Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation

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1 Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation Jin-Seok Kim, MD, Fei She, MD, Krit Jongnarangsin, MD, Aman Chugh, MD, Rakesh Latchamsetty, MD, Hamid Ghanbari, MD, Thomas Crawford, MD, Arisara Suwanagool, MD, Mohammed Sinno, MD, Thomas Carrigan, MD, Robert Kennedy, MD, Wouter Saint-Phard, MD, Miki Yokokawa, MD, Eric Good, DO, Frank Bogun, MD, Frank Pelosi Jr, MD, Fred Morady, MD, Hakan Oral, MD From the Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan. BACKGROUND It is not clear whether dabigatran is as safe and effective as uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFA) of atrial fibrillation (AF). OBJECTIVE To compare the safety and efficacy of dabigatran by using a novel administration protocol and uninterrupted anticoagulation with warfarin for periprocedural anticoagulation in patients undergoing RFA of AF. METHODS In this case-control analysis, 763 consecutive patients (mean age years) underwent RFA of AF using dabigatran (N ¼ 191) or uninterrupted warfarin (N ¼ 572) for periprocedural anticoagulation. In all patients, anticoagulation was started Z4 weeks before RFA. Dabigatran was held after the morning dose on the day before the procedure and resumed 4 hours after vascular hemostasis was achieved. RESULTS A transesophageal echocardiogram performed in all patients receiving dabigatran did not demonstrate an intracardiac thrombus. There were no thromboembolic complications in either group. The prevalence of major (4 of 191, 2.1%)andminor(5of191, 2.6%) bleeding complications in the dabigatran group were similar to those in the warfarin group (12 of 572, 2.1%; P ¼ 1.0 and 19 of 572, 3.3%; P ¼.8, respectively). Pericardial tamponade occurred in 2 of 191 (1%) patients in the dabigatran group and in 7 of 572 (1.2%) patients in the warfarin group (P ¼ 1.0). All patients who had a pericardial tamponade, including 2 in the dabigatran group, had uneventful recovery after perdicardiocentesis. On multivariate analysis, international normalized ratio (odds ratio [OR] 4.0; 95% confidence interval [CI] ; P ¼.04), clopidogrel use (OR 4.2; 95% CI ; P ¼.01), and CHA 2 DS 2 -VASc score (OR 1.4; 95% CI ; P ¼.01) were the independent risk factors of bleeding complications only in the warfarin group. CONCLUSIONS When held for approximately 24 hours before the procedure and resumed 4 hours after vascular hemostasis, dabigatran appears to be as safe and effective as uninterrupted warfarin for periprocedural anticoagulation in patients undergoing RFA of AF. KEYWORDS Atrial fibrillation; Catheter ablation; Warfarin; Dabigatran; Bleeding ABBREVIATIONS ACT ¼ activated clotting time; AF ¼ atrial fibrillation; CI ¼ confidence interval; INR ¼ international normalized ratio; LMWH ¼ low molecular weight heparin; OR ¼ odds ratio; PV ¼ pulmonary vein; RFA ¼ radiofrequency catheter ablation; TEE ¼ transesophageal echocardiogram (Heart Rhythm 2013;10: ) I 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved. Introduction Uninterrupted anticoagulation with warfarin during the periprocedural phase of radiofrequency catheter ablation (RFA) of atrial fibrillation (AF) is associated with a lower risk of thromboembolic and bleeding complications without an increase in the outcomes of serious adverse events such as myocardial perforation. 1 4 However, international normalized ratio (INR) levels often fluctuate during warfarin use and may not be in the optimal therapeutic range in up to 450% of the patients. 5 Lower or higher INR levels on the Address reprint requests and correspondence: Dr Hakan Oral, Cardiovascular Medicine, University of Michigan, SPC 5853, 1500 E Medical Center Dr, Ann Arbor, MI address: oralh@umich.edu. day of RFA may increase the risk of complications. Subtherapeutic INR levels may require bridging with low molecular weight heparin (LMWH) after RFA, and supratherapeutic INR levels may lead to cancellation of the procedure or may increase the risk of vascular complications. As the newer anticoagulants become more widely used, an increasing number of patients presenting for RFA of AF are likely to be taking dabigatran. A prior study reported that periprocedural anticoagulation with dabigatran is associated with less favorable outcomes than uninterrupted warfarin during RFA of AF. 6 However, dabigatran was withheld for only approximately 12 hours before the procedure. The purpose of this study was to determine the safety and efficacy of anticoagulation with /$-see front matter B 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

