Real-World Investigation on Anticoagulation Management Before and After Catheter Ablation for Atrial Fibrillation in Japan　― Periprocedural and Long-Term Outcomes ―

Akihiko Nogami; Kyoko Soejima; Itsuro Morishima; Kenichi Hiroshima; Ritsushi Kato; Satoru Sakagami; Fumiharu Miura; Keisuke Okawa; Tetsuya Kimura; Takashi Inoue; Atsushi Takita; Kikuya Uno; Koichiro Kumagai; Takashi Kurita; Masahiko Gosho; Kazutaka Aonuma; for the RYOUMA Investigators

doi:10.1253/circj.CJ-22-0290

Abstract

Background: Optimal periprocedural oral anticoagulant (OAC) therapy before catheter ablation (CA) for atrial fibrillation (AF) and the safety profile of OAC discontinuation during the remote period (from 31 days and up to 1 year after CA) have not been well defined.

Methods and Results: The RYOUMA registry is a prospective multicenter observational study of Japanese patients who underwent CA for AF in 2017–2018. Of the 3,072 patients, 82.3% received minimally interrupted direct-acting OACs (DOACs) and 10.2% received uninterrupted DOACs. Both uninterrupted and minimally interrupted DOACs were associated with an extremely low thromboembolic event rate. Female, long-standing persistent AF, low creatinine clearance, hepatic disorder, and high intraprocedural heparin dose were independent factors associated with periprocedural major bleeding. At 1 year after CA, DOAC was continued in 55.9% of patients and warfarin in 56.4%. The incidence of thromboembolic and major bleeding events for 1 year was 0.3% and 1.2%, respectively. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding events. Univariate analyses revealed that warfarin continuation and off-label overdose of DOACs were risk factors for major bleeding after CA.

Conclusions: High intraprocedural dose of heparin was associated with periprocedural major bleeding events. At 1 year after CA, over half of the patients had continued OAC therapy. Thromboembolic events were extremely low; however, major bleeding occurred in 1.2%. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding after CA.

Catheter ablation (CA) is a well-established treatment for atrial fibrillation (AF).¹^–⁴ Important complications associated with CA include thromboembolic events. Systemic anticoagulation therapy before and during the CA procedure is important to reduce these thromboembolic risks.¹^–⁶ Randomized studies⁷^–¹⁰ and meta-analyses¹¹^,¹² have revealed that uninterrupted therapy with direct-acting oral anticoagulants (DOACs) reduces the thromboembolic risks. DOAC use before CA in Japan increased to 89.9% in 2017.¹³ Anticoagulation probably contributes to the risk of procedural bleeding complications, which are more common than thromboembolic events and more serious.¹^–⁴^,¹⁴ Current guidelines and consensus statements¹^–⁴ recommend performing CA without the interruption of OAC (Class I/IIa); however, they also state that withholding one to two DOAC doses before CA is reasonable (Class IIa). It is unclear how many patients receive a minimally interrupted DOAC in the real-world setting.

Editorial p 63

Furthermore, it is unclear whether the risk of ischemic stroke is reduced after CA for AF. Although observational studies have suggested reduced risk of ischemic stroke after CA,¹⁵^–¹⁹ the CABANA trial (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation) did not demonstrate a reduction of stroke occurrence.²⁰ OAC therapy is recommended for at least 2–3 months post-ablation; the decision to discontinue OACs beyond this period is determined based on the clinical stroke risk rather than the rhythm status.¹^–⁴ However, it is unclear which patient characteristics should guide the decision-making process²¹^–²⁴ and when OAC therapy can be discontinued.

To investigate the relationship between OAC therapy and efficacy/safety during the periprocedural and long-term follow-up periods in patients undergoing CA for non-valvular AF in the real-world setting, we conducted the RYOUMA (Real-world ablation therapY with anti-cOagUlants in Management of Atrial fibrillation) registry study.

Methods

Study Design

The RYOUMA registry was a multicenter prospective observational study conducted between 2017 and 2018 in 62 institutions in Japan. Demographic information from the patients was obtained during registration, and information was recorded during the periprocedural phase.

This study is in accordance with the tenets of the Declaration of Helsinki and all applicable national legislation. The ethical review board at each participating site approved the research protocol. All patients provided written informed consent for participation before study entry. The study was registered as UMIN000026092 (University Hospital Medical Information Network - Clinical Trial Registry).

Patient Population

All patients with a planned first CA for non-valvular AF were eligible for inclusion. Patients were not excluded from the registry for any preexisting baseline characteristics. All consecutively enrolled patients who completed the required 1-year follow up after the CA procedure were included in the current analysis.

Study Outcomes

The primary endpoint was the overall incidence of adverse events (AEs) during the 1-year follow-up period. Analyses were performed in 2 separate observation periods: the periprocedural period (during and up to 30 days after CA) and the remote period (from 31 days and up to 1 year after CA). All AEs were analysed and classified as serious or non-serious. Serious AEs were evaluated by an event adjudication committee.

