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Comparison of Outcomes After Cardioversion or Atrial Fibrillation Ablation in Patients With Differing Periprocedural Anticoagulation Regimens
Canadian Journal of Cardiology 30 (2014) 1541e1546
Clinical Research
Comparison of Outcomes After Cardioversion or Atrial Fibrillation Ablation in Patients With Differing Periprocedural Anticoagulation Regimens Simon Kochhäuser, MD, Yaariv Khaykin, MD, Jessica Beardsall, BSc, Rasna Juta, BSc, Philip Hache, BSc, Kathleen Trought, BSc, Talia Lenton-Brym, BComm, Bernice Tsang, MD, Alfredo Pantano, MD, Marianne Beardsall, ACNP, Zaev Wulffhart, MD, and Atul Verma, MD, FHRS Southlake Regional Health Centre, Newmarket, Ontario, Canada
ABSTRACT
RESUM E
Background: There is a paucity of data that compare traditional vitamin K antagonist (VKA) with novel oral anticoagulant regimens in periprocedural management of cardioversion or ablation of atrial fibrillation (AF). We sought to compare outcomes of use of VKA, dabigatran (DABI), and rivaroxaban (RIVA) anticoagulation around the time of intervention. Methods: We studied consecutive patients undergoing cardioversion or ablation of AF at our centre from October 2010 to October 2013. There were 3 different anticoagulation groups: warfarin (VKA), DABI, and RIVA. Safety was assessed according to number of strokes, transient ischemic attacks (TIAs), and clinically important and not important bleeding events. Results: Baseline characteristics were well balanced between the groups. Average follow-up was 6 months ( 4 months). A total of 901
es qui permettent de comparer Introduction : Il existe peu de donne l’administration d’antagoniste traditionnel de la vitamine K (VKA) avec celle de nouveaux anticoagulants oraux pour la prise en charge riope ratoire d’une cardioversion ou d’une ablation de la fibrillation pe à comparer les re sultats de auriculaire (FA). Nous avons cherche l’utilisation de VKA, du dabigatran (DABI), et du rivaroxaban (RIVA) au moment de l’intervention. thodes : Nous avons e tudie les patients successifs ayant subi une Me cardioversion ou une ablation de la FA dans notre centre d’octobre finissent trois groupes 2010 à octobre 2013. Les anticoagulants de rents : la warfarine (VKA), le DABI, et le RIVA. L’innocuite ae te diffe value e en fonction du nombre d’accidents vasculaires ce re braux e mies ce re brales transitoires (ICT), et des e pisodes (AVC), d’ische morragiques majeurs ou mineurs. he
Atrial fibrillation (AF) is a type of arrhythmia associated with advancing age and underlying heart disease, such as hypertension, heart failure, left ventricular systolic dysfunction, and valvular heart disease.1 For patients who are symptomatic despite antiarrhythmic drugs, or who cannot tolerate antiarrhythmic drugs, cardioversion or catheter AF ablation can improve quality of life by reduction of symptoms.2-4 Although initial success in restoring sinus rhythm is high, long-term success strongly dependents on the previous duration of AF.3,4 Oral anticoagulation with warfarin or
dabigatran (DABI) is recommenced to reduce the risk of thromboembolism for 3 weeks before cardioversion and at least 4 weeks after cardioversion.3,4 The cornerstone of AF ablation is pulmonary vein isolation. In most cases of AF, the pulmonary veins are responsible for triggering the arrhythmia. AF ablation is very effective in treating AF, particularly in paroxysmal AF. The Canadian guidelines for the ablation of AF recommend anticoagulation with warfarin to reduce the risk of thromboembolism for 1-2 months before ablation and at least 3-6 months after ablation.2,4 For mitigating the increased risk of thromboembolic complications associated with the restoration of sinus rhythm,5,6 warfarin is the traditional approach to anticoagulation before and after the procedure, although the novel oral anticoagulants (NOACs) are becoming the more recommended treatment for anticoagulation.2-4,7,8 Compared with warfarin, there are relatively few data on the efficacy of
Received for publication August 4, 2014. Accepted September 21, 2014. Corresponding author: Dr Atul Verma, Southlake Regional Health Centre, 602-581 Davis Dr, Newmarket, Ontario L3Y 2P6, Canada. Tel.: þ1905-953-7917; fax: þ1-905-953-0046. E-mail: [email protected] See page 1546 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.09.018 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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Canadian Journal of Cardiology Volume 30 2014
patients who underwent cardioversion were studied (VKA [n ¼ 471], DABI [n ¼ 288] and RIVA [n ¼ 141]). In these patients there were no strokes seen during follow-up and 2 TIAs in the DABI group. Bleeding rates were low, with no significant difference between the 3 groups. A total of 680 patients who underwent ablation were studied (VKA [n ¼ 319], DABI [n ¼ 220] and RIVA [n ¼ 171]). There were no strokes reported during follow-up and 3 TIAs: 2 in the VKA group and 1 in the DABI group not resulting in a significant difference between the groups. Bleeding rates were low, with no significant difference between the groups. Conclusions: Overall, there was a low incidence of adverse events for all anticoagulation regimens. Warfarin, DABI, and RIVA use around the time of the procedure are safe and reasonable options for patients who undergo cardioversion or AF ablation.
sultats : Les caracte ristiques initiales e taient bien e quilibre es entre Re tait de 6 mois ( 4 mois). Un total de 901 les groupes. Le suivi moyen e te e tudie s (VKA [n ¼ 471], patients ayant subi une cardioversion ont e DABI [n ¼ 288] et RIVA [n ¼ 141]). Chez ces patients, aucun AVC n’a te re pertorie au cours du suivi tandis que 2 ICT l’ont e te dans le e taient faibles, sans diffe rence groupe DABI. Les taux de saignements e significative entre les 3 groupes. Un total de 680 patients qui ont subi te e tudie s (VKA [n ¼ 319], DABI [n ¼ 220] et RIVA une ablation ont e te rapporte au cours du suivi alors que 3 [n ¼ 171]). Aucun AVC n’a e te : 2 dans le groupe VKA et 1 dans le groupe DABI, insufICT l’ont e tablir une diffe rence significative entre les groupes. Les fisant pour e taient faibles, sans diffe rence significative entre taux de saignements e les groupes. Conclusions : Dans l’ensemble, il y avait une faible incidence des sirables pour tous les re gimes d’anticoagulation. L’usage de effets inde dure sont des options warfarine, DABI, et RIVA au cours de la proce sûres et raisonnables pour les patients qui subissent une cardioversion ou une ablation de la FA.
the NOACs for periprocedural anticoagulation. There are also very few studies that compared the 3 main NOACs with each another. There is a high heterogeneity concerning the anticoagulation regimes especially around the time of ablation,9 showing the need for reliable data about the safety and efficiency of different approaches. The goal of this retrospective study was to compare the safety of periprocedural warfarin, DABI, and rivaroxaban (RIVA) around the time of elective cardioversion or pulmonary vein isolation procedure (PVI) in a large number of patients.
