New Oral Anticoagulants in Patients Undergoing Atrial Flutter Radiofrequency Catheter Ablation: an Observational Study

ABSTRACT 

Aim: Atrial flutter (AFL) ablation requires optimal periprocedural anticoagulation in order to minimize thromboembolic events/bleeding risk. This study describes the characteristics of patients receiving new oral anticoagulants before AFL ablation and assesses complications. Methods: This multicenter, retrospective study reports ischemic and hemorrhagic predischarge, postprocedural complications. Results: We evaluated 60 patients (62.3% male; mean age: 69.2 ± 9.7 years; CHA₂DS₂-VASc score: 2.44 ± 1.46, HAS-BLED score: 1.14 ± 0.7). Twenty-one (35.0%) and 23 patients (38.3%) received twice-daily dabigatran 110 or 150 mg; 16 patients (26.6%) received once-daily rivaroxaban (15 mg [n = 5] or 20 mg [n = 11]). Four cases of postprocedural minor bleeding were reported. Conclusion: This is the first study assessing new oral anticoagulants for periprocedural anticoagulation, specifically in patients undergoing AFL ablation. No major bleeding was reported. Further prospective investigation is warranted.

KEYWORDS :

• atrial flutter
• dabigatran
• new oral anticoagulants
• radiofrequency ablation
• rivaroxaban
• stroke

Background

Atrial flutter (AFL) is a frequent supraventricular arrhythmia, representing one of the major indications for catheter ablation procedures in a significant number of centers [1]. AFL is associated with a risk of stroke that is similar to that associated with atrial fibrillation (AF) [2]. The annual risk of stroke without anticoagulation is estimated to be between 3 and 6% [2,3]. Thus, AFL requires anticoagulation using strategies that are similar to those applied for AF. However, new oral anticoagulants (NOACs; dabigatran, rivaroxaban and apixaban) have not yet been evaluated in AFL, particularly in the setting of catheter ablation.

Cavotricuspid isthmus ablation, the main strategy for AFL treatment, is recommended in patients with a history of AFL [4,5]. AFL ablation is a class I indication for recurrent and well-tolerated AFL, for poorly tolerated AFL and for AFL appearing in patients receiving antiarrhythmic drugs. AFL ablation is a class IIa indication for a first episode of well-tolerated AFL. Thus, AFL ablation may be a routine strategy in a substantial number of AFL patients.

AFL ablation requires optimal periprocedural anticoagulation in order to minimize thromboembolic events and the risk of bleeding. A recent analysis showed that AFL ablation without interruption of warfarin appears to be safer and more cost effective than periprocedural conversion to low-molecular-weight heparin [6]. To date, there have been few to no data on the use of NOACs as alternatives to vitamin K antagonists (VKAs) periablation for AFL ablations. The objective of the current observational pilot study was to describe the characteristics of patients taking NOACs and in whom AFL radiofrequency catheter ablation (RFA) was performed, and to describe the complications and the safety of NOACs in these patients.

Methods

We performed a multicenter (n = 8), retrospective analysis of patient records from November 2012 to July 2013. The analysis included all patients receiving a NOAC before undergoing cavotricuspid isthmus ablation as a sole radiofrequency therapy for AFL.

All patients were required to have an AFL at admission or in at least one ECG during the previous 3 months. Patients were included if they were receiving dabigatran 110 or 150 mg twice daily or rivaroxaban 15 or 20 mg once daily. Patients with creatinine clearance (CrCl) <30 ml/min, with valvular AF or a valvular prosthesis (mechanical or biological valve) were excluded. Transesophageal echocardiography (TEE) was performed by the practising physician before the procedure according to their standard practice.

The objective of this study was to report on the predischarge ischemic and hemorrhagic complications associated with AFL ablation. Stroke was defined as the sudden onset of a focal neurologic deficit in a location that is consistent with the territory of a major cerebral artery and categorized as ischemic, hemorrhagic or unspecified. Intracranial hemorrhage consisted of hemorrhagic stroke and subdural or subarachnoid hemorrhage. Systemic embolism was defined as an acute vascular occlusion of an extremity or organ, documented by means of imaging, surgery or autopsy. Major bleeding was defined as a reduction in the hemoglobin level of ≥20 g/l, transfusion of at least 2 units of blood or symptomatic bleeding in a critical area or organ. Life-threatening bleeding was a subcategory of major bleeding that consisted of fatal bleeding, symptomatic intracranial bleeding, bleeding with a decrease in the hemoglobin level of ≥50 g/l or bleeding requiring the transfusion of at least 4 units of blood or inotropic agents or necessitating surgery. All other bleeding was considered minor. Hematoma was defined as significant or minor. A significant hematoma was defined as one requiring reoperation, producing impending or actual wound breakdown/skin necrosis, requiring prolongation of hospitalization or rehospitalization or requiring the interruption of anticoagulation for >24 h.

