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An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted anticoagulation in atrial fibrillation catheter ablation

Published:September 13, 2017DOI:https://doi.org/10.1016/j.hrthm.2017.09.011

      Background

      Catheter ablation is recommended as a first- or second-line rhythm control therapy for selected patients with atrial fibrillation (AF). There is a wide variability in the periprocedural management of oral anticoagulation in patients undergoing AF ablation.

      Objective

      We aimed to perform an updated meta-analysis of novel oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) as uninterrupted anticoagulation in patients undergoing AF ablation.

      Methods

      Databases and conference abstracts were searched. Studies were excluded if oral anticoagulants were held at any periprocedural period. The primary outcomes were stroke or transient ischemic attack (TIA) and major bleeding.

      Results

      Twelve studies and 4962 patients were included. Stroke or TIA was rare (NOAC, 0.08%; VKA, 0.16%) and not different between groups (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.19–2.30). The incidence of silent cerebral embolic events was also not significantly different between NOACs (8%) and VKAs (9.6%) (OR 0.86; 95% CI 0.42–1.76). Major bleeding was significantly reduced in the NOAC group (0.9%) as compared with VKA-treated patients (2%) (OR 0.50; 95% CI 0.30–0.84; P < .01). This finding was confirmed in a subgroup analysis of randomized and cohort studies with matched controls (OR 0.45; 95% CI 0.24–0.83; P = .01). There was no significant difference in the outcomes of individual NOACs and VKAs, although these analyses may have been underpowered to detect minor differences in such rare outcomes.

      Conclusion

      In patients undergoing AF ablation, uninterrupted periprocedural NOACs are associated with a low incidence of stroke or TIA and a significant reduction in major bleeding as compared with uninterrupted VKAs.

      Keywords

      Introduction

      Atrial fibrillation (AF) affects >30 million patients worldwide and its prevalence is expected to double in the upcoming decades.
      • Chugh S.S.
      • Havmoeller R.
      • Narayanan K.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      Catheter ablation has been established as a safe and effective alternative for rhythm control in AF. For patients who are refractory to antiarrhythmic drugs, ablation is recommended as a class I indication for paroxysmal AF and as a class IIa for persistent AF. In addition, ablation is recommended as a first-line rhythm control strategy in selected patients with symptomatic AF.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      • 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.
      The periprocedural anticoagulation management for AF ablation is the topic of much debate. A European survey demonstrated substantial heterogeneity in periprocedural anticoagulation practices among different countries and electrophysiologists.
      • Potpara T.S.
      • Larsen T.B.
      • Deharo J.C.
      • Rossvoll O.
      • Dagres N.
      • Todd D.
      • Pison L.
      • Proclemer A.
      • Purefellner H.
      • Blomstrom-Lundqvist C.
      Oral anticoagulant therapy for stroke prevention in patients with atrial fibrillation undergoing ablation: results from the First European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA).
      Novel oral anticoagulants (NOACs) have been increasingly used as an alternative to vitamin K antagonists (VKAs) in the management of AF, including in patients undergoing ablation.
      • Potpara T.S.
      • Larsen T.B.
      • Deharo J.C.
      • Rossvoll O.
      • Dagres N.
      • Todd D.
      • Pison L.
      • Proclemer A.
      • Purefellner H.
      • Blomstrom-Lundqvist C.
      Oral anticoagulant therapy for stroke prevention in patients with atrial fibrillation undergoing ablation: results from the First European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA).
      A recent meta-analysis found similar efficacy and reduced bleeding in patients receiving NOACs as compared with VKAs. However, that study included both continuous and interrupted anticoagulation in both groups.
      • Zhao Y.
      • Yang Y.
      • Tang X.
      • Yu X.
      • Zhang L.
      • Xiao H.
      New oral anticoagulants compared to warfarin for perioperative anticoagulation in patients undergoing atrial fibrillation catheter ablation: a meta-analysis of continuous or interrupted new oral anticoagulants during ablation compared to interrupted or continuous warfarin.
      Importantly, uninterrupted oral anticoagulation (OAC) is associated with a lower incidence of stroke and bleeding as compared with bridging heparin.
      • Di Biase L.
      • Burkhardt J.D.
      • Santangeli P.
      • et al.
      Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial.
      • Nairooz R.
      • Sardar P.
      • Payne J.
      • Aronow W.S.
      • Paydak H.
      Meta-analysis of major bleeding with uninterrupted warfarin compared to interrupted warfarin and heparin bridging in ablation of atrial fibrillation.
      A previous meta-analysis showed no difference in bleeding or thromboembolic events between uninterrupted NOACs and VKAs in patients undergoing AF ablation.
      • Nairooz R.
      • Ayoub K.
      • Sardar P.
      • Payne J.
      • Almomani A.
      • Pothineni N.V.
      • Shailesh F.
      • Aronow W.S.
      • Mukherjee D.
      Uninterrupted new oral anticoagulants compared with uninterrupted vitamin K antagonists in ablation of atrial fibrillation: a meta-analysis.
      However, because of relatively small sample sizes in individual studies and rare outcomes, these results may have been underpowered. More recently, numerous studies were published, including additional randomized data that may strengthen the power of pooled outcomes.
      • Calkins H.
      • Willems S.
      • Gerstenfeld E.P.
      • et al.
      RE-CIRCUIT Investigators
      Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation.
      • 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.
      • Tao S.
      • Otomo K.
      • Ono Y.
      • Osaka Y.
      • Hirao T.
      • Koura K.
      • Manno T.
      • Ueshima D.
      • Shimizu S.
      • Isobe M.
      • Hirao K.
      Efficacy and safety of uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation of atrial fibrillation compared to uninterrupted warfarin.
      • Yoshimura A.
      • Iriki Y.
      • Ichiki H.
      • Oketani N.
      • Okui H.
      • Maenosono R.
      • Namino F.
      • Miyata M.
      • Ohishi M.
      Evaluation of safety and efficacy of periprocedural use of rivaroxaban and apixaban in catheter ablation for atrial fibrillation.
      Therefore, we aimed to perform an updated systematic review and meta-analysis to investigate the efficacy and safety of NOACs vs VKAs for uninterrupted OAC in patients with AF undergoing catheter ablation.

