- Email: [email protected]
Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation
Accepted Manuscript Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation Ruchit R. Shah, MD, Ajay Pillai, MD, Pascha Schafer, MD, David Meggo, MD, Tom McElderry, MD, Vance Plumb, MD, Takumi Yamada, MD, Vineet Kumar, MD, Harish Doppalapudi, MD, Alicia Gunter, BS, Emily Pentecost, RN, BSN, William R. Maddox, MD PII:
S0002-9149(17)30777-4
DOI:
10.1016/j.amjcard.2017.04.041
Reference:
AJC 22600
To appear in:
The American Journal of Cardiology
Received Date: 22 February 2017 Revised Date:
11 April 2017
Accepted Date: 19 April 2017
Please cite this article as: Shah RR, Pillai A, Schafer P, Meggo D, McElderry T, Plumb V, Yamada T, Kumar V, Doppalapudi H, Gunter A, Pentecost E, Maddox WR, Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation, The American Journal of Cardiology (2017), doi: 10.1016/j.amjcard.2017.04.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation
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Ruchit R. Shah MDa, Ajay Pillai MDb, Pascha Schafer MDa, David Meggo MDc, Tom McElderry MDc, Vance Plumb MDc, Takumi Yamada MDc, Vineet Kumar MDc, Harish Doppalapudi MDc,
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Alicia Gunter BSc, Emily Pentecost RN, BSNc, and William R. Maddox MDc
a. Division of Cardiology, Department of Internal Medicine at the Medical College of Georgia at Augusta University
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b. Department of Internal Medicine at the Medical College of Georgia at Augusta University c. Division of Cardiology, Department of Internal Medicine at the University of Alabama at Birmingham
Address for correspondence:
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William R. Maddox, M.D., F.H.R.S Assistant Professor of Medicine
Clinical Cardiac Electrophysiology
University of Alabama at Birmingham
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510 – 20th Street South
Faculty Office Tower, Room 930C
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Birmingham, AL 35294
Email: [email protected] Telephone Number: (205)934-3614 Fax Number: (205)934-3950
Conflict of Interests or Funding: None Running Title: Safety and efficacy of apixaban Work was performed at: Medical College of Georgia at Augusta University and University of Alabama at Birmingham
ACCEPTED MANUSCRIPT 2 ABSTRACT Thromboembolic cerebrovascular accident remains a rare but potentially devastating
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complication of catheter based atrial fibrillation (AF) ablation. Uninterrupted oral anticoagulant (OAC) therapy with warfarin has become the standard of care when performing catheter based AF ablation. Compared with warfarin, apixaban, a factor Xa inhibitor, has been shown to reduce the risk of stroke and major bleeding in non-valvular AF. With an increase in apixaban use for
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stroke prophylaxis in AF patients there is an increased interest in the safety and efficacy of
uninterrupted apixaban therapy during AF ablation. We compared the safety and efficacy of
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uninterrupted OA therapy with either warfarin or apixaban in all patients who underwent catheter based AF ablation at the University of Alabama at Birmingham and at Augusta University Medical Center between January 7, 2013 and February 25, 2016. All patients underwent a transesophageal echocardiogram (TEE) on the day of their ablation to assess for
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the presence of intracardiac thrombi. All complications were identified and classified as bleeding, thromboembolic events, or other. A total of 627 patients were analyzed as described above. There were 310 patients in the warfarin group and 317 patients in the apixaban group.
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There were 8 complications in the warfarin group and 5 complications in the apixaban group (P = 0.38). There were no thromboembolic complications in either group. In conclusion, the use of
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apixaban is as safe and effective as warfarin for uninterrupted OA therapy during catheter based ablation of AF.
Key words: anticoagulation, apixaban, atrial fibrillation, catheter ablation
ACCEPTED MANUSCRIPT 3
INTRODUCTION
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The safety and efficacy of uninterrupted dabigatran and rivaroxaban have shown to be as safe as uninterrupted warfarin therapy during AF ablation (1,2). Apixaban is a direct factor Xa inhibitor, and in the randomized ARISTOTLE trial, apixaban was demonstrated to be superior to
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warfarin anticoagulation for the prevention of stroke in non-valvular AF with a lower incidence bleeding (3). As such, apixaban is being used with increasing frequency, and patients are often
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on apixaban prior to AF ablation. A few studies have demonstrated the safety and efficacy profile of apixaban therapy compared to warfarin for peri-procedural anticoagulation in the setting of AF ablation (4,5,6,7,8). This multicenter study was designed to further validate the safety and efficacy of uninterrupted apixaban versus warfarin anticoagulation in the peri-
METHODS
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procedural AF ablation setting.
All patients undergoing catheter based AF ablation via pulmonary vein isolation
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between January 7, 2013 and February 25, 2016 at the University of Alabama at Birmingham Medical Center (UABMC) and Augusta University Medical Center (AUMC) were evaluated for
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enrollment in this study. The study protocol and procedures were approved through the Institutional Review Boards of AUMC and UABMC prior to study initiation and adhered to the guidelines of the Declaration of Helsinki. The need for informed consent was waived for study participants. All patients undergoing AF ablation had either paroxysmal or persistent nonvalvular AF. Patients who were not on apixaban or warfarin for at least 4 weeks prior to AF ablation, on other NOACs prior to AF ablation, or did not have at least 90 days of follow up were excluded from the study. As the majority of patients were already managed on an outpatient
ACCEPTED MANUSCRIPT 4 anticoagulation regimen, the choice of anticoagulant was deferred to the referring physician. All patients were continued on their oral agent as previously prescribed. Patients anticoagulated with vitamin K antagonist, warfarin, underwent dose adjustment to maintain a target
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international normalized ratio (INR) of 2.0-3.0. Patients received apixaban at doses of either
2.5mg or 5mg twice daily based on the manufacture’s dosing guideline. Ingestion of morning anticoagulant dose was confirmed in the pre-procedural period. Post-procedural
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anticoagulation was continued as prescribed without interruptions. All patients were maintained on oral anticoagulation for a minimum of 90 days following AF ablation.
