Outcomes of uninterrupted vs interrupted Periprocedural direct oral Anticoagulants in atrial Fibrillation ablation: A meta‐analysis

Abstract Background Studies indicate that uninterrupted anticoagulation (UA) is superior to interrupted anticoagulation (IA) in the periprocedural period during catheter ablation of atrial fibrillation. Still IA is followed in many centers considering the bleeding risk. This meta‐analysis compares interrupted and uninterrupted direct oral anticoagulation during catheter ablation of atrial fibrillation. Methods A systematic search into PubMed, EMBASE, and the Cochrane databases was performed and five studies were selected that directly compared IA vs UA before ablation and reported procedural outcomes, embolic, and bleeding events. The primary outcome of the study was major adverse cerebro‐cardiovascular events. Results The meta‐analysis included 840 patients with UA and 938 patients with IA. Median follow‐up was 30 days. Activated clotting time (ACT) before first heparin bolus was significantly longer with UA (P = .006), whereas mean ACT was similar between the two groups (P = .19). Total heparin dose needed was significantly higher with IA (mean, ‒1.61; 95% CI, ‒2.67 to ‒0.55; P = .003). Mean procedure time did not vary between groups (P = .81). Overall complication rates were low, with similar major adverse cerebro‐cardiovascular event (P = .40) and total bleeding (P = .55) rates between groups. Silent cerebral events (SCEs) were significantly more frequent with IA (log odds ratio, ‒0.90; 95% CI, ‒1.59 to ‒0.22; P < .01; I 2, 33%). Rates of major bleeding, minor bleeding, pericardial effusion, cardiac tamponade, and puncture complications were similar between groups. Conclusions UA during atrial fibrillation ablation has similar bleeding event rates, procedural times, and mean ACTs as IA, with fewer SCEs.


| INTRODUC TI ON
Catheter ablation of atrial fibrillation (AF) has expanded enormously over recent years, given improvements in available hardware, newer technologies, and growing evidence that the procedure is effective for rhythm control in patients with AF. 1 Although catheter ablation of AF is relatively safe in experienced hands, it is occasionally complicated by periprocedural thromboembolism, including stroke or transient ischemic attack (TIA), resulting from catheter manipulation and lesion creation in the left atrium; further, puncture complications and cardiac tamponade are not uncommon, because of multiple large sheaths and background anticoagulation. 2 Understandably, determining the optimum anticoagulation regimen for catheter ablation of AF is of utmost importance, both to balance the risks for ischemic and bleeding events during the procedure and to accommodate sameday discharge protocols. 3 Direct oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have largely replaced the vitamin K antagonist warfarin in recent years, as they are associated with lower risk for bleeding events and thus better stroke prevention in patients with AF. 4 Even so, many operators believe it wise to allow a 24-hour gap in the DOAC regimen before catheter ablation of AF to avoid bleeding risks, despite the fact that guidelines recommend uninterrupted DOAC administration in the periprocedural period [5][6][7] and that studies have shown better results from uninterrupted vs interrupted anticoagulation regimens, with better prevention of embolic events. 8 Studies addressing the safety and efficacy of an interrupted DOAC regimen during catheter ablation of AF are few and are limited by small sample sizes, short follow-up periods, rare events, and variable outcomes. We therefore conducted a meta-analysis comparing procedural characteristics and embolic and bleeding events between uninterrupted and interrupted DOAC regimens for catheter ablation of AF. 9 2 | ME THODS

| Study selection
For the qualitative synthesis of the meta-analysis, we selected studies that (a) directly compared uninterrupted anticoagulation (UA) vs interrupted anticoagulation (IA) with a DOAC regimen before catheter ablation of AF and (b) provided procedural outcomes and embolic and bleeding events. Studies that involved both UA and IA with DOACs but did not report comparative outcome data for each regimen were excluded from the quantitative meta-analysis.
Single-arm studies, case reports, case series, and cohort studies that had < 10 participants or that did not present adequate safety or efficacy outcome data also were excluded. See eFigure 1 in the Online Supplement.

| Data extraction
Baseline characteristics and safety and efficacy outcome data were extracted from each of the selected studies and entered into a Microsoft Excel spreadsheet by authors DK, AM, and SS.
Baseline characteristics included DOAC regimen, number of participants, maximum follow-up duration, age, sex, CHA 2 DS 2 -VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65 to 74 years, and sex category) score, HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs, or alcohol) score, left ventricular ejection fraction (LVEF), left atrium diameter, creatinine clearance, associated antiplatelet drugs, dimerized plasmin fragment D (D-dimer) and brain natriuretic peptide levels, and presence of paroxysmal AF, coronary artery disease, chronic kidney disease, or structural heart disease. Procedural outcomes included procedure time, activated clotting time (ACT), heparin dose, cardioversion, and use of protamine. Efficacy outcomes included embolic events and silent cerebral events (SCEs). Safety outcomes included major bleeding events (eg, cardiac tamponade, pseudoaneurysm, retroperitoneal hematoma, and intracranial hemorrhage) and minor bleeding events (eg, groin hematoma, pericardial effusions, and rebleeding from venous sites).

| Outcomes
The primary outcome of the study was major adverse cerebro-cardiovascular events (MACCVEs), which was a composite of stroke or TIA and major bleeding, total bleeding (composite of major and minor bleedings), and SCE. The secondary outcomes were cerebral embolic stroke or TIA, major and minor bleeding, total pericardial effusion, cardiac tamponade, and total puncture complications (composite of pseudoaneurysms, retroperitoneal hematomas, and rebleeding from venous sites).

