in their analysis when referring to the ASCERTAIN trial, because they used preliminary data published in the Circulation Supplement for Abstracts presented at the American Heart Association 2016 meeting. The final, definitive data of the ASCERTAIN trial were published as a full paper in JACC: Clinical Electrophysiology in December 2018 (26). A second meta-analysis by Cardoso et al. (27) found significantly decreased MBEs using uninterrupted DOACs. The authors included a total of 12 studies in its analysis, 3 of which were RCTs (4,8,19). The
investigators
found
significantly
decreased
Risk of bias summary: review authors’ judgements about each risk
MBEs in a dedicated quantitative synthesis of
of bias item for each included study. ASCERTAIN ¼ Asymptom-
studies with a lower risk of selection bias, which
atic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation; AXAFA ¼ Apixaban During Atrial Fibrillation Catheter
included the previously mentioned 3 RCTs and 3
Ablation; ELIMINATE-AF ¼ Uninterrupted edoxaban vs. vitamin K
additional studies: a multicenter prospective registry
antagonists for ablation of atrial fibrillation; RE-CIRCUIT ¼
that assessed uninterrupted apixaban versus unin-
Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial
terrupted VKAs by Di Biase et al (28); a study by
Fibrillation; VENTURE-AF ¼ Uninterrupted rivaroxaban vs.
Dillier et al. (10) that matched patients in the inter-
uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
vention
arm
(uninterrupted
rivaroxaban)
with
control subjects (uninterrupted VKA) by age, sex, and type of AF (10); and a multicenter prospective registry that matched patients on uninterrupted
first-line therapy. These conclusions fall in line with
rivaraxoban with patients on uninterrupted VKAs by
the recent consensus statement on the use of unin-
Lakireddy et al. (9).
terrupted DOACs for CA of AF that gave a class I
We want to highlight that our meta-analysis was
recommendation for the use of uninterrupted dabi-
the only one to include only RCTs in its analysis and
gatran or rivaroxaban (1). DOACs are more convenient
to include all DOACs currently on the market, and to
for both the patient and the physician, have fewer
reclassify
interactions with medications and food, and do not
classification.”
all
bleeding
events
using
the
BARC
require frequent blood testing to monitor the inter-
STUDY LIMITATIONS. Our meta-analysis had some
national normalized ratio.
limitations. Most of the RCTs included in our meta-
The results of our meta-analysis proved that there
analysis were exploratory trials with administra-
was a significant decrease in the risk of MBEs between
tively determined trial sizes, because the sample
uninterrupted DOACs and uninterrupted VKAs during
required to provide sufficient power to establish
7
8
Romero et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019 - 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
F I G U R E 4 Forest Plot for Major Bleeding Events
The diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% confidence interval [CI]); width of the shaded square is the size of the population. The random effects model was used in the major bleeding events outcome as I2 >25%, the fixed-effect model was used in all other outcomes. DOAC ¼ direct oral anticoagulant; MH ¼ Mantel–Haenszel; VKA ¼ vitamin K antagonists.
formal noninferiority would have made them unfea-
Another limitation of our study was that the event
sible. The AXAFA (Apixaban) trial was the exception,
frequency of TEs was quite low; it was not specifically
because it was designed from the beginning to accu-
powered to measure this outcome, which might pre-
mulate sufficient events for a formal noninferiority
dispose to a type II error.
analysis by selecting patients with at least 1 risk factor for stroke (20).
The results of our study should generate interest in the design of larger, well-designed RCTs comparing
F I G U R E 5 Forest Plot of Minor Bleeding Events and Thromboembolic Events
(A) Minor bleeding events. (B) Thromboembolic events. The diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% CI); width of the shaded square is the size of the population. Fixed-effect model model was used as I2 #25%. Abbreviations as in Figure 4.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019
Romero et al.
- 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
F I G U R E 6 Forest Plot of Silent Cerebral Infarction
Silent cerebral infarction as demonstrated by post-catheter ablation diffusion-weighted imaging brain magnetic resonance imaging. The diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% CI); width of the shaded square is the size of the population. Fixed-Effect model model was used as I2 #25%. Abbreviations as in Figure 4.
the safety and efficacy, not only of uninterrupted DOACs versus uninterrupted VKAs in CA of AF, but
ADDRESS FOR CORRESPONDENCE: Dr. Luigi Di
also compare the differences in outcomes when using
Biase, Montefiore-Einstein Center for Heart and
the different DOACs now available in the market. As
Vascular Care, Montefiore Medical Center, Albert
in our previous study, we believe the number of pa-
Einstein College of Medicine, 111 East 210th Street,
tients assessed for SCI was still insufficient to deter-
Bronx, New York 10467. E-mail: [email protected].
mine if there was a difference between uninterrupted DOACs and uninterrupted VKAs. Finally, we believe
PERSPECTIVES
that the main limitation of our analysis lies in the low COMPETENCY IN MEDICAL KNOWLEDGE: As a group,
number of events.
DOACs can be safely used as first-line anticoagulation therapy in patients undergoing CA of NVAF, because they are significantly
CONCLUSIONS
less likely to cause a major bleeding event than VKAs. There is no
An uninterrupted DOACs strategy for CA of NVAF carries a lower risk of MBEs compared with uninterrupted VKAs. There were no significant differences among the other outcomes (minor bleeding events, TE, SCI) between groups. We thus believe DOACs should be considered a first option to offer to patients
difference between groups in minor bleeding events or TEs. TRANSLATIONAL OUTLOOK: Additional research is necessary to determine if post-ablation SCI can be prevented with oral anticoagulation and, if so, which kind would offer the best protectiondDOACs or VKAs.
undergoing CA of AF, over traditional VKAs.
