Ischemic stroke risk during long-term follow up in patients with successful catheter ablation for atrial fibrillation in Korea
Ischemic stroke risk during long-term follow up in patients with successful catheter ablation for atrial fibrillation in Korea
Dong-Hyeok Kim 0 2
Dae-In Lee 2
Jinhee Ahn 2
Kwang-No Lee 0 2
Seung-Young Roh 1 2
Jaemin Shim 0 2
Jong-Il Choi 0 2
Young-Hoon Kim 0 2
0 Division of Cardiology, Department of Internal Medicine, Korea University College of Medicine, Korea University Medical Center , Seoul , Republic of Korea, 2 Division of Cardiology, Chungbuk National University Hospital , Cheongju , Korea , 3 Division of Cardiology, Pusan National University Hospital , Busan , Korea
1 Division of Cardiology, Dongguk University College of Medicine and Dongguk University Medical Center , Goyang , Korea
2 Editor: Giuseppina Novo, University of Palermo , ITALY
The interruption of oral anticoagulation therapy (OAC) after CA of atrial fibrillation (AF) is controversial. The purpose of this study was to evaluate the relationship between successful long-term outcomes of catheter resection and SR maintenance and ischemic stroke risk in Korea. We studied 1,548 consecutive patients who were followed up for more than 2 years after CA of AF. We investigated the incidence of ischemic stroke during long-term follow-up. Compared to the AF recurrence group (n = 619), the sinus rhythm (SR) maintenance group (n = 929) had more paroxysmal AF (74.6% versus 44.4%, p<0.001), smaller LA size (39.9 ?5.7mm versus 42.3?6.0mm, p<0.001), and younger age (54.2?10.9 years versus 56.4 ?10.6 years, p<0.001). However, CHA2DS2-VASc scores were not significantly different between the two groups (0.9 vs. 1.1, p = 0.053). The overall incidence of ischemic stroke during the mean follow-up period of 54 months after CA was 0.6%, and was significantly lower in the SR group than the AF recurrence group (0.3% vs. 1.1%, log-rank test p<0.001). However, in sub-analysis in the SR group, the rate of ischemic stroke was significantly increasing in patients with a CHA2DS2-VASc score 4 compared to those with a CHA2DS2VASc score < 4 (4.3% vs. 0.2%, log-rank test p<0.001). In conclusion, this long-term followup data in patients with AF who underwent successful CA showed that SR maintenance was correlated with a lower rate of ischemic stroke in Korea. However, it was only observed in patients with CHA2DS2-VASc score 3.
Data Availability Statement: All relevant data are
within the paper.
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Abbreviations: AF, atrial fibrillation; CA, catheter
ablation; SR, sinus rhythm; OAC, oral
anticoagulation therapy; TE, thromboembolic
events; AAD, antiarrhythmic drugs; PVI, pulmonary
Current guidelines demonstrate that atrial fibrillation (AF) catheter ablation (CA) to restore
sinus rhythm (SR) should not be performed only for stop of anticoagulation, which is a class III
recommendation with level C evidence [
]. The CHA2DS2-VASc score is the only risk
stratification tool for oral anticoagulation therapy (OAC) before and after CA . This recommendation
vein isolation; CFAE, complex fractionated
electrogram; ECG, electrocardiogram.
is based on the belief that the baseline risk of thromboembolic events (TE) remains unchanged
despite successful CA . However, it is reasonable to speculate that elimination of AF may
reduce the risk of TE.
Many studies have demonstrated that OAC can be discontinued after successful CA for
patients with a relatively low risk of TE events [4?6]. Saad EB et al. showed that there is no
significant TE-related morbidity of patients with antiarrhythmic drugs (AAD) and
discontinuation of OAC after successful CA and CHADS2 scores 3 . Roger A. A nationwide cohort
study in Denmark also demonstrated that TE risk beyond 3 months after CA was relatively
low compared with a matched non-ablated AF cohort . A study from the Swedish health
registries showed that ablation may be associated with a lower incidence of ischemic stroke
and death in patients with AF . However, this is not clear in Korea patients. Therefore, we
hypothesized that patients after successful CA experience fewer TE events if there is a
longterm SR maintenance and a relatively low stroke risk in Korea.
We studied 1,548 consecutive patients with AF and more than 2 years of follow-up from
February 2000 to March 2013. Total 1,548 patients were divided into two groups (Fig 1). The SR
maintenance group was defined as patients who underwent CA and remained in SR even after
1 year. The recurrence group was defined as patients who underwent CA and had an AF
recurrence within 1 year. If a patient who had AF recurrence after 1 year, the patient was defined as
SR maintenance group because that AF was not documented and SR maintenance until 1 year.