      Methods

      Eligibility criteria

      Inclusion in this meta-analysis was restricted to studies that met all the following eligibility criteria: (1) randomized trials or nonrandomized cohorts; (2) those comparing uninterrupted NOACs with uninterrupted VKAs as an anticoagulation strategy; (3) those in patients undergoing AF catheter ablation; and (4) those reporting any of the outcomes of interest. We excluded studies with (1) no control group; (2) bridging anticoagulant therapies; (3) an interrupted NOAC or VKA regimen, including those that held or decreased the OAC dose on the day of the procedure; or (4) overlapping patient populations. In the last case, only the study with the highest number of patients was included.

      Search strategy and data extraction

      We systematically searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials in July 2017 using the following medical subject heading terms: atrial fibrillation, ablation, pulmonary vein isolation, PVI, warfarin, vitamin K antagonist, VKA, coumadin, phenprocoumon, acenocoumarol, NOAC, DOAC, dabigatran, rivaroxaban, apixaban, and edoxaban. We also searched for abstracts presented in cardiovascular and electrophysiology conferences from 2011 to 2017. The references from all included studies and previous reviews were also manually searched. Three authors (R.C., L.K., and M.R.) independently extracted the data after predefined search criteria and quality assessment.

      End points and subgroup analyses

      The primary outcomes of interest were the incidence of stroke or transient ischemic attack (TIA) and major bleeding. Other prespecified outcomes included silent cerebral thromboembolic events, groin hematoma, pseudoaneurysm, bleeding requiring procedural intervention, surgery, and red blood cell transfusion, gastrointestinal bleeding, intracranial bleeding, pericardial effusion without tamponade, and minor bleeding. We aimed to perform subgroup analyses of (1) data from randomized and control-matched studies and (2) individual NOACs compared with VKAs.

      Quality assessment

      Nonrandomized studies were appraised with the Newcastle-Ottawa Scale (NOS).
      • Wells G.A.
      • Shea B.
      • O'Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • Tugwell P.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses.
      In the NOS, each study is scored on a 0 to 9 scale according to the quality of participant selection, comparability of groups, and outcome adjudication. Quality assessment of randomized controlled trials (RCTs) was performed with Cochrane's tool for assessing bias in randomized trials,
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • Juni P.
      • Moher D.
      • Oxman A.D.
      • Savovic J.
      • Schulz K.F.
      • Weeks L.
      • Sterne J.A.
      The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
      wherein studies are scored as high, low, or unclear risk of bias in 5 domains: selection, performance, detection, attrition, and reporting. Publication bias was investigated with funnel plot analysis of the primary outcomes.

      Statistical analysis

      The systematic review and meta-analysis were performed in accordance with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      Pooled treatment effects for binary end points were compared using odds ratio (OR) with 95% confidence interval (CI). Heterogeneity was examined with Cochran Q test and I2 statistics. A fixed effect model was used for outcomes with low heterogeneity (I2 < 25%). Otherwise, the DerSimonian and Laird random effects model was used. We also obtained pooled estimates (incidence rate ratios) using the Poisson mixed effects model to account for zero events and variable follow-up time and compared them with the Mantel-Haenszel estimates to ensure robustness of results (see references 1–3 in Supplement References). Review Manager 5.1 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata 13 (StataCorp LLC, College Station, TX) were used for statistical analysis.