Ablation protocol
Methods Study design and participants Patients who underwent electrical cardioversion or PVI from October 2010 to October 2013 at our institution were retrospectively analyzed. Patients were divided into 3 groups: vitamin K antagonist (VKA), DABI, or RIVA according to the used anticoagulant. Anticoagulation with VKA before the procedure was confirmed according to weekly international normalized ratios (INRs) between 2.0 and 3.0. Compliance with NOACs (DABI or RIVA) was assessed according patient self-report. Cardioversion protocol For all 3 anticoagulation groups, it was recommended that they have a minimum of 3 weeks of therapeutic anticoagulation before cardioversion and a minimum of 4 weeks after cardioversion. Anticoagulation was continued uninterrupted. Anticoagulation was maintained > 4 weeks in patients with thromboembolic risk according to their Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) score. For patients with < 3 weeks anticoagulation before cardioversion, a transesophageal echocardiogram (TEE) was performed to rule out left atrial thrombus. In the absence of a thrombus, cardioversion was performed.
For all 3 anticoagulation groups, patients needed a minimum of 4 weeks therapeutic anticoagulation before ablation and a minimum of 3 months after ablation. All patients underwent preprocedural TEE to rule out left atrial thrombus. In absence of a thrombus ablation was performed. For the VKA group, warfarin was stopped 4 days in advance of ablation. Before ablation, 2 days of full-dose low molecular weight heparin (LMWH) bridging was given, with the last dose the night before the procedure. Starting at 8 hours after sheath removal, patients were bridged for 2 days with half-dose LMWH. Warfarin was restarted the same day of ablation at double- dose for 2 days, returning to full-dose on the third day, and continued for a minimum of 3 months. For the NOAC groups (DABI and RIVA), NOACs were stopped 24 hours before the procedure with the last dose in the morning of the day before the procedure. Anticoagulation was resumed 8 hours after sheath removal, and continued for a minimum of 3 months. For the procedure, two 8-French (F) right femoral sheaths were used for transseptals, one 11-F left femoral sheath was used for intracardiac echocardiogram, and one 5-F internal jugular sheath was used for the coronary sinus catheter. During the procedure, patients were given intravenous heparin to maintain activated clotting time (ACT) > 350 seconds. After the procedure, a maximum of 30 mg protamine sulfate was given if the last ACT was > 350 seconds (typically none if ACT was < 300 seconds, 20 mg if ACT was 300-400 seconds, 30 mg if ACT was > 400 seconds). Sheaths were pulled when ACT decreased to < 250 seconds. Outcomes Safety outcomes were stroke, transient ischemic attack (TIA), and “clinically important” and “clinically not important” bleeding events. Bleeding was considered “clinically important” if it required: hospitalization, transfusion, or cessation of anticoagulation for > 7 days. All other bleeding was considered minor. Stroke was defined as a sudden, focal neurologic deficit lasting > 24 hours, and presumed to be
Kochhäuser et al. Outcomes According to Periprocedural Anticoagulation Regimens
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Table 1. Participant characteristics
A. Cardioversion group Age, mean SD Male sex, % CHADS2 score, mean SD CHA2DS2-VASc score, mean SD HAS-BLED score, mean SD Persistent AF, % LA diameter (mm), mean SD Percentage with TEE Thrombus on TEE, n B. Patients undergoing AF ablation Age, mean SD Male sex, % CHADS2 score, mean SD CHA2DS2-VASc score, mean SD HAS-BLED score, mean SD Persistent AF, % LA diameter (mm), mean SD Percentage with TEE, % Thrombus on TEE, n Intraprocedural ACT (sec), mean SD Protamine given after procedure (mg), mean SD Average time without therapy before ablation (hours), mean SD Average time until therapy restarted (hours), mean SD Low molecular weight heparin bridging before ablation, % Low molecular weight heparin after ablation, %
VKA (n ¼ 471)
DABI (n ¼ 288)
RIVA (n ¼ 141)
P
68 10 64 1.9 1.2 2.7 1.5 1.6 1.0 60 46 5 23 0
65 10 63 1.7 1.1 2.4 1.4 1.4 1.0 66 45 5 21 0
62 10 63 1.6 1.1 2.3 1.4 1.3 1.0 67 44 6 20 0
0.06 0.41 0.07 0.09 0.10 0.09 0.19 0.56 0.99
VKA (n ¼ 319)
DABI (n ¼ 220)
RIVA (n ¼ 141)
62 11 73 0.9 0.6 1.5 0.8 0.7 0.3 31 42 6 100 1 347 32 21 5
60 10 76 0.8 0.5 1.4 0.8 0.6 0.4 27 41 5 100 1 352 38 22 6
60 10 75 0.8 0.6 1.4 0.8 0.6 0.4 25 41 4 100 0 351 40 20 5
97 26
27 10
28 11
8 0.4
8 0.5
8 0.4
0.52 0.22 0.45 0.34 0.69 0.07 0.26 0.99 0.18 0.25 0.30 < 0.001 0.48
100
0
0
-
100
0
0
-
ACT, activated clotting time; AF, atrial fibrillation; CHADS2, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female); DABI, dabigatran; HAS-BLED, Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 Years), Drugs/Alcohol Concomitantly; INR, international normalized ratio; LA, left atrial; RIVA, rivaroxaban; TEE, transesophageal echo; VKA, vitamin K antagonist.