This study was approved by the institutional review board in Korea University Medical Center
(AN17210-002). Consent was waived by the ethics committee.
Procedures for catheter ablation
Prior to the CA procedure, all antiarrhythmic drugs were discontinued, and more than 5
halflives were allowed to pass. Circumferentially antral pulmonary vein isolation (PVI) with
electrical isolation was performed. When AF followed PVI, either linear ablation or complex
fractionated electrogram (CFAE) ablation was also performed. The endpoints of the ablation were
AF or AT termination. During the enrollment period, the CA strategy was changed from PVI
in paroxysmal AF to combination of PVI with linear ablation or/and CFAE ablation in
persistent or long-standing persistent AF.
To assess the efficacy of catheter ablation, we investigated freedom from atrial tachyarrhythmia
(= AF or AT) after the procedure. After ablation, patients were asked to visit the outpatient
clinic at 1, 3, 6, and 12 months and then every 6 months thereafter or whenever they
experienced tachycardia-related symptoms. Electrocardiogram (ECG) was performed at every visit.
Holter monitor recording was performed in patients who were thought to have
arrhythmiarelated intermittent symptoms. Recurrence of atrial tachyarrhythmia was defined as an event
lasting more than 30 seconds after a 3-month blanking period. AADs were taken during the
first 3 months after the ablation. Discontinuation of AADs was determined at the physicians'
discretion. During follow-up, ischemic stroke was investigated by a neurologist's diagnosis
and brain imaging.
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Fig 1. Study flow chart and patient population. The flow diagram shows patients population, AF recurrence and
sinus rhythm maintenance group after 1 year RFCA.
All values are expressed as means ? SD or as numbers and percentages where appropriate.
Categorical data were compared with the ?2 test. Continuous variable data were compared by the
independent samples t-test when the distribution was normal or by the Mann-Whitney U test
if it the distribution was not normal. Kaplan-Meier analysis with the log-rank test was used to
determine the probability of ischemic stroke. P<0.05 was considered statistically significant.
Statistical analyses were performed using SPSS Statistics 19.0 software (SPSS Inc., Chicago, IL,
Clinical characteristics at baseline are summarized in Table 1. Compared to the AF recurrence
group (n = 619), the SR maintenance group (n = 929) had younger age (54.2?10.9 years versus
Values are expressed as means ? SDs and numbers (percentages). AF; atrial fibrillation, LVEF; left ventricular ejection fraction, LA; left atrium, CHF; congestive heart
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56.4?10.6 years, p<0.001), shorter time of AF onset (31.0?43.9 months versus 44.9?58.7
months, p<0.001), more paroxysmal AF (74.6% versus 44.4%, p<0.001), and smaller LA size
(39.9?5.7mm versus 42.3?6.0mm, p<0.001). However, CHA2DS2-VASc scores were not
significantly different between the two groups (0.9 vs. 1.1, p = 0.053).
AAD use and antithrombotic therapy after CA
Ischemic stroke events after successful CA
The overall incidence of ischemic stroke after CA was 0.6% in the follow-up period of
54 months. The incidence of ischemic stroke was significantly lower in the SR
maintenance group than in the AF recurrence group (0.3% vs. 1.1%, log-rank test, p<0.001,
1) CHA2DS2-VASc score. Ischemic stroke events are shown in Table 3. In the SR
maintenance group, most ischemic events were reported in patients with high CHA2DS2-VASc
scores: CHA2DS2-VASc score 0 (n = 1, 0.2%), CHA2DS2-VASc score 4 (n = 1, 5.5%),
CHA2DS2-VASc score 5 (n = 1, 25%). However, in the AF recurrence group, ischemic stroke
events were reported in patients with low and high CHA2DS2-VASc scores: CHA2DS2-VASc
score 0 (n = 2, 0.9%), CHA2DS2-VASc score 1 (n = 4, 1.9%), CHA2DS2-VASc score 5 (n = 1,
11.1%). All 10 patients with stroke events were on OAC in 3 in the SR group and 7 in the
recurrence group. There was no difference of OAC therapy for patients with stroke events
after ablation in both groups.
2) Risk factors for ischemic stroke. Table 4 shows risk factors for ischemic stroke.
Univariate analysis showed lower CHA2DS2-VASc score (HR 1.540, p = 0.049), AAD use after CA
(HR 0.207, p = 0.048), and SR maintenance (HR 0.122, p = 0.005) reduced the risk of ischemic
stroke. However, multivariate analysis showed SR maintenance (HR 0.151, p = 0.013) was the
only factor that reduced risk.