      Results

      Study selection and characteristics

      The initial search yielded 683 results. After removal of duplicate records and unrelated studies, 70 remained and were fully reviewed for the inclusion criteria (Figure 1). Of those, 12 were included in the qualitative and quantitative review after exclusion of studies with interrupted OAC (n = 54) or overlapping populations (n = 4). A total of 4962 patients were included from 3 RCTs and 9 cohorts. Uninterrupted NOACs were used in 2504 patients (50.5%). Baseline characteristics were comparable between groups (Table 1), even in nonrandomized studies. Nevertheless, a subgroup analysis of randomized and control-matched studies was performed to minimize the risk of selection bias. Dillier et al
      • Dillier R.
      • Ammar S.
      • Hessling G.
      • et al.
      Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures.
      used phenprocoumon as VKA, whereas warfarin was used in all other studies. The target international normalized ratio (INR) in the VKA group was 2.0–3.0 in all studies, except for patients in Yoshimura et al
      • Yoshimura A.
      • Iriki Y.
      • Ichiki H.
      • Oketani N.
      • Okui H.
      • Maenosono R.
      • Namino F.
      • Miyata M.
      • Ohishi M.
      Evaluation of safety and efficacy of periprocedural use of rivaroxaban and apixaban in catheter ablation for atrial fibrillation.
      (target INR not reported) and patients aged 70 years and older in Nagao et al
      • Nagao T.
      • Inden Y.
      • Yanagisawa S.
      • Kato H.
      • Ishikawa S.
      • Okumura S.
      • Mizutani Y.
      • Ito T.
      • Yamamoto T.
      • Yoshida N.
      • Hirai M.
      • Murohara T.
      Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation.
      (target INR 1.6–2.6).
      Figure thumbnail gr1
      Figure 1PRISMA flow diagram of study screening and selection.
      Table 1Baseline characteristics of the included studies
      StudyStudy designCenterNo. of patients: NOAC/VKAPercentage of patients with PAF: NOAC/VKAPercentage of male patients: NOAC/VKAAge (y)
      Mean or median.
      : NOAC/VKA
      CHA2DS2-VASc score
      Mean or median.
      : NOAC/VKA
      HAS-BLED score
      Mean or median.
      : NOAC/VKA
      Preprocedural OAC (d)Standard

      NOAC dose
      Target ACT (seconds)Follow-up time
      Di Biase et al
      • Di Biase L.
      • Lakkireddy D.
      • Trivedi C.
      • et al.
      Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: results from a multicenter study.
      Non-RCT
      Matched controls.
      4; US, Eur200/20016/1671/7165/652.28/2.301.74/1.7430A: 5 mg BID>30030 d
      Dillier et al
      • Dillier R.
      • Ammar S.
      • Hessling G.
      • et al.
      Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures.
      Non-RCT
      Matched controls.
      1; Eur272/27249/4668/6862/631.8/2.0NA30R: 20 mg QD270–300Inhospital
      Konduru et al
      • Konduru S.V.
      • Cheema A.A.
      • Jones P.
      • Li Y.
      • Ramza B.
      • Wimmer A.P.
      Differences in intraprocedural ACTs with standardized heparin dosing during catheter ablation for atrial fibrillation in patients treated with dabigatran vs. patients on uninterrupted warfarin.
      Non-RCT1; US11/5279/5579/6756/60NANANAD: dose NA>350NA
      Kuwahara et al
      • 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.
      RCT3; JPN100/10059/6075/7265/662.1/2.4NA30A: 5 mg BID>3007 d
      Lakkireddyet al
      • Lakkireddy D.
      • Reddy Y.M.
      • Di Biase L.
      • et al.
      Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry.
      Non-RCT
      Matched controls.
      8; NAmer321/32151/5169/6963/632.17/2.211.47/1.7030R: 20 mg QD300–40030 d
      Maddox et al
      • Maddox W.
      • Kay G.N.
      • Yamada T.
      • Osorio J.
      • Doppalapudi H.
      • Plumb V.J.
      • Gunter A.
      • McElderry H.T.
      Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation.
      Non-RCT1; US212/25163/5776/6762/621.73/1.69NA30D: 150 mg BID>350–400Inhospital
      Nagao et al
      • Nagao T.
      • Inden Y.
      • Yanagisawa S.
      • Kato H.
      • Ishikawa S.
      • Okumura S.
      • Mizutani Y.
      • Ito T.
      • Yamamoto T.
      • Yoshida N.
      • Hirai M.
      • Murohara T.
      Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation.
      Non-RCT1; JPND: 239