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Baseline demographics for each patient including age, sex, history of CVA, nature of atrial fibrillation (paroxysmal or persistent), race, weight, history of diabetes or hypertension, procedure time, presence of left atrial appendage (LAA) thrombus during pre-procedure transesophageal echocardiogram (TEE), pre-procedure left ventricular ejection fraction (LVEF),
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length of stay, prothrombin time (PT), activated partial thromboplastin time (aPTT), INR, blood urea nitrogen (BUN), creatinine (Cr), and activated clotting time (ACT) before, during, and at the end of the case were recorded. Also, post-procedure complications of bleeding,
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thromboembolic events, and other complications were recorded. A TEE was performed on all patients the morning of the procedure to exclude the
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presence of intracardiac thrombus. The patient was sedated by anesthesiology using general anesthesia. Venous access was obtained in the right common femoral vein (CFV) and three sheaths were placed in this vein. A decapolar catheter was advanced into the coronary sinus (CS) and a quadripolar catheter was advanced across the tricuspid annulus to record a His bundle electrogram. Trans-septal access was performed in the usual fashion using a Brockenbrough needle, biplane fluoroscopy, and intracardiac echocardiography. Intravenous unfractionated heparin (UH) was administered by bolus injection just prior to transseptal
ACCEPTED MANUSCRIPT 5 puncture to achieve an ACT of 300-400 seconds per guidelines (9). The ACT was measured regularly throughout the case to maintain an ACT of greater than 400 seconds.
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A multielectrode mapping catheter was used to map the left atrium using a threedimensional (3D) mapping system via the transseptal sheath. This was either a circular catheter or a multi-arm, multielectrode catheter. The PV were then anatomically encircled and
electrically isolated using radio frequency (RF) energy delivered from an open irrigated ablation
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catheter using a wide area catheter ablation (WACA) technique. PVI was considered successful
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when exit and entrance block was demonstrated by 3D mapping and pacing from within the PV. Following completion of ablation, all catheters were removed from the body and protamine sulfate was administered intravenously. All groin sheaths were removed when the ACT had declined to less than 200 seconds. Patients were routinely monitored overnight on telemetry and discharged the following morning.
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All data was organized in Microsoft Excel (Microsoft Corp., Redmond, Washington). Data was stratified based on oral anticoagulation strategy (apixaban vs. warfarin). Summaries for continuous variables are presented as means ± standard deviations. Discrete variables are
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presented as totals with percentages. Comparative analysis was performed with unpaired
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Student’s t-test for continuous variables assuming equal or unequal variance as appropriate. Descriptive statistics were explored utilizing chi-square test to compare demographics and other proportions between groups including sex distribution, race, and type of AF. A P-value of <0.05 was considered significant. RESULTS Between January 7, 2013 and February 25, 2016, a total of 627 patients were analyzed and included in this retrospective study after application of the inclusion and exclusion criteria.
ACCEPTED MANUSCRIPT 6 Baseline characteristics are shown in Table 1. Overall, the groups were reasonably matched. The mean age in the warfarin group was slightly greater than the apixaban group, however the apixaban group mirrored the warfarin group in proportion of patients with a prior history of CVA
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and both groups had similar renal function. Average CHADS2 scores were significantly lower in the apixaban group compared to the warfarin group and LVEF was slightly higher. As
anticipated, the warfarin group had a significantly higher INR, PT, and aPTT prior to the
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procedure.
The relevant procedure related variables are outlined in Table 2. Average heparin doses
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did not differ significantly between groups. Interestingly, the average ACT following initial heparin bolus was lower in the apixaban group, and the minimum ACT during the procedure was subsequently higher in the apixaban group. Average ACT at time of sheath removal did not differ significantly. Procedure time in minutes was slightly longer in the apixaban group. This
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was contrasted by a slightly shorter length of hospital stay in the apixaban group when compared to the warfarin group.
Procedure related complications are outline in Table 3. There was a total of 8
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complications in the warfarin group and 5 in the apixaban group. All complications were related to bleeding. There were no thromboembolic complications in either the warfarin or the
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apixaban group. There was no statistically significant difference in the total complication rate or in subgroup analyses. DISCUSSION
Patients with non-valvular AF have an increased risk of a thromboembolic CVA. Warfarin and, more recently, NOACs are used to lower the risk of CVA in patients with AF (10). Those who continue to have AF activity despite being on anti-arrhythmic therapy are frequently referred for
ACCEPTED MANUSCRIPT 7 AF ablation via a PVI technique (9). Uninterrupted warfarin therapy has been the standard of care in patients undergoing PVI (11,12). Given data showing less bleeding and incidence of stroke with apixaban as compared to warfarin (3), more patients are being switched from
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warfarin to apixaban. As the use of apixaban for CVA prevention increases, the safety of uninterrupted apixaban therapy during AF ablation versus warfarin is an important
consideration. Recent studies have demonstrated that uninterrupted apixaban anticoagulation
further validates the findings of the earlier studies.
