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Activity OverviewIn this CME-certified activity, designed for electrophysiologists who manage patients with atrialfibrillation, faculty expert, Gerald Naccarelli, MD, discusses the periprocedural management of patients who are receiving novel oral anticoagulants and undergoing cardiac ablation to restore sinus rhythm.

Target Audience

This activity is intended for electrophysiologists.

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Indiana University School of Medicine designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Accreditation / Designation Statements

Disclosure PolicyIn accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, and planning committee members par-ticipating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity.

Indiana University School of Medicine and Med-IQ require any person in a position to control the content of an educational activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as those in any amount occurring within the past 12 months, including those of a spouse/life partner, that could create a conflict of interest (COI). Individuals who refuse to disclose will not be permitted to contribute to this CME activity in any way. Med-IQ has policies in place that will identify and resolve COIs prior to this educational activity. Med-IQ also requires faculty to disclose discussions of investigational products or unlabeled/unapproved uses of drugs or devices regulated by the US Food and Drug Administration.

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Disclosure Statement

The content of this activity has been peer reviewed and has been approved for compliance. The faculty and contributors have indicated the following financial relationships, which have been resolved through an established COI resolution process, and have stated that these reported relationships will not have any impact on their ability to give an unbiased presentation.

Disclosure Statements

Gerald V. Naccarelli, MD Consulting fees/advisory boards: Biosense Webster, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Daiichi Sankyo, Co., Ltd., GlaxoSmithKline, Janssen Pharmaceuticals, Inc., OtsukaAmerica Pharmaceutical, Inc., Pfizer, Inc., Sanofi-aventisU.S. Inc., Xention, Ltd

None of the employees of Med-IQ or Indiana University School of Medicine CME Office who have worked on this activity have any financial relationships to disclose.

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Statement of Need

Atrial fibrillation (AF) is a common cardiac arrhythmia that affects approximately 2% of the population. Because AF confers an increased risk of stroke, one goal in managing these patients is the long-term prevention of thromboembolic events. Cardiac ablation may be required to restore rhythm in patients with AF, and anticoagulation is indicated in the periprocedural period. However, recommendations for patients who are taking novel oral anticoagulants (NOACs) are unclear. Therefore, clinicians need education and guidance to help navigate the challenges of managing patients who are receiving NOACs and undergoing AF ablation.

Statement of Evidence-Based ContentEducational activities that assist physicians in carrying out their professional responsibilities more effectively and efficiently are consistent with the ACCME definition of CME. As an ACCME-accredited provider of CME, it is the policy of Med-IQ to review and ensure that all the content and any recommendations, treatments, and manners of practicing medicine in CME activities are scientifically based, valid, and relevant to the practice of medicine. Med-IQ is responsible for validating the content of the CME activities it provides. Specifically, (1) all recommendations addressing the medical care of patients must be based on evidence that is scientifically sound and recognized as such within the profession; (2) all scientific research referred to, reported or used in CME in support or justification of a patient care recommendation must conform to generally accepted standards of experimental design, data collection and analysis.

Med-IQ is not liable for any decision made or action taken in reliance upon the information provided through this activity.

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To receive credit, read the introductory CME material, participate in the Audiocast, and complete the evaluation, attestation, and post-test, answering at least 70% of the post-test questions correctly.

The evaluation, attestation, and post-test will be accessible by clicking the “Get Credit” tab at the bottom of the Audiocast at the conclusion of the activity.

Call (toll-free) 866 858 7434E-mail info@med-iq.com

Please visit us online at www.Med-IQ.com for additional activities sponsored by Med-IQ.

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Contact Information

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Acknowledgment of Commercial Support

This activity is supported by an educational grant from Janssen Pharmaceuticals, Inc., administered by Janssen Scientific Affairs, LLC.

Copyright© 2015 Med-IQ. All rights reserved.

