Efficacy and Safety of Uninterrupted Periprocedural Edoxaban in Patients Undergoing Catheter Ablation for Atrial Fibrillation　― The Prospective KYU-RABLE Study ―

Abstract

Background: The KYU-RABLE study, a prospective, multicenter, single-arm interventional study, evaluated the efficacy and safety of uninterrupted oral edoxaban in patients undergoing catheter ablation (CA) for atrial fibrillation (AF).

Methods and Results: We enrolled patients with AF from 23 centers in Japan. Edoxaban 60 mg (30 mg in patients indicated for dose adjustment) was administered uninterrupted, once daily in the morning for ≥4 weeks before CA and 4 weeks ±7 days after CA with one dose delayed on the procedural day. The primary endpoint was a composite of thromboembolism and major bleeding during 4 weeks from the procedural day. Among the 513 eligible patients who underwent CA, 63.5% received edoxaban 60 mg/day and 36.1% received 30 mg/day. For the primary endpoint, no thromboembolism and 1 major bleeding event (0.2%, cardiac tamponade) were observed. The plasma edoxaban concentration decreased depending on the time from the last administration to the CA procedure. However, plasma levels of coagulative biomarkers were within appropriate ranges regardless of the interval from the last administration of edoxaban.

Conclusions: The present study provided evidence of the efficacy and safety of uninterrupted edoxaban administered once daily in the morning, with one dose delayed on procedural day, in patients with AF undergoing CA. Edoxaban was associated with a low risk of periprocedural thromboembolic and bleeding complications.

Catheter ablation (CA) for atrial fibrillation (AF) is a therapeutic procedure that may be associated with complications including periprocedural thromboembolism and procedure-related major bleeding.¹ In the periprocedural period of CA for AF, uninterrupted vitamin K antagonist (VKA) therapy has been reported to reduce the risk of both thromboembolic and hemorrhagic complications compared with interrupted VKA.² For direct oral anticoagulants (DOACs), recent clinical studies have demonstrated both interrupted and uninterrupted protocols are effective and safe.^3–8 Accordingly, recent guidelines recommend uninterrupted administration of VKA or DOACs^9,10 or, alternatively, withholding one to two doses of DOACs prior to CA and reinitiating after ablation; however, the evidence for withholding doses is limited to data from 1 registry study.⁹

Edoxaban is a widely used anticoagulant for patients with AF. In a subgroup of patients from the ENGAGE AF-TIMI 48 trial undergoing CA, in which edoxaban was interrupted in 81% of patients, edoxaban was associated with a low risk of ischemic and bleeding events during the first 30 days after CA.¹¹ The ELIMINATE-AF study was conducted to assess the safety and efficacy of uninterrupted edoxaban, administered once daily in the evening, compared with VKA in AF patients undergoing CA, and found a lower incidence of the composite endpoint of all-cause death, stroke, or major bleeding with edoxaban.¹² Evidence supporting the use of edoxaban as periprocedural therapy in patients with AF undergoing CA, especially as uninterrupted periprocedural therapy, however, remains limited. The present KYU-RABLE (multicenter study associated with KYU-shu to evaluate the efficacy and safety of edoxaban in patients with non-valvulaR Atrial fiBriLlation undergoing cathEter ablation) was conducted to assess the safety and efficacy of uninterrupted edoxaban administered once daily in the morning, with one dose delayed on the procedural day, in patients with AF, and to evaluate the change in coagulative biomarkers and edoxaban concentration.

Methods

Study Design and Patients

This was a prospective, multicenter, single-arm, interventional study conducted at 23 institutions in Japan between December 2017 and September 2018 (Supplementary Appendix). Eligible participants were aged ≥20 years and scheduled to undergo CA for AF. Key exclusion criteria were: contraindication for treatment with edoxaban; contraindication for CA (thrombus formation in the left atrial appendage by transesophageal echocardiography, CT or MRI scanning); creatinine clearance (CrCL) <30 mL/min; history of thromboembolism or myocardial infarction within 2 months prior to enrollment; history of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intra-articular bleeding; and history of gastrointestinal bleeding or major bleeding with the International Society of Thrombosis and Hemostasis (ISTH) definition within 4 weeks prior to enrollment.

