Introduction

Catheter ablation (CA) of atrial fibrillation (AF) is an effective therapeutic option in symptomatic, drug-refractory AF.¹ CA is a technically difficult procedure with potentially serious complications, such as stroke, transient ischemic attack, and systemic embolism, with reported incidence of adverse events as high as 4.6%.² The COMPARE study (Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation [AF] Patients Undergoing Catheter Ablation) established uninterrupted warfarin as the standard of care of patients undergoing CA of AF.³ This randomized controlled trial (RCT) demonstrated that performing this procedure without interrupting oral anticoagulation with warfarin was associated with a decreased risk of stroke and minor bleeding complications.

Clinical Trials

After the introduction of direct oral anticoagulants (DOACs), several studies have tried to establish their non-inferiority to vitamin K antagonists (VKA) in CA of AF, including some RCTs. VENTURE-AF (A Study Exploring Two Treatment Strategies in Patients With Atrial Fibrillation Who Undergo Catheter Ablation Therapy) was the first RCT comparing uninterrupted DOAC (rivaroxaban) with uninterrupted VKA.⁴ After this study, several others came out comparing outcomes between dabigatran versus VKA and rivaroxaban versus VKA during CA of AF.

Guideline Recommendations

Based on these studies, the Heart Rhythm Society and European Heart Rhythm Association published their updated expert consensus statement regarding catheter and surgical ablation of AF in 2017.¹ The current standard of care incorporates the use of uninterrupted VKAs (international normalized ratio goal 2.0-3.0), uninterrupted dabigatran (Evidence Class IA), or uninterrupted rivaroxaban (Class I-BR).

Despite these studies providing evidence for individual DOACs, analyses of the benefits of DOACs (as a class) over VKA during CA of AF are scant. We thus decided to conduct a rigorous meta-analysis⁵ with the data obtained by the ASCERTAIN trial (Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation: Comparing Uninterrupted Rivaroxaban and Warfarin) and the recently published ELIMINATE-AF (A Prospective, Randomized, Open-Label, Blinded Endpoint Evaluation Parallel Group Study Comparing Edoxaban vs. VKA in Subjects Undergoing Catheter Ablation of Non-valvular Atrial Fibrillation).^6,7 Our goal was to determine the existence of any statistically significant benefit of uninterrupted DOACs over uninterrupted VKA for CA of AF.

Primary and Secondary Outcomes

The primary outcomes of this study were 1) major bleeding events, 2) minor bleeding events, and 3) thromboembolic events. The secondary outcome was silent cerebral infarction as detected by post-procedural diffusion-weighted imaging brain magnetic resonance imaging (MRI). Major bleeding events were defined by using the Bleeding Academic Research Consortium (BARC) criteria, with a BARC scale ≥2 being considered major bleeding. Minor bleeding events were all reported bleeding events not fulfilling this criterion. Thromboembolic events were defined as stroke, transient ischemic attack, other systemic embolism, or development of an intracardiac thrombus post-procedure. Finally, silent cerebral infarction was defined as clinically silent new brain lesions detected by diffusion-weighted imaging brain MRI post-procedurally.

Pertinent Findings

The benefit of uninterrupted DOACs over VKA was analyzed from 6 RCTs that enrolled a total of 2,256 patients (male: 72.7%; average age 61.3 ± 2.6 years) with non-valvular AF, with significant benefit in major bleeding events (relative risk [RR] 0.45; 95% confidence interval [CI], 0.20-0.99; p = 0.05). Uninterrupted dabigatran was used in 317 patients (14.1%),⁸ rivaroxaban in 187 (8.3%),^4,7 apixaban in 418 (18.5%),^9,10 and edoxaban in 316 (14.0%).⁶ The rest (1,018 participants, 45.1%) were on uninterrupted VKA. No significant differences were found in minor bleeding events (RR 1.12; 95% CI, 0.87-1.43; p = 0.39), thromboembolic events (RR 0.75; 95% CI, 0.26-2.14; p = 0.59), or post-procedural silent cerebral infarction (RR 1.09; 95% CI, 0.80-1.49; p = 0.58) (Figure 1).

Figure 1: Summary of Study Outcomes

Discussion

The use of uninterrupted DOACs during CA of AF has been steadily increasing, mainly due to the published literature showing that DOACs have a favorable safety and efficacy profile.^11,12 The concern of not having readily available reversal agents in case a life-threatening bleeding (such as a pericardial tamponade) may be allayed by the US Food and Drug Administration approval of andexanet alfa as a reversal agent for rivaroxaban and apixaban, as well as idarucizumab for dabigatran.