Since this retrospective, observational analysis of medical records was anonymous and did not involve the manipulation of the subject or the subject’s environment, institutional review board submission was waived. Informed consent was obtained from each patient prior to the original AFL ablation procedure, but was not required for the current analysis.

Results

The study included 60 patients. All of the patients had an AFL at admission or in at least one ECG during the previous 3 months. The mean patient age was 69.2 ± 9.7 years (range: 45–87 years) and 62.3% of the patients were male. The main characteristics of the population are presented in Table 1. The mean CHA₂DS₂-VASc score was 2.44 ± 1.46, the mean HAS-BLED score was 1.14 ± 0.7 and the mean CrCl was 81 ± 29 ml/min (according to the Cockcroft–Gault formula); 51 patients (85%) had CrCl ≥50 ml/min and nine patients (15%) had CrCl ≥30 and <50 ml/min.

Patients received treatment for a mean of 31 ± 15 days before the ablation procedure; 53 patients (88%) received treatment for >21 days. Twenty-three patients (38.3%) received dabigatran 150 mg twice daily, 21 patients (35%) received dabigatran 110 mg twice daily, 11 patients (18.3%) received rivaroxaban 20 mg once daily and five patients (8.3%) received rivaroxaban 15 mg once daily (Table 2). The last dabigatran dose was administered 13.3 ± 16.6 h before ablation (ranging from 2 to 24 h according to the individual center’s protocol). Dabigatran was interrupted ≥24 h (withdrawal of two or more doses) before ablation in 17 out of 44 patients (38.6%), ≥12 and <24 h (withdrawal of one dose) in seven out of 44 patients (16%) and was uninterrupted in 20 out of 44 patients (45.4%). The last rivaroxaban dose was administered 20 ± 2 h before ablation (ranging from 15 to 24 h; no administration in the 12 h before the procedure). All patients restarted the same anticoagulation therapy 12 h after the end of the procedure. TEE was performed in 12 patients (five patients receiving dabigatran 150 mg twice daily, three patients receiving dabigatran 110 mg twice daily and four patients receiving rivaroxaban). Immediately before ablation, TEE was negative for the presence of left atrial appendage thrombus. During the ablation procedure, a bolus of heparin was given to 36 patients (65%) because of dabigatran (n = 23) or rivaroxaban (n = 13) discontinuation.

AFL ablation was performed in patients still in AFL in 37 patients (61.6%) and in sinus rhythm in 23 patients (38.4%). All patients were in sinus rhythm at the end of the procedure (Table 3). The ablation procedure necessitated a double venous femoral puncture in 24 patients (40%) and a triple venous puncture in 36 patients (60%). The mean duration of the procedure was 137 ± 131 min.

Four cases of postprocedural minor bleeding (bleeding at the puncture site without hematoma) were reported (three patients receiving dabigatran 150 mg twice daily and one patient receiving rivaroxaban 20 mg once daily) (Table 4). One patient (male, aged 76 years) experienced an ischemic stroke 27 h after RFA associated with an electrical cardioversion (failed cavotricuspid isthmus ablation due to a left AFL). The stroke occurred in sinus rhythm. The patient was initially hospitalized for management of a recent AFL associated with palpitations. At admission, the patient showed normal renal function (urea = 5.2 mmol/l; creatinine = 74 µmol/l; glomerular filtration rate = 94 ml/min [Cockcroft–Gault]), with an international normalized ratio of 1.18 and an activated partial thromboplastin time (aPTT) ratio of 2.12 (under dabigatran treatment). After the failure of combination therapy with a β-blocker and calcium channel blocker in order to slow the heart rate, the patient was referred for AFL ablation. The patient’s cardiovascular risk factors were arterial hypertension and hypercholesterolemia. The CHA₂DS₂-VASc score was 3 and the HAS-BLED score was 2. The patient was receiving dabigatran 110 mg twice daily uninterrupted before or after the procedure. As the duration of anticoagulation was <3 weeks, the patient underwent a preprocedural TEE (3 days before the ablation), which ruled out a left atrial thrombus. An injected brain tomography confirmed the diagnosis of an acute ischemic stroke due to occlusion of the third segment of the left middle cerebral artery without stenosis in the carotid arteries. An emergency thromboaspiration was performed and the patient recovered completely. This patient received dabigatran 150 mg twice daily at discharge.

