Editor's Note: This article is based on Verma A, Tsang B. The use of anticoagulation during the periprocedure period of atrial fibrillation ablation. Curr Opin Cardiol 2012;27:55-61.

Introduction

Radiofrequency ablation is becoming increasingly employed in patients with drug-refractory, symptomatic atrial fibrillation (AF). However, the potential benefit of ablation must be weighed against the risks. The two most common periprocedural risks are bleeding and thromboembolism.⁽¹⁾ Both of these are influenced by the choice and duration of anticoagulation before and after the ablation. To date, the two most commonly employed strategies for periprocedural anticoagulation have been the bridging strategy and the continuous warfarin strategy.⁽²⁾ In the bridging strategy, warfarin is discontinued for a 2-4 days prior to the ablation and the patient is covered with full dose low molecular weight heparin (LMWH). Post-ablation, warfarin is resumed the same day with a few days of post-ablation LMWH often given in half dose. In the continuous warfarin strategy, warfarin is continued right through the ablation while keeping the international normalized ratio (INR) ideally between 2.0-2.52. There are some data suggesting that the latter approach may reduce both the risk of stroke and bleeding compared to the bridging strategy.⁽³⁾

Recently, novel oral anticoagulants have become available for prevention of stroke in nonvalvular AF.⁽²⁾ Whether direct thrombin inhibitors (like dabigatran) or factor Xa inhibitors (rivaroxaban, apixaban) can replace warfarin and LMWH for AF ablation is not known. The obvious advantage to these agents is their short half-life which may allow cessation and resumption of therapy without the need for bridging. On the other hand, there is no antidote for these agents in case of a bleed. The study by Lakkireddy et al. represents a prospective registry evaluating the safety of using dabigatran for anticoagulation around the time of AF ablation compared to continuous warfarin.⁽⁴⁾

Methods

This study was a multicenter, prospective registry of patients undergoing AF ablation at 8 high-volume centers in the US. The dabigatran group consisted of patients receiving 150 mg of dabigatran etexilate (Pradaxa) twice daily for at least one month pre-ablation. Dabigatran was held the morning of the procedure and then restarted 3 hours after hemostasis. An equal number of patients matched for age, sex, and type of AF were also evaluated during the same period except these patients were prescribed warfarin for 30 days pre-ablation. These patients did not stop warfarin prior to the ablation and were excluded if the INR was not between 2.0 and 3.5 at the time of ablation. Routine pre-ablation transesophageal echocardiography was performed on the dabigatran group, but not on the warfarin group. Both groups were anticoagulated further with IV unfractionated heparin during the procedure to keep the ACT between 300 and 400 sec.

All ablation procedures consisted of pulmonary vein antrum isolation with a maximum of 40-45 W on the anterior segments and 30-35 W on the posterior segments. Additional ablation of complex fractionated electrograms as well as mapping and ablation of non-pulmonary vein triggers was performed in patients with persistent AF.

The primary safety endpoint was a composite of bleeding and thromboembolic events. A total of 290 patients were studied with 145 in each group.

Results

Comparison of the two groups showed that there was no significant difference in age, sex, CHADS2 score, CHA2DS2-VASc score, or HASBLED scores. The ejection fraction and LA size of both groups was also similar. About 60% of both groups were paroxysmal AF while 40% were persistent AF. There was also no significant difference in the procedural characteristics, radiofrequency ablation time, or acute procedural success between groups. In all, the characteristics were quite typical for a population of AF ablation patients.

In the dabigatran arm, 20 patients (14%) had a bleeding complication compared to only 9 (6%) in the warfarin arm (p=0.031). Six of the bleeds were major in the dabigatran arm, all of which were pericardial bleeds with tamponade which required drainage. In contrast, only one bleed was major in the warfarin arm and it too was a pericardial effusion (p=0.019 compared to dabigatran arm). No fatal or intracranial bleeds occurred. Three thromboembolic events occurred in the dabigatran arm versus none in the warfarin arm, but this number was too small to be statistically significant. All thromboembolic events resolved within 30 days all occurred in persistent AF patients. The only multivariable predictors of complications were use of dabigatran (OR 2.76, p=0.01) and age >75 (OR 3.82, p=0.04).