2 484 dabigatran by using a novel protocol for periprocedural anticoagulation in patients undergoing RFA of AF. Outcomes were compared with those of a control group of patients who underwent ablation during uninterrupted anticoagulation with warfarin. Methods Study subjects The subjects of this study were 191 consecutive patients who underwent RFA of AF and received dabigatran etexilate for perioperative anticoagulation between January 2011 and August The mean age of the patients was years. There were 153 men and 38 women. AF was paroxysmal in 102 (53%), persistent in 84 (44%), and long-standing persistent in 5 (3%) patients. The mean left atrial diameter and left ventricular ejection fraction were 43 7 mm and , respectively. The estimated glomerular filtration rate was similar between the 2 groups (Table 1). The CHA 2 DS 2 -VASc and HAS-BLED 7 scores were determined for all patients. The control group consisted of 572 consecutive patients who were treated with uninterrupted warfarin for RFA of AF during the same period and who had an INR between 2.0 and 3.0 on the day of the procedure (Table 1). Study protocol The study protocol of this case-control analysis was approved by the Institutional Review Board. Patients were anticoagulated by using dabigatran or warfarin as follows (Figure 1): 1. Dabigatran group: Patients were administered dabigatran etexilate (150 mg po bid) Z4 weeks before RFA. Patients were instructed to take only the morning dose of dabigatran (150 mg) on the day before the procedure (24 30 hours preprocedure) and to skip the evening dose on the day before the procedure and the morning dose on the day of the procedure. Dabigatran was resumed 4 hours after vascular hemostasis was achieved following sheath removal. A transesophageal echocardiogram (TEE) was performed before the procedure in all patients who received dabigatran. 2. Warfarin group: Patients were administered warfarin Z4 weeks before the procedure, with a therapeutic INR goal of INR levels were measured on the same day of the procedure. A TEE was performed in all patients who had persistent AF or who had a history of a thromboembolic event or left atrial appendage thrombus. In all patients, unfractionated heparin was administered as both a bolus and a continuous infusion after the transeptal puncture to maintain an activated clotting time (ACT) of seconds. The sheaths were removed once the ACT returned to baseline after the procedure. Anticoagulation with warfarin or dabigatran was continued for Z3 months after RFA. Heart Rhythm, Vol 10, No 4, April 2013 Table 1 Clinical characteristics of study subjects Dabigatran (150 mg) Warfarin (INR 2 3) N ¼ 191 N ¼ 572 P Age (y) Sex: Female 38 (20) 146 (26).12 Race: Caucasian 184 (96) 553 (97).82 BMI (kg/m 2 ) Nonparoxysmal AF 89 (47) 296 (52).22 Previous RFA for AF 83 (44) 263 (46).7 Previous surgical maze 6 (3.1) 16 (2.8).81 Coronary artery disease 26 (14) 82 (14).88 Heart failure 17 (9) 30 (5).08 Hypertension 109 (57) 332 (58).81 Diabetes mellitus 22 (12) 82 (14).33 Previous TIA or stroke 5 (3) 48 (8).006 CHADS 2 score CHA 2 DS 2 -VASc score Mean (22) 115 (20) (27) 179 (31).23 Z2 97 (51) 278 (49).6 HAS-BLED score LA size (mm) LVEF (%) INR o.001 Serum creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Medications Aspirin 64 (34) 220 (39).3 Clopidogrel 4 (2) 27 (5).14 ACE inhibitor or ARB 73 (38) 232 (41).71 Beta-blocker 116 (61) 394 (69).08 Calcium-channel 54 (28) 182 (32).45 blocker Amiodarone 11 (6) 41 (7).55 Statins 68 (36) 305 (53) o.001 Antiacids or PPI 75 (39) 266 (47).13 Values are n (%) ormean SD. ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; ARB ¼ angiotensin-receptor blocker; BMI ¼ body mass index; egfr ¼ estimated glomerular filtration rate; INR ¼ international normalized ratio; LA ¼ left atrium; LVEF ¼ left ventricular ejection fraction; RFA ¼ radiofrequency catheter ablation; PPI ¼ proton-pump inhibitor; TIA ¼ transient ischemic attack. Periprocedural complications were compared as study end points. Complications were analyzed in 3 categories: (1) major bleeding complications, (2) minor bleeding complications, and (3) thromboembolic complications. Major bleeding complications were defined as (1) pericardial tamponade that required percutaneous or surgical drainage or repair and (2) vascular complications such as arteriovenous fistula, pseudoaneurysm, or hematoma that required percutaneous/ surgical intervention, rehospitalization and/or longer hospital stay, or blood transfusion. Minor bleeding complications were defined as a small groin hematoma, any bleeding that did not require an intervention, or pericardial effusion without tamponade. Groin hematoma was considered as any symptomatic swelling at the vascular access site with obvious collection of blood. Thromboembolic complications included ischemic stroke, transient ischemic events, and systemic thromboembolic events.

3 Kim et al Dabigatran and Ablation of Atrial Fibrillation 485 Postprocedural management and follow-up All patients were examined and had electrocardiographic monitoring during an overnight hospital stay after RFA. In patients who had a complication, further diagnostic and therapeutic interventions were performed as appropriate. All patients were seen in an outpatient clinic 3 months after the procedure or sooner as necessary. Patients were instructed to call a clinical coordinator whenever they experienced symptoms suggestive of a complication and were also monitored periodically. Figure 1 Anticoagulation protocol using dabigatran or warfarin in patients undergoing RFA of atrial fibrillation. ACT ¼ activated clotting time; RFA ¼ radiofrequency catheter ablation. Electrophysiologic study and radiofrequency catheter ablation Antiarrhythmic drugs except for amiodarone were discontinued 5 half-lives before the procedure. Amiodarone was discontinued 6 8 weeks before the procedure. Electrophysiologic study and RFA was performed in the fasting state under moderate or deep sedation by using propafol, fentanyl sodium, and midazolam at the direction of an anesthesiologist. Vascular access was obtained through a femoral vein. A steerable decapolar catheter (Biosense Webster, Diamond Bar, CA) was positioned in the coronary sinus for recording electrograms and atrial pacing. Bipolar electrograms were displayed and recorded at filter settings of Hz (EPMed Systems, West Berlin, NJ). After the transeptal puncture, antral pulmonary vein (PV) isolation was performed in all patients with the guidance of a 3-dimensional electroanatomical mapping system (Carto 3, Biosense Webster). All PVs were mapped with a circular deca- or duodecapolar catheter (Lasso, Biosense Webster). The ablation of complex fractionated atrial electrograms or linear ablation was performed at the discretion of the operator. A 3.5-mm, open-irrigation-tip catheter (Thermocool, Biosense Webster) was used for mapping and radiofrequency energy delivery at a maximum power of 35 W, a flow rate of 30 ml/ min, and a maximum temperature of 481C. The power was adjusted to W at a flow rate of 17 ml/min during applications of energy near the ostium of the PVs, at the posterior left atrium, and within the coronary sinus. The course of the esophagus along the posterior left atrial wall was monitored either by barium swallow or with a nasogastric probe. The same operators performed the ablation procedures in both groups, and techniques of vascular access and ablation strategy were similar between the 2 groups. Statistical analysis Continuous variables were expressed as mean SD and compared by using the Student t test or Wilcoxon sum rank whenever the distribution was not normal. Categorical variables were reported as counts and percentages and compared by using the w 2 test or Fisher exact test as appropriate. A