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Feasibility And Safety of uninterrupted periprocedural Apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results From a Multicenter Study Luigi Di Biase MD, Ph.D., Dhanujaya Lakkireddy MD, Chintan Trivedi MD, MPH, Thomas Deneke MD, Martin Martinek MD, Sanghamitra Mohanty MD, Prasant Mohanty MBBS, MPH, Sameer Prakash BS, Rong Bai MD, Madhu Reddy MD, Carola Gianni MD, Rodney Horton MD, Shane Bailey MD, Elisabeth Sigmund MD, Michael Derndorfer MD, Anja Schade MD, Patrick Mueller MD, Atilla Szoelloes MD, Javier Sanchez MD, Amin AlAhmad MD, Patrick Hranitzky MD, G. Joseph Gallinghouse MD, Richard H. Hongo MD, Salwa Beheiry RN, Helmut Pürerfellner MD, J. David Burkhardt MD, Andrea Natale MD

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S1547-5271(15)00248-9 http://dx.doi.org/10.1016/j.hrthm.2015.02.028 HRTHM6146

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Heart Rhythm

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Cite this article as: Luigi Di Biase MD, Ph.D., Dhanujaya Lakkireddy MD, Chintan Trivedi MD, MPH, Thomas Deneke MD, Martin Martinek MD, Sanghamitra Mohanty MD, Prasant Mohanty MBBS, MPH, Sameer Prakash BS, Rong Bai MD, Madhu Reddy MD, Carola Gianni MD, Rodney Horton MD, Shane Bailey MD, Elisabeth Sigmund MD, Michael Derndorfer MD, Anja Schade MD, Patrick Mueller MD, Atilla Szoelloes MD, Javier Sanchez MD, Amin Al-Ahmad MD, Patrick Hranitzky MD, G. Joseph Gallinghouse MD, Richard H. Hongo MD, Salwa Beheiry RN, Helmut Pürerfellner MD, J. David Burkhardt MD, Andrea Natale MD, Feasibility And Safety of uninterrupted peri-procedural Apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results From a Multicenter Study, Heart Rhythm, http://dx. doi.org/10.1016/j.hrthm.2015.02.028

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Feasibility And Safety of uninterrupted peri-procedural Apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results From a Multicenter Study Luigi Di Biase* † ‡ §, MD, PhD; Dhanujaya Lakkireddy‖‖, MD, Chintan Trivedi*, MD, MPH, Thomas Deneke¶, MD, Martin Martinek#, MD, Sanghamitra Mohanty*, MD, Prasant Mohanty*, MBBS, MPH, Sameer Prakash††,,BS, Rong Bai*, MD, Madhu Reddy, MD‖‖; Carola Gianni*, MD; Rodney Horton*, MD, Shane Bailey*, MD, Elisabeth Sigmund#, MD, Michael Derndorfer#, MD, Anja Schade¶, MD; Patrick Mueller¶, MD; Atilla Szoelloes¶, MD; Javier Sanchez*, MD, Amin Al-Ahmad*, MD, Patrick Hranitzky*, MD, G. Joseph Gallinghouse*, MD, Richard H. Hongo‡‡, MD, Salwa Beheiry‡‡,RN, Helmut Pürerfellner#, MD, J. David Burkhardt*, MD, Andrea Natale*‡ ‡‡ §§ ***

†††

, MD

Affiliations: * Texas Cardiac Arrhythmia Institute at St David’s Medical Center, Austin, TX, USA † Albert Einstein College of Medicine at Montefiore Hospital, New York, New York ‡ Department of Biomedical Engineering, University of Texas, Austin, Texas § Department of Cardiology, University of Foggia, Foggia, Italy ‖‖ Division of Cardiovascular Diseases, Cardiovascular Research Institute, Mid America Cardiology, University of Kansas Hospital & Medical Center, Kansas City, KS ¶ Klinik für Kardiologie mit interventioneller Elektrophysiologie, Herz- und Gefäßklinik Bad Neustadt a. d. Saale, Salzburger Leite 1, 97616, Bad Neustadt a. d. Saale, Germany # Elisabehinen University Teaching Hospital Linz, Austria †† Texas College of Osteopathic Medicine, Fort worth, Texas ‡‡ California Pacific Medical Center, San Francisco, CA §§ Division of Cardiology, Stanford University, California *** Case Western Reserve University, Cleveland, Ohio ¶¶ Interventional Electrophysiology, Scripps Clinic, San Diego, California

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Corresponding author: Andrea Natale, MD, FACC, FHRS, FESC Executive Medical Director of the Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, Texas. Consulting Professor, Division of Cardiology, Stanford University, Palo Alto, California. Clinical Associate Professor of Medicine, Case Western Reserve University, Cleveland, Ohio. Director, Interventional Electrophysiology, Scripps Clinic, San Diego, California. Senior Medical Director EP and Arrhythmia Services, California Pacific Medical Center, San Francisco, California.