(n = 1548)
(n = 619)
(n = 929)
Fig 2. Comparison of freedom from atrial tachyarrhythmia after catheter ablation. The Kaplan-Meier survival
curves for freedom from ischemic stroke after successful RFCA between AF recurrence and sinus rhythm maintenance
Cut off-value of CHA2DS2-VASc score for ischemic stroke after CA
The CHA2DS2-VASc score is already the main tool for stratification of ischemic stroke risk.
Table 5 shows Cox regression analysis for stroke risk in the SR maintenance group.
VASc score was the main factor for stroke risk (HR 2.11, CI 1.08?4.12, p = 0.028). However,
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Values are expressed as HR (95% CI). CI; confidence interval, CHF; congestive heart failure, AAD; antiarrhythmic drug, CA; catheter ablation, OAC; oral
anticoagulation therapy, SR; sinus rhythm
Male sex, n (%)
AF type, paroxysmal
AAD use after CA
OAC after CA
the cut-off value for differentiating stroke events was not CHA2DS2-VASc score 2 (HR 0.11,
CI 0.01?1.21, p = 0.072) nor 3 (HR 0.16, CI 0.01?1.89, p = 0.149), but 4 (HR 17.65, CI
1.59?195.5, p = 0.019). In patients with CHA2DS2-VASc score of 4 or more, the risk of
ischemic stroke increased even after successful CA and SR maintenance. However, this showed the
trend of low stroke event in CHA2DS2-VAS 2 or 3 in patients with SR maintenance after
This long-term follow-up data in patients with AF who underwent catheter ablation showed
that SR maintenance after successful CA was correlated with a lower rate of ischemic stroke.
However, it was only observed in patients with CHA2DS2-VASc score 3 in Korea.
PLOS ONE | https://doi.org/10.1371/journal.pone.0201061
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Comparison of previous studies of ischemic stroke after catheter ablation
Many studies demonstrated that OAC can be discontinued after successful CA for patients
with a relatively low risk of TE [4?9]. According to the current guidelines [
], even after CA of
AF, anticoagulation therapy should be continued when the CHA2DS2-VASc score remains
2. This recommendation is based on the belief that the baseline risk of TE remains
unchanged despite a successful CA . However, there is no randomized study to support
this, and this guideline recommendation is class III, but evidence level C. A study from a
Danish cohort showed that TE risk beyond 3 months after CA was relatively low compared with a
matched non-ablated AF cohort . The bleeding risk score HAS-BLED increased with
CHA2DS2-VASc score. Practical clinicians take bleeding risk into consideration. Karasoy D
et al. also emphasized that serious bleeding risk associated with OAC seems to outweigh the
benefits of TE risk reduction . When considering the SR maintenance duration, another
study showed that the risk of stroke is low in patients with no recurrence in first 1 year after
CA . In our study, we defined patients with no AF recurrence for at least 1 year as the SR
maintenance group, and this was consistent with their results .
Another study pointed out a CHA2DS2-VASc cut-off value for stroke . Saad EB et al.
demonstrated that no significant TE-related morbidity was observed when AAD and OAC
were discontinued after successful CA in patients with a CHADS2 score 3 who were
maintained on antiplatelet therapy during long-term follow-up. This suggests the existence of a gray
zone which has a relatively low risk of ischemic stroke after successful CA. In our results,
antiplatelet therapy was used more than OAC in the SR group than the recurrence group (70.9%
versus 16.7%, p<0.001, respectively). CHA2DS2-VASc scores of 2 and 3 are relatively low-risk
if SR is maintained after successful CA. Themistoclakis S et al. showed that the risk-benefit
ratio favored the suspension of OAC after successful CA in patients at moderate-high risk of
TE . They also emphasized that the CHADS2 score system probably is not the most
appropriate system for assessing TE risk and establishing an anticoagulation strategy after CA.
On contrary, there were studies which concluded inevitable OAC after successful CA [11?
15]. Oral H et al. demonstrated that sufficient safety data are as yet unavailable to support
discontinuation of OAC in patients older than 65 years or with a history of stroke . Patients
older than 65 years or with a history of stroke have a high risk of TE events and higher
CHA2DS2-VASc scores. If those patients have a history of stroke and older than 65 years,
CHA2DS2-VASc scores is 3 in male and 4 in female. Our results showed that stroke events
mostly occurred in patients with CHA2DS2-VASc scores 4, and the cut-off value for
differentiating ischemic stroke events was 3. The number of stroke event was very low in SR
group. And stroke event was mostly detected in patients CHA2DS2-VASc score 4 (Table 3).