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strategy exhibited a similar safety profile to warfarin therapy (4,5,6,7,8). This multi-center study
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Patients in the warfarin cohort were older on average with higher CHADS2 and CHA2DS2VASc scores than their counterparts in the apixaban cohort. However, there were no thromboembolic events in either group and no difference in complications overall. In the ARISTOTLE trial, where groups were well matched, apixaban was found to be superior to
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warfarin for the prevention of CVA (3). Additionally, subgroup analyses in the ARISTOTLE trial demonstrated that in the apixaban group, there was a statistically significant decreased incidence of CVA and bleeding in patients older than 65 as well as a lower CVA incidence in
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patients with a CHADS2 score >3 (3). This suggests that the difference in CVA risk assessment between the two groups likely did not confound the results of the study.
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During AF ablation, the average ACT following initial heparin bolus was lower in the
apixaban group, while minimum ACT throughout AF ablation was higher. This is not unexpected as a recent study demonstrated that patients on warfarin compared to NOACS reached target ACT faster. The study also reported that patients on warfarin required less overall heparin compared to NOACs (13). Our investigation showed that the heparin requirement was the same for both warfarin and apixaban. The difference between our study and the findings expressed by Brienco, et al may be due to the fact they compared warfarin to NOACs in general without
ACCEPTED MANUSCRIPT 8 separating the individual NOACs. Of more interest is the potential advantage of peri-procedural apixaban anticoagulation leading to a more consistent ACT during the procedure in our study. This could, conceivably, lead to a lower risk of complications, although our study did not
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demonstrate this.
Additional differences were noted in baseline characteristics of the two cohorts as
evidenced by the lower LVEF in the warfarin cohort. While it is initially unclear as to why this
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would be, we have anecdotally observed that a greater proportion of cardiomyopathy patients in our institutions appear to have reduced access to care and medication assistance. This may
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result in a larger proportion of these patients electing to pursue warfarin anticoagulation over a NOAC such as apixaban. Higher INR, aPTT and PT values in the warfarin group were expected as a result of the mechanism of action of vitamin K antagonism. Finally, the length of stay was statistically higher in the warfarin group. Given the small difference, we do not feel it
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demonstrates any clinical relevance.
There are several limitations to this study. While the study was multicenter in design, the retrospective nature of this analysis limits conclusions to hypothesis generating in objective.
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In the same regard, given the retrospective design, the study may not have been powered to detect a statistical difference in thromboembolic events. The choice of warfarin or apixaban was
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not randomized, and appears to have introduced some bias into the study in regards to baseline cohort characteristics. Early in the study period, more patients on warfarin underwent uninterrupted therapy during AF ablation than did patients on uninterrupted apixaban therapy. While both centers are experienced, high volume centers, this temporal practice pattern may have resulted in increased operator proficiency as uninterrupted apixaban therapy became more widely implemented at an institutional level. Third, as only the right femoral vein was
ACCEPTED MANUSCRIPT 9 routinely cannulated during the ablation procedure, bleeding risk may be lower than for centers who routinely obtain vascular access in both groins.
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CONCLUSIONS When apixaban is utilized for uninterrupted OAC therapy during AF catheter ablation, a similar safety and efficacy profile is observed when compared to uninterrupted warfarin OAC
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therapy and validates the findings of previous studies. There was no difference in the risk of
bleeding or thromboembolic complications. These data suggest that either agent may be used
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safely and effectively for uninterrupted anticoagulation during catheter ablation of atrial
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fibrillation.
ACCEPTED MANUSCRIPT 10 1. Maddox W, Kay GN, Yamada T, Osorio J, Doppalapudi H, Pulmb VJ, Gunter A, McElderry HT. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2013; 24: 861-865.
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2. Cappato R, Marchlinski FE, Hohnloser SH, Naccarelli GV, Xiang J, Wilber DJ, Ma CS, Hess S, Wells DS, Juang G, Vijgen J, Hugl BJ, Balasubramaniam R, De Chillou C, Davies DW, Fields LE, Natale A; VENTURE-AF Investigators. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists
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for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805-1811.
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Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L: ARISTOLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N
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Engl J Med 2011;365:981-992.
4. Kuwahara T, Abe M, Yamaki M, Fujieda H, Abe Y, Hashimoto K, Ishiba M, Sakai H, Hishikari K, Takigawa M, Okubo K, Takagi K, Tanaka Y, Nakajima J, Takahashi A. Apixaban versus Warfarin for
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the Prevention of Periprocedural Cerebral Thromboembolism in Atrial Fibrillation Ablation: Multicenter Prospective Randomized Study. J Cardiovascular Electrophysiol 2016; 27: 549-554.
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5. Nagao T, Inden Y, Shimano M, Fujita M, Yanagisawa S, Kato H, Ishikawa S, Miyoshi A, Okumura S, Ohguchi S, Yamamoto T, Yoshida N, Hirai M, Murohara T. Efficacy and Safety of Apixaban in the Patients Undergoing the Ablation of Atrial Fibrillation. Pacing Clin Electrophysiol 2015; 38:155163.