cerebrovascular in origin.10 If such a deficit lasted < 24 hours it was considered a TIA. All patients were seen routinely for follow-up at our institution because we are the regional centre for our catchment area. Cardioversion patients were followed for a median time of 6 months (ranging from 4 to 8 months). Ablation patients were followed for a median time of 12 months (ranging from 11 to 18 months). Statistical analysis Groups were compared using analysis of variance or c2 with a threshold of P < 0.05 for significance. Results Participant characteristics Participant characteristics are summarized in Table 1. Patient characteristics were well balanced for patients who underwent cardioversion and for patients who underwent PVI (Table 1). There were no significant differences between the VKA, DABI, and RIVA groups for age, male sex, CHADS2 score, Congestive Heart Failure, Hypertension, Age ( 75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA2DS2-VASc)
score, Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) score, persistent AF, left atrial diameter, percentage with TEE, and percentage with thrombus on TEE. With regard to the ablation procedure, there were no significant differences in intraprocedural ACT, protamine given after the procedure, average time until therapy restarted, and LMWH bridging before and after ablation. There was a significant difference between the groups in average time without therapy before ablation because of the ablation protocol (treatment stopped 4 days before the procedure for VKA and 24 hours for NOACs; P < 0.001). Outcomes: Cardioversion There were no significant differences between the VKA, DABI, and RIVA groups for any of the thromboembolic or bleeding outcomes for the patients undergoing cardioversion (Table 2, A). On the day of the procedure or the day after there were no thromboembolic or bleeding events. There were also no strokes within 30 days of the procedure but one TIA in the DABI group (P ¼ 0.70). There were no clinically important bleeding events within 30 days after cardioversion. Unrelated to the procedure, 2 patients experienced clinically not
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Canadian Journal of Cardiology Volume 30 2014
Table 2. Stroke and bleeding outcomes
A. Cardioversion group Stroke < 30 days, n TIA < 30 days, n Clinically important bleeding < 30 days, n Clinically not important bleeding < 30 days, n Stroke > 30 days, n TIA > 30 days, n Clinically important bleeding > 30 days, n Clinically not important bleeding > 30 days, n B. AF ablation group Stroke < 30 days, n TIA < 30 days, n Clinically important bleeding < 30 days, n Clinically not important bleeding < 30 days, n Tamponade, n Stroke > 30 days, n TIA > 30 days, n Clinically important bleeding > 30 days, n Clinical not important bleeding > 30 days, n
VKA (n ¼ 471)
DABI (n ¼ 288)
RIVA (n ¼ 141)
P
0 0 0 1 0 0 3 8
0 1 0 1 0 1 1 3
0 0 0 0 0 0 1 1
0.99 0.70 0.99 0.81 0.99 0.37 0.24 0.67
VKA (n ¼ 319)
DABI (n ¼ 220)
RIVA (n ¼ 141)
0 1 4 6 3 0 1 0 2
0 1 2 5 2 0 0 0 1
0 0 1 1 1 0 0 0 0
0.99 0.11 0.23 0.06 0.40 0.99 0.10 0.99 0.09
AF, atrial fibrillation; DABI, dabigatran; RIVA, rivaroxaban; TIA, transient ischemic attack; VKA, vitamin K antagonist.
important bleeding within 30 days, 1 in the VKA group and 1 in the DABI group (P ¼ 0.81). There were no strokes from 30 days after cardioversion until the end of follow-up and 1 TIA in the DABI group (P ¼ 0.37). There were 5 clinically important bleeding events from 30 days after cardioversion until the end of follow-up: 3 in the VKA group (2 gastrointestinal bleeds and 1 severe epistaxis), 1 in the DABI group (gastrointestinal bleed) and 1 in the RIVA group (P ¼ 0.24). There were also 12 clinically not important bleeding events during this period: 8 in the VKA group (4 gastrointestinal bleeds, 3 epistaxis, and 1 hemoptysis), 1 in the DABI group (gastrointestinal bleed) and 1 in the RIVA group (epistaxis; P ¼ 0.67). Outcomes: Ablation There were no significant differences between the VKA, DABI, and RIVA groups for any of the thromboembolic or bleeding outcomes for the patients undergoing AF ablation (Table 2, B). There were 2 TIAs, 12 clinically not important bleeds, and 7 clinically important bleeds on the day of or the day after ablation. There were no strokes within 30 days after ablation. The 2 acute TIAs were within 30 days after ablation (1 in the VKA group and 1 in the DABI group; P ¼ 0.11). Similarly, the 12 acute clinically not important bleeding events were the only to occur within 30 days of the procedure. All of the clinically not important bleeds were puncture site hematomas, 6 in the VKA group, 5 in the DABI group, and 1 in the RIVA group (P ¼ 0.06). The 7 acute clinically important bleeds were also only in the 30-day time period: 4 in the VKA group (3 tamponade and 1 retroperitoneal), 2 in the DABI group (both tamponades) and 1 in the RIVA group (tamponade; P ¼ 0.23). From 30 days after ablation until the end of follow-up, there were no strokes but 1 TIA in the VKA group (P ¼ 0.10). There were no clinically important bleeding events during this period and 3 clinically not important
bleeds: 2 in the VKA group (1 gastrointestinal bleed and 1 epistaxis) and 1 in the DABI group (gastrointestinal bleed; P ¼ 0.09). Discussion Main findings There were no major differences in safety outcomes between anticoagulation regimens for patients who underwent cardioversion or PVI. Overall, there were no strokes observed during the study period and low rates of TIA and bleeding in all arms. Although anticoagulation was uninterrupted in the cardioversion group, warfarin and NOACs were not continuous in the ablation group (stopped 4 days before ablation for warfarin and 24 hours before ablation for DABI and RIVA). Despite stopping anticoagulation for patients who underwent ablation, the rates of thromboembolic or bleeding events were still very low. Comparison with other cardioversion studies The Canadian Cardiovascular Society guidelines recommend that oral anticoagulation with warfarin (INR, 2-3) or DABI be started 3 weeks before cardioversion and continued at least 4 weeks after cardioversion in hemodynamically stable patients with AF for 48 hours or longer.3,4 The 2012 European Society of Cardiology guidelines offer the same recommendation.7 These 2012 guidelines noted that there were no published data on cardioversion with RIVA or apixaban. The safety and efficiency of warfarin around the time of cardioversion is well established.3,7 DABI was the first NOAC to be evaluated against warfarin around the time of cardioversion in a large clinical trial.11 The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial evaluated 110 mg and 150 mg DABI vs warfarin in 18,113 patients with AF, 1270 of whom underwent cardioversion during the study (7%). The frequency of stroke or major bleeding within
Kochhäuser et al. Outcomes According to Periprocedural Anticoagulation Regimens
30 days of cardioversion was low and in the 2 DABI groups similar to the warfarin group. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, fewer patients received cardioversion (321 [2.3%]).11,12 There were no differences in long-term stroke or survival rates in these patients for RIVA vs warfarin. Our study, like the ROCKET AF and RE-LY post hoc analyses, demonstrated that the NOACs DABI and RIVA are safe alternatives to warfarin around the time of cardioversion.11,12 A small, retrospective cohort study from 2012 to 2013 at Northwestern Memorial Hospital also found no difference in outcome with DABI or RIVA.13 Our study provides one of the largest head-to-head comparisons of DABI vs RIVA vs warfarin around the time of cardioversion in a large number of patients, and demonstrated that there is no difference in safety outcomes between these agents.