multivariate logistic regression analysis was performed to determine predictors of complications. All univariate parameters suggestive of an association with complications (P o.15) were included in a stepwise regression analysis, and results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). All data were analyzed by using SPSS statistical software (SPSS, Chicago, IL). A P value of o.05 indicated statistical significance. Results CHA 2 DS 2 -VASc and HAS-BLED scores AF was paroxysmal in 102 of 191 (53%) and 276 of 572 (48%) patients in the dabigatran and warfarin groups, respectively (P ¼.2). The mean CHA 2 DS 2 -VASc score was (range 0 6) in the dabigatran group and (range 0 8) in the warfarin group (P ¼.8). The mean HAS-BLED score was in the dabigatran group and in the warfarin group (P ¼.11). A higher proportion of patients (48 of 572, 8%) in the warfarin group had a prior transient ischemic attack or a cerebrovascular accident than patients in the dabigatran group (5 of 191, 3%; P ¼.006). The use of antiplatelet agents, aspirin or clopidogrel, and other clinical characteristics were similar between the 2 groups (Table 1). TEE, RFA, and anticoagulation The mean INR on the day of the procedure in the dabigatran and warfarin groups was and , respectively (P o.001). There was no left atrial appendage thrombus detected on TEE in any of the patients in either group. The baseline ACT in the dabigatran group ( seconds) was significantly lower than that in the warfarin group ( seconds; P o.001). The mean ACT during the procedure in the dabigatran group ( seconds) was also lower than in the warfarin group ( seconds; P o.001). There was no difference in the mean of maximum ACT during the procedure between the dabigatran and warfarin groups ( seconds vs seconds; P ¼.09; Figure 2A).

4 486 Heart Rhythm, Vol 10, No 4, April 2013 Figure 2 Comparison of ACT levels (baseline, mean, and maximum ACT [seconds]) and heparin requirements during radiofrequency catheter ablation between dabigatran (A) and warfarin (B). ACT ¼ activated clotting time; UFH ¼ unfractionated heparin. The mean of total unfractionated heparin requirements to maintain a therapeutic ACT during RFA was significantly higher in the dabigatran group ( U/kg) than that in the warfarin group ( U/kg; P o.001; Figure 2B). Total procedure time ( minutes vs minutes; P ¼.74) and total duration of radiofrequency ablation (52 23 minutes vs minutes; P ¼.11) were similar between the dabigatran and warfarin groups. Antral pulmonary vein isolation was performed in all patients in both groups. Additional ablation including ablation of complex electrograms and linear ablation was performed in 35% and 38% of the patients in the dabigatran and warfarin groups, respectively (P ¼.49). Procedural complications There were no thromboembolic complications in either group. Periprocedural complications primarily consisted of bleeding complications in 40 of 763 (5%) patients in the overall study population (Table 2). Major bleeding complications occurred in 16 (2%), cardiac tamponade occurred in 9 (1.2%), and vascular complications occurred in 7 (0.9%) patients. Minor bleeding complications occurred in 24 (3%) patients. The prevalence of total bleeding complications was similar between the dabigatran (4.7%) and warfarin (5.4%) groups (P ¼.85; Table 2 and Figure 3). Major bleeding complications occurred in 4 of 191 (2.1%) patients in the dabigatran group and in 12 of 572 (2.1%) patients in the warfarin group (P ¼ 1.0). Minor bleeding complications also occurred in a similar proportion of patients in the dabigatran (5 of 191, 2.6%) and warfarin (19 of 572, 3.3%) groups, respectively (P ¼.81). Pericardial tamponade occurred in 2 of 191 (1%) patients in the dabigatran group and in 7 of 572 (1.2%) patients in the warfarin group (P ¼ 1.0). All patients with pericardial tamponade had an uneventful recovery after perdicardiocentesis. None of the patients who had pericardial tamponade in the dabigatran group received coagulation factor complexes or hemodialysis, but 1 patient received a transfusion of 1 pack of red blood cells. There were no other complications