Minimally interrupted novel oral anticoagulant versus uninterrupted vitamin K antagonist during atrial fibrillation ablation
Journal of Interventional Cardiac Electrophysiology
Minimally interrupted novel oral anticoagulant versus uninterrupted vitamin K antagonist during atrial fibrillation ablation
John De Heide 0
Christiaan J. Vroegh 0
Rohit E. Bhagwandien 0
Sip A. Wijchers 0
Tamas Szili-Torok 0
Felix Zijlstra 0
Mattie J. Lenzen 0
S. C. Yap 0
0 Department of Cardiology, Erasmus Medical Center , P.O. Box 2040, 3000 CA Rotterdam , the Netherlands
Purpose The safety and efficacy of a minimally interrupted novel oral anticoagulant (NOAC) strategy at the time of atrial fibrillation (AF) ablation is uncertain. The purpose of this study was to compare rates of bleeding and thromboembolic events between minimally interrupted NOAC and uninterrupted vitamin K antagonist (VKA) in patients undergoing AF ablation. Methods This was a retrospective single-center cohort study of consecutive patients who underwent AF catheter ablation between January 2013 and April 2017. Endpoints included major bleeding, clinically relevant non-major bleeding and systemic thromboembolic event from the time of ablation through 30 days. Bleeding events were defined by the Bleeding Academic Research Consortium (BARC) and International Society on Thrombosis and Haemostasis (ISTH). Results A total of 637 patients were included in the analysis, 520 patients used uninterrupted VKA and 117 patients minimally interrupted NOAC (dabigatran: n = 68; apixaban: n = 30; rivaroxaban, n = 14; edoxaban, n = 5). The rate of clinically relevant non-major bleeding was lower in the NOAC group in comparison to the VKA group (BARC type 2: 2.6% versus 8.3%, P = 0.03; ISTH: 0% versus 3.8%, P = 0.03). Rates of major bleeding were similar between groups (BARC type 3 to 5: 3.4% versus 4.2%, P = NS; ISTH: 6.0% versus 8.7%, P = NS; for NOAC and VKA groups, respectively). Rates of systemic embolism were 0% with minimally interrupted NOAC, and 0.6% with uninterrupted VKA (P = NS). Conclusions In patients undergoing AF ablation, anticoagulation with minimally interrupted NOAC was associated with fewer clinically relevant non-major bleeding events in comparison with uninterrupted VKA without compromising thromboembolic safety.
Atrial fibrillation; Novel oral anticoagulation; Vitamin-K antagonist; Catheter ablation; Bleeding; Stroke
Catheter ablation is increasingly used for the treatment of
symptomatic atrial fibrillation (AF). Although catheter
ablation of AF is considered safe, it may be associated with a low
risk of stroke. One of the strategies to reduce this risk is to
perform AF ablation with continuous oral anticoagulation.
This strategy has been shown to be safe and effective with
vitamin K antagonists (VKAs) [
]. However, there is an
increased use of novel oral anticoagulants (NOACs) in the
current AF population undergoing catheter ablation. NOACs
have several advantages, including a rapid onset of therapeutic
range of anticoagulation, predictability of the anticoagulant
effect, and relatively short time to reversal of anticoagulation
when the medication is withheld [
]. Several observational
and randomized controlled trials (RCTs) have demonstrated
that uninterrupted NOAC is as safe and effective in
comparison to uninterrupted VKA in patients undergoing AF ablation
]. A recent meta-analysis demonstrated that NOAC was
even associated with less major bleeding compared with VKA
in pooled RCTs . The 2016 ESC guidelines give a class IIa
indication to perform AF ablation with continuous oral
anticoagulation with either VKA or NOAC .
However, the uninterrupted NOAC strategy does not reflect
current clinical practice as most centers still use a minimally
interrupted NOAC strategy . There is limited data
demonstrating the safety and efficacy of a minimally interrupted NOAC
strategy. The aim of the present study was to compare the
incidence of bleeding and thromboembolic complications of
minimally interrupted NOAC versus uninterrupted VKA in
patients undergoing catheter ablation of AF.
restarted NOAC in the evening of the procedure. Patients
continued their oral anticoagulation for at least 3 months after the
2.1 Study population
We evaluated consecutive patients who underwent catheter
ablation of AF from January 2013 to April 2017 in the
Erasmus Medical Center, Rotterdam, the Netherlands. We
included patients with 2 specific anticoagulation regimens. The
first group included patients who used periprocedural
uninterrupted VKA (either acenocoumarol or marcoumar). The
strategy of uninterrupted VKA was introduced in our institution at
the end of 2012. The second group included patients who used
periprocedural minimally interrupted NOAC (1 or 2 doses
withheld). In February 2013, our first patient underwent
catheter ablation using a minimally interrupted NOAC strategy.
Patients who did not use oral anticoagulation and were
accepted for catheter ablation of AF usually received a NOAC.