REFERENCES 1. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Europace 2018;20:e1–160. 2. Chen J, Dagres N, Hocini M, et al. Catheter ablation for atrial fibrillation: results from the first European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA) Part II. Europace 2015;17:1727–32.
(COMPARE) randomized trial. Circulation 2014; 129:2638–44.
atrial fibrillation. J Interv Card Electrophysiol 2013;37:233–9.
4. Cappato R, Marchlinski FE, Hohnloser SH, et al.
7. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter pro-
Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015;36:1805–11. 5. Kaiser DW, Streur MM, Nagarakanti R, Whalen SP, Ellis CR. Continuous warfarin versus periprocedural dabigatran to reduce stroke and systemic embolism in patients undergoing cath-
spective registry. J Am Coll Cardiol 2012;59: 1168–74.
3. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation man-
eter ablation for atrial fibrillation or left atrial flutter. J Interv Card Electrophysiol 2013;37:241–7.
tran versus warfarin for ablation in atrial fibrillation. N Engl J Med 2017;377:495–6.
agement: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation
6. Haines DE, Mead-Salley M, Salazar M, et al. Dabigatran versus warfarin anticoagulation before and after catheter ablation for the treatment of
9. Lakkireddy D, Reddy YM, Di Biase L, et al.
8. Calkins H, Nordaby M. Uninterrupted dabiga-
Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients
9
10
Romero et al.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL.
-, NO. -, 2019 - 2019:-–-
Benefit of DOACs Versus VKA During CA of AF
undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014;63:982–8.
17. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.
24. Pollack CV Jr., Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017;377:431–41.
10. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhyth Electrophysiol 2014;7:576–82.
18. Zhu J, Gao RJ, Liu Q, et al. Metabolic benefits of rivaroxaban in non-valvular atrial fibrillation patients after radiofrequency catheter ablation. J Zhejiang Univ Sci B 2017;18:946–54.
25. Zhao Y, Lu Y, Qin Y. A meta-analysis of randomized controlled trials of uninterrupted periprocedural anticoagulation strategy in patients
11. Romero J, Cerrud-Rodriguez RC, Diaz JC, et al. Uninterrupted direct oral anticoagulants vs. uninterrupted vitamin K antagonists during catheter ablation of non-valvular atrial fibrillation: a systematic review and meta-analysis of randomized controlled trials. Europace 2018;20:1612–20.
19. Kuwahara T, Abe M, Yamaki M, et al. Apixaban versus warfarin for the prevention of periprocedural cerebral thromboembolism in atrial fibrillation ablation: multicenter prospective randomized study. J Cardiovasc Electrophysiol 2016;27: 549–54.
12. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019 April 11 [E-pub ahead of print].
20. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J 2018;39: 2942–55.
13. Kimura T, Kashimura S, Nishiyama T, et al. Asymptomatic cerebral infarction during catheter ablation for atrial fibrillation: comparing uninterrupted rivaroxaban and warfarin (ASCERTAIN). J Am Coll Cardiol EP 2018;4:1598–609.
21. Turagam MK, Garg J, Whang W, et al. Catheter ablation of atrial fibrillation in patients with heart failure: a meta-analysis of randomized controlled trials. Ann Intern Med 2019;170:41–50.
14. Knobloch K, Yoon U, Vogt PM. Preferred reporting items for systematic reviews and metaanalyses (PRISMA) statement and publication bias. J Craniomaxillofac Surg 2011;39:91–2. 15. Cochrane Methods Bias. Assessing risk of bias in included studies. . Available at: http://methods. cochrane.org/bias/assessing-risk-bias-includedstudies. Accessed February 24, 2018. 16. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88.
22. Zhao Y, Yang Y, Tang X, Yu X, Zhang L, Xiao H. New oral anticoagulants compared to warfarin for perioperative anticoagulation in patients undergoing atrial fibrillation catheter ablation: a metaanalysis of continuous or interrupted new oral anticoagulants during ablation compared to interrupted or continuous warfarin. J Interv Card Electrophysiol 2017;48:267–82.
undergoing atrial fibrillation catheter ablation. Int J Cardiol 2018;270:167–71. 26. Takatsuki S, Kimura T, Nakajima K, et al. Abstract 23233: Asymptomatic cerebral infarction during catheter ablation of atrial fibrillation comparing uninterrupted rivaroxaban and warfarin (ASCERTAIN Study). Circulation 2016;134:A23233. 27. Cardoso R, Knijnik L, Bhonsale A, et al. An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted anticoagulation in atrial fibrillation catheter ablation. Heart Rhythm 2018;15:107–15. 28. Di Biase L, Lakkireddy D, Trivedi C, et al. Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: results from a multicenter study. Heart Rhythm 2015;12:1162–8.
KEY WORDS atrial fibrillation, catheter ablation, direct oral anticoagulants, randomized controlled trials, vitamin K antagonists, warfarin
23. Heo YA. Andexanet alfa in the treatment of acute major bleeding related to apixaban and rivaroxaban: a profile of its use in the USA. Drugs Ther Perspect 2018;34:507–12.
A PPE NDI X For an expanded Methods section and the supplemental table, please see the online version of this paper.