Address: 3000 N. I-35, Suite 720; Austin, TX 78705 Email: [email protected] Office phone: +15125448186 Fax: +15125448184

Conflict of Interest Disclosures: Dr. Di Biase is a consultant for Biosense Webster, Boston Scientific and St Jude Medical. Dr Di Biase received speaker honoraria/travel from Medtronic, Atricure, EPiEP and Biotronik. Dr. Natale received speaker honorariums from Boston Scientific, Biosense Webster, St. Jude Medical, Biotronik and Medtronic. Dr Natale is a consultant for Biosense Webster St Jude Medical and Janssen. Dr. Burkhardt is a consultant for Stereotaxis, Biosense Webster, and Boeringer-Ingelheim. All the remaining authors have no disclosures. Funding: No funding

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Keywords: Atrial fibrillation, Catheter Ablation, Anticoagulants, Warfarin, Stroke, Silent Thromboembolic lesions;

Word Count: 4593

Abbreviations: ACT = Activated clotting time; CHADS2 = Congestive heart failure; hypertension; age ≥75 years; type 2 diabetes; and previous stroke, transient ischemic accident or thromboembolism score; CHA2DS2VASc = Congestive heart failure; hypertension; age ≥75 years; type 2 diabetes; previous stroke, TIA, or thromboembolism; vascular disease; age 65–75 years; and sex category dMRI = diffusion magnetic resonance imaging; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history, Labile international normalized ratio (INR), Elderly (age >65 years), drugs or alcohol concomitantly; INR =International normalized ratio; PVAI = Pulmonary vein antral isolation; SCI=Silent cerebral ischemia; TEE = Transesophageal echocardiography TIA = Transient ischemic attack;

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Abstract: Background: Periprocedural anticoagulation management with uninterrupted warfarin with a “therapeutic INR” represents the best approach reducing both thromboembolic and bleeding complications in the setting of catheter ablation for atrial fibrillation (AF). Objective: The purpose of this study was to evaluate the safety and feasibility of uninterrupted apixaban in this setting. Methods: This was a prospective multicenter registry of AF patients undergoing radiofrequency catheter ablation at 4 Institutions in USA and Europe with an uninterrupted apixaban. These patients were compared with an equal number of patients, matched for age, gender and type of AF, undergoing AF ablation on uninterrupted warfarin. The apixaban group comprised of consecutive patients that had their last dose of apixaban the morning of the procedure. A subset of 29 patients underwent dMRI to detect silent cerebral ischemia (SCI) in the apixaban group. Results: A total of 400 patients (200 patients in each group) were included in the study. The average age was 65.9 ± 9.9 years with 286 (71.5%) male and 334 (83.5%) patients having non paroxysmal AF. There were no statistical differences in major (1% vs. 0.5%,p=1.0), minor (3.5% vs. 2.5%,p=0.56) and total bleeding complications (4.5% vs. 3%,p=0.43) between the apixaban and the warfarin group respectively. There were no symptomatic thromboembolic complications. All the dMRIs were negative for “new” SCI in the apixaban group. Conclusions: Uninterrupted apixaban administration in patients undergoing AF ablation, appears to be feasible, and effective in preventing clinical and silent thrombo-embolic events without increasing the risk of major bleedings.

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Introduction: Catheter ablation represents a valid therapeutic option for the treatment of atrial fibrillation (AF) (1). The procedure is relatively complex, and often outcomes are related to the operator experience. Both bleeding and thrombo-embolic events represent the most dangerous periprocedural complications (2-6). Periprocedural anticoagulation management with uninterrupted warfarin with a “therapeutic INR” represents the best approach reducing both thromboembolic and bleeding complications especially in patients with non-paroxysmal atrial fibrillation (7-9). In addition, uninterrupted warfarin protects against silent cerebral ischemia (SCI) (10). In recent years new oral anticoagulants have been introduced for the stroke prevention of patients with AF (11-14). These drugs have shown non-inferiority to warfarin to prevent stroke without increasing the bleeding risk. No randomized study evaluating the safety and feasibility of these drugs in the setting of ablation of AF has been published (15). Non-randomized studies have evaluated the safety and feasibility of dabigatran and xarelto in the setting of AF ablation (16-23). Little data is available in regards to Apixaban ,(direct factor Xa inhibitor) the latest oral anticoagulant approved for the prevention of thrombo-embolism in patients with non-valvular AF in the setting of AF ablation (15, 16). We sought to evaluate in this prospective multicenter study, the safety and feasibility of uninterrupted apixaban administration in the setting of catheter ablation for AF.