Comparison with other ablation studies The 2010 Canadian Cardiovascular Society guidelines for catheter ablation for AF/atrial flutter recommend either maintaining warfarin treatment before the procedure (with INR in the lower end of the therapeutic range) or bridging with LMWH.2 The more recent 2012 update to the European Society of Cardiology AF guidelines recommends that warfarin should be continued throughout ablation at an INR of 2.0-2.5.7 This recommendation is based on several studies that suggested that continuous warfarin is superior to interrupted warfarin for catheter ablation in terms of reducing complications.14-17 As with cardioversion, warfarin is the traditional approach to anticoagulation for PVI.2,7 In our study we used a bridging approach with half-dose LMWH. Nevertheless, rates of stroke, TIA, and bleeding were all low. The Role of COuMadin in Preventing Thromboembolism in Atrial Fibrillation PAtients UndeRgoing CathEter Ablation (COMPARE) trial was the first randomized study to investigate continuous vs interrupted warfarin in preventing thromboembolic and hemorrhagic events around the time of ablation.18 In COMPARE, interrupted warfarin was associated with an increase in thromboembolic events around the time of the procedure. The number of events were highest in the subgroup with long-standing persistent AF. In our study, only approximately a third of patients had persistent AF, which might explain the low rates of thromboembolic events despite interrupted warfarin. Lakkireddy and colleagues published data from 290 consecutive patients undergoing PVI in 8 centres in the United States in 2012.19 They found a significantly increased risk of bleeding and thromboembolic complications for DABI compared with uninterrupted warfarin around the time of the procedure. Subsequent studies and meta-analyses have not supported this finding.20,21 The initial finding of an increased risk might be attributable to late stopping and early restarting of DABI. DABI was held the morning of the procedure and restarted 3 hours afterward.19 Our study had a longer stop and restart time (held 24 hours before the procedure and restarted 8 hours afterward), which likely decreased bleeding risk. Similar to the results of the meta-analyses, we saw no
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difference in thromboembolic or bleeding risk between warfarin and DABI use around the time of ablation.20,21 Lakkireddy and colleagues conducted a similar analysis of patients who underwent ablation who were treated with RIVA or warfarin and found RIVA to be safe despite a short stop and restart time similar to the DABI cohort.22 Post hoc analysis of the large phase III ROCKET AF trial also found no difference in stroke rates or survival for use of RIVA around the time of ablation compared with warfarin. In line with these results, results of our study did not show a significant difference in safety outcomes between all groups, although there was a nonsignificant trend toward a reduced risk of clinically not important bleeding in the RIVA group. This was one of the largest head-to-head comparisons of RIVA, DABI, and warfarin use around the time of ablation in a large number of patients. Our results are consistent with previous head-to-head studies that compared outcomes with RIVA, DABI, or warfarin use around the time of ablation, and demonstrated no difference in safety.23,24 Clinical implications We demonstrated that any of the approaches described herein are reasonable for use around the time of cardioversion and ablation. All 3 agents should continue to be used in clinical practice. Study limitations Our study was limited in that it was experience from a single centre. Although this is one of the largest studies to address this topic, considering the overall low rate of adverse events the study might still be underpowered to detect subtle differences between the 3 groups. Recent research suggests that continuous warfarin has safety superior to interrupted warfarin for ablation.14-17 Our study did not have a continuous warfarin arm, thus we cannot comment on its safety in comparison with interrupted warfarin or NOACs. We cannot comment on the safety of continuous NOAC therapy for ablation. Studies are under way to assess the safety and efficacy of this approach. Conclusion Overall, we found a low incidence of thromboembolic or bleeding events around the time of the procedure for patients with AF who underwent cardioversion or ablation. Rates of stroke, TIA, and bleeding complications were not significantly different in the 3 investigated groups. Warfarin, DABI, and RIVA are safe anticoagulation options around the time of the procedure for patients undergoing cardioversion or ablation for AF. Acknowledgements The authors thank Cristi Orth from Meducom Health for her writing assistance. Funding Sources Simon Kochhäuser is supported by a research grant of the German Cardiac Society. Funding for some of the research students was provided by an unrestricted grant from Bayer Inc.
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Disclosures Dr Verma discloses research funding and advisory board activity from Boehringer Ingelheim and Bayer. Dr Wulffhart discloses speaking fees from Boehringer Ingelheim and Bayer. The remaining authors have no conflicts of interest to disclose. References 1. Healey JS, Parkash R, Pollak T, Tsang T, Dorian P. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: etiology and initial investigations. Can J Cardiol 2011;27:31-7. 2. Verma A, Macle L, Cox J, Skanes AC. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: catheter ablation for atrial fibrillation/ atrial flutter. Can J Cardiol 2011;27:60-6. 3. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011;27:74-90. 4. Verma A, Mitchell LB, Macle L, et al. 2014 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. 2014;30:1114-30. 5. Naccarelli GV, Johnston SS, Lin J, Patel PP, Schulman KL. Cost burden of cardiovascular hospitalization and mortality in ATHENA-like patients with atrial fibrillation/atrial flutter in the United States. Clin Cardiol 2010;33:270-9. 6. Santangeli P, Di Biase L, Sanchez JE, Horton R, Natale A. Atrial fibrillation ablation without interruption of anticoagulation. Cardiol Res Pract 2011;2011:837841. 7. Camm AJ, Lip GY, De Caterina R, et al. 2012 Focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47. 8. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36.
Canadian Journal of Cardiology Volume 30 2014 12. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013;61: 1998-2006. 13. Yadlapati A, Groh C, Passman R. Safety of short-term use of dabigatran or rivaroxaban for direct-current cardioversion in patients with atrial fibrillation and atrial flutter. Am J Cardiol 2014;113:1362-3. 14. Page SP, Siddiqui MS, Finlay M, et al. Catheter ablation for atrial fibrillation on uninterrupted warfarin: can it be done without echo guidance? J Cardiovasc Electrophysiol 2011;22:265-70. 15. Gautam S, John RM, Stevenson WG, et al. Effect of therapeutic INR on activated clotting times, heparin dosage, and bleeding risk during ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:248-54. 16. Gopinath D, Lewis WR, Di Biase L, Natale A. Pulmonary vein antrum isolation for atrial fibrillation on therapeutic coumadin: special considerations. J Cardiovasc Electrophysiol 2011;22:236-9. 17. Hakalahti A, Uusimaa P, Ylitalo K, Raatikainen MJ. Catheter ablation of atrial fibrillation in patients with therapeutic oral anticoagulation treatment. Europace 2011;13:640-5. 18. Di Biase L, Burkhardt D, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the “COMPARE” randomized trial. Circulation 2014;129:2638-44. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012;59:1168-74. 20. Shurrab M, Morillo CA, Schulman S, et al. Safety and efficacy of dabigatran compared with warfarin for patients undergoing radiofrequency catheter ablation of atrial fibrillation: a meta-analysis. Can J Cardiol 2013;29:1203-10. 21. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013;15:1412-20.
9. Mardigyan V, Verma A, Birnie D, et al. Anticoagulation management pre- and post atrial fibrillation ablation: a survey of Canadian centres. Can J Cardiol 2013;29:219-23.
22. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014;63:982-8.
10. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J 2010;159:340-347.e1.
23. Stepanyan G, Badhwar N, Lee RJ, et al. Safety of new oral anticoagulants for patients undergoing atrial fibrillation ablation. J Interv Card Electrophysiol 2014;40:33-8.
11. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011;123:131-6.
24. Providencia R, Marijon E, Albenque JP, et al. Rivaroxaban and dabigatran in patients undergoing catheter ablation of atrial fibrillation. Europace 2014;16:1137-44.
Clinical Research
Comparison of Outcomes After Cardioversion or Atrial Fibrillation Ablation in Patients With Differing Periprocedural Anticoagulation Regimens Simon Kochhäuser, MD, Yaariv Khaykin, MD, Jessica Beardsall, BSc, Rasna Juta, BSc, Philip Hache, BSc, Kathleen Trought, BSc, Talia Lenton-Brym, BComm, Bernice Tsang, MD, Alfredo Pantano, MD, Marianne Beardsall, ACNP, Zaev Wulffhart, MD, and Atul Verma, MD, FHRS Southlake Regional Health Centre, Newmarket, Ontario, Canada
ABSTRACT
RESUM E
Background: There is a paucity of data that compare traditional vitamin K antagonist (VKA) with novel oral anticoagulant regimens in periprocedural management of cardioversion or ablation of atrial fibrillation (AF). We sought to compare outcomes of use of VKA, dabigatran (DABI), and rivaroxaban (RIVA) anticoagulation around the time of intervention. Methods: We studied consecutive patients undergoing cardioversion or ablation of AF at our centre from October 2010 to October 2013. There were 3 different anticoagulation groups: warfarin (VKA), DABI, and RIVA. Safety was assessed according to number of strokes, transient ischemic attacks (TIAs), and clinically important and not important bleeding events. Results: Baseline characteristics were well balanced between the groups. Average follow-up was 6 months ( 4 months). A total of 901
es qui permettent de comparer Introduction : Il existe peu de donne l’administration d’antagoniste traditionnel de la vitamine K (VKA) avec celle de nouveaux anticoagulants oraux pour la prise en charge riope ratoire d’une cardioversion ou d’une ablation de la fibrillation pe à comparer les re sultats de auriculaire (FA). Nous avons cherche l’utilisation de VKA, du dabigatran (DABI), et du rivaroxaban (RIVA) au moment de l’intervention. thodes : Nous avons e tudie les patients successifs ayant subi une Me cardioversion ou une ablation de la FA dans notre centre d’octobre finissent trois groupes 2010 à octobre 2013. Les anticoagulants de rents : la warfarine (VKA), le DABI, et le RIVA. L’innocuite ae te diffe value e en fonction du nombre d’accidents vasculaires ce re braux e mies ce re brales transitoires (ICT), et des e pisodes (AVC), d’ische morragiques majeurs ou mineurs. he
Atrial fibrillation (AF) is a type of arrhythmia associated with advancing age and underlying heart disease, such as hypertension, heart failure, left ventricular systolic dysfunction, and valvular heart disease.1 For patients who are symptomatic despite antiarrhythmic drugs, or who cannot tolerate antiarrhythmic drugs, cardioversion or catheter AF ablation can improve quality of life by reduction of symptoms.2-4 Although initial success in restoring sinus rhythm is high, long-term success strongly dependents on the previous duration of AF.3,4 Oral anticoagulation with warfarin or
dabigatran (DABI) is recommenced to reduce the risk of thromboembolism for 3 weeks before cardioversion and at least 4 weeks after cardioversion.3,4 The cornerstone of AF ablation is pulmonary vein isolation. In most cases of AF, the pulmonary veins are responsible for triggering the arrhythmia. AF ablation is very effective in treating AF, particularly in paroxysmal AF. The Canadian guidelines for the ablation of AF recommend anticoagulation with warfarin to reduce the risk of thromboembolism for 1-2 months before ablation and at least 3-6 months after ablation.2,4 For mitigating the increased risk of thromboembolic complications associated with the restoration of sinus rhythm,5,6 warfarin is the traditional approach to anticoagulation before and after the procedure, although the novel oral anticoagulants (NOACs) are becoming the more recommended treatment for anticoagulation.2-4,7,8 Compared with warfarin, there are relatively few data on the efficacy of
Received for publication August 4, 2014. Accepted September 21, 2014. Corresponding author: Dr Atul Verma, Southlake Regional Health Centre, 602-581 Davis Dr, Newmarket, Ontario L3Y 2P6, Canada. Tel.: þ1905-953-7917; fax: þ1-905-953-0046. E-mail: [email protected] See page 1546 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2014.09.018 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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patients who underwent cardioversion were studied (VKA [n ¼ 471], DABI [n ¼ 288] and RIVA [n ¼ 141]). In these patients there were no strokes seen during follow-up and 2 TIAs in the DABI group. Bleeding rates were low, with no significant difference between the 3 groups. A total of 680 patients who underwent ablation were studied (VKA [n ¼ 319], DABI [n ¼ 220] and RIVA [n ¼ 171]). There were no strokes reported during follow-up and 3 TIAs: 2 in the VKA group and 1 in the DABI group not resulting in a significant difference between the groups. Bleeding rates were low, with no significant difference between the groups. Conclusions: Overall, there was a low incidence of adverse events for all anticoagulation regimens. Warfarin, DABI, and RIVA use around the time of the procedure are safe and reasonable options for patients who undergo cardioversion or AF ablation.
sultats : Les caracte ristiques initiales e taient bien e quilibre es entre Re tait de 6 mois ( 4 mois). Un total de 901 les groupes. Le suivi moyen e te e tudie s (VKA [n ¼ 471], patients ayant subi une cardioversion ont e DABI [n ¼ 288] et RIVA [n ¼ 141]). Chez ces patients, aucun AVC n’a te re pertorie au cours du suivi tandis que 2 ICT l’ont e te dans le e taient faibles, sans diffe rence groupe DABI. Les taux de saignements e significative entre les 3 groupes. Un total de 680 patients qui ont subi te e tudie s (VKA [n ¼ 319], DABI [n ¼ 220] et RIVA une ablation ont e te rapporte au cours du suivi alors que 3 [n ¼ 171]). Aucun AVC n’a e te : 2 dans le groupe VKA et 1 dans le groupe DABI, insufICT l’ont e tablir une diffe rence significative entre les groupes. Les fisant pour e taient faibles, sans diffe rence significative entre taux de saignements e les groupes. Conclusions : Dans l’ensemble, il y avait une faible incidence des sirables pour tous les re gimes d’anticoagulation. L’usage de effets inde dure sont des options warfarine, DABI, et RIVA au cours de la proce sûres et raisonnables pour les patients qui subissent une cardioversion ou une ablation de la FA.
the NOACs for periprocedural anticoagulation. There are also very few studies that compared the 3 main NOACs with each another. There is a high heterogeneity concerning the anticoagulation regimes especially around the time of ablation,9 showing the need for reliable data about the safety and efficiency of different approaches. The goal of this retrospective study was to compare the safety of periprocedural warfarin, DABI, and rivaroxaban (RIVA) around the time of elective cardioversion or pulmonary vein isolation procedure (PVI) in a large number of patients.