Our meta-analysis incorporates all published RCT data that compare the outcomes of uninterrupted DOACs of all kinds to uninterrupted VKA on major bleeding events, minor bleeding events, thromboembolic events, and silent cerebral infarction. We included a total of 2,256 participants undergoing CA of AF. The pertinent findings of this study follow:

1. Uninterrupted DOACs provide a significant benefit toward fewer major bleeding events (relative risk reduction 45%; absolute risk reduction 2.9%; p = 0.05) compared with uninterrupted VKA.
2. There were no statistically significant differences between groups in the outcomes of minor bleeding events and thromboembolic events, nor in post-CA silent cerebral infarction. It is worth noting that our paper was not specifically powered to detect thromboembolic events, and the overall event rate was very low. This, in turn, increases the risk of a type II error.

Given our findings, we believe it is reasonable and beneficial to offer patients who need to undergo CA of AF uninterrupted anticoagulation with DOACs as first-line therapy. These conclusions fall in line with the recent consensus statement on the use of uninterrupted DOACs for CA of AF, which gave a Class I recommendation for the use of uninterrupted dabigatran or rivaroxaban.¹ DOACs are more convenient for both the patient and the physician, have fewer interactions with medications and food, and don't require frequent blood testing to monitor the international normalized ratio.

The results of our meta-analysis indicate that there is a significant decrease in the risk of major bleeding events between uninterrupted DOACs and uninterrupted VKA during CA of nonvalvular AF. A previous study by our research group failed to reach statistical significance likely as a result of a lack of statistical power due to its smaller sample size.¹³ This lack of power was solved with the inclusion of the data published by both the ASCERTAIN trial and ELIMINATE-AF.^6,7

Conclusions

An uninterrupted DOACs strategy for CA of nonvalvular AF carries a lower risk of major bleeding events compared with uninterrupted VKA. There were no significant differences among the other outcomes (minor bleeding events, thromboembolic events, and silent cerebral infarction) between groups. We thus believe that DOACs should be considered a first option to offer to patients undergoing CA of AF over traditional VKAs.

References

1. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Europace 2018;20:e1-e160.
2. Chen J, Dagres N, Hocini M, et al. Catheter ablation for atrial fibrillation: results from the first European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA) Part II. Europace 2015;17:1727-32.
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;121:2550-6.
4. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015;36:1805-11.
5. Romero J, Cerrud-Rodriguez RC1, Alviz I, et al. Significant Benefit of Uninterrupted DOACs Versus VKA During Catheter Ablation of Atrial Fibrillation. JACC Clin Electrophysiol 2019;5:1396-1405.
6. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019;40:3013-21.
7. Kimura T, Kashimura S, Nishiyama T, et al. Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation: Comparing Uninterrupted Rivaroxaban and Warfarin (ASCERTAIN). JACC Clin Electrophysiol 2018;4:1598-609.
8. Calkins H, Nordaby M. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017;377:495-6.
9. Kuwahara T, Abe M, Yamaki M, et al. Apixaban versus Warfarin for the Prevention of Periprocedural Cerebral Thromboembolism in Atrial Fibrillation Ablation: Multicenter Prospective Randomized Study. J Cardiovasc Electrophysiol 2016;27:549-54.
10. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J 2018;39:2942-55.
11. Haines DE, Mead-Salley M, Salazar M, et al. Dabigatran versus warfarin anticoagulation before and after catheter ablation for the treatment of atrial fibrillation. J Interv Card Electrophysiol 2013;37:233-9.
12. Kaiser DW, Streur MM, Nagarakanti R, Whalen SP, Ellis CR. Continuous warfarin versus periprocedural dabigatran to reduce stroke and systemic embolism in patients undergoing catheter ablation for atrial fibrillation or left atrial flutter. J Interv Card Electrophysiol 2013;37:241-7.
13. Romero J, Cerrud-Rodriguez RC, Diaz JC, et al. Uninterrupted direct oral anticoagulants vs. uninterrupted vitamin K antagonists during catheter ablation of non-valvular atrial fibrillation: a systematic review and meta-analysis of randomized controlled trials. Europace 2018;20:1612-20.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Noninvasive Imaging, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Magnetic Resonance Imaging

Keywords: Arrhythmias, Cardiac, Warfarin, Ischemic Attack, Transient, Atrial Fibrillation, International Normalized Ratio, Risk, Confidence Intervals, Prospective Studies, Standard of Care, Pyridones, Pyrazoles, Pyridines, Thiazoles, Thromboembolism, Anticoagulants, Stroke, Catheter Ablation, Embolism, Cerebral Infarction, Vitamin K, Magnetic Resonance Imaging, Thrombosis

< Back to Listings