      R: 102

      A: 158

      VKA: 370
      D: 71

      R: 79

      A: 78

      VKA: 73
      D: 79

      R: 69

      A: 69

      VKA: 74
      D: 59

      R: 61

      A: 61

      VKA: 61
      D: 1.4

      R: 1.8

      A: 1.5

      VKA: 1.5
      D: 0.8

      R: 1.1

      A: 0.9

      VKA: 0.9
      30D: 150 mg BID

      R: 15 mg QD

      A: 5 mg BID
      300–35030 d
      RE-CIRCUIT
      • Calkins H.
      • Willems S.
      • Gerstenfeld E.P.
      • et al.
      RE-CIRCUIT Investigators
      Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation.
      RCT104; JPN, Eur, RUS, NAmer317/31867/6872/7759/592.0/2.2NA30 to 60D: 150 mg BID>3008 wk
      Shah et al
      • Shah R.R.
      • Pillai A.
      • Schafer P.
      • Meggo D.
      • McElderry T.
      • Plumb V.
      • Yamada T.
      • Kumar V.
      • Doppalapudi H.
      • Gunter A.
      • Pentecost E.
      • Maddox W.R.
      Safety and efficacy of uninterrupted apixaban therapy versus warfarin during atrial fibrillation ablation.
      Non-RCT2; US317/31075/6265/5563/662.1/2.8NA28A: 5 mg BID>30090 d
      Tao et al
      • Tao S.
      • Otomo K.
      • Ono Y.
      • Osaka Y.
      • Hirao T.
      • Koura K.
      • Manno T.
      • Ueshima D.
      • Shimizu S.
      • Isobe M.
      • Hirao K.
      Efficacy and safety of uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation of atrial fibrillation compared to uninterrupted warfarin.
      Non-RCT1; JPN76/7172/7774/6666/662.2/2.51.4/1.530R: 15 mg QD>30030 d
      VENTURE-AF
      • Cappato R.
      • Marchlinski F.E.
      • Hohnloser S.H.
      • et al.
      Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
      RCT46; US124/12476/7069/7276/701.5/1.7NA21
      1–7 d if transesophageal echocardiography showed no thrombus.
      R: 20 mg QD300–40030 d
      Yoshimura et al
      • Yoshimura A.
      • Iriki Y.
      • Ichiki H.
      • Oketani N.
      • Okui H.
      • Maenosono R.
      • Namino F.
      • Miyata M.
      • Ohishi M.
      Evaluation of safety and efficacy of periprocedural use of rivaroxaban and apixaban in catheter ablation for atrial fibrillation.
      Non-RCT1; JPN55/6960/50.781/7559/601.7/1.51.4/1.1NAR: dose NA>30010 d
      A = apixaban; ACT = activated clotting time; BID = twice a day; D = dabigatran; Eur = Europe; JPN = Japan; NA = not available; NAmer = North America; NOAC = novel oral anticoagulant; OAC = oral anticoagulant; PAF = paroxysmal atrial fibrillation; QD = once a day; R = rivaroxaban; RCT = randomized controlled trial; RUS = Russian Federation; US = United States; VKA = vitamin K antagonist.
      Mean or median.
      Matched controls.
      1–7 d if transesophageal echocardiography showed no thrombus.
      Radiofrequency was the only energy source used in 9 studies. In the RE-CIRCUIT study,
      • Calkins H.
      • Willems S.
      • Gerstenfeld E.P.
      • et al.
      RE-CIRCUIT Investigators
      Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation.
      80% of AF ablation procedures were with radiofrequency energy. The types of AF ablation energy sources were not reported in VENTURE-AF
      • Cappato R.
      • Marchlinski F.E.
      • Hohnloser S.H.
      • et al.
      Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
      and Konduru et al.
      • Konduru S.V.
      • Cheema A.A.
      • Jones P.
      • Li Y.
      • Ramza B.
      • Wimmer A.P.
      Differences in intraprocedural ACTs with standardized heparin dosing during catheter ablation for atrial fibrillation in patients treated with dabigatran vs. patients on uninterrupted warfarin.
      Major bleeding was defined according to the International Society on Thrombosis and Hemostasis criteria in RE-CIRCUIT
      • Calkins H.
      • Willems S.
      • Gerstenfeld E.P.
      • et al.
      RE-CIRCUIT Investigators
      Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation.
      and Kuwahara et al.
      • 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.
      In VENTURE-AF,
      • Naccarelli G.V.
      • Cappato R.
      • Hohnloser S.H.
      • Marchlinski F.E.
      • Wilber D.J.
      • Xiang J.
      • Ma C.
      • Hess S.
      • Davies D.W.
      • Fields L.E.
      • Natale A.
      Rationale and design of VENTURE-AF: a randomized, open-label, active-controlled multicenter study to evaluate the safety of rivaroxaban and vitamin K antagonists in subjects undergoing catheter ablation for atrial fibrillation.
      major bleeding was defined according to the International Society on Thrombosis and Hemostasis, Thrombolysis in Myocardial Infarction, and Global Use of Strategies to Open Occluded Coronary Arteries criteria. For all other studies, major bleeding was defined as that severe enough to require blood transfusion, surgery, or pericardial drainage.
      • Tao S.
      • Otomo K.
      • Ono Y.
      • Osaka Y.
      • Hirao T.
      • Koura K.
      • Manno T.
      • Ueshima D.
      • Shimizu S.
      • Isobe M.
      • Hirao K.
      Efficacy and safety of uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation of atrial fibrillation compared to uninterrupted warfarin.
      • Di Biase L.
      • Lakkireddy D.
      • Trivedi C.
      • et al.
      Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: results from a multicenter study.
      • Dillier R.
      • Ammar S.
      • Hessling G.
      • et al.
      Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures.
      • Lakkireddy D.
      • Reddy Y.M.
      • Di Biase L.
      • et al.
      Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry.
      • Maddox W.
      • Kay G.N.
      • Yamada T.
      • Osorio J.
      • Doppalapudi H.
      • Plumb V.J.
      • Gunter A.
      • McElderry H.T.
      Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation.
      • Nagao T.
      • Inden Y.
      • Yanagisawa S.
      • Kato H.
      • Ishikawa S.
      • Okumura S.
      • Mizutani Y.
      • Ito T.
      • Yamamoto T.
      • Yoshida N.
      • Hirai M.
      • Murohara T.
      Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation.
      In the COMPARE study
      • Di Biase L.
      • Burkhardt J.D.
      • Santangeli P.
      • et al.
      Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial.
      of continuous vs interrupted warfarin, major bleeding was defined more broadly as cardiac tamponade, hematoma requiring intervention, massive hemoptysis, hemothorax, retroperitoneal bleeding, need for transfusion, or bleeding causing symptoms. As reported in Table 1, follow-up for bleeding end points ranged from inhospital to as much as 90 days. The heterogeneous duration of follow-up between studies was accounted for with the use of Poisson distribution and mixed effects pooled estimates of incidence rate ratios, which compute the occurrence of events over a person-time denominator (Supplemental Table 1).