The protocol was approved by the institutional review board or independent ethics committee at each participating center, and the study was performed in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice Guidelines. Written informed consent was given by all patients prior to participation. This trial was registered in the UMIN-CTR (UMIN000029693).

Ablation Procedure

Decisions regarding the ablation procedure and energy source were at the investigator’s discretion. Heparin use and dosage for maintenance of activated clotting time (ACT) during the ablation procedure was determined by the physician performing CA. ACT was maintained at ≥300 s while the procedures in the left atrium were performed as indicated by the 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement.⁹

Study Treatment

For at least 4 weeks prior to CA, patients received edoxaban 60 mg (30 mg if they met ≥1 of the criteria for dose adjustment) once daily in the morning, and this treatment was continued for 4 weeks ±7 days after CA (Supplementary Figure). Edoxaban 30 mg was administered if any of the following characteristics were present at the time of enrollment to the study: estimated CrCL ≤50 mL/min, body weight ≤60 kg, and the concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors). On the day of the procedure, edoxaban was administered immediately after confirmation of hemostasis following the removal of the sheath, rather than before CA. Thus, uninterrupted edoxaban treatment in this study was defined as “one dose delayed” administration after CA on the procedural day.

On the day after CA (Day 1), edoxaban was administered at an interval of at least 12 h after the previous administration of edoxaban on the day of the CA procedure (Day 0). From Day 2, edoxaban was administered in the morning for 4 weeks ±7 days. With the exception of heparin, concomitant use of anticoagulants was prohibited during the study period. In addition, concomitant use of antiplatelet drugs was prohibited within the week prior to the CA procedure.

Study Endpoints

The primary endpoint was the composite incidence of thromboembolism (stroke and systemic embolism except for transient ischemic attack [TIA]) and major bleeding events during 4 weeks from the procedural day. Secondary endpoints included all-cause death, stroke and systemic embolism except for TIA, major bleeding, clinically relevant non-major bleeding, minor bleeding, cardiovascular events, and all adverse events. Major bleeding was based on the ISTH definition as follows: fatal bleeding; retroperitoneal, intracranial, intraocular, intrathecal, intra-articular, or pericardial bleeding, or intramuscular bleeding with symptoms of compartment syndrome; clinically overt bleeding that required a transfusion. Clinically relevant non-major bleeding was defined as clinically overt bleeding requiring intervention, including laboratory tests, diagnostic imaging, endoscopy, colonoscopy, cystoscopy, bronchoscopy, and compression hemostasis. Minor (not clinically relevant) bleeding was defined as evident bleeding that did not meet the criteria for major bleeding or clinically relevant non-major bleeding. The primary and secondary outcome events were adjudicated by an independent event adjudication committee.

Pharmacokinetic and Coagulative Biomarkers Assessment

The plasma edoxaban concentration and edoxaban-equivalent level using anti-Xa activity were measured on Day 0 (immediately before the CA procedure), Day 1 (prior to the next administration of edoxaban), and 4 weeks after CA (±7 days) or on the day of treatment discontinuation. Plasma levels of coagulative biomarkers were measured at enrollment (approximately 28 days prior to the CA procedure), Day 0, Day 1, and 4 weeks after CA (±7 days) or on the day of treatment discontinuation. In the present analysis, only the data for Day 0 are shown.