in either group. Predictors of bleeding complications On univariate analysis, there were no predictors of complications in the dabigatran group (Table 3). In the warfarin group, clopidogrel use (16% vs 4%; P ¼.002), a higher INR ( vs ; P ¼.03), a higher CHA 2 DS 2 -VASc score ( vs ; P ¼.01), and a higher HAS- BLED score ( vs ; P ¼.005) were associated with complications (Table 3). On multivariate analysis, INR (OR 4.0; 95% CI ; P ¼.04), clopidogrel use (OR 4.2; 95% CI ; P ¼.01), and CHA 2 DS 2 -VASc score (OR 1.4; 95% CI ; P ¼.01) were predictive of complications only in the warfarin group. Postoperative complications During a mean follow-up of months after RFA, none of the patients in either group had thromboembolic or bleeding complications. Among the 191 patients in the dabigatran group, 4 (2%) discontinued dabigatran, 2 switched to warfarin owing to anorexia and delayed hematuria, and 2 switched to rivaroxaban owing to headache and dyspepsia. Among the 572 patients in the warfarin group, Table 2 Complications. Complications Dabigatran (N ¼ 191) Warfarin (N ¼ 572) P Hemorrhagic complications 9 (4.7) 31 (5.4).85 Major bleeding 4 (2.1) 12 (2.1) 1 complications Cardiac tamponade 2 (1) 7 (1.2) 1 Vascular complications 2 (1) 5 (0.9) 1 Minor bleeding 5 (2.6) 19 (3.3).81 complications Groin hematoma 4 (2.1) 19 (3.3).47 Pericardial effusion 1 (0.5) 0.25 without tamponade Thromboembolic complications Stroke or TIA Values are n (%). TIA ¼ transient ischemic attack.

5 Kim et al Dabigatran and Ablation of Atrial Fibrillation 487 with a higher risk of periprocedural bleeding complications in patients receiving warfarin; and (4) a higher preprocedural INR is also an independent predictor of bleeding complications in patients receiving warfarin, even when the INR is within the therapeutic range of Figure 3 Complications in the dabigatran and warfarin groups. 9 (1.6%) switched to dabigatran or rivaroxaban after the ablation procedure. Discussion Main findings The main findings of this study are as follows: (1) dabigatran is as safe and effective as uninterrupted anticoagulation with warfarin for RFA of AF when held for hours preablation; (2) there seems to be no risk of left atrial appendage thrombus formation after holding dabigatran hours pre-rfa; (3) concomitant use of clopidogrel and higher CHA 2 DS 2 -VASc score are independently associated Dabigatran vs warfarin as periprocedural anticoagulants Warfarin has slow onset and offset of action and requires frequent monitoring owing to its narrow therapeutic window. Although prior studies suggested that periprocedural anticoagulation with uninterrupted warfarin is associated with a lower risk of bleeding and thromboembolic complications, patients were required to have an INR between 2.0 and 3.0 in those studies, and it has been long recognized that up to Z50% of the patients may not have an INR within the therapeutic window. 8 Furthermore, higher INR levels, even within the optimal therapeutic window, were predictive of bleeding complications in this study. INR levels may often vary before a scheduled procedure owing to changes in diet, medication, and NPO status. Peak plasma concentrations of dabigatran usually occur within 2 hours. Dabigatran is eliminated by renal excretion, with an estimated serum half-life of hours. 9 The shorter half-life of dabigatran enables discontinuation of the drug approximately 24 hours before an invasive procedure. 10 Table 3 Univariate predictors of bleeding complications. Dabigatran (N ¼ 191) Warfarin (N ¼ 572) All groups (N ¼ 763) Complications Complications Complications Yes No P Yes No P Yes No P No. of patients Age (y) Sex: Female 2 (22) 36 (20) (26) 138 (26) (25) 174 (24).89 BMI (kg/m 2 ) Nonparoxysmal AF 2 (22) 87 (49) (55) 279 (52) (48) 366 (51).70 Previous RFA 3 (33) 82 (45%) (48) 248 (46) (45) 328 (46).94 LVEF (%) CHADS 2 mean score CHA 2 DS 2 -VASc score Mean (22) 41 (22).98 3 (10) 112 (21).17 5 (12) 153 (21) (22) 49 (27).76 5 (16) 174 (32).07 7 (18) 223 (31).07 Z2 5 (56) 92 (51) (74) 255 (47) (70) 347 (48).01 HAS-BLED score Aspirin 3 (33) 62 (34%) (45) 206 (38) (43) 267 (37).50 Clopidogrel 0 4 (2.2) (16) 22 (4) (13) 26 (4).01 Dabigatran 9 (100) 182 (100) 0 (0) 0 (0) 9 (23) 182 (25).70 INR Baseline ACT (s) Mean ACT (s) Maximum ACT (s) UFH (U/kg) Values are n (%) or mean SD. ACT ¼ activated clotting time; AF ¼ atrial fibrillation; BMI ¼ body mass index; INR ¼ international normalized ratio; RFA ¼ radiofrequency catheter ablation; UFH ¼ unfractionated heparin; VEF ¼ left ventricular ejection fraction.