      Pooled analysis of all studies

      The incidence of ischemic stroke or TIA was low (NOAC, 0.08%; VKA, 0.16%) and not significantly different between groups (OR 0.66; 95% CI 0.19–2.30; P = .51; I2 = 0%) (Figure 2A). Three studies evaluated the incidence of silent cerebral embolic events with magnetic resonance imaging and reported a similar incidence between NOACs (8%) and VKAs (9.6%) (OR 0.86; 95% CI 0.42–1.76; P = .68; I2 = 0%) (Figure 2B). Only 1 death was reported in all studies.
      • Cappato R.
      • Marchlinski F.E.
      • Hohnloser S.H.
      • et al.
      Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
      Figure thumbnail gr2
      Figure 2A: The incidence of stroke or transient ischemic attack was not significantly different between groups (P = .51). B: The incidence of silent cerebral embolism was not significantly different between groups (P = .68). CI = confidence interval; M-H = Mantel-Haenszel method; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist.
      Major bleeding was significantly lower in the uninterrupted NOAC group (20 of 2120 [0.9%]) than in the uninterrupted VKA group (40 of 2024 [2.0%]) (OR 0.50; 95% CI 0.30–0.84; P < .01; I2 = 0%) (Figure 3A). The incidence of pericardial tamponade was not significantly different between groups (OR 0.86; 95% CI 0.47–1.58; P = .63; I2 = 0%) (Figure 3B). Supplemental Table 2 outlines the outcomes of patients who developed cardiac tamponade on uninterrupted OAC. All patients with reported outcomes required pericardiocentesis or surgical intervention. In addition, red blood cell transfusion and reversal of OAC with plasma or other blood products were needed in 13% (5 of 38) and 37% (14 of 38) of patients, respectively. Idarucizumab, a specific dabigatran reversal agent, was not used in any patient, although it may not have been available yet in some of the studies. Surgical interventions were required in 5% of patients (2 of 38) who developed cardiac tamponade. In studies that discussed follow-up, all patients had an uneventful recovery. Maddox et al
      • Maddox W.
      • Kay G.N.
      • Yamada T.
      • Osorio J.
      • Doppalapudi H.
      • Plumb V.J.
      • Gunter A.
      • McElderry H.T.
      Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation.
      reported a 2- to 3-day extension in length of stay in those with tamponade. In general, OAC was resumed before discharge.
      • Lakkireddy D.
      • Reddy Y.M.
      • Di Biase L.
      • et al.
      Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry.
      • Nagao T.
      • Inden Y.
      • Yanagisawa S.
      • Kato H.
      • Ishikawa S.
      • Okumura S.
      • Mizutani Y.
      • Ito T.
      • Yamamoto T.
      • Yoshida N.
      • Hirai M.
      • Murohara T.
      Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation.
      Four studies reported routine protamine use before sheath removal.
      • Tao S.
      • Otomo K.
      • Ono Y.
      • Osaka Y.
      • Hirao T.
      • Koura K.
      • Manno T.
      • Ueshima D.
      • Shimizu S.
      • Isobe M.
      • Hirao K.
      Efficacy and safety of uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation of atrial fibrillation compared to uninterrupted warfarin.
      • Maddox W.
      • Kay G.N.
      • Yamada T.
      • Osorio J.
      • Doppalapudi H.
      • Plumb V.J.
      • Gunter A.
      • McElderry H.T.
      Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation.
      • Nagao T.
      • Inden Y.
      • Yanagisawa S.
      • Kato H.
      • Ishikawa S.
      • Okumura S.
      • Mizutani Y.
      • Ito T.
      • Yamamoto T.
      • Yoshida N.
      • Hirai M.
      • Murohara T.
      Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation.
      • Shah R.R.
      • Pillai A.
      • Schafer P.
      • Meggo D.
      • McElderry T.
      • Plumb V.
      • Yamada T.
      • Kumar V.
      • Doppalapudi H.
      • Gunter A.
      • Pentecost E.
      • Maddox W.R.
      Safety and efficacy of uninterrupted apixaban therapy versus warfarin during atrial fibrillation ablation.
      A subgroup analysis of these studies showed no significant difference between the 2 groups in pericardial tamponade (OR 0.68; 95% CI 0.24–1.89; P = .46; I2 = 0%) and major bleeding (OR 0.66; 95% CI 0.23–1.86; P = .43; I2 = 0%). This should not be interpreted as definitive evidence given the limited power of this analysis (2106 patients and 4 studies).
      Figure thumbnail gr3
      Figure 3A: The incidence of major bleeding was significantly lower in the NOAC group (P < .01). B: The incidence of pericardial tamponade was not significantly different between groups (P = .63). CI = confidence interval; M-H = Mantel-Haenszel method; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist.
      There was no significant difference between the 2 anticoagulation strategies in secondary bleeding end points: bleeding requiring surgery (OR 0.64; 95% CI 0.18–2.32; P = 0.50; I2 = 0%), bleeding requiring intervention (OR 0.76; 95% CI 0.43–1.36; P = .36; I2 = 13%), bleeding requiring red blood cell transfusion (OR 0.41; 95% CI 0.13–1.26; P = .12; I2 = 0%), minor bleeding (OR 1.0; 95% CI 0.78–1.27; P = .99; I2 = 0%), groin hematoma (OR 0.98; 95% CI 0.69–1.39; P = .90; I2 = 0%), vascular pseudoaneurysm (OR 1.30; 95% CI 0.35–4.86; P = .70; I2 = 0%), gastrointestinal bleeding (OR 1.23; 95% CI 0.27–5.58; P = .79; I2 = 0%), and pericardial effusions without tamponade (OR 0.64; 95% CI 0.27–1.48; P = .29; I2 = 20%). In studies that reported vascular injuries, the pooled rate of access site complications was 2.9% (72 of 2448) and 3.3% (79 of 2386) for NOACs and VKAs, respectively. Vascular surgery was required in 3 patients in the NOAC group and in 6 patients receiving VKAs.