Definitions

DOAC dose categories were defined as: (1) on-label standard dose; (2) on-label reduced dose; (3) off-label overdose; and (4) off-label under dose according to the approved dose reduction criteria in Japan (Supplementary Table 1). Major bleeding events were defined according to the International Society on Thrombosis and Haemostasis criteria.²⁵

Statistical Analyses

Continuous variables were expressed as means and standard deviations or medians and interquartile ranges (IQRs). Categorical variables were summarized using n (%). Baseline characteristics were compared using the chi-squared test or Fisher’s exact test for categorical variables; and Student’s t-test or Wilcoxon’s rank sum test for continuous variables. Kaplan-Meier methods were used to estimate AEs and the continuation rates of OACs during the follow-up period. The log-rank test was used to evaluate the difference between groups. Receiver operating characteristic (ROC) curve analysis was used to define the optimal cut-off value based on the point closest to (0,1) corner in the ROC plane. Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for AEs during the periprocedural period (during and up to 30 days after CA). Cox regression hazard models were used to estimate the hazard ratios and 95% CIs for AEs during the remote period after CA (from 31 days and up to 1 year after CA). Variables with P<0.05 in univariate analysis were evaluated in the multivariate models. We considered a 2-sided P<0.05 statistically significant. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Patients

A total of 3,170 patients were enrolled during the registration period, of whom 33 were excluded. Fifty-nine patients were further excluded because they did not undergo CA, and 6 were excluded due to incomplete data. The flowchart of participants is shown in Supplementary Figure 1. In total, 3,072 patients underwent CA and were included in the analyses.

Patient Characteristics

The baseline patient characteristics are described in Table 1. The median age was 68.0 years and 71.1% were men. More than half of the patients (64.2%) had paroxysmal AF (PAF) and 36.6% had a CHADS₂ score of ≥2. Most patients (92.6%) had received DOACs. The warfarin group was significantly older and had a significantly lower creatinine clearance (CrCl), higher CHADS₂, CHA₂DS₂-VASc, and HAS-BLED scores than the DOAC group.

Table 1. Baseline Demographic and Clinical Characteristics of Study Patients

	Total (n=3,072)	Warfarin (n=156)	DOACs (n=2,844)	No use of OAC (n=72)	P value (Warfarin vs. all DOACs)
Age, years	68.0 [60.0–74.0]	70.0 [64.0–75.0]	68.0 [60.0–73.0]	64.5 [58.0–71.0]	0.0005*
Male sex	2,183 (71.1)	111 (71.2)	2,016 (70.9)	56 (77.8)	0.9428^†
Body weight, kg	64.8 [56.9–73.4]	65.5 [57.8–70.6]	64.9 [56.9–73.7]	62.8 [55.5–67.9]	0.5245*
BMI, kg/m²	23.8 [21.7–26.2]	24.2 [21.8–26.1]	23.8 [21.8–26.3]	22.6 [21.4–24.3]	0.7636*
Creatinine clearance, mL/min	76.3 [60.4–95.6]	60.2 [36.1–82.2]	76.9 [61.4–96.0]	82.4 [58.2–101.7]	<0.0001*
AF type					0.4793^†
Paroxysmal	1,973 (64.2)	96 (61.5)	1,821 (64.0)	56 (77.8)
Persistent	762 (24.8)	38 (24.4)	711 (25.0)	13 (18.1)
Long-standing persistent	337 (11.0)	22 (14.1)	312 (11.0)	3 (4.2)
CHADS₂ score	1.0 [0.0–2.0]	2.0 [1.0–3.0]	1.0 [0.0–2.0]	1.0 [0.0–2.0]	<0.0001*
≥2	1,123 (36.6)	86 (55.1)	1,016 (35.7)	21 (29.2)	<0.0001^†
≥1	2,244 (73.0)	142 (91.0)	2,062 (72.5)	40 (55.6)	<0.0001^†
CHA₂DS₂-VASc score	2.0 [1.0–3.0]	3.0 [2.0–4.0]	2.0 [1.0–3.0]	1.0 [1.0–3.0]	<0.0001*
≥3	1,303 (42.4)	93 (59.6)	1,191 (41.9)	19 (26.4)	<0.0001^†
≥2	2,019 (65.7)	128 (82.1)	1,856 (65.3)	35 (48.6)	<0.0001^†
HAS-BLED score	2.0 [1.0–3.0]	3.0 [2.0–4.0]	2.0 [1.0–3.0]	2.0 [1.0–2.0]	<0.0001*
≥3	1,021 (33.2)	90 (57.7)	914 (32.1)	17 (23.6)	<0.0001^†
Comorbidity
Hypertension	1,879 (61.2)	126 (80.8)	1,722 (60.5)	31 (43.1)	<0.0001^†
Diabetes	531 (17.3)	36 (23.1)	483 (17.0)	12 (16.7)	0.0501^†
Heart disease	853 (27.8)	81 (51.9)	756 (26.6)	16 (22.2)	<0.0001^†
Kidney disease	294 (9.6)	56 (35.9)	229 (8.1)	9 (12.5)	<0.0001^†
Hemodialysis	27 (0.9)	22 (14.1)	2 (0.1)	3 (4.2)	<0.0001^†
Hepatic disorder	193 (6.3)	11 (7.1)	176 (6.2)	6 (8.3)	0.6643^†
Cerebrovascular disease	351 (11.4)	31 (19.9)	314 (11.0)	6 (8.3)	0.0008^†
Thromboembolism	113 (3.7)	13 (8.3)	98 (3.4)	2 (2.8)	0.0016^†
Dementia	18 (0.6)	2 (1.3)	15 (0.5)	1 (1.4)	0.2215^†
Antiarrhythmics use	2,150 (70.0)	124 (79.5)	1,978 (69.5)	48 (66.7)	0.0083^†
Amiodarone	140 (4.6)	16 (10.3)	123 (4.3)	1 (1.4)	0.0006^†
Verapamil	344 (11.2)	12 (7.7)	321 (11.3)	11 (15.3)	0.1641^†
Diltiazem	59 (1.9)	2 (1.3)	54 (1.9)	3 (4.2)	1.000^†
Type of DOACs
Dabigatran			377 (13.3)
Rivaroxaban			784 (27.6)
Apixaban			766 (26.9)
Edoxaban			917 (32.2)
Dose of DOACs
Off-label overdose			134 (4.7)
On-label standard dose			1,820 (64.0)
On-label reduced dose			516 (18.1)
Off-label underdose			372 (13.1)
Others			2 (0.1)
OAC interruption before ablation
Interrupted	2,603 (84.7)	75 (48.1)	2,528 (88.9)
Uninterrupted	395 (12.9)	81 (51.9)	314 (11.0)
Type of AF ablation procedure
Radiofrequency	1,901 (61.9)	95 (60.9)	1,764 (62.0)	42 (58.3)	0.7775^†
Cryoballoon	1,087 (35.4)	55 (35.3)	1,001 (35.2)	31 (43.1)	0.9879^†
Hot balloon	103 (3.4)	7 (4.5)	94 (3.3)	2 (2.8)	0.4255^†
Visually guided laser balloon	11 (0.4)	0 (0.0)	11 (0.4)	0 (0.0)	0.4365^†