2.4 Study endpoints
Primary bleeding endpoints were major bleeding (within
30 days) as defined by the Bleeding Academic Research
Consortium (BARC) and International Society on
Thrombosis and Haemostasis (ISTH) [17, 18]. The reason to
choose both classifications is that clinical trials reporting
major bleeding either use ISTH and/or BARC classification. In
our study, BARC types 3 to 5 were considered a major
bleeding. Secondary bleeding endpoints were the individual BARC
bleeding types (types 2, 3a, 3b, 3c, 5), clinically relevant
nonmajor bleeding (CRNMB) according to ISTH , and any
clinically relevant bleeding (BARC types 2 to 5; ISTH major
bleeding and CRNMB). BARC type 2 bleeding most closely
aligns with the ISTH CRNMB .
The primary thromboembolic endpoint was a composite of
stroke, transient ischemic attack (TIA), or other systemic
embolism within 30 days.
2.2 Pre- and periprocedural protocol
2.5 Statistical analysis
All patients received therapeutic oral anticoagulation for at
least 3 weeks prior to ablation. In patients using VKA the
target INR level at the day of the procedure was 2.0 to 2.5.
In patients using NOACs, anticoagulation was withheld for
24 h before the procedure (1 or 2 doses withheld). A cardiac
CT was routinely performed weeks to months prior to
ablation. CT imaging was mainly used to assess PV anatomy.
Rarely, a left atrial thrombus could be found as an incidental
finding. A preprocedural transesophageal echocardiogram
was routinely performed on the same day or 1 day prior to
ablation to exclude left atrial appendage (LAA) thrombus. In
the case of LAA thrombus the procedure was canceled or
postponed. During the procedure, a bolus of heparin was
administered after sheath placement. Furthermore, immediately
after transseptal puncture another bolus of heparin was given
and a continuous heparin pump was started and adjusted to
maintain an ACT of at least 300 s. We did not administer
protamine routinely at the end of the procedure.
2.3 Postprocedural protocol
VKA patients, who had an INR 2.0 or greater at the day of the
procedure, continued their anticoagulation regimen with a
target INR level of 2.0–3.0. VKA patients who had an INR
below 2.0 at the day of the procedure were bridged with
intravenous UFH for 24 h (starting 2 h after removal of sheaths).
After these 24 h they received low molecular weight heparin
until their INR level was equal or above 2.0. NOAC patients
Continuous parameters are presented as the mean ± SD as they
were normally distributed. Categorical data are presented as
frequencies and percentages. Comparisons between groups
were performed with an independent Student t test, chi-square
tests, or Fisher exact test. A P-value < 0.05 was considered
statistically significant. Statistical analyses were performed using
SPSS software (SPSS, version 21; IBM, Chicago, Illinois).
A total of 637 patients (mean age 60 ± 9 years, 69% male)
were included in the analysis, 520 patients (82%) used
uninterrupted VKAs and 117 patients (18%) had a minimally
interrupted NOAC strategy. In the NOAC group, the
following NOACs were used: dabigatran (n = 68), apixaban (n = 30),
rivaroxaban (n = 14), and edoxaban (n = 5). The NOAC group
comprised more patients with long-standing persistent AF and
a lower proportion of patients with a CHA2DS2-VASc ≥ 2
(Table 1). All other baseline variables were similar between
groups. Figure 1 demonstrates the increased use of NOAC
over the years in our AF ablation population.
3.1 Bleeding complications
The rates of major bleeding, either by BARC or ISTH criteria,
were similar between groups (Table 2). The rate of any
clinically relevant bleeding (BARC types 2–5; composite of ISTH
LA = left atrium, NOAC = novel oral anticoagulant, VKA = vitamin K antagonist
major bleeding and CRNMB) was lower with NOACs
compared with VKAs. This difference was mainly due to a
difference in clinically relevant non-major bleeding (CRNMB or
BARC type 2) (Table 2). No patient in either group had a
BARC type 3c (i.e., intracranial bleeding) or type 5 bleeding
(i.e., fatal bleeding). Cardiac tamponade occurred in 4 patients
(0.8%) of the VKA group and in 1 patient (0.9%) of the
NOAC group (P = 1.00).
3.2 Thromboembolic complications
There were no differences in the systemic thromboembolic
event rates between both groups (0.6% versus 0%, P = 1.00)
(Table 2). In the VKA group, 1 patient (0.2%) experienced a
Fig. 1 Proportion of periprocedural NOAC and VKA use over the years
vertebrobasilar stroke 3 days after the procedure. Three
months after the procedure, this patient had a modified
Rankin score of 1. Furthermore, 2 patients (0.4%) in the
VKA group experienced a TIA 1 day after the procedure.
They had an uneventful recovery. No patient in the NOAC
group experienced a systemic thromboembolic event. No
The main findings of our study are that (1) the rate of clinically
relevant non-major bleeding was lower in patients with a
minimally interrupted NOAC strategy compared with those with
an uninterrupted VKA strategy, and (2) the rates of major
bleeding and thromboembolic events were similar between
Uninterrupted use of vitamin K antagonists (VKA) as
periprocedural anticoagulant is currently widely accepted for
patients undergoing catheter ablation of AF who are using
VKA. However, there is an increased use of NOACs in the
current AF ablation population. Despite initial concerns on the
safety of using periprocedural NOAC , nowadays, several
large RCTs have demonstrated the safety and efficacy of
uninterrupted use of NOACs (i.e., dabigatran, rivaroxaban,
apixaban) during AF ablation [
5, 6, 12
] (Table 3).