The plasma edoxaban concentrations were measured by solid phase extraction using liquid chromatography–tandem mass spectrometry system (SCIEX, Framingham, MA, USA) at Shin Nippon Biomedical Laboratories, Ltd. (Wakayama, Japan). Edoxaban-equivalent levels were assessed by LSI Medience Corporation (Tokyo, Japan) using a commercially available anti-FXa activity assay (STA®-Liquid Anti-Xa; Diagnostica Stago, Asnières sur Seine, France) with an edoxaban-specific setup using the STA®-Edoxaban Calibrator and STA®-Edoxaban Control on the STA®-R analyzer (Diagnostica Stago). D-dimer was measured by Latex Immunoturbidimetric assay using LATECLE D-dimer reagent (KAINOS Laboratories, Inc., Tokyo, Japan) at SRL Medisearch Inc. (Tokyo, Japan). Prothrombin fragment 1+2 (F1+2) was measured by ELISA using Enzygnost F1+2 monoclonal (Siemens Healthineers AG, Erlangen, Germany) at SRL Medisearch Inc. Soluble fibrin monomer complex (SFMC) was measured by Latex Immunoturbidimetric assay using Auto LIA FM (Nissui Pharmaceutical Co, Ltd., Tokyo, Japan) at SRL Medisearch lnc.

Sample Size and Statistical Analysis

Target sample size was based on an estimated incidence of thromboembolic and major bleeding events of approximately 0.6%, as observed in the JACRE registry study reported from Japan.⁵ To ensure accuracy within the 95% confidence interval (CI), an incidence of ±0.7% was used to calculate a sample size of 500 patients. The full analysis set (FAS) comprised all enrolled patients who subsequently underwent the CA procedure.

Clinical events were analyzed in the FAS, and the plasma concentrations of edoxaban and coagulative biomarkers were analyzed in the per protocol set (PPS). The number of patients reporting the composite event of thromboembolism and major bleeding events during the 4-week period following the CA procedure was determined, and the incidence and 95% CIs of the combined events were calculated. The significance level was 5% two-tailed, and 95% CIs were used when section estimation was performed. The changes in the plasma concentrations of edoxaban and coagulative biomarkers against the time from the last edoxaban administration to the CA procedure, classified into 4 categories (<24 h, 24–27 h, 27–30 h, and ≥30 h), and were verified using the Jonckheere-Terpstra test (two-tailed). The differences in the concentrations were also assessed in patients undergoing CA in the morning compared with the afternoon, and verified using the Mann-Whitney test (two-tailed). All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Patient Disposition and Baseline Characteristics

A total of 537 eligible patients with AF were enrolled and of them, 513 underwent CA, comprising the FAS. The PPS consisted of 477 patients for the analyses of the plasma edoxaban concentration and plasma levels of coagulative biomarkers (Figure 1). Mean age was 64.7±10.0 years, and a majority (70.2%) were male (Table 1). Mean CHADS₂ score was 1.2±0.9 and the mean CHA₂DS₂-VASc score 2.1±1.3. Regarding the type of AF, 58.3% of patients had paroxysmal AF, 31.2% had persistent AF, and 10.1% had long-standing persistent AF. Frequent baseline comorbidities were hypertension (57.5%), hyperlipidemia (31.4%), and diabetes (15.0%). Of the 513 patients who underwent CA, 75.2% had radiofrequency CA and 23.0% had cryoballoon CA. Mean duration after CA procedure to restarting edoxaban was 6.3±4.1 h, and that from the last edoxaban administration before CA to restarting after CA was 36.1±4.8 h (Table 2). Among the patients undergoing CA, 63.5% received edoxaban 60 mg/day, and 36.1% had 30 mg/day (Table 2). The numbers of patients who met the criteria for dose adjustment are shown in Table 2.

Figure 1.

Patient disposition. CA, catheter ablation.