      Subgroup analyses

      NOACs were also compared individually with uninterrupted VKAs. As shown in Supplemental Table 3, there was no significant difference in bleeding and thromboembolic outcomes between VKAs and dabigatran (4 studies), rivaroxaban (6 studies), or apixaban (4 studies). It should be noted, however, that the sample size is appreciably lower in these subgroup analyses and thus may be underpowered. Finally, we also performed a dedicated quantitative synthesis of studies with a lower risk of selection bias. This analysis included RCTs and cohort studies that matched patients in the intervention arm to controls by age, sex, and type of AF. There was a significantly lower rate of major bleeding with NOACs than with VKAs (OR 0.45; 95% CI 0.24–0.83; P = .01; I
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      = 16%) (Figure 4). There were no significant differences between groups with regard to pericardial tamponade (OR 0.75; 95% CI 0.31–1.78; P = .51; I2 = 1%), bleeding requiring intervention (OR 0.79; 95% CI 0.21–2.99; P = .73; I2 = 39%), bleeding requiring surgery (OR 0.61; 95% CI 0.03–12.4; P = .75; I2 = 47%), and stroke or TIA (OR 0.50; 95% CI 0.09–2.73; P = .42; I2 = 0%). Similar results and inferences were obtained using the Poisson mixed effects model (Supplemental Table 1).
      Figure thumbnail gr4
      Figure 4In studies at lower risk of selection bias, major bleeding was significantly lower with NOACs. CI = confidence interval; M-H = Mantel-Haenszel method; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist.

      Quality assessment

      The appraisal of RCTs is reported in Supplemental Table 4. Patients and investigators were unblinded in all RCTs. RE-CIRCUIT
      • Calkins H.
      • Willems S.
      • Gerstenfeld E.P.
      • et al.
      RE-CIRCUIT Investigators
      Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation.
      and VENTURE-AF
      • Cappato R.
      • Marchlinski F.E.
      • Hohnloser S.H.
      • et al.
      Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
      blinded outcome adjudicators. Three observational studies performed matching of intervention and control patients. All the 9 nonrandomized publications achieved ≥7 points in the NOS. A funnel plot analysis of the primary outcome showed a symmetric distribution of studies with similar weights and point estimates that converged toward the pooled treatment effect as weight increased (Figure 5). Therefore, no evidence of publication bias was found.
      Figure thumbnail gr5
      Figure 5Funnel plot analysis shows no evidence of publication bias. OR = odds ratio; SE = standard error.