Data are shown as median [IQR, Q1–Q3] or n (%), unless otherwise stated. *Wilcoxon rank sum test. ^†Chi-squared test or Fisher’s exact test. AF, atrial fibrillation; BMI, body mass index; DOAC, direct-acting oral anticoagulant; IQR, interquartile range; OAC, oral anticoagulant.

In patients with DOACs, 40.2% received twice-daily (BID) DOACs and 59.8% received once-daily (QD) DOACs. Most patients (82.3%) had received minimally interrupted DOAC therapy before the CA (Figure 1). Regarding the interval between the last DOAC administration and the first puncture for the CA (D–A interval), of the 1,143 patients receiving BID-DOACs, the D–A interval was <12 h in 123 (10.8%), 12 to <24 h in 793 (69.4%), and ≥24 h in 170 (14.9%). Of the 1,701 patients who received QD-DOACs, the D–A interval was <24 h in 325 (19.1%), 24 to <36 h in 1,185 (69.7%), and ≥36 h in 65 (3.8%). Most patients had one dose held for both BID and QD-DOACs. The intraprocedural heparin requirement was significantly higher in the DOAC subgroups who had a D‒A interval of 12 to <24 h (median 11,500 IU [IQR, 9,000–14,900]) and ≥24 h (12,000 IU [IQR, 10,000–15,000]) than in the DOAC subgroup who had D‒A intervals <12 h (8,000 IU [IQR, 6,000–11,141]) (all P<0.0001). The median intraprocedural heparin requirement in the warfarin group was 8,700 IU (IQR, 7,000–11,000).

Figure 1.

Oral anticoagulant therapy upon AF ablation. BID, twice-daily; DOACs, direct-acting oral anticoagulants; OAC, oral anticoagulant; QD, once-daily.

Periprocedural Outcomes

Serious AEs during the periprocedural period (during and up to 30 days after CA) are shown in Table 2A. The incidence rates of ischemic stroke/systemic embolic events (SEEs) during the periprocedural period were low in both the warfarin (0.6%; 95% CI, 0.0–3.5) and DOAC (0.2%; 95% CI, 0.1–0.4) groups. The incidence of major bleeding events during the periprocedural period was 4.5% (95% CI, 1.8–9.0) in the warfarin group vs. 3.8% (95% CI, 3.1–4.6) in the DOAC group. Details about major bleeding events are shown in Supplementary Table 2A. For AEs, these occurred in 29.5% of the warfarin group and in 29.4% of the DOAC group.

Table 2. Serious Adverse Events in the Periprocedural Period and the Remote Period