6. Rillig A, Lin T, Plesman J, Heeger CH, Lemes C, Metzner A, Mathew S, Wissner E, Wohlmuth P, Ouyang F, Kuck KH, Tilz RR. Apixaban, Rivaroxaban, and Dabigatran in Patients Undergoing Atrial Fibrillation Ablation. J Cardiovascular Electrophysiol 2016; 27: 147-153.
ACCEPTED MANUSCRIPT 11 7. Di Biase L, Lakkireddy D, Trivedi C, Deneke T, Martinek M, Mohanty S, Mohanty P, Prakash S, Bai R, Reddy M, Gianni C, Horton R, Bailey S, Sigmund E, Derndorfer M, Schade A, Mueller P, Szoelloes A, Sanchez J, Al-Ahmad A, Hranitzky P, Gallinghouse GJ, Hongo RH, Beheiry S,
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Purefellner H, Burkhardt JD, Natale A. Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results from a multicenter study. Heart Rhythm 2015; 12:1162-1168.
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8. Blandino A, Bianchi F, Biondi-Zoccai G, Grossi S, Conte MR, Rametta F, Gaita F. Apixaban for
periprocedural anticoagulation during catheter ablation of atrial fibrillation: a systematic review
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and meta-analysis of 1691 patients. J Interv Card Electrophysiol 2016; 46:225-236. 9. Calkins H, Kuck K, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns, HJ, Daminao RJ Jr, Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Kottamp H, Kumagai K, Lindsay BD, Mansour M, Marchilnski FE, McCarthy PM, Mont JL,
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Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D. et al. HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations
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10. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;130:2071-2104.
ACCEPTED MANUSCRIPT 12 11. Wazni OM, Beheiry S, Fahmy T, Barrett C, Hao S, Patel D, Di Biase L, Martin DO, Kanj M, Arruda M, Cummings J, Schweikert R, Saliba W, Natale A. Atrial fibrillation ablation in patients with therapeutic international normalized ratio: Comparison of strategies of anticoagulation
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management in the periprocedural period. Circulation 2007; 116:2531-2534.
12. Di Biase L, Burkhardt JD, Santangeli P, Mohanty P, Sanchez JE, Horton R, Gallinghouse GJ,
Themistoclakis S, Rossilo A, Lakkireddy D, Reddy M, Hao S, Hongo R, Beheiry S, Zagrodzky J, Rong
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B, Mohanty S, Elayi CS, Forleo G, Pelargonio G, Narducci ML, Dello Russo A, Casella M, Fassini G, Tondo C, Schweikert RA, Natale A. Periprocedural stroke and bleeding complications in patients
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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. Circulation 2014; 129:2638-2644.
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13. Briceno DF, Villablanca PA, Lupercio F, Kargoli F, Jagannath A, Londono A, Patel J, Otusanya O, Brevik J, Maraboto C, Berardi C, Krumerman A, Palma E, Kim SG, Natale A, Di Biase L. Clinical Impact of Heparin Kinetics During Catheter Ablation of Atrial Fibrillation: Meta-Analysis and
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Meta-Regression. J Cardiovasc Electrophysiol 2016; 27:683-693.
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Table 1. Baseline Demographics and Clinical Parameters
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66.16 ± 9.68 138 (44.52%) 282 (90.97%) 28 (9.03%) 93.08 ± 22.86 34 (10.97%) 1.66 ± 1.12 2.80 ± 1.45 191 (61.61%) 49.2 ± 12% 17.9 ± 9.3 1.2 ± 1.6 2.39 ± 0.55 25.78 ± 5.53 39.56 ± 8.02
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Variable Age (years) Women White Non-white Weight (kg) Prior Cerebrovascular Accident Average CHADS2 (SD) Average CHA2DS2Vasc (SD) Paroxysmal Atrial Fibrillation Left Ventricular Ejection Fraction (%) Blood Urea Nitrogen (mg/dL) Creatinine (mg/dL) International Normalized Ratio Prothrombin Time (sec) Activated Partial Thromboplastin Time (sec) Values are mean±SD or n (%).
Apixaban (n=317)
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Warfarin (n =310)
62.92 ± 11.25 111 (35.02%) 297 (93.69%) 20 (6.31%) 92.56 ± 20.90 34 (10.73%) 1.19 ± 1.08 2.08 ± 1.42 237 (74.76% 54.2 ± 8% 17.1 ± 6.4 2.1 ± 13.5 1.17 ± 0.15 14.77 ± 1.80 32.48 ± 4.63
P-Value
<0.01 0.059 0.72 0.21 0.76 0.92 <0.01 <0.01 0.046 <0.01 0.17 0.22 <0.01 <0.01 <0.01
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Table 2. Procedural Values
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P-Value
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17,281 ± 3982 376 ± 88 315 ± 76 175 ± 37
137.9 ± 49.7 1.08 ± 0.40
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Average heparin bolus at time of 17129 ± 4789 transseptal (IU) 439 ± 145 ACT after heparin bolus (seconds) Minimum ACT during procedure 284 ± 109 (seconds) ACT at time of sheath removal 179 ± 19 (seconds) 129.17 ± 49.75 Procedure time (minutes) 1.21 ± 1.12 Length of stay (days) Values are mean±SD or n (%). ACT = activated clotting time; IU = international units.