Discussion

To date, there have been few to no data on the use of dabigatran as an alternative to VKA periablation for AFL ablation. Only six patients in one study [7] and an unspecified number of patients in a more recent study [8] received dabigatran and underwent AFL ablation. A number of studies have evaluated dabigatran in patients undergoing AF ablation [7–17]. With the exception of a small randomized controlled trial that included 90 patients [14], these studies were observational, case–control and/or registry analyses [7–13,15–17]. However, it is important to note that all of these studies included patients with a specific indication for AF (not AFL) ablation.

The current investigation is the first study to specifically evaluate NOACs for periprocedural anticoagulation in patients undergoing AFL RFA. Our study reported no major hemorrhagic complications. We recorded four cases of postprocedural minor bleeding without hematoma. These complications represent minor complications without significant consequences. The single case of ischemic stroke in one of the patients, related to a cardioversion, is a surprising and uninterpretable complication. The patient was receiving dabigatran 110 mg twice daily, with an aPTT ratio of 2.12 (under dabigatran treatment). Preprocedural TEE ruled out an atrial thrombus. However, according to the patient profile and the dabigatran summary of product characteristics [18], this patient should have been receiving dabigatran at a dose of 150 mg twice daily.

Our study highlights the low level of major complications in patients undergoing an AFL ablation and taking NOACs. To date, as outlined in the following overview of the literature, studies have evaluated periprocedural complications in patients undergoing AF ablation and receiving NOACs.

Several studies have evaluated dabigatran in patients undergoing AF ablation. In a case–control study, Kim et al. evaluated the use of dabigatran or warfarin in 763 patients undergoing AF ablation (dabigatran 150 mg twice daily [n = 191] or warfarin [n = 572]) [9]. Treatment with dabigatran was stopped 24–30 h before the procedure and restarted 4 h after the procedure. The study found no differences between the two treatment groups regarding major bleeding (2.1 vs 2.1%, respectively), minor bleeding (2.6 vs 3.3%) and pericardial tamponade (1.0 vs 1.1%). Snipelisky and colleagues included 156 patients (31 receiving dabigatran 150 mg twice daily [n = 31] or warfarin [n = 125]) undergoing AF ablation (for AFL ablation, six and 27 patients were on dabigatran or warfarin, respectively) [7]. Treatment was not stopped for the procedure. Patients in this study experienced no major bleeding complications in the week following ablation.

In a study by Winkle and colleagues, 34 patients received dabigatran 150 mg twice daily (stopped 36 h before the ablation) and 89 patients received a VKA [10]. No cases of bleeding complication or stroke were reported. Kaseno et al. included 110 patients receiving dabigatran 110 mg twice daily and 101 patients receiving warfarin [11]. While warfarin was continued throughout the procedure, dabigatran was stopped 12 h before the procedure and resumed 12–15 h after the ablation. Total bleeding events were less frequent in patients receiving dabigatran than in those on warfarin (4.5 vs 12.9%; p < 0.05). However, there were no significant between-group differences in the rates of major or minor bleeding events. Hematoma at the puncture site was noted in 4.5 and 10.9% of patients receiving dabigatran or warfarin, respectively (p = 0.12). Lakkireddy et al. analyzed complications during the first 30 days after the ablation procedure in patients treated with dabigatran 150 mg twice daily (n = 145) or uninterrupted warfarin (n = 145) [12]. No thromboembolic complications were observed in patients on warfarin, compared with an incidence of 2.1% in patients on dabigatran (p = 0.25). The rate of total bleeding complications was higher in 14% of patients on dabigatran compared with those on warfarin (14 vs 6%; p = 0.031), and major bleeding complications were noted in 6 and 1% of patients in the dabigatran and VKA groups, respectively (p = 0.019). In this study, treatment with dabigatran was a predictive factor for bleeding events (odds ratio: 2.34; 95% CI: 1.02–5.39; p = 0.046) and thromboembolic complications (odds ratio: 2.76; 95% CI: 1.22–6.25; p < 0.01).