Ablation protocol
Methods Study design and participants Patients who underwent electrical cardioversion or PVI from October 2010 to October 2013 at our institution were retrospectively analyzed. Patients were divided into 3 groups: vitamin K antagonist (VKA), DABI, or RIVA according to the used anticoagulant. Anticoagulation with VKA before the procedure was confirmed according to weekly international normalized ratios (INRs) between 2.0 and 3.0. Compliance with NOACs (DABI or RIVA) was assessed according patient self-report. Cardioversion protocol For all 3 anticoagulation groups, it was recommended that they have a minimum of 3 weeks of therapeutic anticoagulation before cardioversion and a minimum of 4 weeks after cardioversion. Anticoagulation was continued uninterrupted. Anticoagulation was maintained > 4 weeks in patients with thromboembolic risk according to their Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS2) score. For patients with < 3 weeks anticoagulation before cardioversion, a transesophageal echocardiogram (TEE) was performed to rule out left atrial thrombus. In the absence of a thrombus, cardioversion was performed.
For all 3 anticoagulation groups, patients needed a minimum of 4 weeks therapeutic anticoagulation before ablation and a minimum of 3 months after ablation. All patients underwent preprocedural TEE to rule out left atrial thrombus. In absence of a thrombus ablation was performed. For the VKA group, warfarin was stopped 4 days in advance of ablation. Before ablation, 2 days of full-dose low molecular weight heparin (LMWH) bridging was given, with the last dose the night before the procedure. Starting at 8 hours after sheath removal, patients were bridged for 2 days with half-dose LMWH. Warfarin was restarted the same day of ablation at double- dose for 2 days, returning to full-dose on the third day, and continued for a minimum of 3 months. For the NOAC groups (DABI and RIVA), NOACs were stopped 24 hours before the procedure with the last dose in the morning of the day before the procedure. Anticoagulation was resumed 8 hours after sheath removal, and continued for a minimum of 3 months. For the procedure, two 8-French (F) right femoral sheaths were used for transseptals, one 11-F left femoral sheath was used for intracardiac echocardiogram, and one 5-F internal jugular sheath was used for the coronary sinus catheter. During the procedure, patients were given intravenous heparin to maintain activated clotting time (ACT) > 350 seconds. After the procedure, a maximum of 30 mg protamine sulfate was given if the last ACT was > 350 seconds (typically none if ACT was < 300 seconds, 20 mg if ACT was 300-400 seconds, 30 mg if ACT was > 400 seconds). Sheaths were pulled when ACT decreased to < 250 seconds. Outcomes Safety outcomes were stroke, transient ischemic attack (TIA), and “clinically important” and “clinically not important” bleeding events. Bleeding was considered “clinically important” if it required: hospitalization, transfusion, or cessation of anticoagulation for > 7 days. All other bleeding was considered minor. Stroke was defined as a sudden, focal neurologic deficit lasting > 24 hours, and presumed to be
Kochhäuser et al. Outcomes According to Periprocedural Anticoagulation Regimens
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Table 1. Participant characteristics
A. Cardioversion group Age, mean SD Male sex, % CHADS2 score, mean SD CHA2DS2-VASc score, mean SD HAS-BLED score, mean SD Persistent AF, % LA diameter (mm), mean SD Percentage with TEE Thrombus on TEE, n B. Patients undergoing AF ablation Age, mean SD Male sex, % CHADS2 score, mean SD CHA2DS2-VASc score, mean SD HAS-BLED score, mean SD Persistent AF, % LA diameter (mm), mean SD Percentage with TEE, % Thrombus on TEE, n Intraprocedural ACT (sec), mean SD Protamine given after procedure (mg), mean SD Average time without therapy before ablation (hours), mean SD Average time until therapy restarted (hours), mean SD Low molecular weight heparin bridging before ablation, % Low molecular weight heparin after ablation, %
VKA (n ¼ 471)
DABI (n ¼ 288)
RIVA (n ¼ 141)
P
68 10 64 1.9 1.2 2.7 1.5 1.6 1.0 60 46 5 23 0
65 10 63 1.7 1.1 2.4 1.4 1.4 1.0 66 45 5 21 0
62 10 63 1.6 1.1 2.3 1.4 1.3 1.0 67 44 6 20 0
0.06 0.41 0.07 0.09 0.10 0.09 0.19 0.56 0.99
VKA (n ¼ 319)
DABI (n ¼ 220)
RIVA (n ¼ 141)
62 11 73 0.9 0.6 1.5 0.8 0.7 0.3 31 42 6 100 1 347 32 21 5
60 10 76 0.8 0.5 1.4 0.8 0.6 0.4 27 41 5 100 1 352 38 22 6
60 10 75 0.8 0.6 1.4 0.8 0.6 0.4 25 41 4 100 0 351 40 20 5
97 26
27 10
28 11
8 0.4
8 0.5
8 0.4
0.52 0.22 0.45 0.34 0.69 0.07 0.26 0.99 0.18 0.25 0.30 < 0.001 0.48
100
0
0
-
100
0
0
-
ACT, activated clotting time; AF, atrial fibrillation; CHADS2, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack; CHA2DS2-VASc, Congestive Heart Failure, Hypertension, Age ( 75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female); DABI, dabigatran; HAS-BLED, Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 Years), Drugs/Alcohol Concomitantly; INR, international normalized ratio; LA, left atrial; RIVA, rivaroxaban; TEE, transesophageal echo; VKA, vitamin K antagonist.