	Total (n=3,072)	Warfarin (n=156)	DOACs (n=2,844)	No OAC before ablation (n=72)
A. Periprocedural period (during and up to 30 days after ablation)
Ischemic stroke/systemic embolic events	7 (0.2) [0.1–0.5]	1 (0.6) [0.0–3.5]	5 (0.2) [0.1–0.4]	1 (1.4) [0.0–7.5]
Major bleeding events	119 (3.9) [3.2–4.6]	7 (4.5) [1.8–9.0]	108 (3.8) [3.1–4.6]	4 (5.6) [1.5–13.6]
Clinically relevant non-major bleeding	26 (0.8) [0.6–1.2]	0 (0.0)	25 (0.9) [0.6–1.3]	1 (1.4) [0.0–7.5]
Major bleeding events/clinically relevant non-major bleeding	145 (4.7) [4.0–5.5]	7 (4.5) [1.8–9.0]	133 (4.7) [3.9–5.5]	5 (6.9) [2.3–15.5]
Intracranial hemorrhage	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Gastrointestinal bleeding	9 (0.3) [0.1–0.6]	0 (0.0)	9 (0.3) [0.1–0.6]	0 (0.0)
All-cause death	1 (0.0) [0.0–0.2]	0 (0.0)	0 (0.0)	1 (1.4) [0.0–7.5]
Cardiovascular death	1 (0.0) [0.0–0.2]	0 (0.0)	0 (0.0)	1 (1.4) [0.0–7.5]
B. Remote period (during follow-up period from 31 days up to 1 year after ablation)
Ischemic stroke/systemic embolic events	8 (0.3) [0.1–0.5]	0 (0) [0.0–1.9]	7 (0.2) [0.1–0.5]	1 (1.4) [0.0–7.5]
Major bleeding events	37 (1.2) [0.8–1.7]	6 (3.8) [1.4–8.2]	31 (1.1) [0.7–1.5]	0 (0) [0.0–4.1]
Clinically relevant non-major bleeding	16 (0.5) [0.3–0.8]	0 (0.0) [0.0–1.9]	14 (0.5) [0.3–0.8]	2 (2.8) [0.3–9.7]
Major bleeding events/clinically relevant non-major bleeding	53 (1.7) [1.3–2.3]	6 (3.8) [1.4–8.2]	45 (1.6) [1.2–2.1]	2 (2.8) [0.3–9.7]
Intracranial hemorrhage	11 (0.4) [0.2–0.6]	2 (1.3) [0.2–4.6]	9 (0.3) [0.1–0.6]	0 (0.0) [0.0–4.1]
Gastrointestinal bleeding	35 (1.1) [0.8–1.6]	1 (0.6) [0.0–3.5]	32 (1.1) [0.8–1.6]	2 (2.8) [0.3–9.7]
All-cause death	16 (0.5) [0.3–0.8]	2 (1.3) [0.2–4.6]	12 (0.4) [0.2–0.7]	2 (2.8) [0.3–9.7]
Cardiovascular death	3 (0.1) [0.0–0.3]	0 (0) [0.0–1.9]	2 (0.1) [0.0–0.3]	1 (1.4) [0.0–7.5]

Data are presented as n (%) (multiple count allowed) and 95% confidence interval of incidence in square brackets. DOAC, direct-acting oral anticoagulant.

Risk factors for major bleeding during the periprocedural period were analyzed (Table 3). Multivariate analysis revealed that female sex, long-standing persistent AF, CrCl <67 mL/min, hepatic disorder, no antiarrhythmic drug use, and total intraprocedural heparin dose ≥12,000 IU were independently associated with periprocedural major bleeding.

Table 3. Associations of Baseline Characteristics With Periprocedural Major Bleeding During and up to 30 Days After Ablation

Variables / Category	Number of patients	Univariate analysis			Multivariate analysis
		Odds ratio		P value	Odds ratio		P value
		Estimate	95% CI	P value	Estimate	95% CI	P value
Sex
Female	873	1.54	1.05–2.26	0.0285	1.74	1.02–2.95	0.0415
Age, years
≥71	1,067	1.76	1.21–2.56	0.0030
<71	1,933	Ref.
Body weight, kg
per 1 kg	3,000	0.99	0.97–1.00	0.1142
Body mass index, kg/m²
per 1 kg/m²	2,997	1.01	0.96–1.06	0.7754
AF types
Paroxysmal	1,917	Ref.			Ref.
Persistent	749	1.23	0.80–1.90	0.3522
Long-standing persistent	334	1.72	1.02–2.91	0.0432	1.88	1.04–3.38	0.0361
Creatinine clearance, mL/min
<67	1,025	2.13	1.46–3.09	<0.0001	2.06	1.25–3.39	0.0045
≥67	1,938	Ref.			Ref.
Hypertension
Yes	1,848	1.13	0.77–1.67	0.5369
Diabetes
No	2,481	1.21	0.72–2.05	0.4675
Heart disease
Yes	837	1.14	0.76–1.70	0.5368
Kidney disease
Yes	285	1.95	1.17–3.24	0.0100
Hepatic disorder
Yes	187	2.57	1.48–4.45	0.0008	2.51	1.35–4.68	0.0037
Smoking
Current	382	0.76	0.41–1.40	0.3804
Former	1,239	0.74	0.49–1.11	0.1426
Never	1,379	Ref.
Alcohol habits
No	1,251	1.61	1.11–2.34	0.0126
Antiarrhythmic drug use
No	540	1.89	1.25–2.86	0.0027	1.94	1.24–3.05	0.0039
Antiplatelets use
Yes	280	1.03	0.55–1.94	0.9298
Type of OACs
Warfarin	156	1.19	0.55–2.60	0.6625
DOAC	2,844	Ref.
Type of DOACs
QD	1,701	1.30	0.87–1.95	0.2012
BID	1,143	Ref.
Interval from the last DOAC administration to AF ablation procedure, h
<12	324	Ref
12 to <24	1,001	1.14	0.59–2.19	0.6972
≥24	1,475	0.99	0.52–1.87	0.9705
Heparin bridge before procedure
No	2,544	2.40	1.16–4.96	0.0180
Total heparin dose to reach target ACT, IU
≥11,000	872	1.68	1.14–2.47	0.0083
<11,000	1,851	Ref.
Total heparin dose, IU
≥12,000	1,381	2.57	1.71–3.86	<0.0001	2.51	1.46–4.30	0.0008
<12,000	1,557	Ref.			Ref.
Total heparinization time, min
≥89	1,547	2.36	1.50–3.70	0.0002
<89	1,181	Ref.
CHADS₂ score
<2	1,898	Ref.
≥2	1,102	1.25	0.85–1.82	0.2569
CHA₂DS₂-VASc score
<3	1,716	Ref.
≥3	1,284	1.48	1.02–2.15	0.0393
HAS-BLED score
<3	1,996	Ref.
≥3	1,004	1.50	1.03–2.19	0.0352