Apixaban
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Warfarin
0.67 <0.01 <0.01 0.07 0.02 0.04
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Table 3. Procedure-related Complications P-Value
8 (2.58%) 8 (2.58%) 4 (1.29%) 1 (0.32%) 1 (0.32%) 2 (0.64%) 0 (0%)
5 (1.57%) 5 (1.57%) 3 (0.94%) 2 (0.63%) 0 (0%) 0 (0%) 0 (0%)
0.38 0.38 0.68 0.57 0.31 0.68 ---
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Apixaban
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Total complications Total bleeding complications Significant groin hematoma Pericardial tamponade Retroperitoneal hematoma Hemoptysis Thromboembolic complications Values are n (%).
Warfarin
S0002-9149(17)30777-4
DOI:
10.1016/j.amjcard.2017.04.041
Reference:
AJC 22600
To appear in:
The American Journal of Cardiology
Received Date: 22 February 2017 Revised Date:
11 April 2017
Accepted Date: 19 April 2017
Please cite this article as: Shah RR, Pillai A, Schafer P, Meggo D, McElderry T, Plumb V, Yamada T, Kumar V, Doppalapudi H, Gunter A, Pentecost E, Maddox WR, Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation, The American Journal of Cardiology (2017), doi: 10.1016/j.amjcard.2017.04.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation
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Ruchit R. Shah MDa, Ajay Pillai MDb, Pascha Schafer MDa, David Meggo MDc, Tom McElderry MDc, Vance Plumb MDc, Takumi Yamada MDc, Vineet Kumar MDc, Harish Doppalapudi MDc,
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Alicia Gunter BSc, Emily Pentecost RN, BSNc, and William R. Maddox MDc
a. Division of Cardiology, Department of Internal Medicine at the Medical College of Georgia at Augusta University
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b. Department of Internal Medicine at the Medical College of Georgia at Augusta University c. Division of Cardiology, Department of Internal Medicine at the University of Alabama at Birmingham
Address for correspondence:
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William R. Maddox, M.D., F.H.R.S Assistant Professor of Medicine
Clinical Cardiac Electrophysiology
University of Alabama at Birmingham
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510 – 20th Street South
Faculty Office Tower, Room 930C
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Birmingham, AL 35294
Email: [email protected] Telephone Number: (205)934-3614 Fax Number: (205)934-3950
Conflict of Interests or Funding: None Running Title: Safety and efficacy of apixaban Work was performed at: Medical College of Georgia at Augusta University and University of Alabama at Birmingham
ACCEPTED MANUSCRIPT 2 ABSTRACT Thromboembolic cerebrovascular accident remains a rare but potentially devastating
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complication of catheter based atrial fibrillation (AF) ablation. Uninterrupted oral anticoagulant (OAC) therapy with warfarin has become the standard of care when performing catheter based AF ablation. Compared with warfarin, apixaban, a factor Xa inhibitor, has been shown to reduce the risk of stroke and major bleeding in non-valvular AF. With an increase in apixaban use for
SC
stroke prophylaxis in AF patients there is an increased interest in the safety and efficacy of
uninterrupted apixaban therapy during AF ablation. We compared the safety and efficacy of
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uninterrupted OA therapy with either warfarin or apixaban in all patients who underwent catheter based AF ablation at the University of Alabama at Birmingham and at Augusta University Medical Center between January 7, 2013 and February 25, 2016. All patients underwent a transesophageal echocardiogram (TEE) on the day of their ablation to assess for
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the presence of intracardiac thrombi. All complications were identified and classified as bleeding, thromboembolic events, or other. A total of 627 patients were analyzed as described above. There were 310 patients in the warfarin group and 317 patients in the apixaban group.
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There were 8 complications in the warfarin group and 5 complications in the apixaban group (P = 0.38). There were no thromboembolic complications in either group. In conclusion, the use of
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apixaban is as safe and effective as warfarin for uninterrupted OA therapy during catheter based ablation of AF.
Key words: anticoagulation, apixaban, atrial fibrillation, catheter ablation
ACCEPTED MANUSCRIPT 3
INTRODUCTION
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The safety and efficacy of uninterrupted dabigatran and rivaroxaban have shown to be as safe as uninterrupted warfarin therapy during AF ablation (1,2). Apixaban is a direct factor Xa inhibitor, and in the randomized ARISTOTLE trial, apixaban was demonstrated to be superior to
SC
warfarin anticoagulation for the prevention of stroke in non-valvular AF with a lower incidence bleeding (3). As such, apixaban is being used with increasing frequency, and patients are often
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on apixaban prior to AF ablation. A few studies have demonstrated the safety and efficacy profile of apixaban therapy compared to warfarin for peri-procedural anticoagulation in the setting of AF ablation (4,5,6,7,8). This multicenter study was designed to further validate the safety and efficacy of uninterrupted apixaban versus warfarin anticoagulation in the peri-
METHODS
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procedural AF ablation setting.