      Discussion

      In this systematic review and meta-analysis of 12 studies and 4962 patients, we compared NOACs with VKAs as uninterrupted anticoagulation strategies for patients undergoing catheter ablation for AF. The main findings from the pooled analyses were as follows: (1) the risk of clinical thromboembolic events with either uninterrupted strategy is exceedingly rare (NOAC, 0.08%; VKA, 0.16%) and not significantly different between groups; (2) silent cerebral events can occur in ∼1 in 10 patients, despite uninterrupted OAC with either agent; (3) major bleeding was halved with continuous NOACs as compared with uninterrupted VKAs; and (4) this difference was persistent in a subgroup analysis of randomized and cohort studies with matched controls.
      Because of the potential implications of ischemic strokes, the prevention of thromboembolic events is paramount when comparing periprocedural anticoagulation for AF ablation. Therefore, the low incidence of ischemic stroke or TIA (∼1–2 in 1000 procedures) in this pooled analysis is certainly reassuring. It should be emphasized, however, that these results apply only to strict uninterrupted periprocedural anticoagulation. Even brief interruptions of OAC are associated with a 3-fold increase in the risk of stroke or systemic embolism.
      • Sticherling C.
      • Marin F.
      • Birnie D.
      • et al.
      Antithrombotic management in patients undergoing electrophysiological procedures: a European Heart Rhythm Association (EHRA) position document endorsed by the ESC Working Group Thrombosis, Heart Rhythm Society (HRS), and Asia Pacific Heart Rhythm Society (APHRS).
      Therefore, withholding or decreasing the OAC dose before ablation was an exclusion criterion for our meta-analysis. In contrast, the incidence of cerebral thromboembolic complications after AF ablation with interrupted VKAs has been reported as 10 times higher (1.2%) in a meta-analysis of ∼10,000 patients.
      • Nairooz R.
      • Sardar P.
      • Payne J.
      • Aronow W.S.
      • Paydak H.
      Meta-analysis of major bleeding with uninterrupted warfarin compared to interrupted warfarin and heparin bridging in ablation of atrial fibrillation.
      In COMPARE study,
      • Di Biase L.
      • Burkhardt J.D.
      • Santangeli P.
      • et al.
      Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial.
      patients randomized to warfarin discontinuation with low-molecular-weight heparin bridging had an incidence of stroke or TIA of 4.9% (39 of 790). Similarly, a strategy of short NOAC interruption (<24–48 hours) before catheter ablation has been associated with an incidence of stroke or TIA in the range of 0.5%–2%.
      • Zhao Y.
      • Yang Y.
      • Tang X.
      • Yu X.
      • Zhang L.
      • Xiao H.
      New oral anticoagulants compared to warfarin for perioperative anticoagulation in patients undergoing atrial fibrillation catheter ablation: a meta-analysis of continuous or interrupted new oral anticoagulants during ablation compared to interrupted or continuous warfarin.
      • Lakkireddy D.
      • Reddy Y.M.
      • 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.
      Asymptomatic cerebral embolism has been reported in up to 17% of patients after AF ablation.
      • Gaita F.
      • Leclercq J.F.
      • Schumacher B.
      • Scaglione M.
      • Toso E.
      • Halimi F.
      • Schade A.
      • Froehner S.
      • Ziegler V.
      • Sergi D.
      • Cesarani F.
      • Blandino A.
      Incidence of silent cerebral thromboembolic lesions after atrial fibrillation ablation may change according to technology used: comparison of irrigated radiofrequency, multipolar nonirrigated catheter and cryoballoon.
      Our meta-analysis found a pooled incidence of 8% and 9.6% in the NOAC and VKA groups, respectively, with no significant difference between groups. The clinical significance of these findings remains to be determined; however, silent brain infarcts have been linked to early cognitive decline and dementia.
      • Vermeer S.E.
      • Prins N.D.
      • den Heijer T.
      • Hofman A.
      • Koudstaal P.J.
      • Breteler M.M.
      Silent brain infarcts and the risk of dementia and cognitive decline.
      The elevated and similar rate of events with NOACs and VKAs may indicate a nonthrombotic mechanism, such as air embolism due to microbubbles created during energy delivery, or alternatively a thrombotic etiology not prevented by uninterrupted anticoagulation, such as the development of thermal thrombus with radiofrequency delivery.
      • Tao S.
      • Otomo K.
      • Ono Y.
      • Osaka Y.
      • Hirao T.
      • Koura K.
      • Manno T.
      • Ueshima D.
      • Shimizu S.
      • Isobe M.
      • Hirao K.
      Efficacy and safety of uninterrupted rivaroxaban taken preoperatively for radiofrequency catheter ablation of atrial fibrillation compared to uninterrupted warfarin.
      Given the efficacy of uninterrupted NOACs and VKAs in preventing thromboembolic events, the safety of each regimen must be carefully considered to decide the most favorable periprocedural antithrombotic management. Our meta-analysis found a 50% relative risk reduction in major bleeding with uninterrupted NOACs (0.9%) as compared with uninterrupted VKAs (2.0%). The shorter half-life of NOACs and the more targeted mechanism of anticoagulation (direct thrombin or factor Xa inhibition) have been implicated in the reduction of major bleeding with these agents as compared with VKAs.
      • Calkins H.
      • Willems S.
      • Gerstenfeld E.P.
      • et al.
      RE-CIRCUIT Investigators
      Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation.
      The rates of major bleeding with uninterrupted NOACs in the literature ranges between 0% and 1.6%.
      • Calkins H.
      • Willems S.
      • Gerstenfeld E.P.
      • et al.
      RE-CIRCUIT Investigators
      Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation.
      • Lakkireddy D.
      • Reddy Y.M.
      • Di Biase L.
      • et al.
      Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry.
      • Cappato R.
      • Marchlinski F.E.
      • Hohnloser S.H.
      • et al.
      Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.
      These numbers are similar to the 1.1% incidence of major bleeding reported in studies that discontinued NOACs 12–48 hours before catheter ablation.
      • Zhao Y.
      • Yang Y.
      • Tang X.
      • Yu X.
      • Zhang L.
      • Xiao H.
      New oral anticoagulants compared to warfarin for perioperative anticoagulation in patients undergoing atrial fibrillation catheter ablation: a meta-analysis of continuous or interrupted new oral anticoagulants during ablation compared to interrupted or continuous warfarin.
      The incidence of pericardial tamponade was low (NOACs, 0.7%; VKAs, 0.9%) and not significantly different between groups (Figure 3B). A previous cohort study also showed no differences in the volume of pericardial drainage, duration of drainage, and the need for reversal of anticoagulation among patients with interrupted and uninterrupted VKAs.
      • Latchamsetty R.
      • Gautam S.
      • Bhakta D.
      • Chugh A.
      • John R.M.
      • Epstein L.M.
      • Miller J.M.
      • Michaud G.F.
      • Oral H.
      • Morady F.
      • Jongnarangsin K.
      Management and outcomes of cardiac tamponade during atrial fibrillation ablation in the presence of therapeutic anticoagulation with warfarin.
      While the great majority of patients in our systematic review responded to pericardiocentesis, 5% required emergent cardiac surgery. In addition, reversal of OAC with blood products was attempted in ∼40% of patients. These findings are consistent with prior reports. In a case series of 16 patients on uninterrupted NOACs and postablation tamponade, 2 patients needed surgery and 11 required 4-factor prothrombin complex concentrates.
      • Gianni C.
      • DI Biase L.
      • Mohanty S.
      • Trivedi C.
      • et al.
      Management of periprocedural and early pericardial effusions with tamponade following ablation of atrial fibrillation with uninterrupted factor Xa inhibitors: a case series.
      These results underscore the critical importance of having specific reversal agents for NOACs available at the time of AF ablation. One can speculate that if a specific NOAC reversal agent had been available in these prior reports, administration of blood products and cardiac surgery may have been avoided. At the present time, dabigatran is the only NOAC with an available reversal agent. Idarucizumab is a specific reversal agent for dabigatran that has been Food and Drug Administration approved and is clinically available throughout the world.
      • Pollack Jr., C.V.
      • Reilly P.A.
      • Eikelboom J.
      • et al.
      Idarucizumab for dabigatran reversal.
      The HRS/EHRA/ECAS/APHRS/SOLAECE 2017 expert consensus statement on catheter and surgical ablation of AF supports uninterrupted OAC for patients undergoing catheter ablation. This recommendation is a class 1 (level of evidence A) for VKAs and dabigatran, class 1 (level of evidence B–R) for rivaroxaban, and a class 2A for other NOACs. The option to hold 1 or 2 NOAC doses before ablation is also considered a reasonable alternative (class 2A) for patients anticoagulated with NOACs.
      • 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.
      The 2016 European guidelines on the management of AF recommend continuation of NOACs during the procedure (class IIa, level of evidence C).
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • et al.
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      A recent survey of 13 European countries showed that 55% of AF ablations were performed on uninterrupted VKAs, whereas only 4% opted for a regimen of continued NOACs. There was substantial heterogeneity in the time NOACs were discontinued, and ∼1 in 7 procedures were still performed with an extended period of interrupted OAC followed by bridging with a parenteral agent.
      • Potpara T.S.
      • Larsen T.B.
      • Deharo J.C.
      • Rossvoll O.
      • Dagres N.
      • Todd D.
      • Pison L.
      • Proclemer A.
      • Purefellner H.
      • Blomstrom-Lundqvist C.
      Oral anticoagulant therapy for stroke prevention in patients with atrial fibrillation undergoing ablation: results from the First European Snapshot Survey on Procedural Routines for Atrial Fibrillation Ablation (ESS-PRAFA).
      The present meta-analysis adds to the body of recent data suggesting that uninterrupted NOACs may be the optimal strategy for periprocedural antithrombotic management, given the efficacy in preventing thromboembolic events and the improved safety profile as compared with VKAs.