ACT, activated clotting time; AF, atrial fibrillation; CI, confidence interval; DOAC, direct-acting oral anticoagulant; OAC, oral anticoagulant; Ref., reference.

Continuation/Discontinuation of OAC Therapy During the Remote Period After CA

Figure 2 shows the continuation rates of the OACs during the follow-up period. At 1 year after CA, there was no difference between the warfarin (56.4%; 95% CI, 48.1–63.9) and DOAC (55.9%; 95% CI, 54.0–57.8) groups (Figure 2A). Although there was no difference in the warfarin continuation rate among CHADS₂ score subgroups (Figure 2B), DOAC continuation rates decreased significantly after 90 days as the CHADS₂ score decreased (Figure 2C). However, DOAC continuation rates at 1 year for CHADS₂ score 0 and 1 categories were still high (37.5% [95% CI, 34.0–41.0] and 53.5% [95% CI, 50.3–56.5], respectively). The DOAC continuation rates were significantly higher in the long-standing persistent AF (LS-PsAF) (62.6%; 95% CI, 56.8–67.9; P=0.001) and persistent AF (PsAF) (62.3%, 95% CI, 58.5–65.8; P<0.001) groups than in the PAF group (52.3%; 95% CI, 49.9–54.6) (Supplementary Figure 2B).

Figure 2.

Continuation rate of OACs during the follow-up period after ablation. (A) One year after the procedure, there was no difference between the warfarin and DOAC groups. (B) There were no differences in the continuation rates among the CHADS₂ score categories in the warfarin group. (C) In the DOAC group, the DOAC continuation rates beyond 90 days decreased significantly as the CHADS₂ score decreased. DOACs, direct-acting oral anticoagulants; OAC, oral anticoagulant.

Outcomes During the Remote Period

Outcomes during the remote period after CA (from 31 days and up to 1 year after CA) are shown in Table 2B and Supplementary Table 2B. The incidence rates of ischemic stroke/SEEs during the remote period were extremely low in both the warfarin (0.00%) and DOAC (0.26%; 95% CI, 0.12–0.54) groups (Figure 3A). All 8 patients who had ischemic stroke/SEE were in the DOAC group. One patient discontinued DOAC before ischemic stroke/SEE and 2 were taking off-label underdose. Three patients had a documented AF recurrence. Cox regression analysis could not find any significant risk factors for ischemic stroke/SEE.

Figure 3.

Kaplan-Meier plot of the time to the first major event adjudicated during the remote period. (A) The cumulative event rates of ischemic stroke/systemic embolic events at 1 year after ablation were similarly extremely low in the warfarin and DOAC groups. (B) The cumulative event rate of major bleeding 1 year after CA was significantly lower in the DOAC group than in the warfarin group. DOACs, direct-acting oral anticoagulants; OACs, oral anticoagulants.

The incidence of major bleeding events during the remote period was significantly higher in the warfarin group (3.99% [95% CI, 1.81–8.67]) than in the DOAC group (1.14% [95% CI, 0.80–1.61]; P=0.0021) (Figure 3B). The risk factors for major bleeding during the remote period were analyzed (Table 4). Univariate analysis revealed that age ≥73 years, hemoglobin <13 g/dL, CrCl <67 mL/min, malignancy, dementia, CHADS₂ score ≥2, CHA₂DS₂-VASc score ≥3, HAS-BLED score ≥3, antiplatelet use, OAC continuation at the time of the event or last follow up, warfarin continuation at the time of the event or last follow up, an off-label overdose of DOACs, and AF recurrence after 31 days following CA were associated with major bleeding during the remote period after CA. The warfarin continuation was associated with major bleeding; however, the DOAC continuation was not. Multivariate analysis revealed that age ≥73 years, dementia, and AF recurrence after 31 days following CA were independent risk factors for major bleeding events during the remote period.