Table 1. Patients’ Baseline Characteristics

	n=513
Age, years	64.7±10.0
Male sex	360 (70.2)
Weight, kg	67.0±14.0
≤60	169 (32.9)
BMI, kg/m2	24.6±4.2
CrCL, mL/min	82.6±27.7
≤50	45 (8.8)
CHADS2 score	1.2±0.9
≥2	149 (29.0)
CHA2DS2-VASc score	2.1±1.3
≥2	320 (62.4)
HAS-BLED score	1.2±0.7
≥3	15 (3.1)
Type of AF
Paroxysmal	299 (58.3)
Persistent	160 (31.2)
Long-standing persistent	52 (10.1)
Permanent	2 (0.4)
Treatment of AF
Rate control	183 (35.7)
Rhythm control	191 (37.2)
Previous treatment of ablation	76 (14.8)
Concomitant use of P-glycoprotein inhibitor	47 (9.2)
Comorbidities
Hypertension	295 (57.5)
Hyperlipidemia	161 (31.4)
Diabetes	77 (15.0)
Arrhythmia other than AF	50 (9.7)
Congestive heart failure	42 (8.2)
Ulcer/reflux esophagitis	31 (6.0)
Angina pectoris	27 (5.3)
Renal disease	27 (5.3)

Values are expressed as mean±SD, n (%). AF, atrial fibrillation; BMI, body mass index; CA, catheter ablation; CrCL, creatinine clearance.

Table 2. Procedural and Dosing Characteristics

	n=513
CA
Radiofrequency	386 (75.2)*
Cryoballoon	118 (23.0)
Hot balloon	5 (1.0)
Laser balloon	10 (1.9)
Total procedure duration, min	174.4±67.6
The starting time of CA (AM/PM)**
AM	306 (59.6)
PM	206 (40.2)
Administration of heparin before atrial septal puncture	466 (90.8)
Average total heparin dose, units	9,358.3±4,835.8
During procedure at AM	8,938.9±4,995.7
During procedure at PM	9,960.5±4,531.6§
Activated clotting time (mean of the longest values), s	351.7±70.3
During procedure in AM	351.0±80.2
During procedure in PM	352.8±52.8
Duration after CA procedure to restart edoxaban, h	6.3±4.1
Duration from last edoxaban administration before CA to restart after CA, h	36.1±4.8
Dose of edoxaban at 4 weeks before CA
60 mg	327 (63.7)
30 mg	185 (36.1)
Patients with criterion for dose adjustment
Body weight ≤60 kg	169 (32.9)
CrCL ≤50 mL/min	45 (8.8)
Concomitant use of P-glycoprotein inhibitor	47 (9.2)

Data are mean±SD unless otherwise specified, n (%). *In six cases, radiofrequency ablation was added to the other ablation procedures. **In one case, time of ablation initiation was not reported. ^§P<0.05 vs. dose in AM. AM, morning; CA, catheter ablation; CrCL, creatinine clearance; PM, afternoon.

Primary Outcome

As shown in Table 3, no thromboembolism and 1 major bleeding event (cardiac tamponade) (0.2%) were observed during the 4 weeks from the procedural day. One case of cardiac tamponade occurred during the CA procedure, and the patient was treated with pericardial drainage and recovered without blood transfusion. No deaths occurred. Clinically relevant non-major bleeding events were observed in 7 patients (1.4%), the majority of which were puncture site hemorrhage. Minor bleeding events were observed in 10 patients (1.9%). The majority (12/18, 66.7%) of bleeding events and other adverse events occurred on Days 0 and 1 (Table 4).

Table 3. Incidence of Primary and Secondary Endpoints

Event	n=513	Details (n)
Primary endpoint
Composite of thromboembolism and major bleedinga	1 (0.2)	Cardiac tamponade
Secondary endpoints
All-cause death	0 (0.0)
Thromboembolism	0 (0.0)
Major bleeding	1 (0.2)	Cardiac tamponade
Clinically relevant non-major bleeding	7 (1.4)	Bleeding at puncture site (5)
		Bilateral femoral hematoma (1)
		Alveolar hemorrhage (1)
Minor bleeding	10 (1.9)	Hematoma at groin (7)
		Hematuria (2)
		Bleeding at puncture site (1)
Cardiovascular events	1 (0.2)	Percutaneous coronary intervention

Data are n (%). ^aPrimary endpoint of composite/combined thromboembolism and major bleeding events during 4 weeks from the procedural day.

Table 4. Time Course of Occurrence of Bleeding Events

Events	Days after CA							Total
	0	1	2–7	8–14	15–21	22–28	29–35
Major bleeding	1							1
Clinically non-major relevant bleeding	6	1						7
Minor bleeding	5	3	2					10
Total	12	4	2					18

CA, catheter ablation.