All patients undergoing catheter based AF ablation via pulmonary vein isolation
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between January 7, 2013 and February 25, 2016 at the University of Alabama at Birmingham Medical Center (UABMC) and Augusta University Medical Center (AUMC) were evaluated for
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enrollment in this study. The study protocol and procedures were approved through the Institutional Review Boards of AUMC and UABMC prior to study initiation and adhered to the guidelines of the Declaration of Helsinki. The need for informed consent was waived for study participants. All patients undergoing AF ablation had either paroxysmal or persistent nonvalvular AF. Patients who were not on apixaban or warfarin for at least 4 weeks prior to AF ablation, on other NOACs prior to AF ablation, or did not have at least 90 days of follow up were excluded from the study. As the majority of patients were already managed on an outpatient
ACCEPTED MANUSCRIPT 4 anticoagulation regimen, the choice of anticoagulant was deferred to the referring physician. All patients were continued on their oral agent as previously prescribed. Patients anticoagulated with vitamin K antagonist, warfarin, underwent dose adjustment to maintain a target
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international normalized ratio (INR) of 2.0-3.0. Patients received apixaban at doses of either
2.5mg or 5mg twice daily based on the manufacture’s dosing guideline. Ingestion of morning anticoagulant dose was confirmed in the pre-procedural period. Post-procedural
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anticoagulation was continued as prescribed without interruptions. All patients were maintained on oral anticoagulation for a minimum of 90 days following AF ablation.
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Baseline demographics for each patient including age, sex, history of CVA, nature of atrial fibrillation (paroxysmal or persistent), race, weight, history of diabetes or hypertension, procedure time, presence of left atrial appendage (LAA) thrombus during pre-procedure transesophageal echocardiogram (TEE), pre-procedure left ventricular ejection fraction (LVEF),
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length of stay, prothrombin time (PT), activated partial thromboplastin time (aPTT), INR, blood urea nitrogen (BUN), creatinine (Cr), and activated clotting time (ACT) before, during, and at the end of the case were recorded. Also, post-procedure complications of bleeding,
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thromboembolic events, and other complications were recorded. A TEE was performed on all patients the morning of the procedure to exclude the
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presence of intracardiac thrombus. The patient was sedated by anesthesiology using general anesthesia. Venous access was obtained in the right common femoral vein (CFV) and three sheaths were placed in this vein. A decapolar catheter was advanced into the coronary sinus (CS) and a quadripolar catheter was advanced across the tricuspid annulus to record a His bundle electrogram. Trans-septal access was performed in the usual fashion using a Brockenbrough needle, biplane fluoroscopy, and intracardiac echocardiography. Intravenous unfractionated heparin (UH) was administered by bolus injection just prior to transseptal
ACCEPTED MANUSCRIPT 5 puncture to achieve an ACT of 300-400 seconds per guidelines (9). The ACT was measured regularly throughout the case to maintain an ACT of greater than 400 seconds.
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A multielectrode mapping catheter was used to map the left atrium using a threedimensional (3D) mapping system via the transseptal sheath. This was either a circular catheter or a multi-arm, multielectrode catheter. The PV were then anatomically encircled and
electrically isolated using radio frequency (RF) energy delivered from an open irrigated ablation
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catheter using a wide area catheter ablation (WACA) technique. PVI was considered successful
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when exit and entrance block was demonstrated by 3D mapping and pacing from within the PV. Following completion of ablation, all catheters were removed from the body and protamine sulfate was administered intravenously. All groin sheaths were removed when the ACT had declined to less than 200 seconds. Patients were routinely monitored overnight on telemetry and discharged the following morning.
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All data was organized in Microsoft Excel (Microsoft Corp., Redmond, Washington). Data was stratified based on oral anticoagulation strategy (apixaban vs. warfarin). Summaries for continuous variables are presented as means ± standard deviations. Discrete variables are
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presented as totals with percentages. Comparative analysis was performed with unpaired
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Student’s t-test for continuous variables assuming equal or unequal variance as appropriate. Descriptive statistics were explored utilizing chi-square test to compare demographics and other proportions between groups including sex distribution, race, and type of AF. A P-value of <0.05 was considered significant. RESULTS Between January 7, 2013 and February 25, 2016, a total of 627 patients were analyzed and included in this retrospective study after application of the inclusion and exclusion criteria.
ACCEPTED MANUSCRIPT 6 Baseline characteristics are shown in Table 1. Overall, the groups were reasonably matched. The mean age in the warfarin group was slightly greater than the apixaban group, however the apixaban group mirrored the warfarin group in proportion of patients with a prior history of CVA
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and both groups had similar renal function. Average CHADS2 scores were significantly lower in the apixaban group compared to the warfarin group and LVEF was slightly higher. As
anticipated, the warfarin group had a significantly higher INR, PT, and aPTT prior to the
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procedure.
The relevant procedure related variables are outlined in Table 2. Average heparin doses
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did not differ significantly between groups. Interestingly, the average ACT following initial heparin bolus was lower in the apixaban group, and the minimum ACT during the procedure was subsequently higher in the apixaban group. Average ACT at time of sheath removal did not differ significantly. Procedure time in minutes was slightly longer in the apixaban group. This
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was contrasted by a slightly shorter length of hospital stay in the apixaban group when compared to the warfarin group.
Procedure related complications are outline in Table 3. There was a total of 8
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complications in the warfarin group and 5 in the apixaban group. All complications were related to bleeding. There were no thromboembolic complications in either the warfarin or the
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apixaban group. There was no statistically significant difference in the total complication rate or in subgroup analyses. DISCUSSION
Patients with non-valvular AF have an increased risk of a thromboembolic CVA. Warfarin and, more recently, NOACs are used to lower the risk of CVA in patients with AF (10). Those who continue to have AF activity despite being on anti-arrhythmic therapy are frequently referred for
ACCEPTED MANUSCRIPT 7 AF ablation via a PVI technique (9). Uninterrupted warfarin therapy has been the standard of care in patients undergoing PVI (11,12). Given data showing less bleeding and incidence of stroke with apixaban as compared to warfarin (3), more patients are being switched from
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warfarin to apixaban. As the use of apixaban for CVA prevention increases, the safety of uninterrupted apixaban therapy during AF ablation versus warfarin is an important
consideration. Recent studies have demonstrated that uninterrupted apixaban anticoagulation
further validates the findings of the earlier studies.