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Methods: We performed a prospective multicenter registry of AF patients undergoing their first radiofrequency catheter ablation at 4 Institutions in USA and Europe between June 2013 and July 2014 with uninterrupted apixaban administration. This was not a randomized controlled trial. The study protocol was approved by the institutional review board and informed consent was obtained from all patients. The apixaban group comprised of all consecutive patients who were on twice daily 5 or 2.5 mg Apixaban for at least 30 days prior to the catheter ablation procedure. These patients were compared with an equal number of patients, matched for age, gender, type of AF, undergoing ablation on uninterrupted warfarin (with a “therapeutic INR”) during the same time period. Peri-procedural anticoagulation regimen Apixaban was prescribed at doses of 5 mg or 2.5 mg, twice a day based on the creatinine clearance and others high-risk features as directed in the package insert (age, weight, and serum creatinine) (19). Patients were asked to take their apixaban dose the morning of the procedure without any discontinuation and to take their dose the same night of the procedure. Patients had to be on apixaban for at least three weeks prior to the procedure. No bridging with low weight molecular heparin was allowed. Transesophageal echocardiogram (TEE) the morning of the procedure was not mandated by protocol. In the warfarin group, AF ablation was performed without discontinuation. Each patient was asked to maintain a “therapeutic” INR for at least three weeks prior to the procedure (7,9). Outpatient monitoring of the INR was performed by the nursing stuff.

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Patients in the warfarin group did not undergo TEE unless they had an INR 300 secs when compared to uninterrupted warfarin. Although only a few effusions occurred in the apixaban group, we showed that PCC-4 (K centra) was able to successfully reverse the apixaban effect and effusions were treated conservatively. Randomized controlled trial comparing uninterrupted warfarin strategies vs uninterrupted noacs are on their way and will solve some but not all unanswered questions.

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Tables: Table 1.

Comparison of Baseline Demographics, Clinical parameters, Medication Use between Patients on Apixaban and Warfarin Characteristics

Apixaban

Warfarin

p-value

(N=200)

(N=200)

Age (years)

65.9 ± 9.9

65.9 ± 9.9

1.0

Male

143 (71.5)

143 (71.5)

1.0

Caucasian

183 (91.5)

187 (93.5)

0.45

Body Mass Index

29.4 ± 6.0

30.1 ± 6.5

0.25

Paroxysmal AF

33 (16.5)

33 (16.5)

Persistent AF

117 (58.5)

117 (58.5)

Long-standing Persistent AF

50 (25.0)

50 (25.0)

Duration of AF, Median (Interquartile range)

36 (10.5, 84)

36 (12.0, 96)

0.62

Heart Failure

23 (11.5)

19 (9.5)

0.51

Hypertension

136 (68.0)

138 (69.0)

0.82

Coronary Artery Disease

29 (14.5)

29 (14.5)

1.0

Dyslipidemia

106 (53.0)

114 (57.0)

0.42

Sleep Apnea

22 (11.0)

14 (7.0)

0.16

Transient Ischemic attack/ Stroke

11 (5.5)

10 (5.0)

0.82

Diabetes

37 (18.5)

39 (19.5)

0.80

Chronic Renal Insufficiency

14 (7.0)

8 (4.0)

0.19

CHADS2 score

1.28 ± 0.9

1.27 ± 0.8

0.95

Demographics

Medical History Type of AF 1.0

CHADS2 score

0.89 21

0

39 (19.5)

36(18.0)

1

82 (41.0)

85 (42.5)

≥2

79 (39.5)

79 (39.5)

CHA2DS2 -VASc score

2.28 ± 1.4

2.30 ± 1.4

0.88

HAS-BLED score

1.74 ± 0.98

1.74 ± 0.94

0.96

Left Atrial size(cm)

4.5 ± 0.8

4.5 ± 0.9

0.73

LV ejection fraction (%)

56.1 ± 9.4

56.9 ± 10.6

0.48

Aspirin

56(28.0)

67 (33.5)

0.23

Clopidogrel

5 (2.5)

10 (5.0)

0.19

ACE inhibitors/ARBs

56 (28.0)

50 (25.0)

0.50

Digoxin

29 (14.5)

35 (17.5)

0.41

Statins

93 (46.5)

93 (46.5)

1.00

Pre-procedure Echo Parameters

Medications

Values are reported as Mean ± SD, n (%), or median (interquartile range). ACE: angiotensin-converting enzyme; AF: atrial fibrillation; ARB: angiotensin receptor blocker; LV: Left Ventricular.

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Table 2. Comparison of Procedural Characteristics between Patients on Apixaban and Warfarin

Apixaban

Warfarin

(N=200)

(N=200)

Baseline INR

1.90 ± 0.5

2.46 ± 0.5

Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results from a multicenter study.

Periprocedural anticoagulation management with uninterrupted warfarin and a "therapeutic" international normalized ratio is the best approach for redu...
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