Plasma Concentration of Edoxaban and Coagulative Biomarkers

The plasma edoxaban concentration and edoxaban-equivalent level using anti-Factor Xa activity (data not shown) measured on Day 0 (immediately before CA) were dependent on the time from the last administration of edoxaban before CA (P<0.0001, Figure 2). When the time from the last edoxaban administration to the CA procedure was divided into 4 categories, although the plasma edoxaban concentration decreased with time (P<0.0001), the plasma levels of coagulative biomarkers (D-dimer, F1+2 and SFMC) remained unchanged, being within their normal ranges (<1.0 µg/mL for D-dimer and 69–229 pmol/L for F1+2) (Figure 3, SFMC data not shown). Furthermore, the plasma edoxaban concentration was lower in patients who underwent CA in the afternoon than in those who underwent CA in the morning (P<0.0001). However, the plasma levels of coagulative biomarkers did not differ between the groups undergoing CA in the morning or the afternoon (Figure 4).

Figure 2.

Plasma concentration of edoxaban according to the time from the last administration of edoxaban before catheter ablation (CA).

Figure 3.

Plasma concentrations of edoxaban and plasma levels of coagulative biomarkers according to the time from the last administration of edoxaban before catheter ablation (CA). Data are presented as box-and-whisker plots, in which the boxes represent medians (Q1;Q3), bars represent 90th and 10th percentiles, and dots represent 95th and 5th percentiles. Significance among the 4 categories was verified using the Jonckheere-Terpstra test (two-tailed).

Figure 4.

Plasma concentrations of edoxaban and plasma levels of coagulative biomarkers according to the timing of catheter ablation (CA). Data are presented as box-and-whisker plots, in which the boxes represent medians (Q1;Q3), bars represent 90th and 10th percentiles, and dots represent 95th and 5th percentiles. Differences were verified by the Mann-Whitney test (two-tailed).

ACT and Total Heparin Dose

The ACTs (mean of the longest values) and total heparin doses are shown in Table 2 for all patients and for the patient groups in which ablation was done in the morning or afternoon. The mean ACTs during the morning and afternoon procedures were 351.7±80.2 s and 352.8±52.8 s, respectively (P=NS). The average total heparin doses during the morning procedures (8,938.9±4,995.7 units) was less than those done in the afternoon (9,960.5±4,531.6 units, P<0.05).

Discussion

The findings of this prospective, multicenter, interventional study supported the efficacy and safety of uninterrupted edoxaban administered once daily in the morning, with one dose delayed after CA on the procedural day in patients with AF. The results were consistent regardless of whether CA was performed in the morning or afternoon. Furthermore, although the plasma edoxaban concentration decreased gradually after the last dose before CA, especially in the afternoon of the CA procedure day, the levels of coagulative biomarkers remained unchanged within their normal ranges, even in patients undergoing CA in the afternoon. To the best of our knowledge, this is the first study demonstrating that coagulative status did not change despite delaying one dose of edoxaban after the CA procedure. There may be an argument that the use of the term “uninterrupted” is not correct in our protocol. However, there was no day on which the patients did not take edoxaban. In addition, edoxaban is a once-daily drug. So, we adopted the expression “uninterrupted edoxaban administered once daily in the morning, with one dose delayed after CA on the procedural day”.

The type of CA performed in participants in this study included radiofrequency in 75.2% of patients and cryoballoon in 23.0%, and these rates are similar to those reported in a recent epidemiological investigation in Japan.¹³ Thus, the patient population included in this study reflects the population undergoing CA in real-world clinical practice in Japan.