| Data analysis
To compare the safety and efficacy outcomes in the UA and IA groups, we used hypergeometric-normal modeling to approximate the exact likelihood, as the number of events in each study was small relative to group size and included many zero events.
To negate the small study effect, we calculated logarithmic odds ratios (log ORs) with 95% CIs and then used R software 10 to backtransform the results to predicted exponential ORs and 95% CIs. 11 Heterogeneity was assessed by I 2 , and publication bias was assessed by funnel plot.

| RE SULTS
Five studies with a total of 840 UA patients and 938 IA patients were included in the meta-analysis; of these, three were randomized trials, [12][13][14] and two were observational studies. 15,16 Two identified studies were excluded because of lack of comparative data. 17,18 See eFigure 1 in the Supplement. The three randomized studies were critically appraised using the Risk of Bias 2.0 Scale, and the two observational studies were appraised using the Newcastle-Ottawa Scale (eTable 1 in the Supplement).

| Baseline characteristics
The various anticoagulant regimens are described in Table 1, along with baseline characteristics across the five studies. Follow-up periods differed across studies; the median duration being 30 days.
Mean age, mean CHA 2 DS 2 -VASc score, and the number of participants who had paroxysmal AF, had received antiplatelet drugs, or had structural heart disease were similar in both UA and IA groups across all studies. Maximum left atrial diameter, LVEF, creatinine clearance, and D-dimer and brain natriuretic peptide levels did not vary significantly between the UA and IA groups. Figure 1 and Table 2   Antiplatelets 43 (29) 28 (19) 27 (27) 31 (31) ----7 (6) 17 (7) D-dimer,

| Outcomes
Clinical outcomes across the studies are described in eTable 2 in the Supplement, and statistical comparisons of these outcome characteristics between the UA and IA groups are outlined in Table 3.

| Primary outcomes
The UA and IA groups did not differ significantly in terms of MACCVE

| Secondary outcomes
There was no significant difference in stroke or TIA incidence be-

| D ISCUSS I ON
Catheter ablation for AF is associated with a risk for major bleeding because of multiple vascular accesses, transseptal puncture, and catheter manipulation inside left atrium. 1,17,18 An international survey of AF ablation procedures found a 4.5% major complication rate. 19 Therefore, the key pursuit is to find an optimal balance between thromboembolism and bleeding. To our knowledge, the current meta-analysis is the first to compare procedural characteristics and embolic and bleeding events between uninterrupted and interrupted DOAC regimens for catheter ablation of AF.

| Heterogeneity in anticoagulation protocols
The trials described above used direct anticoagulants that have important differences in pharmacodynamics and dosing, and they also used different protocols, resulting in heterogeneity. The two studies using a once-daily DOAC shifted the last anticoagulant dose to the night before the procedure. In VENTURE-AF, the last dose of rivaroxaban was administered predominantly on the evening before the procedure. Patients randomized to uninterrupted edoxaban in the ELIMINATE-AF trial also took their scheduled doses in the evening. 23 In contrast, more than 80% of the patients treated with dabigatran in the RE-CIRCUIT trial received the last dose < 8 hours before the ablation. 20,22 In the AXAFA-AFNER study, apixaban treatment was

| Thrombosis risk
The incidence of periprocedural thromboembolism in patients with AF undergoing ablation ranges from 0.9% to 5% and depends on the diagnostic modality. 13 Possible mechanisms include blood coming in contact with foreign surfaces, endothelial injury and inflammation in the left atrium, cellular damage and release of components, and blood flow alteration after sinus rhythm is established. 26 Unfractionated heparin prevents common extrinsic and intrinsic coagulation pathway activation when administered before septal puncture. 14 Artificial surface-induced thrombosis is not prevented effectively by DOACs. 14 29 Several studies found low rates of major bleeding in both UA and IA groups and similar incidences of minor bleeding, which was attributed to postprocedural protamine use and postprocedural unfractionated heparin use. [12][13][14] In keeping with the above findings, total bleeding, major bleeding, and minor bleeding were similar in the two groups in our meta-analysis. Similarly, total pericardial effusion, cardiac tamponade, and total puncture complications did not differ significantly between the IA and UA groups, nor did protamine use. A recently published meta-analysis found that the rate of vascular complications in electrophysiology procedures-and thus, major and minor bleeding-can be reduced by using ultrasound-guided femoral access. 30

| MACCVE
MACCVE is a novel composite endpoint, we looked into, which comprised of major bleeding events as well as thrombotic events.
In our meta-analysis, MACCVE did not differ significantly between the UA and IA groups. Although SCE was noted more in relation to interrupted DOACs, the overall outcomes were comparable between the two groups which suggest that even with uninterrupted periprocedural anticoagulation, patients can be discharged safely from hospital following AF ablation on the same day. 29

| Predictors of silent cerebral events
To date, the clinical relevance of SCE remains unclear. Some data suggest that SCE is associated with cognitive impairment occurring after an AF ablation procedure. 31 This represents a real cause for concern for some authors, 21,32 whereas the relationship between SCE and cognitive impairment is disputed by others. 2 36 However, this study did not explore the procedural aspects, especially in relation to use of heparin and ACT.
Also our results are statistically more relevant as we accounted the necessary modifications to address sparse binary events.

| DECL AR ATION
• Ethics approval and consent to participate-Not applicable