A small randomized controlled study published by Nin et al. included 90 patients (45 patients on dabigatran and 45 patients on warfarin) [14]. Treatment was stopped the day before the ablation. Bleeding events at the puncture site were less frequent in patients receiving dabigatran (20 vs 44%; p = 0.013). Recently, Bassiouny et al. published a case–control study with propensity score matching in which patients received dabigatran 150 mg twice daily (n = 344) or warfarin (n = 344) [13]. One or two doses of dabigatran were not taken by the patient before the procedure. Rates of total hemorrhagic and thromboembolic complications were similar in the two groups (3.2 vs 4.1%; p = 0.53). Total hemorrhagic complications were observed in 1.2 and 1.5% of patients, respectively (p = 0.74). A single thromboembolic complication was observed in each group.

With regards to the use of rivaroxaban, a substudy of the ROCKET AF study has been published recently, reporting outcomes for patients who were undergoing pharmacological or electrical cardioversion or an AF ablation [19]. Seventy-nine patients underwent AF ablation. Treatment was withdrawn (stopped) in 49% of patients. The rates of stroke or systemic embolism were not different between the rivaroxaban and warfarin treatment groups (1.88 vs 1.86%). Major or non-major but clinically relevant bleeding rates were also similar in the two groups (18.75 vs 13.04%).

The current study has some limitations, including the fact that it was a small observational/naturalistic pilot study with no matched control group treated with VKAs; however, unlike studies published previously in patients undergoing AF ablation, this is the first analysis of the ‘real-world’ use of NOACs in patients with a specific indication for AFL RFA anticoagulation. Hence, this cohort is a heterogeneous group from different centers (some with limited experience with NOACs in this indication) with various methods of ablation (different numbers of punctures and heterogeneous durations of procedures; e.g., NOAC dosage and time of NOAC arrest). It must be acknowledged that only a minority of patients (26.7%) received rivaroxaban and further clinical experience with rivaroxaban and other NOACs in the setting of AFL ablation is warranted. Only a minority of patients (15%) had CrCl ≥30 and <50 ml/min; therefore, data from the current study do not allow an evaluation of the use of dabigatran in patients with moderate renal failure undergoing AFL ablation. In addition, the current study only included patients with a sole AFL ablation, rather than patients also undergoing AF ablation in the same procedure. It is also important to acknowledge that, although the majority of patients were discharged within 24 h of undergoing AFL ablation and there is a possibility that complications may have been missed, all patients were subsequently followed-up at 3 months postprocedure; no complications were observed. Furthermore, given that NOACs are now used widely, it is important that specific prospective data (including registries) are obtained in order to assess how these treatments are managed in the case of ablations and, specifically, in the case of AFL ablation. On this basis, we are currently planning a prospective trial.

Conclusion & future perspective

Current Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society (HRS/EHRA/ECAS) guidelines recognize that the predictable pharmacological profile of NOACs allows for their use without the requirement for routine coagulation monitoring (as is the case with VKAs) [5]. However, the guidelines also acknowledge that there is limited clinical experience with NOACs for AF ablation, with no clear management protocol for anticoagulation in AF ablation [5]. Nevertheless, with the continually growing body of evidence, recently published systematic reviews and meta-analyses conclude that, for periprocedural anticoagulation during AF ablation, interrupted dabigatran has similar efficacy and safety compared with warfarin, with no significant differences in bleeding and thromboembolism [20,21]. While this is the current situation with regards to NOACs in AF ablation, what will the future hold for the potential use of NOACs in patients undergoing AFL ablation? It is important to acknowledge that trials that have validated NOACs in AF (e.g., RE-LY, ROCKET AF, ARISTOTLE and, more recently, ENGAGE AF) did not include patients with AFL. To the best of our knowledge, our current study presents the first observations assessing the use and safety of NOACs for periprocedural anticoagulation specifically in patients undergoing AFL RFA. As anticipated, no major hemorrhagic events were observed in this study. However, due to the small sample size, the observed postprocedural ischemic event and the few minor hemorrhagic events after AFL ablation under NOACs, further investigation in terms of a larger well-designed, prospective study with propensity score matching cohorts is warranted. Following on from our initial observations reported here, a prospective trial is planned in order to evaluate all patients undergoing AFL ablation and receiving NOACs, and future observations are awaited with interest.

Table 1. Baseline patient demographics.

