Author + information
- Luigi Di Biase, MD, PhD∗ ( and )
- Jorge Romero, MD
- Division of Cardiology at Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
- ↵∗Address for correspondence:
Dr. Luigi Di Biase, Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, New York 10467.
Atrial fibrillation (AF) is the most common arrhythmia in the elderly population (age >65 years) (1). AF is a strong independent factor for stroke, with a 5-fold increased risk of thromboembolic events throughout all ages (1). The percentage of strokes attributable to AF increases steeply from 1.5% at 50 to 59 years of age to 23.5% at 80 to 89 years of age (1). Additionally, the prevalence of AF and the associated risk of ischemic stroke might be substantially underestimated given that AF is frequently asymptomatic and undiagnosed (2). This assumption has been validated by a study in which subclinical atrial tachyarrhythmias without clinical AF occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism (3).
It has been established that radiofrequency ablation, particularly pulmonary vein isolation, is the most effective treatment for AF. Although this procedure is considered to be relatively safe and is routinely performed worldwide, it does have rare but severe potential periprocedural complications. One of the most feared complications of this procedure is a cerebral thromboembolic event. Catheter ablation of AF in older patients (age >80 years) is associated with a higher total complication rate (9.37%) in comparison with younger patients (p < 0.001) in some series (4). From 2000 to 2014, the approximate risk of stroke during AF ablation was estimated at 1% (4). Periprocedural anticoagulation management could play an important role in mitigating the risk of stroke or transient ischemic events.
In 2014, COMPARE (Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation [AF] Patients Undergoing Catheter Ablation) was the first randomized controlled trial (RCT) assessing the role of continuous warfarin therapy in preventing periprocedural thromboembolic and hemorrhagic events after radiofrequency catheter ablation. In this study, patients were randomly assigned in a 1:1 ratio to be off- or on-warfarin. In the off-warfarin group, 5% of patients experienced thromboembolic events compared with 0.25% of patients in the uninterrupted warfarin group (p < 0.001). Warfarin discontinuation emerged as a strong predictor of periprocedural thromboembolism, with an odds ratio of 13.0 (95% confidence interval: 3.1 to 55.6; p < 0.001). This was the first RCT demonstrating that performing catheter ablation of AF without warfarin discontinuation reduces the occurrence of periprocedural stroke and minor bleeding complications compared with bridging with low-molecular-weight heparin. Importantly, this difference was mostly driven by patients with long standing persistent atrial fibrillation (LSPAF) (5).
Subsequently, the VENTURE-AF (ActiVe-controlled multi-cENTer stUdy with blind-adjudication designed to evaluate the safety of uninterrupted Rivaroxaban and uninterrupted vitamin K antagonists in subjects undergoing cathEter ablation for non-valvular Atrial Fibrillation) trial was the first RCT of uninterrupted rivaroxaban versus warfarin in patients with nonvalvular AF undergoing catheter ablation. The numbers of any adjudicated events, any bleeding events, and any other procedure-attributable events were similar between both groups (6). This trial demonstrated that in patients undergoing ablation of AF, the use of uninterrupted oral rivaroxaban was feasible and event rates were similar to those for uninterrupted warfarin therapy. Likewise, the RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy) RCT assigned patients scheduled for catheter ablation of AF to receive either dabigatran or warfarin. Uninterrupted dabigatran was associated with fewer bleeding and thromboembolic complications than uninterrupted warfarin (7). The efficacy and safety of periprocedural anticoagulation with apixaban was evaluated by the AXAFA-AFNET 5 (Anticoagulation using the direct factor Xa inhibitor apixaban during Atrial Fibrillation catheter Ablation: comparison to VKA therapy) RCT (8). The primary outcome was similar in patients randomized to apixaban when compared with patients randomized to warfarin (noninferiority p = 0.0002) (8).
In this issue of JACC: Clinical Electrophysiology, Yanagisawa et al. (9) evaluated the efficacy and safety of uninterrupted new oral anticoagulant (NOAC) and uninterrupted warfarin administration in elderly patients (age >75 years) undergoing catheter ablation of AF. In the elderly group, there were no significant statistical differences in major bleeding events (2.2% vs. 4.3%; p = 0.34) and minor bleeding events (9.7% vs. 8.6%; p = 0.748) in the NOAC and warfarin groups, respectively. No significant difference in major and minor bleeding events among the 4 different NOACs was found. After adjustment using propensity score-matching analyses for the NOAC and warfarin groups in the matched elderly and younger patients, no significant differences in the incidence of thromboembolic and bleeding events were observed between the 2 groups of both patients age ≥75 and <75 years, respectively (9).