Primary bleeding endpoints
BARC 3–5 bleeding, n (%)
ISTH major bleeding, n (%)
Secondary bleeding endpoints
Bleeding requiring medical attention that does not fit the criteria for types 3–5 (BARC 2), n (%)
Bleeding with hemoglobin drop of 30 to < 50 g/L or requiring transfusion (BARC 3a), n (%)
Bleeding with hemoglobin drop of ≥ 50 g/L, or requiring surgery or iv vasoactive agents, or
cardiac tamponade (BARC 3b), n (%)
BARC 2–5 bleeding, n (%)
CRNMB, n (%)
ISTH major bleeding and CRNMB, n (%)
Primary thromboembolic endpoint
Stroke, TIA, or other systemic embolism, n (%)
In clinical practice, however, most centers still use a
minimally interrupted NOAC strategy . The European
Snapshot Survey on Procedural Routines in Atrial
Fibrillation Ablation (ESS-PRAFA) in 2015 demonstrated
that AF ablations were performed with a minimally
interrupted NOAC strategy (1–2 doses withheld) in 53% of
procedures, interrupted NOAC ≥2 days in 34%, and an
uninterrupted NOAC strategy in 14% . The ABlation
peRIoperative DabiGatran in use Envisioning in Japan
( A B R I D G E - J) r a nd o m i ze d t ri a l d e m o n s t r a t e d t h at
anticoagulation with minimally interrupted dabigatran (1 or
2 doses withheld) was associated with fewer ISTH major
bleeding complications than uninterrupted VKA with no
increase in thromboembolic events (Table 3) . In addition,
the Apixaban Evaluation of Interrupted Or Uninterrupted
anticoagulation for ablation of atrial fibrillation (AEIOU)
randomized trial showed no difference between continuous
apixaban compared with minimally interrupted apixaban (1
dose withheld) with regard to major bleeding (BARC 3–5)
or thromboembolic events (Table 3) . Finally, a recent
meta-analysis of 4 randomized and 9 prospective
observational studies (N = 5463) found that minimally interrupted and
continuous NOAC strategy were both safe and non-inferior
strategies compared with uninterrupted VKA . Our study
extends on these results demonstrating less clinically relevant
non-major bleeding events with minimally interrupted NOAC
in comparison with uninterrupted VKA without
compromising thromboembolic safety.
One of the reasons to choose an uninterrupted NOAC
strategy instead of a minimally interrupted NOAC strategy is to
maximally reduce the incidence of thromboembolic events.
However, the risk of a systemic thromboembolic event using
a minimally interrupted NOAC strategy is already low (<
0.7%) [13, 14, 21]. Furthermore, continuous anticoagulation
does not prevent all acute brain lesions, which can be caused
by debris from ablation lesions, air emboli, or small thrombi
. This was demonstrated by the MRI substudy of the
AXAFA trial in which acute brain lesions occurred in 27%
of patients despite uninterrupted apixaban . Further
research is required to establish the optimal NOAC dosing
strategy (minimally interrupted or uninterrupted) with regard to
both bleeding and thromboembolic risk. Another question is
w h e t h e r e v e r y N O A C i s e f f e c t i v e i n p r e v e n t i n g
periprocedural thromboembolic complications. RCTs with
dabigatran (RE-CIRCUIT) and rivaroxaban
(VENTUREAF) did not show any thromboembolic events [
RCTs with apixaban (AXAFA, AEIOU) showed a low
thromboembolic event rate [12, 21].
4.1 Study limitations
There were differences in baseline characteristics between the
study groups. The VKA group had a higher proportion of
patients with a CHA2DS2-VASc ≥ 2 in comparison to the
NOAC group (47% versus 34%). This difference can be
explained by the fact that in patients who did not use an oral
anticoagulant (low CHA2DS2-VASc score) and were accepted
for catheter ablation, a NOAC was preferentially started as
periprocedural anticoagulation regime. This difference in
CHA2DS2-VASc score could potentially lower the risk of
thromboembolic and bleeding events in the NOAC group.
Furthermore, patients used different NOACs in the present
study. The limited number of NOAC patients precluded
further subanalysis for the different NOACs.
In patients undergoing catheter ablation of AF, a minimally
interrupted NOAC strategy was associated with fewer
clinically relevant non-major bleeding compared with
uninterrupted VKA. The risk of major bleeding and thromboembolic
events was similar between both strategies. Our study
reinforces the safety and efficacy of a minimally interrupted
NOAC strategy as periprocedural anticoagulant in patients
undergoing catheter ablation of AF.
Compliance with ethical standards
The Medical Ethics Committee of the Erasmus Medical Center reviewed
the study (MEC-2015-073), and this retrospective study was not
subjected to the Dutch Medical Research Involving Human Subjects
Act. The study was carried out according to the ethical principles for
medical research involving human subjects established by Declaration
of Helsinki, protecting the privacy of all the participants and the
confidentiality of their personal information.
Conflict of interest The authors declare that they have no conflict of
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