cerebrovascular in origin.10 If such a deficit lasted < 24 hours it was considered a TIA. All patients were seen routinely for follow-up at our institution because we are the regional centre for our catchment area. Cardioversion patients were followed for a median time of 6 months (ranging from 4 to 8 months). Ablation patients were followed for a median time of 12 months (ranging from 11 to 18 months). Statistical analysis Groups were compared using analysis of variance or c2 with a threshold of P < 0.05 for significance. Results Participant characteristics Participant characteristics are summarized in Table 1. Patient characteristics were well balanced for patients who underwent cardioversion and for patients who underwent PVI (Table 1). There were no significant differences between the VKA, DABI, and RIVA groups for age, male sex, CHADS2 score, Congestive Heart Failure, Hypertension, Age ( 75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA2DS2-VASc)
score, Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) score, persistent AF, left atrial diameter, percentage with TEE, and percentage with thrombus on TEE. With regard to the ablation procedure, there were no significant differences in intraprocedural ACT, protamine given after the procedure, average time until therapy restarted, and LMWH bridging before and after ablation. There was a significant difference between the groups in average time without therapy before ablation because of the ablation protocol (treatment stopped 4 days before the procedure for VKA and 24 hours for NOACs; P < 0.001). Outcomes: Cardioversion There were no significant differences between the VKA, DABI, and RIVA groups for any of the thromboembolic or bleeding outcomes for the patients undergoing cardioversion (Table 2, A). On the day of the procedure or the day after there were no thromboembolic or bleeding events. There were also no strokes within 30 days of the procedure but one TIA in the DABI group (P ¼ 0.70). There were no clinically important bleeding events within 30 days after cardioversion. Unrelated to the procedure, 2 patients experienced clinically not
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Table 2. Stroke and bleeding outcomes
A. Cardioversion group Stroke < 30 days, n TIA < 30 days, n Clinically important bleeding < 30 days, n Clinically not important bleeding < 30 days, n Stroke > 30 days, n TIA > 30 days, n Clinically important bleeding > 30 days, n Clinically not important bleeding > 30 days, n B. AF ablation group Stroke < 30 days, n TIA < 30 days, n Clinically important bleeding < 30 days, n Clinically not important bleeding < 30 days, n Tamponade, n Stroke > 30 days, n TIA > 30 days, n Clinically important bleeding > 30 days, n Clinical not important bleeding > 30 days, n
VKA (n ¼ 471)
DABI (n ¼ 288)
RIVA (n ¼ 141)
P
0 0 0 1 0 0 3 8
0 1 0 1 0 1 1 3
0 0 0 0 0 0 1 1
0.99 0.70 0.99 0.81 0.99 0.37 0.24 0.67
VKA (n ¼ 319)
DABI (n ¼ 220)
RIVA (n ¼ 141)
0 1 4 6 3 0 1 0 2
0 1 2 5 2 0 0 0 1
0 0 1 1 1 0 0 0 0
0.99 0.11 0.23 0.06 0.40 0.99 0.10 0.99 0.09
AF, atrial fibrillation; DABI, dabigatran; RIVA, rivaroxaban; TIA, transient ischemic attack; VKA, vitamin K antagonist.
important bleeding within 30 days, 1 in the VKA group and 1 in the DABI group (P ¼ 0.81). There were no strokes from 30 days after cardioversion until the end of follow-up and 1 TIA in the DABI group (P ¼ 0.37). There were 5 clinically important bleeding events from 30 days after cardioversion until the end of follow-up: 3 in the VKA group (2 gastrointestinal bleeds and 1 severe epistaxis), 1 in the DABI group (gastrointestinal bleed) and 1 in the RIVA group (P ¼ 0.24). There were also 12 clinically not important bleeding events during this period: 8 in the VKA group (4 gastrointestinal bleeds, 3 epistaxis, and 1 hemoptysis), 1 in the DABI group (gastrointestinal bleed) and 1 in the RIVA group (epistaxis; P ¼ 0.67). Outcomes: Ablation There were no significant differences between the VKA, DABI, and RIVA groups for any of the thromboembolic or bleeding outcomes for the patients undergoing AF ablation (Table 2, B). There were 2 TIAs, 12 clinically not important bleeds, and 7 clinically important bleeds on the day of or the day after ablation. There were no strokes within 30 days after ablation. The 2 acute TIAs were within 30 days after ablation (1 in the VKA group and 1 in the DABI group; P ¼ 0.11). Similarly, the 12 acute clinically not important bleeding events were the only to occur within 30 days of the procedure. All of the clinically not important bleeds were puncture site hematomas, 6 in the VKA group, 5 in the DABI group, and 1 in the RIVA group (P ¼ 0.06). The 7 acute clinically important bleeds were also only in the 30-day time period: 4 in the VKA group (3 tamponade and 1 retroperitoneal), 2 in the DABI group (both tamponades) and 1 in the RIVA group (tamponade; P ¼ 0.23). From 30 days after ablation until the end of follow-up, there were no strokes but 1 TIA in the VKA group (P ¼ 0.10). There were no clinically important bleeding events during this period and 3 clinically not important
bleeds: 2 in the VKA group (1 gastrointestinal bleed and 1 epistaxis) and 1 in the DABI group (gastrointestinal bleed; P ¼ 0.09). Discussion Main findings There were no major differences in safety outcomes between anticoagulation regimens for patients who underwent cardioversion or PVI. Overall, there were no strokes observed during the study period and low rates of TIA and bleeding in all arms. Although anticoagulation was uninterrupted in the cardioversion group, warfarin and NOACs were not continuous in the ablation group (stopped 4 days before ablation for warfarin and 24 hours before ablation for DABI and RIVA). Despite stopping anticoagulation for patients who underwent ablation, the rates of thromboembolic or bleeding events were still very low. Comparison with other cardioversion studies The Canadian Cardiovascular Society guidelines recommend that oral anticoagulation with warfarin (INR, 2-3) or DABI be started 3 weeks before cardioversion and continued at least 4 weeks after cardioversion in hemodynamically stable patients with AF for 48 hours or longer.3,4 The 2012 European Society of Cardiology guidelines offer the same recommendation.7 These 2012 guidelines noted that there were no published data on cardioversion with RIVA or apixaban. The safety and efficiency of warfarin around the time of cardioversion is well established.3,7 DABI was the first NOAC to be evaluated against warfarin around the time of cardioversion in a large clinical trial.11 The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial evaluated 110 mg and 150 mg DABI vs warfarin in 18,113 patients with AF, 1270 of whom underwent cardioversion during the study (7%). The frequency of stroke or major bleeding within
Kochhäuser et al. Outcomes According to Periprocedural Anticoagulation Regimens
30 days of cardioversion was low and in the 2 DABI groups similar to the warfarin group. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, fewer patients received cardioversion (321 [2.3%]).11,12 There were no differences in long-term stroke or survival rates in these patients for RIVA vs warfarin. Our study, like the ROCKET AF and RE-LY post hoc analyses, demonstrated that the NOACs DABI and RIVA are safe alternatives to warfarin around the time of cardioversion.11,12 A small, retrospective cohort study from 2012 to 2013 at Northwestern Memorial Hospital also found no difference in outcome with DABI or RIVA.13 Our study provides one of the largest head-to-head comparisons of DABI vs RIVA vs warfarin around the time of cardioversion in a large number of patients, and demonstrated that there is no difference in safety outcomes between these agents.