Table 4. Associations of Characteristics With Major Bleeding During the Remote Follow-up Period From 31 Days and up to 1 Year After the Ablation

Variables / Category	Number of patients	Univariate analysis			Multivariate analysis
		Hazard ratio		P value	Hazard ratio		P value
		Estimate	95% CI	P value	Estimate	95% CI	P value
Sex
Female	873	1.04	0.52–2.11	0.9092
Age, years
≥73	867	4.08	2.10–7.92	<0.0001	3.72	1.78–7.77	0.0005
<73	2,133	Ref.			Ref.
Body weight, kg
per 1 kg	3,000	0.98	0.95–1.00	0.1017
Body mass index, kg/m²
per 1 kg/m²	2,997	0.95	0.86–1.04	0.2498
AF type
Paroxysmal	1,917	Ref.
Persistent	749	1.53	0.75–3.12	0.2473
Long-standing persistent	334	1.45	0.54–3.85	0.4603
Hemoglobin, g/dL
<13	687	2.27	1.18–4.37	0.0144
≥13	2,286	Ref.
Creatinine clearance, mL/min
<67	1,025	2.78	1.44–5.36	0.0022
≥67	1,938	Ref.
Hypertension
Yes	1,848	1.69	0.82–3.49	0.1564
Diabetes
Yes	519	1.56	0.74–3.31	0.2455
Heart disease
Yes	837	1.59	0.82–3.08	0.1729
Kidney disease
Yes	285	1.48	0.58–3.80	0.4133
Hepatic disorder
Yes	187	2.33	0.91–5.97	0.0790
Malignancy
Yes	310	2.39	1.09–5.23	0.0290
Dementia
Yes	17	11.25	2.71–46.77	0.0009	8.08	1.87–34.89	0.0051
Smoking
Current	382	0.72	0.21–2.49	0.6026
Former	1,239	1.40	0.71–2.75	0.3314
Never	1,379	Ref.
Alcohol habit
No	1,251	1.08	0.56–2.06	0.8260
Antiplatelets use
Yes	280	2.28	1.00–5.18	0.0499
CHADS₂ score
<2	1,898	Ref.
≥2	1,102	2.29	1.20–4.39	0.0124
CHA₂DS₂-VASc score
<3	1,716	Ref.
≥3	1,284	1.99	1.03–3.84	0.0397
HAS-BLED score
<3	1,996	Ref.
≥3	1,004	2.09	1.10–3.99	0.0246
OACs continuation at the time of event or the last follow up
Yes	1,891	2.59	1.14–5.90	0.0232
Warfarin continuation at the time of event or the last follow up
Yes	99	4.77	1.86–12.25	0.0012
DOACs continuation at the time of event or the last follow up
Yes	1,792	1.44	0.72–2.87	0.2994
Type of DOACs
QD	1,701	Ref.
BID	1,143	1.39	0.69–2.81	0.3620
DOAC dose
On-label dose	2,336	Ref.
Off-label overdose	134	3.33	1.14–9.69	0.0276
Off-label underdose	372	1.83	0.74–4.53	0.1930
AF recurrence (after 31 days post-CA)
Yes	274	2.31	1.01–5.26	0.0462	3.10	1.33–7.22	0.0086
AF recurrence (after 91 days post-CA)
Yes	172	1.96	0.69–5.53	0.2046

AF, atrial fibrillation; CA, catheter ablation; CI, confidence interval; DOAC, direct-acting oral anticoagulant; OAC, oral anticoagulant; Ref., reference.

Outcomes during the remote period were examined using DOAC dose categories (Figure 4). The cumulative rates of ischemic stroke/SEEs at 1 year after CA were similarly extremely low in the DOAC dose categories (Figure 4A). Conversely, the cumulative major bleeding events at 1 year after CA were significantly higher in the off-label overdose DOAC subgroup (3.03%; 95% CI, 1.15–7.86) than in the on-label dose DOAC subgroup (0.94%, 95%CI, 0.61–1.44; P=0.0195) (Figure 4B).

Figure 4.

Kaplan-Meier plot of the time to the first adjudicated major event during the remote period according to the DOAC dose categories. (A) The cumulative event rates of ischemic stroke/systemic embolic events 1 year after CA were extremely low in the DOAC dose categories. (B) The cumulative event rate of major bleeding at 1 year after CA was significantly higher in the off-label overdose DOAC subgroup than in the on-label dose subgroup. DOAC, direct-acting oral anticoagulant.

Discussion

Periprocedural Period

In this large, multicenter prospective registry study including 3,072 Japanese patients with AF who underwent CA, the majority (82.3%) of the patients received minimally interrupted DOACs. The rates of thromboembolic events in the periprocedural period were extremely low (0.2%; 95% CI, 0.1–0.5), and the rate of major bleeding events was 3.9% (95% CI, 3.2–4.6). Female sex, long-standing persistent AF, lower CrCl, hepatic disorder, no antiarrhythmic drug use, and higher total intraprocedural heparin dose were independently associated with periprocedural major bleeding.

In a 2014 European survey, only 14% of DOACs were uninterrupted.²⁶ A 2018 German survey reported that 54.3% of the centers used minimally interrupted DOACs, 37.2% used completely interrupted DOACs, and only 8.5% used continued DOACs.²⁷ The guidelines recommend truly uninterrupted DOAC use; however, the adoption of this strategy has been delayed and only a few centers have implemented the uninterrupted DOAC strategies in Europe and Japan.

Several trials have compared the randomized groups treated with uninterrupted and interrupted DOACs, and no differences in thromboembolic and major bleeding events were observed.²⁸^–³⁰ In contrast, Nagao et al³¹ observed significantly higher silent cerebral ischemic lesions by brain magnetic resonance imaging in patients receiving interrupted DOACs (27%) than in those receiving uninterrupted DOACs (4%).