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strategy exhibited a similar safety profile to warfarin therapy (4,5,6,7,8). This multi-center study
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Patients in the warfarin cohort were older on average with higher CHADS2 and CHA2DS2VASc scores than their counterparts in the apixaban cohort. However, there were no thromboembolic events in either group and no difference in complications overall. In the ARISTOTLE trial, where groups were well matched, apixaban was found to be superior to
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warfarin for the prevention of CVA (3). Additionally, subgroup analyses in the ARISTOTLE trial demonstrated that in the apixaban group, there was a statistically significant decreased incidence of CVA and bleeding in patients older than 65 as well as a lower CVA incidence in
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patients with a CHADS2 score >3 (3). This suggests that the difference in CVA risk assessment between the two groups likely did not confound the results of the study.
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During AF ablation, the average ACT following initial heparin bolus was lower in the
apixaban group, while minimum ACT throughout AF ablation was higher. This is not unexpected as a recent study demonstrated that patients on warfarin compared to NOACS reached target ACT faster. The study also reported that patients on warfarin required less overall heparin compared to NOACs (13). Our investigation showed that the heparin requirement was the same for both warfarin and apixaban. The difference between our study and the findings expressed by Brienco, et al may be due to the fact they compared warfarin to NOACs in general without
ACCEPTED MANUSCRIPT 8 separating the individual NOACs. Of more interest is the potential advantage of peri-procedural apixaban anticoagulation leading to a more consistent ACT during the procedure in our study. This could, conceivably, lead to a lower risk of complications, although our study did not
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demonstrate this.
Additional differences were noted in baseline characteristics of the two cohorts as
evidenced by the lower LVEF in the warfarin cohort. While it is initially unclear as to why this
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would be, we have anecdotally observed that a greater proportion of cardiomyopathy patients in our institutions appear to have reduced access to care and medication assistance. This may
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result in a larger proportion of these patients electing to pursue warfarin anticoagulation over a NOAC such as apixaban. Higher INR, aPTT and PT values in the warfarin group were expected as a result of the mechanism of action of vitamin K antagonism. Finally, the length of stay was statistically higher in the warfarin group. Given the small difference, we do not feel it
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demonstrates any clinical relevance.
There are several limitations to this study. While the study was multicenter in design, the retrospective nature of this analysis limits conclusions to hypothesis generating in objective.
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In the same regard, given the retrospective design, the study may not have been powered to detect a statistical difference in thromboembolic events. The choice of warfarin or apixaban was
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not randomized, and appears to have introduced some bias into the study in regards to baseline cohort characteristics. Early in the study period, more patients on warfarin underwent uninterrupted therapy during AF ablation than did patients on uninterrupted apixaban therapy. While both centers are experienced, high volume centers, this temporal practice pattern may have resulted in increased operator proficiency as uninterrupted apixaban therapy became more widely implemented at an institutional level. Third, as only the right femoral vein was
ACCEPTED MANUSCRIPT 9 routinely cannulated during the ablation procedure, bleeding risk may be lower than for centers who routinely obtain vascular access in both groins.
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CONCLUSIONS When apixaban is utilized for uninterrupted OAC therapy during AF catheter ablation, a similar safety and efficacy profile is observed when compared to uninterrupted warfarin OAC
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therapy and validates the findings of previous studies. There was no difference in the risk of
bleeding or thromboembolic complications. These data suggest that either agent may be used
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safely and effectively for uninterrupted anticoagulation during catheter ablation of atrial
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fibrillation.
ACCEPTED MANUSCRIPT 10 1. Maddox W, Kay GN, Yamada T, Osorio J, Doppalapudi H, Pulmb VJ, Gunter A, McElderry HT. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2013; 24: 861-865.
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2. Cappato R, Marchlinski FE, Hohnloser SH, Naccarelli GV, Xiang J, Wilber DJ, Ma CS, Hess S, Wells DS, Juang G, Vijgen J, Hugl BJ, Balasubramaniam R, De Chillou C, Davies DW, Fields LE, Natale A; VENTURE-AF Investigators. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists
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for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805-1811.
3. Granger CB, Alexander JH, McMurray JJV, Lopes ED, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J,
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Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L: ARISTOLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N
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Engl J Med 2011;365:981-992.
4. Kuwahara T, Abe M, Yamaki M, Fujieda H, Abe Y, Hashimoto K, Ishiba M, Sakai H, Hishikari K, Takigawa M, Okubo K, Takagi K, Tanaka Y, Nakajima J, Takahashi A. Apixaban versus Warfarin for
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the Prevention of Periprocedural Cerebral Thromboembolism in Atrial Fibrillation Ablation: Multicenter Prospective Randomized Study. J Cardiovascular Electrophysiol 2016; 27: 549-554.