In the present study, the incidence of the composite primary endpoint (thromboembolism and major bleeding) was only 1 event (0.2%, cardiac tamponade). Neither thromboembolism nor death occurred. The event rates occurring in this study were comparable with those shown in the VENTURE-AF trial,⁴ JACRE study,⁵ RE-CIRCUIT trial,⁶ AXAFA-AFNET 5 trial,⁷ and AEIOU trial.¹⁴

In the recently reported ELIMINATE-AF trial,¹² a lower incidence of the composite endpoint of all-cause death, stroke, and major bleeding was observed with the use of uninterrupted evening administration of edoxaban in AF patients undergoing ablation. One of the notable characteristics of the present study was that edoxaban morning administration was uninterrupted throughout the periprocedural period with one dose delayed after CA on the procedure day. The mean duration from the last edoxaban administration before CA to restarting the drug after CA was 36.1±4.8 h. However, the plasma levels of coagulative biomarkers remained within their normal ranges and no thromboembolic event occurred. Thus, delaying one dose of edoxaban on the procedural day appeared to have no adverse effects on the outcome.

The plasma edoxaban concentration was decreased in relation to the time from the last dose administered before CA, and its trough level was similar to that shown in a previous study.¹⁵ Elevation of plasma D-dimer level reflects the presence of cross-linked fibrin. F1+2 and SFMC are indices of thrombin generation, and elevated levels indicate activation of the coagulation system. In the present analysis, following ≥4 weeks of edoxaban treatment prior to CA, the periprocedural plasma levels of coagulative biomarkers were not affected by the decrease in edoxaban concentration observed prior to CA. Furthermore, we found no significant differences in the plasma levels of coagulative biomarkers between patients undergoing CA in the morning and those in the afternoon. This finding suggested the efficacy of uninterrupted edoxaban with one dose delayed in patients undergoing CA. The issue of morning dosing may be relevant in many cases; older patients already take their dose of DOAC in the morning. The prevalence of AF increases with aging, and an increasing number of older patients undergo CA for AF.¹⁶ It is therefore important to establish the optimal periprocedural anticoagulation management strategy while reflecting changes in the clinical setting for AF management.

This study demonstrated that the average total heparin dose used to maintain ACT >300 s during CA was significantly higher in the patient group in which CA was done in the afternoon than in the group in which CA was in the morning. The mean ACT did not differ between these 2 groups. Because the plasma edoxaban concentration and edoxaban-equivalent level using anti-Factor Xa activity were lower in patients who underwent CA in the afternoon than in those in the morning, a higher heparin dose seemed to be required in the former to obtain a similar ACT.

Study Limitations

First, the study was open-label in design, with a single-arm of edoxaban. It is therefore not possible to compare efficacy or safety between edoxaban and a comparator such as a VKA. Furthermore, as there was only one endpoint event, this study is underpowered with respect to determining the safety of edoxaban in this setting. However, the safety of uninterrupted edoxaban has been demonstrated compared with both warfarin, in the ENGAGE AF-TIMI 48,¹¹ and phenprocoumon, in a 2018 study by Kottmaier et al.¹⁷ Finally, the 4-week follow-up period was relatively short. However, based on the time course of adverse events, which mostly occur in the periprocedural period, it is unlikely that any additional risks would be identified in a longer follow-up period.

Conclusions

The KYU-RABLE study provided evidence of the efficacy and safety of uninterrupted periprocedural edoxaban administered once daily in the morning, with one dose delayed after CA on procedural day, in AF patients undergoing CA. Our findings support the recommendations reported in the guidelines^9,10 for withholding one dose of DOACs prior to CA and reinitiating DOACs after ablation. This treatment strategy was associated with a low risk of periprocedural bleeding and thromboembolic complications, which appeared to correlate with the maintenance of the plasma levels of coagulative biomarkers independent of the plasma edoxaban concentration.

Acknowledgment

We thank Clare Cox, PhD, of Edanz Medical Writing for medical writing assistance, which was funded by Daiichi Sankyo Co., Ltd.

Disclosures

This work was supported by Daiichi Sankyo Co., Ltd.

N.T. received remuneration from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer Japan, and received research funding from Ono Pharmaceutical. K.O. received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. T.K., K.Y., and T.M. are employees of Daiichi Sankyo.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-19-0535

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