Characteristic	Value
Patients (n)	60
Age (years)	69.2 ± 9.7
Male/female	46 (76.7%)/14 (23.3%)
Hypertension	27 (45.0%)
Diabetes	13 (21.7%)
Previous stroke or embolism	2 (3.3%)
Heart failure or EF <40%	18 (30.0%)
Vascular disease (coronary, peripheral or cerebrovascular)	11 (18.3%)
CHA2DS2-VASc score	2.44 ± 1.46
HAS-BLED score	1.14 ± 0.7
Creatinine clearance (ml/min)	81 ± 29

Data are presented as mean ± standard deviation or n (%), unless stated otherwise.

EF: Ejection fraction.

Table 2. Anticoagulation strategy.

Parameter	Dabigatran	Rivaroxaban
No. of patients (%)	44 (73.3)	16 (26.7)
No. of patients (%) receiving dabigatran 150 mg twice daily or rivaroxaban 20 mg once daily	23 (38.3)	11 (18.3)
No of patients (%) receiving dabigatran 110 mg twice daily or rivaroxaban 15 mg once daily	21 (35.0)	5 (8.3)
Time from last dose before ablation (h)	13.3 ± 16.6	20 ± 2
Time until next dose after ablation (h)	12	12
Duration of treatment before ablation (days)	34 ± 18	24 ± 12
Administration of heparin/LMWH, n (%)	23 (52.8)	13 (81.3)
TEE, n (%)	8 (18.2)	4 (25.0)

LMWH: Low-molecular-weight heparin; TEE: Transesophageal echocardiography.

Table 3. Atrial flutter ablation characteristics.

Parameter	Dabigatran	Rivaroxaban
Flutter before ablation, n (%)	35 (79.5)	12 (75.0)
Ablation in sinus rhythm, n (%)	9 (20.5)	4 (25.0)
Sinus rhythm at the end of the procedure, n (%)	44 (100)	16 (100)
Procedures with double venous access, n (%)	14 (31.8)	10 (62.5)
Procedures with triple venous access, n (%)	30 (68.2)	6 (37.5)

Table 4. Bleeding and ischemic complications after atrial flutter ablation.

Complication	Dabigatran		Rivaroxaban
	110 mg b.i.d. (n = 21)	150 mg b.i.d. (n = 23)	15 mg o.d. (n = 5)	20 mg o.d. (n = 11)
Major bleeding complications	0	0	0	0
Minor bleeding complications	0	3 (13.0%)	0	1 (9.1%)
Hemorrhagic stroke	0	0	0	0
Ischemic stroke	1 (4.8%)	0	0	0
Death	0	0	0	0

b.i.d.: Twice daily; o.d.: Once daily.

EXECUTIVE SUMMARY

• Atrial flutter (AFL) ablation requires optimal periprocedural anticoagulation in order to minimize thromboembolic events and bleeding risk.

• Although the use of new oral anticoagulants has been evaluated in patients undergoing atrial fibrillation radiofrequency catheter ablation, information regarding their use in AFL ablation is scarce.

• This multicenter, retrospective, observational study describes the characteristics of 60 patients receiving new oral anticoagulants prior to AFL ablation and assesses ischemic and hemorrhagic predischarge, postprocedural complications.

• No major bleeding episodes were observed. Four cases of postprocedural minor bleeding (bleeding at the puncture site without hematoma) were reported (dabigatran 150 mg [three patients] and rivaroxaban 20 mg [one patient]). One patient (dabigatran 110 mg) experienced an ischemic stroke 27 h after ablation and conversion in sinus rhythm; preprocedural transesophageal echocardiography ruled out a left atrial thrombus.

Ethical conduct of research

The authors state that they have obtained appropriate insti­tutional review board approval or have followed the princi­ples outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investi­gations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

The authors would like to thank A Elhraiech for providing assistance with the statistical analysis.

Financial & competing interests disclosure

W Amara has received speaker honoraria from Boehringer Ingelheim, Bayer and Bristol-Myers Squibb. J Taieb has acted as an expert consultant for Bayer and Bristol-Myers Squibb. N Saoudi declares being a shareholder and scientific advisory board member of Endosense and has received honoraria from Stereotaxis and lecture fees from Sanofi, Bayer and Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors would like to thank DP Figgitt (Content Ed Net) for providing editorial assistance in the preparation of this manuscript; funding for this editorial assistance was provided by Boehringer Ingelheim SAS, France.