Conclusion

In patients undergoing AF ablation, continuation of dabigatran during the periprocedural period is associated with an increased risk of bleeding and composite of bleeding or embolic complications compared with uninterrupted warfarin.

Perspective

The RELY study demonstrated that dabigatran at a dose of 150 mg twice daily is superior to warfarin in prevention of stroke for nonvalvular AF.⁽⁵⁾ Furthermore, this superior reduction in stroke was associated with a reduced incidence of intracerebral and fatal bleeding. It is for this reason that the FDA overwhelmingly voted to approve this medication for the treatment of stroke prevention in AF. It is also why numerous guidelines have started to recommend dabigatran not only as an alternative to warfarin, but perhaps a preferred therapy.⁽⁶⁾

As more patients get initiated on dabigatran, more will present themselves on this treatment at the time of ablation. There is very little known about the optimal timing of cessation and reinitiation of this drug around the time of ablation. In the RELY study, the drug was stopped 3-4 doses prior to an elective procedure and often restarted after 24 hours. However, most of these procedures were not catheter ablations and the prolonged time off anticoagulation is not ideal for patients with AF. In the present study, however, it could be argued that dabigatran was used too aggressively. Although dabigatran has a rapid onset of action (within 30 to 120 min), the half life of the drug is 12-14 hours. By stopping the drug only on the morning of the procedure, there likely was still significant residual therapeutic effect of the drug. Furthermore, the drug was restarted post-ablation within only three hours of the procedure. It is perhaps not surprising, then, that dabigatran was associated with a significantly increased risk of bleeding compared to continuous warfarin. Little is known about the interaction of dabigatran and simultaneous unfractionated heparin, and this too may have increased the risk of bleed. Perhaps if dabigatran was stopped 24 hours prior to ablation, most of the drug would have been cleared by the start of the ablation and there would still be no need for bridging. Similarly, the post-ablation dose could have been delayed beyond 3 hours given the rapid onset of action of dabigatran. Such protocols are currently the subject of further study.

Despite the aggressive use of dabigatran, there was paradoxically a trend of increased risk of thromboembolism in that arm. All three thromboembolic events occurred in patients with persistent AF on dabigatran. The number was too small to be statistically different from the warfarin arm, but it does raise questions as to why this may have happened. The study unfortunately does not comment on timing of the embolic events. We know there was an increased risk of bleed with dabigatran and if the drug was being suspended to stop this bleeding, that may have increased the risk of stroke over the subsequent few days. We do know that all of the neurological deficits cleared within 30 days, but what was the severity of these deficits in the first place? The method of assessing and defining a thromboembolic complication was not clearly defined by the study. The use of dabigatran with cardiac instrumentation has not yet been studied (for example, there is no study on the use of dabigatran with artificial valves) and thus, we do not know if it has a similar safety profile to warfarin.

The authors should be applauded for undertaking this first important step in defining how to use the novel anticoagulants peri-catheter ablation for AF. However, many other aspects of how these agents are specifically used must be clarified before we will know the safety of using them for anticoagulation around the time of AF ablation. Further studies are underway and should offer clarity in the near future.

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References

1. Dagres N, Hindricks G, Kottkamp H, et al. Complications of atrial fibrillation ablation in a high-volume center in 1,000 procedures: Still cause for concern? J Cardiovasc Electrophysiol 2009; 20:1014-1019.
2. Verma A, Tsang B. The use of anticoagulation during the periprocedure period of atrial fibrillation ablation. Curr Opin Cardiol 2012; 27:55-61.
3. 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; 121:2550-2556.
4. 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; 59:1168-1174.
5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-1151.
6. 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; 28:125-136.

Keywords: Anticoagulants, Atrial Fibrillation, Catheter Ablation, Factor Xa, Hemostasis, Heparin, Low-Molecular-Weight, International Normalized Ratio, Pericardial Effusion, Stroke, Thromboembolism, Warfarin

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