6 488 The cumulative anticoagulant effect of concomitant dabigatran and heparin use is unknown and is probably associated with an excessive risk of bleeding complications as was observed in a prior study. 6 Therefore, the rationale of this study was that the residual anticoagulant effect of dabigatran after being held hours pre-rfa would be sufficient to protect against intracardiac thrombus formation without exerting an excessive incremental anticoagulant effect during intraprocedural anticoagulation with heparin. A TEE performed in all patients who received dabigatran confirmed the absence of a left atrial appendage thrombus during this period in this study. The advantages of dabigatran over warfarin are as follows: (1) rapid onset of action with shorter time to therapeutic anticoagulation than warfarin so that dabigatran can be readministered shortly after vascular hemostasis is achieved without the need for bridging with heparin products; (2) no concern of a sub- or supratherapeutic INR on the day of procedure, which may lead to the cancellation of the procedure or prompt an unscheduled TEE; and (3) no need for postprocedural bridging in patients receiving warfarin who have a subtherapeutic INR on the day of RFA. The disadvantages of dabigatran over warfarin are as follows: (1) lack of a specific antidote compared to warfarin, the anticoagulant effects of which can be acutely and effectively reversed with F VII complex and a variety of blood products; (2) need for dose adjustments in patients with renal dysfunction; a dose of 75 mg twice daily is recommended in patients with creatinine clearance ml/min 11 and it is also recommended to discontinue dabigatran at least 48 hours earlier before an invasive procedure in patients with renal dysfunction; 12 (3) much higher cost; and (4) the absence of a routine clinical coagulation test to confirm patient compliance. Predictors of complications In the warfarin group, INR was identified as an independent risk factor for complications in this study. It is noteworthy that even in patients who presented with an INR of , higher INR levels were associated with a 4-fold increase in the risk of complications, suggesting that a safe INR window may have to be narrower than or lesser amounts of intraprocedural heparin with a lower ACT goal may need to be adopted. However, the utility of these approaches in minimizing both thromboembolic and bleeding complications will require validation in large-scale prospective studies. Consistent with the findings of prior studies, the CHA2DS2-VASc and HAS-BLED scores and clopidogrel use were also independent predictors of complications. 7,13,14 Although there were no independent predictors of complications in the dabigatran group in this study, the same variables as in the warfarin group are likely to be associated with complications in a larger study population. In a post hoc analysis of the RE-LY study, 13 the CHADS 2 score was associated with bleeding complications and stroke in both the warfarin and dabigatran groups. An association between Heart Rhythm, Vol 10, No 4, April 2013 clopidogrel use and risk of bleeding complications after RFA, independent of concomitant warfarin use, was also reported previously. 