Discussion
To the best of our knowledge, our study is the first prospective RCT to evaluate the safety of a single bolus administration of heparin (100 U/kg) without ACT monitoring under the condition of uninterrupted NOACs in patients with AF undergoing CBA. No thromboembolic or fatal events occurred during the 30-day follow-up period following CBA.
Notwithstanding the low CHA2DS2-VASc scores, patients undergoing AF ablation have the greatest risk for intra- and post-procedural thromboembolism development. An appropriate anticoagulation management is, therefore, essential throughout the entire procedural period. Current guidelines recommend uninterrupted systemic OAC therapy for at least 3 weeks before and 2 months after AF ablation, regardless of the CHA2DS2-VASc score. Moreover, intra-procedural administration of unfractionated heparin prior to or immediately after transseptal puncture as well as additional dose adjustment every 15-30 min to maintain ACT above 300 s should be recommended. However, this recommendation about intra-procedural heparin administration was based on the results of studies using VKA in patients with AF undergoing RFCA.
In terms of the initial loading dose of heparin, previous studies revealed that the administration of a higher dose of heparin was required to achieve the target ACT in AF patients with uninterrupted NOACs intake than in those with uninterrupted VKA intake.15-18 In addition, Yamaji et al.19 reported that an adequate loading dose of heparin was different for each NOAC because NOACs have different mechanisms of action. In the present study, although the average ACT in the ACT group was over 300 seconds (335.2±59.9), there was significant difference in mean ACT between patients who took rivaroxaban and those who took edoxaban (p=0.003). This finding is in line with that reported in previous studies.
A previous study demonstrated that radiofrequency (RF) energy was significantly more thrombogenic than cryoenergy, with a higher incidence of thrombus formation and larger thrombus volumes.20Compared to cryoablation, RF ablation resulted in a >5-fold increased risk of thrombus formation with larger thrombus volumes for endocardial ablation lesions of equal size in equivalent cardiac chambers. Specifically, the thrombus volume was positively correlated with the extent of hyperthermic tissue injury, whereas it was not related to the degree of hypothermic tissue injury. They suggested that these results probably reflected the histological observation that cryoablation resulted in well-delineated and discrete lesions with preservation of tissue ultrastructure, including the endothelial cell layer. In contrast, RF energy-induced lesions had serrated edges with extensive endothelial cell destruction.
However, several studies evaluating the incidence of acute silent cerebral lesions after PVI using magnetic resonance imaging (MRI) have demonstrated that CBA may not be associated with a lower risk of thromboembolic cerebral events than RFCA.21-23 These results underline the hypothesis that thrombus formation originating from an extended destruction of the endothelium surface is probably not the only cause of acute cerebral lesions. Although the definite cause of micro-cerebral infarctions associated with AF ablation has not been fully elucidated, several possible embolic sources are considered, such as gaseous emboli or microthrombi entrapped within the sheath during catheter insertion or extraction, platelet-rich microthrombi formed at the endothelial injury site, gaseous emboli formed during blood heating, and microparticles (char) as a result of rapid hyperthermal tissue damage. Among these possible embolic sources, the first can be the presumable cause of microthromboembolism associated with CBA. Therefore, the systemic use of intravenous heparin does not appear to fully eliminate the CBA-related microthromboembolic risk. Instead, intermittent flushing with heparinized saline through the central lumen of the steerable sheath during the entire CBA procedure appears to be more effective in preventing the formation of gaseous emboli or microthrombi at the gap portion between the steerable sheath and CB shaft.24
A recent meta-analysis demonstrated a significantly shorter procedure time in CBA compared to RFCA.25 The total procedural time in previous studies has been reported from 73.5±16 min to 192.9±44 min during CBA and from 118.5±15 minutes to 283.7±78.0 minutes during RFCA.26 In the present study, the total procedure and LA indwelling times were 79.0±14.3 min and 60.4±13.2 min, respectively. If the LA indwelling time is less than 60 min, additional administration of heparin would not be necessary, especially in patients with ACT of above 300 s at 30-min after transseptal puncture. Peripheral vascular complications are cumulatively reported in approximately 1-2% of cases, and cardiac perforation was noted in 0.1-3.2% of cases.27-29 The incidence of stroke or TIA has been reported to be lower than 1% despite a relatively high rate of silent cerebral embolic lesions.30 In the present study, no patient developed thromboembolic events and fatal complications. Any bleeding rate was 3.2% in all enrolled patients. Minor bleeding complications, including groin hematoma, laryngopharyngeal bleeding, and hemoptysis, were only observed in the ACT group, with no statistically different between two groups.
As VKA and NOACs have different effects on the intrinsic and/or extrinsic blood coagulation cascade, the same intra-procedural anticoagulation strategy could not be applied in patients with uninterrupted VKA and NOACs intake. However, the recommendation about intra-procedural anticoagulation regimens has not been changed, even though different ablation modalities such as CBA are widely used in clinical practice. Indeed, intra-procedural anticoagulation with unfractionated heparin might cause minor or major bleeding complications, which could be increased in patients undergoing CBA for whom a 15-Fr sheath is used. Therefore, the results of the present study may be meaningful for reappraising the intra-procedural anticoagulation strategy under the condition of uninterrupted NOACs at timely manner.
This study had several limitations. First, the sample size was not large enough and the number of events was small. Thus, it might be insufficient to identify a significant difference in clinical outcomes depending on whether or not an additional dose of heparin was administered. Furthermore, highly experienced operators performed the procedure in the present study, which could reduce the sensitivity of the results. Second, only two NOACs were evaluated in this study. In order to maintain a similar inhibitory effect of endogenous factor Xa between two groups, we enrolled only patients who had been taking once-daily NOACs (rivaroxaban and edoxaban) at night, and the maximum interval between the last pre-ablation NOACs dose and the ablation procedure was 12 h. Therefore, the results could not be extrapolated to all NOACs. Third, silent stroke was not reflected in thromboembolic events because routine MRI before and after CBA was not performed in this study. Lastly, we could not measure the peak level of ACT because we measured ACT at 30 min after the initial bolus administration of heparin. However, it might be unnecessary to assess the peak ACT level because the LA indwelling time was relatively short.