A recent 2021 European Heart Rhythm Association Practical Guide⁴ described whether opting to administer the last DOAC dose shortly before the procedure for BID-DOACs or choosing a short discontinuation period may depend on factors, including renal function. Switching the QD-DOACs intake to the evening period in advance has also been recommended. Considering the interval between the last DOAC administration and procedure is more important than whether the dosing is uninterrupted or minimally interrupted. In the RE-CIRCUIT trial (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy),⁷ all major bleeding events in the dabigatran arm occurred in patients with a status of ≤8 h since the last administration. Therefore, skipping the morning dose on the day of CA may be a valid option for BID-DOACs. An integrated analysis³² of the RE-CIRCUIT study⁷ and ABRIDGE-J study (Ablation Perioperative Dabigatran in Use Envisioning in Japan)³³ with minimally interrupted dabigatran evaluated the relationship between bleeding events and the D–A interval. The rates for major bleeding events were 1.9% with a D–A interval <8 h, 0% for a D–A interval 8–24 h, and 3.5% for a D–A interval >24 h (3-group comparison, P=0.026). No thromboembolic events occurred in the study patients. Surprisingly, this integrated analysis revealed that major bleeding increased even if the D–A interval became longer. This may be related to increased intraprocedural heparin dosing with a longer discontinuation of DOAC therapy. In the RYOUMA registry, the intraprocedural heparin requirement was significantly higher with a D–A interval ≥12 h than with a D–A interval <12 h; further, a higher intraprocedural heparin dose was an independent risk factor for periprocedural major bleeding events. Sairaku et al³⁴ observed that the DOAC type and regimen determined the remaining DOAC activity that influenced the intraprocedural heparin requirement. Several studies have indicated that dabigatran is more sensitive to activated clotting time (ACT) assays compared with other DOACs.³⁵^–³⁷

The Remote Period After CA

The RYOUMA registry also provides valuable data on the continuation of OAC and outcomes during the remote period after CA. At 1 year after CA, DOAC therapy was continued in 55.9% of patients and warfarin therapy in 56.4% of patients. Surprisingly, even patients with a low risk of thromboembolism continued DOACs at a rate that was not low (37.5% for CHADS₂=0 and 53.5% for CHADS₂=1). The incidence of thromboembolic and major bleeding events at 1 year after CA was 0.3% and 1.2%, respectively. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding events.

The CABANA trial²⁰ could not demonstrate a reduction in stroke risk after CA. However, several studies have demonstrated a low incidence of thromboembolic events after CA for AF, suggesting that elimination of AF can decrease the risk of thromboembolic events.¹⁵^,¹⁷^–¹⁹ Themistoclakis et al¹⁵ reported the findings of a large retrospective study involving 3,355 patients who underwent CA for AF, of whom 2,692 (80.2%) discontinued anticoagulant use 3–6 months after CA. They observed that 0.07% of patients in the off-OAC group and 0.45% of patients in the on-OAC group had an ischemic stroke during the 2 years of follow up. No patient in the off-OAC group with a CHADS₂ risk score of ≥2 suffered from a stroke. Major hemorrhage events occurred significantly more frequently in the on-OAC group (2%) than in the off-OAC group (0.04%). The authors concluded that the risk-benefit ratio favored discontinuation of OAC therapy after successful CA of AF, even in patients at moderate/high-risk of thromboembolism. In a Danish registry,¹⁶ 55.7% of low-risk (CHA₂DS₂-VASc=0), 64.7% of intermediate-risk (CHA₂DS₂-VASc=1), and 70.4% of high-risk patients (CHA₂DS₂-VASc score ≥2) continued OAC therapy 1 year after CA. The rates of thromboembolic events were similarly low among patients who discontinued and continued OAC therapy (0.93 and 0.97 per 100 patient years, respectively). They suggested that the serious bleeding risk associated with OACs appeared to outweigh the benefits of thromboembolism reduction. The factor influencing the use of OACs was the detection of AF recurrence, but not the CHADS₂ score, in the observational study.²² This might result in overtreatment of low-risk patients with OACs.

Many studies have emphasized the importance of the patient’s risk score when deciding to discontinue OAC therapy. In the Japanese AF Frontier Ablation Registry, Okumura et al²⁴ investigated the effects of discontinuing OAC therapy on the post-ablation clinical outcomes in 3,451 patients. OAC therapy was discontinued in 53.2% of the patients, and discontinuation occurred more frequently in younger patients and patients with lower CHA₂DS₂-VASc scores. Overall, 1.5% of the patients experienced cerebral ischemic events and 2.1% experienced major bleeding during follow up. The occurrence of cerebral ischemic events was strongly associated with a high CHA₂DS₂-VASc score at baseline rather than with the status of OAC discontinuation. Noseworthy et al³⁸ also reported that OAC discontinuation after ablation was associated with a higher risk of thromboembolism for high- but not low-risk patients based on the analysis of an administrative claims database of CA for AF. A German registry study²³ revealed that, even in patients with a history of stroke, OAC therapy was frequently discontinued during follow up following PAF ablation and that thromboembolic events occurred significantly more frequently in these high-risk patients. These data argued against discontinuation of OAC therapy in patients who had suffered from a previous stroke.

A meta-analysis of 3,436 patients examined the controversial practice of discontinuing OAC therapy after CA in high-risk patients with a CHADS₂ or CHA₂DS₂-VASc score of ≥2.³⁹ The pooled analysis revealed no significant differences between patients who continued or discontinued OAC therapy regarding the risk of stroke or SEEs, although OAC continuation was associated with an increased risk of major bleeding.