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5. Nagao T, Inden Y, Shimano M, Fujita M, Yanagisawa S, Kato H, Ishikawa S, Miyoshi A, Okumura S, Ohguchi S, Yamamoto T, Yoshida N, Hirai M, Murohara T. Efficacy and Safety of Apixaban in the Patients Undergoing the Ablation of Atrial Fibrillation. Pacing Clin Electrophysiol 2015; 38:155163.
6. Rillig A, Lin T, Plesman J, Heeger CH, Lemes C, Metzner A, Mathew S, Wissner E, Wohlmuth P, Ouyang F, Kuck KH, Tilz RR. Apixaban, Rivaroxaban, and Dabigatran in Patients Undergoing Atrial Fibrillation Ablation. J Cardiovascular Electrophysiol 2016; 27: 147-153.
ACCEPTED MANUSCRIPT 11 7. Di Biase L, Lakkireddy D, Trivedi C, Deneke T, Martinek M, Mohanty S, Mohanty P, Prakash S, Bai R, Reddy M, Gianni C, Horton R, Bailey S, Sigmund E, Derndorfer M, Schade A, Mueller P, Szoelloes A, Sanchez J, Al-Ahmad A, Hranitzky P, Gallinghouse GJ, Hongo RH, Beheiry S,
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Purefellner H, Burkhardt JD, Natale A. Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results from a multicenter study. Heart Rhythm 2015; 12:1162-1168.
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8. Blandino A, Bianchi F, Biondi-Zoccai G, Grossi S, Conte MR, Rametta F, Gaita F. Apixaban for
periprocedural anticoagulation during catheter ablation of atrial fibrillation: a systematic review
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and meta-analysis of 1691 patients. J Interv Card Electrophysiol 2016; 46:225-236. 9. Calkins H, Kuck K, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns, HJ, Daminao RJ Jr, Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Kottamp H, Kumagai K, Lindsay BD, Mansour M, Marchilnski FE, McCarthy PM, Mont JL,
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ACCEPTED MANUSCRIPT 12 11. Wazni OM, Beheiry S, Fahmy T, Barrett C, Hao S, Patel D, Di Biase L, Martin DO, Kanj M, Arruda M, Cummings J, Schweikert R, Saliba W, Natale A. Atrial fibrillation ablation in patients with therapeutic international normalized ratio: Comparison of strategies of anticoagulation
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B, Mohanty S, Elayi CS, Forleo G, Pelargonio G, Narducci ML, Dello Russo A, Casella M, Fassini G, Tondo C, Schweikert RA, Natale A. Periprocedural stroke and bleeding complications in patients
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Table 1. Baseline Demographics and Clinical Parameters
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66.16 ± 9.68 138 (44.52%) 282 (90.97%) 28 (9.03%) 93.08 ± 22.86 34 (10.97%) 1.66 ± 1.12 2.80 ± 1.45 191 (61.61%) 49.2 ± 12% 17.9 ± 9.3 1.2 ± 1.6 2.39 ± 0.55 25.78 ± 5.53 39.56 ± 8.02
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Variable Age (years) Women White Non-white Weight (kg) Prior Cerebrovascular Accident Average CHADS2 (SD) Average CHA2DS2Vasc (SD) Paroxysmal Atrial Fibrillation Left Ventricular Ejection Fraction (%) Blood Urea Nitrogen (mg/dL) Creatinine (mg/dL) International Normalized Ratio Prothrombin Time (sec) Activated Partial Thromboplastin Time (sec) Values are mean±SD or n (%).
Apixaban (n=317)
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Warfarin (n =310)
62.92 ± 11.25 111 (35.02%) 297 (93.69%) 20 (6.31%) 92.56 ± 20.90 34 (10.73%) 1.19 ± 1.08 2.08 ± 1.42 237 (74.76% 54.2 ± 8% 17.1 ± 6.4 2.1 ± 13.5 1.17 ± 0.15 14.77 ± 1.80 32.48 ± 4.63
P-Value
<0.01 0.059 0.72 0.21 0.76 0.92 <0.01 <0.01 0.046 <0.01 0.17 0.22 <0.01 <0.01 <0.01
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Table 2. Procedural Values
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P-Value
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17,281 ± 3982 376 ± 88 315 ± 76 175 ± 37
137.9 ± 49.7 1.08 ± 0.40
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Average heparin bolus at time of 17129 ± 4789 transseptal (IU) 439 ± 145 ACT after heparin bolus (seconds) Minimum ACT during procedure 284 ± 109 (seconds) ACT at time of sheath removal 179 ± 19 (seconds) 129.17 ± 49.75 Procedure time (minutes) 1.21 ± 1.12 Length of stay (days) Values are mean±SD or n (%). ACT = activated clotting time; IU = international units.
Apixaban
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Warfarin
0.67 <0.01 <0.01 0.07 0.02 0.04
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Table 3. Procedure-related Complications P-Value
8 (2.58%) 8 (2.58%) 4 (1.29%) 1 (0.32%) 1 (0.32%) 2 (0.64%) 0 (0%)
5 (1.57%) 5 (1.57%) 3 (0.94%) 2 (0.63%) 0 (0%) 0 (0%) 0 (0%)
0.38 0.38 0.68 0.57 0.31 0.68 ---
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Apixaban
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Total complications Total bleeding complications Significant groin hematoma Pericardial tamponade Retroperitoneal hematoma Hemoptysis Thromboembolic complications Values are n (%).
Warfarin