14 A concern with the use of dabigatran has been the lack of a specific antidote for reversal of anticoagulation. With the specific administration protocol, the outcomes of complications including pericardial tamponade were similar between the dabigatran and warfarin groups in this study. No reversal agents or dialysis was used in any of the patients. Although there were a few patients with pericardial tamponade, it is likely that holding dabigatran for hours before the procedure eliminates excessive bleeding risk without an increase in the risk of thromboembolic complications. Prior studies In a prior study, 15 dabigatran was discontinued hours before ablation in 34 of 123 patients who already were on dabigatran. Warfarin was discontinued in 56 patients 5 days before the procedure, and enoxaparin was used to bridge anticoagulation until the day before the procedure. All patients received 2 doses of enoxaparin, administered immediately at the end of procedure, and dabigatran was administered 22 hours after the procedure. There were no bleeding or thromboembolic complications in any patient during the 30-day follow-up. Bridging with LMWH was used in all patients, a practice that has been associated with a higher risk of bleeding and thromboembolic complications most likely owing to unpredictable anticoagulant effects of LMWH. 3,16 In a more recent nonrandomized study from a multicenter registry, 6 the perioperative use of dabigatran for RFA of AF was associated with a higher risk of bleeding or thromboembolic complications compared to uninterrupted warfarin therapy. However, dabigatran was just held on the morning of the procedure and readministered within 3 hours after hemostasis. Therefore, residual anticoagulant effects of dabigatran, which may have been potentially augmented by intraprocedural heparin, may have led to excessive anticoagulation, increasing the risk of bleeding complications. Study limitations This was a nonrandomized case-control study. However, the data were prospectively collected from a large number of patients. A second limitation is that given the low event rate for thromboembolic events, the study may have been underpowered for the assessment of efficacy in prevention of thromboembolic events and a multivariate model to identify predictors of bleeding complications could not be constructed in the dabigatran group. However, it should be noted that in large randomized studies, dabigatran was found to be as or more effective than warfarin for the prevention of stroke. 17 Furthermore, in all patients a TEE was performed and there was no evidence of an intracardiac thrombus. The optimal timing and dosing of dabigatran for periprocedural anticoagulation in patients with renal insufficiency was not assessed in this study.

7 Kim et al Dabigatran and Ablation of Atrial Fibrillation 489 Conclusions When held hours before the procedure and resumed 4 hours after vascular hemostasis, dabigatran appears to be as effective and safe as uninterrupted anticoagulation with warfarin for periprocedural anticoagulation in patients undergoing RFA of AF. Nearly half of the patients on warfarin may not present with an optimal INR of on the day of procedure and are at a higher risk for bleeding and thromboembolic complications, particularly at increasing INR levels, even within the optimal therapeutic INR range. In patients receiving dabigatran, it appears to be safe to proceed with RFA as long as dabigatran is administered with the specified protocol and patient compliance is confirmed. Although a specific antidote for dabigatran is not available, the outcomes of serious complications such as pericardial tamponade do not appear to be any different with dabigatran than with warfarin. Nevertheless, a large-scale prospective randomized study will be helpful to confirm the findings of this study. It remains to be determined whether the other newer anticoagulants can also be used for RFA of AF with protocols that incorporate the specific pharmacokinetics of each anticoagulant. References 1. Di Biase L, Burkhardt JD, Mohanty P, et al. Periprocedural stroke and management of major bleeding complications in patients undergoing catheter ablation of atrial fibrillation: the impact of periprocedural therapeutic international normalized ratio. Circulation 2010;121: Hussein AA, Martin DO, Saliba W, et al. Radiofrequency ablation of atrial fibrillation under therapeutic international normalized ratio: a safe and efficacious periprocedural anticoagulation strategy. Heart Rhythm 2009;6: Wazni OM, Beheiry S, Fahmy T, et al. 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