Comparison with other ablation studies The 2010 Canadian Cardiovascular Society guidelines for catheter ablation for AF/atrial flutter recommend either maintaining warfarin treatment before the procedure (with INR in the lower end of the therapeutic range) or bridging with LMWH.2 The more recent 2012 update to the European Society of Cardiology AF guidelines recommends that warfarin should be continued throughout ablation at an INR of 2.0-2.5.7 This recommendation is based on several studies that suggested that continuous warfarin is superior to interrupted warfarin for catheter ablation in terms of reducing complications.14-17 As with cardioversion, warfarin is the traditional approach to anticoagulation for PVI.2,7 In our study we used a bridging approach with half-dose LMWH. Nevertheless, rates of stroke, TIA, and bleeding were all low. The Role of COuMadin in Preventing Thromboembolism in Atrial Fibrillation PAtients UndeRgoing CathEter Ablation (COMPARE) trial was the first randomized study to investigate continuous vs interrupted warfarin in preventing thromboembolic and hemorrhagic events around the time of ablation.18 In COMPARE, interrupted warfarin was associated with an increase in thromboembolic events around the time of the procedure. The number of events were highest in the subgroup with long-standing persistent AF. In our study, only approximately a third of patients had persistent AF, which might explain the low rates of thromboembolic events despite interrupted warfarin. Lakkireddy and colleagues published data from 290 consecutive patients undergoing PVI in 8 centres in the United States in 2012.19 They found a significantly increased risk of bleeding and thromboembolic complications for DABI compared with uninterrupted warfarin around the time of the procedure. Subsequent studies and meta-analyses have not supported this finding.20,21 The initial finding of an increased risk might be attributable to late stopping and early restarting of DABI. DABI was held the morning of the procedure and restarted 3 hours afterward.19 Our study had a longer stop and restart time (held 24 hours before the procedure and restarted 8 hours afterward), which likely decreased bleeding risk. Similar to the results of the meta-analyses, we saw no
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difference in thromboembolic or bleeding risk between warfarin and DABI use around the time of ablation.20,21 Lakkireddy and colleagues conducted a similar analysis of patients who underwent ablation who were treated with RIVA or warfarin and found RIVA to be safe despite a short stop and restart time similar to the DABI cohort.22 Post hoc analysis of the large phase III ROCKET AF trial also found no difference in stroke rates or survival for use of RIVA around the time of ablation compared with warfarin. In line with these results, results of our study did not show a significant difference in safety outcomes between all groups, although there was a nonsignificant trend toward a reduced risk of clinically not important bleeding in the RIVA group. This was one of the largest head-to-head comparisons of RIVA, DABI, and warfarin use around the time of ablation in a large number of patients. Our results are consistent with previous head-to-head studies that compared outcomes with RIVA, DABI, or warfarin use around the time of ablation, and demonstrated no difference in safety.23,24 Clinical implications We demonstrated that any of the approaches described herein are reasonable for use around the time of cardioversion and ablation. All 3 agents should continue to be used in clinical practice. Study limitations Our study was limited in that it was experience from a single centre. Although this is one of the largest studies to address this topic, considering the overall low rate of adverse events the study might still be underpowered to detect subtle differences between the 3 groups. Recent research suggests that continuous warfarin has safety superior to interrupted warfarin for ablation.14-17 Our study did not have a continuous warfarin arm, thus we cannot comment on its safety in comparison with interrupted warfarin or NOACs. We cannot comment on the safety of continuous NOAC therapy for ablation. Studies are under way to assess the safety and efficacy of this approach. Conclusion Overall, we found a low incidence of thromboembolic or bleeding events around the time of the procedure for patients with AF who underwent cardioversion or ablation. Rates of stroke, TIA, and bleeding complications were not significantly different in the 3 investigated groups. Warfarin, DABI, and RIVA are safe anticoagulation options around the time of the procedure for patients undergoing cardioversion or ablation for AF. Acknowledgements The authors thank Cristi Orth from Meducom Health for her writing assistance. Funding Sources Simon Kochhäuser is supported by a research grant of the German Cardiac Society. Funding for some of the research students was provided by an unrestricted grant from Bayer Inc.
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Disclosures Dr Verma discloses research funding and advisory board activity from Boehringer Ingelheim and Bayer. Dr Wulffhart discloses speaking fees from Boehringer Ingelheim and Bayer. The remaining authors have no conflicts of interest to disclose. References 1. Healey JS, Parkash R, Pollak T, Tsang T, Dorian P. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: etiology and initial investigations. Can J Cardiol 2011;27:31-7. 2. Verma A, Macle L, Cox J, Skanes AC. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: catheter ablation for atrial fibrillation/ atrial flutter. Can J Cardiol 2011;27:60-6. 3. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol 2011;27:74-90. 4. Verma A, Mitchell LB, Macle L, et al. 2014 Focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. 2014;30:1114-30. 5. Naccarelli GV, Johnston SS, Lin J, Patel PP, Schulman KL. Cost burden of cardiovascular hospitalization and mortality in ATHENA-like patients with atrial fibrillation/atrial flutter in the United States. Clin Cardiol 2010;33:270-9. 6. Santangeli P, Di Biase L, Sanchez JE, Horton R, Natale A. Atrial fibrillation ablation without interruption of anticoagulation. Cardiol Res Pract 2011;2011:837841. 7. Camm AJ, Lip GY, De Caterina R, et al. 2012 Focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47. 8. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36.
Canadian Journal of Cardiology Volume 30 2014 12. Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013;61: 1998-2006. 13. Yadlapati A, Groh C, Passman R. Safety of short-term use of dabigatran or rivaroxaban for direct-current cardioversion in patients with atrial fibrillation and atrial flutter. Am J Cardiol 2014;113:1362-3. 14. Page SP, Siddiqui MS, Finlay M, et al. Catheter ablation for atrial fibrillation on uninterrupted warfarin: can it be done without echo guidance? J Cardiovasc Electrophysiol 2011;22:265-70. 15. Gautam S, John RM, Stevenson WG, et al. Effect of therapeutic INR on activated clotting times, heparin dosage, and bleeding risk during ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:248-54. 16. Gopinath D, Lewis WR, Di Biase L, Natale A. Pulmonary vein antrum isolation for atrial fibrillation on therapeutic coumadin: special considerations. J Cardiovasc Electrophysiol 2011;22:236-9. 17. Hakalahti A, Uusimaa P, Ylitalo K, Raatikainen MJ. Catheter ablation of atrial fibrillation in patients with therapeutic oral anticoagulation treatment. Europace 2011;13:640-5. 18. Di Biase L, Burkhardt D, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the “COMPARE” randomized trial. Circulation 2014;129:2638-44. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012;59:1168-74. 20. Shurrab M, Morillo CA, Schulman S, et al. Safety and efficacy of dabigatran compared with warfarin for patients undergoing radiofrequency catheter ablation of atrial fibrillation: a meta-analysis. Can J Cardiol 2013;29:1203-10. 21. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013;15:1412-20.
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