Therefore, this showed only trend of distribution of stroke event and further large study would
be needed. The ESS-PRAFA study also showed that after CA, most patients (89.3%) continued
the same anticoagulant as before CA . This trend toward practical OAC was based on the
CHA2DS2-VASc score, but successful CA rate and rhythm status. However, in our results,
rhythm status was the most significant independent predictor of ischemic stroke.
In AFFIRM study, Corley SD et al. showed that rhythm control is not superior to rate
control . However, they demonstrated that OAC with warfarin improved survival, but SR was
an important determinant of survival. The rhythm control strategy with CA improved more
favorable outcomes than the rhythm control strategy with AAD alone or a rate control strategy
[17?20]. CA has been improved and is an efficient tool for maintaining SR . If TE are
assessed not only by CHA2DS2-VASc score but also SR maintenance, modified OAC may be
required after successful CA. However, our study showed that it was only observed in patients
with CHA2DS2-VASc score 3. We cannot recommend discontinuation of OAC for patient
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with SR maintenance after ablation. However, this study shows and emphasizes that gray zone
of stroke risk exists. There was a low risk of stroke in patients with SR maintenance and
CHA2DS2-VASc 2 or 3 after successful ablation. Further randomized and large study should
be needed for recommendation of discontinuation.
First, this was not a randomized trial, but a retrospective study. However, over the past 10
years, the CA strategy has developed from PVI to linear or/and CFAE ablation, the rate of
successful CA has improved, the ratio of sinus rhythm maintenance is high, and the rate of total
ischemic stroke events remains low. Therefore, there were low rates of OAC for patients with
CHA2DS2-VASc scores 2, based on rhythm status, bleeding risk, and compliance. Second,
there is no analysis of asymptomatic AF episodes which were not detected by ECG or Holter
monitoring. Like other AF studies, asymptomatic AF episodes are important and limit the
analysis of AF recurrence. This would underestimate the recurrence of AF after ablation, and
result in misallocation of some patients from recurrence group to SR group. Third, the study
population included patients with a mean CHA2DS2-VASc score of 1.0 and a small number
with a moderate risk of TE events. Therefore, 0.6% of the absolute ischemic stroke event rate
was very low. Patients with CHA2DS2-VASc scores 0 or 1 would not be recommended OAC
by current guidelines, regardless of rhythm status or success of ablation. CHA2DS2-VASc
scores were not significantly different between the two groups (0.9 vs. 1.1, p = 0.053).
Comparison and p value of CHA2DS2-VASc score = 0, 1, and 2 were <0.001, 0.193, <0.001,
respectively. Patients with CHA2DS2-VASc score 2 were lower in SR group. This finding was also
limitation of interpretation of stroke events in both groups. Large population studies with
higher CHA2DS2-VASc scores are necessary to evaluate the role of sinus rhythm status after
successful CA to further address our question. Finally, the ratio of male is much higher than
that of female both AF recurrence (79.5%) and SR maintenance group (79.2%). This had the
limitation of stroke risk for female population. Mean LVEF showed normal function both AF
recurrence (54.6%) and SR maintenance group (55.7%). This also had the limitation of
evaluating catheter ablation for atrial fibrillation in patients with reduced LVEF. And further study
would be needed.
This long-term follow up study in patients with AF who underwent catheter ablation showed
that sinus rhythm maintenance was correlated with a lower rate of ischemic stroke in Korea.
However, it was only observed in patients with CHA2DS2-VASc score 3.
Conceptualization: Dong-Hyeok Kim, Young-Hoon Kim.
Data curation: Dong-Hyeok Kim, Dae-In Lee, Jinhee Ahn, Kwang-No Lee, Seung-Young
Roh, Jaemin Shim, Jong-Il Choi.
Formal analysis: Dong-Hyeok Kim, Dae-In Lee, Jinhee Ahn, Kwang-No Lee, Seung-Young
Roh, Jaemin Shim, Jong-Il Choi, Young-Hoon Kim.
Investigation: Dong-Hyeok Kim, Dae-In Lee, Jinhee Ahn, Kwang-No Lee, Seung-Young Roh,
Jaemin Shim, Jong-Il Choi, Young-Hoon Kim.
Methodology: Dong-Hyeok Kim, Jaemin Shim, Jong-Il Choi.
Writing ? original draft: Dong-Hyeok Kim.
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Writing ? review & editing: Young-Hoon Kim.
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