These results are novel and answer an important question in clinical practice given the fact that the VENTURE, RE-CIRCUIT, and AXAFA-AFNET 5 trials enrolled a relatively young population of patients with AF (mean age 62 years) (6–8). There are currently no data regarding the safety and efficacy of uninterrupted NOAC use in elderly patients during catheter ablation for AF. In the study by Yanagisawa et al. (9), the mean age of the elderly group was 78 ± 3 years compared with 60 ± 10 years in the younger group. Although the patients in this study had a high mean CHA2DS2-VASc score of 3.7 ± 1.1, 70% of the patients had paroxysmal AF requiring only pulmonary vein isolation. As we mentioned previously, in the COMPARE trial it was clearly demonstrated that patients with LSPAF had the highest incidence of periprocedural thromboembolic events (5). This is probably due to the fact that patients with LSPAF often require a more extensive ablation (e.g., posterior wall and left atrial appendage isolation), which may increase the risk of char and coagulum formation. This was also an important criticism for the VENTURE, RE-CIRCUIT, and AXAFA–AFNET 5 trials, which enrolled only 26%, 33%, and 42% of patients with nonparoxysmal AF, respectively (6–8). Moreover, despite the large sample size (2,164 patients), the elderly group represented only 15% of the overall study population. The study may be underpowered to detect differences between anticoagulant types. Nevertheless, we consider that this is the largest series published to date, and it represents an important contribution in anticipation of larger studies.
In addition, in the patients who received rivaroxaban, the drug was administered in the morning of the procedure instead of at night. It has been shown that the absorption of this medication under fasting conditions is significantly decreased. High bioavailability (≥80%) of 15 and 20 mg rivaroxaban is achieved when rivaroxaban is taken with food (10). This is why, at our institution, we recommend patients taking rivaroxaban with breakfast or lunch to switch to a dinner dose at least 1 week before the procedure. This is very important, because patients are asked to fast the morning of the procedure. In this series, many patients took rivaroxaban the morning of the procedure while fasting, which could adversely affect anticoagulant efficacy. Furthermore, most procedures were performed with a 3.5-mm tip, open-irrigated ablation catheter. However, 13% of patients had cryoballoon or Toray balloon ablation, which might have a different risk of stroke compared with radiofrequency ablation.
Thromboembolic events were defined in the study by Yanagisawa et al. (9) as symptomatic cerebral infarction and transient ischemic attack. In case of suspected cerebrovascular events, magnetic resonance imaging was performed. No data on silent ischemia was reported in this study. Noticeably, in the AXAFA-AFNET 5 trial, several magnetic resonance imaging (MRI) sequences (T2-weighted imaging, diffusion-weighted imaging, apparent diffusion coefficient maps, and fluid-attenuated inversion recovery) were used to detect the prevalence and number of MRI-detected acute brain lesions and the association of MRI-detected acute brain lesions with cognitive function after ablation (8). Acute small brain lesions were found in a similar number of patients in each arm (apixaban 27%; warfarin 24.8%; p = 0.64) (8).
Finally, in the current study by Yanagisawa et al. (9), the elderly group (age >75 years) had a higher number of major bleeding events (3.1% vs. 1.3%; p = 0.023) and minor bleeding events (9.2% vs. 5.0%; p = 0.002) when compared with the younger group. However, there was not a significant statistical difference between the patients taking NOAC or warfarin in both groups. These findings are not unexpected because it is well-known that age is a very important risk factor for bleeding. It would be interesting to compare in a randomized fashion whether minimally interrupted anticoagulation in the elderly population could mitigate the high bleeding rates when compared with completely uninterrupted anticoagulation regimens.
The outcomes reported by Yanagisawa et al. (9) are very relevant in current clinical practice, because the advancing age of the population has led to exponential growth in the number of elderly vpatients undergoing catheter ablation of AF. It will be of great interest to determine whether the overall stroke rate in patients undergoing AF ablation in the broader EP community has significantly decreased with increasing adoption of continuous periprocedural anticoagulation strategies.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Di Biase has served as a consultant for Biosense Webster, Stereotaxis, Boston Scientific, and Abbott; and has received speaker honoraria/travel fees from Medtronic, Pfizer, and Biotronik. Dr. Romero has reported that he has no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2018 American College of Cardiology Foundation
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