      Study limitations

      This study has limitations. Most importantly, 9 of the 12 included studies were not randomized. To minimize the effect of differential baseline prognosis between interventions, a subgroup analysis of randomized and cohort studies with matched controls was performed, which showed consistent results of reduced major bleeding and no significant difference in cerebral thromboembolic events. Nevertheless, residual confounding cannot be excluded. There was also some variation in the definition of major bleeding used by different studies. Although these definitions were similar in using transfusion thresholds, pericardial tamponade, and need for surgical repair as criteria for major bleeding, we cannot exclude the possibility that standardized outcome definitions would have led to different results. Finally, the population in this study may still be underpowered to detect small but significant bleeding or thrombotic differences between VKAs and individual NOACs.

      Conclusion

      This meta-analysis including 4962 patients highlights the efficacy and safety of NOACs for uninterrupted periprocedural anticoagulation in patients undergoing AF catheter ablation. The incidence of cerebral thromboembolic events was low with these agents and not significantly different from uninterrupted VKAs, whereas major bleeding was significantly reduced with NOACs. In addition, the pooled incidence of major bleeding in this study was no different than what has been reported for interrupted NOACs whereas thromboembolic events appear to be reduced with an uninterrupted strategy. Altogether, these findings provide support for a strategy of uninterrupted NOACs at the time of AF ablation as recommended by the HRS/EHRA/ECAS/APHRS/SOLAECE 2017 expert consensus statement on catheter and surgical ablation.
      • 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.

      Appendix. Supplementary data

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