Despite current guidelines and consensus statements,¹^–⁴ in the large US registry, ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation),⁴⁰ of the 1,190 patients who underwent CA for AF with a CHA₂DS₂-VASc score of ≥2 for men and ≥3 for women, 23% had discontinued OAC therapy after a median of 6.2 months following CA. Data from an administrative claims database³⁸ suggested an even higher rate of OAC discontinuation in the real-world setting. In a cohort of 6,886 patients who underwent CA for AF, only 38% of high-risk patients (CHA₂DS₂-VASc score ≥2) remained on OACs. These divergences between guideline recommendations and real-life clinical practice may reflect physician perceptions about rhythm control and stroke risk, and patient expectations about the cessation of OAC use after CA.

In this RYOUMA registry study, a univariate analysis revealed that continued warfarin therapy and off-label overdose of DOACs were risk factors for major bleeding events during the remote period. Sairaku et al³⁴ reported that among patients receiving rivaroxaban and dabigatran, the serum DOAC concentration was higher in patients receiving on-label reduced doses than in those receiving standard doses. Therefore, the concentration associated with off-label DOAC overdosing could be much higher, and this should be avoided.

Study Limitations

This study was underpowered to determine differences in thromboembolic rates, and the benefit of OAC therapy in preventing thromboembolism could not be analyzed. For some DOACs, the approved doses and reduction criteria in Japan differed from those in other regions. The decision to discontinue or to continue OAC therapy in our study depended on the physicians’ preference, and the possible reasons and their decision-making processes for the discontinuation of OAC therapy are unknown. The lack of randomized data is a limitation of this study, and more randomized trials are warranted to assess the safety of discontinuing OAC therapy after successful CA for AF. Several upcoming randomized clinical trials will help determine whether successful CA of AF can obviate the need for long-term OAC therapy, the largest of which is the OCEAN trial (Optimal Anti-Coagulation for Enhanced-Risk Patients Post-Catheter Ablation for Atrial Fibrillation).⁴¹

Conclusions

This prospective registry study revealed that a higher dose of intraprocedural heparin was an independent risk factor for the occurrence of periprocedural major bleeding events, and this was related to the D‒A interval ≥12 h. At 1 year after CA, over half of the patients had continued OAC therapy. Age ≥73 years, dementia, and AF recurrence were independently associated with major bleeding during the remote period. Univariate analysis revealed that the continuation of warfarin therapy and off-label overdose of DOACs were risk factors for major bleeding during the remote period. For patients with a low risk of stroke, discontinuation of OAC therapy is recommended. If continuation of DOAC use is needed during the remote period, off-label overdoses should be avoided.

Sources of Funding

This study was supported by DAIICHI SANKYO, Co., Ltd., Tokyo, Japan, which was involved in the study design, planning of the data analysis, data interpretation, and decision to submit the manuscript for publication, but was not directly involved in data management, direct access, or statistical analysis.

Disclosures

A. Nogami has received honoraria from Boehringer Ingelheim, DAIICHI SANKYO, Bristol-Myers Squibb, Abbott, and Johnson & Johnson; and endowments from Medtronic and DVX. K. Soejima has received honoraria from Boehringer Ingelheim, DAIICHI SANKYO, Abbott, Medtronic, and Johnson & Johnson. I. Morishima has received honoraria from DAIICHI SANKYO and Abbott. K. Hiroshima has received honoraria from Abbott, Medtronic, Boston, Johnson & Johnson, and Japan Lifeline. R. Kato has received grant support from Boston Scientific, Abbott, Bayer, and Japan Lifeline. S. Sakagami has received honoraria from Daiichi Sankyo and Johnson & Johnson. F. Miura has received honoraria from Medtronic, Abbott, and Biotronik. K. Okawa has received honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Abbott, Johnson & Johnson, and Medtronic. T. Kimura, T. Inoue, and A. Takita are employees of Daiichi Sankyo. K. Uno has received honoraria from Japan Lifeline. K. Kumagai has received honoraria from Daiichi Sankyo, Boehringer Ingelheim, Fukuda Denshi, Nihon Kohden, Toray, and Japan Lifeline. T. Kurita has received honoraria from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, Abbott, Medtronic, and Johnson & Johnson. M. Gosho has received honoraria from Pfizer, Ferring Pharma, DAIICHI SANKYO, and Novartis. K. Aonuma has received honoraria from Boston Scientific, Japan Lifeline, Nihon Kohden, Biotronik, Toray Industries, ASTEC, Abbott, Boehringer Ingelheim, and Century Medical.

K. Soejima and K. Aonuma are members of Circulation Journal’s Editorial Team.

IRB Information

The ethical committee at each study site approved the study protocol prior to registry commencement (University of Tsukuba Hospital: H28-219).

Data Availability

The deidentified participant data and the study protocol will be shared on a request basis for up to 36 months after the publication of this article. Researchers who make the request should include a methodologically sound proposal on how the data will be used; the proposal may be reviewed by the responsible personnel at Daiichi Sankyo Co. Ltd., and the data requestors will need to sign a data access agreement. Proposals should be directed to akihiko-ind@umin.ac.jp.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-22-0290

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