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Learning Objective

Upon completion, participants should be able to:� Compare the outcomes associated with standard of care

(VKAs) versus NOACs in patients undergoing AF ablation

Gerald V. Naccarelli, MD Professor of Medicine

Bernard Trabin Chair in Cardiology

Chief, Division of Cardiology

Associate Clinical Director, Heart and Vascular Institute

Milton S. Hershey Medical Center

Pennsylvania State University College of Medicine

Hershey, PA

Faculty

Activity PlannerChristie Avraamides, PhDClinical Content ManagerMed-IQBaltimore, MD

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Case Study

• JW is a 70-year-old woman who has a 3-year history of symptomatic paroxysmal AF

• She has a history of hypertension, which is controlled with metoprolol succinate 50 mg daily

• She has been on rivaroxaban 20 mg daily (taken with dinner) for the last 2 years

• Her AF episodes improved on flecainide 150 mg twice daily

• However, recently her symptomatic episodes have become more frequent, and she has decided to proceed with a catheter ablation procedure

AF Ablation Procedure Risks

• Embolic risks– Embolic CVA or TIA (manifest or silent), SE

• Mechanical risks– Phrenic or vagal nerve injury, esophageal injury

• Bleeding risks– Hemorrhagic stroke, groin bleeding, retroperitoneal

hematoma, pericardial tamponade– In a study with 4,156 patients, 5% had periprocedural

complications, most commonly vascular, after initial AF ablation

– Anticoagulation during an AF procedure is necessary to minimize embolic events, yet must be done safely to minimize bleeding events

> 200,000 AF ablations are performed globally every year

Shah R, et al. J Am Coll Cardiol. 2012;59:143-9.

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Oral Anticoagulation and Catheter Ablation for AF

• Anticoagulation is crucial for periprocedural safety and quality outcomes

• Compared with warfarin, NOACs offer– Predictable pharmacokinetics– Shorter half-lives– More convenient and efficient periprocedural

management • Although not a well-studied gold standard,

warfarin has been used in tens of thousands of AF ablation cases, and an uncontrolled body of data exists for its safety and efficacy

Weitz JI, et al. Circulation. 2014;129:1688-94.

Case Study

• Before the procedure, JW is told to continue her rivaroxaban and take her medication the night before the ablation

• She undergoes a cardiac MRI to assess LA and pulmonary vein anatomy 1 week before the procedure

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Proper Anticoagulation Strategy for AF Ablation: Many “Moving Parts”

• Pre-ablation anticoagulation routine• Interrupted or uninterrupted approach• ACT during ablation• Length and aggressiveness of procedure• Paroxysmal, persistent, or long-standing

persistent AF• Postprocedural anticoagulation routine• Renal function or other comorbidities affecting

dose selection

Naccarelli GV, et al. J Int Card Electrophysiol. 2013;36:3-4.

Strategies to Manage Anticoagulation Before, During, and After Ablation

• Interrupted Warfarin– Before ablation

• 5 days prior to procedure: • Stop warfarin • Bridge with LMWH

• 12 hours before procedure: • Stop LMWH

– During ablation• Administer heparin• Achieve an ACT > 300 s

– After ablation• Stop heparin • Consider protamine• Remove sheath when ACT is < 250 s• Restart warfarin and bridge with LMWH

until INR is therapeutic• Reevaluate at 3 months

• Uninterrupted Warfarin– Before ablation

• Continue warfarin– During ablation

• Administer heparin• Achieve an ACT > 300 s

– After ablation• Stop heparin • Consider protamine• Remove sheath when ACT is < 250 s• Continue warfarin • Reevaluate at 3 months

• Interrupted NOAC– Before ablation

5 days or more before procedure:• Stop NOAC • Switch to warfarin or bridge with LMWH

– During ablation• Administer heparin• Achieve an ACT > 300 s

– After ablation• Stop heparin • Consider protamine• Remove sheath when ACT is < 150 s• Resume NOAC 6-8 hours after sheath removal• Reevaluate at 3 months

• Minimally Interrupted or Uninterrupted NOAC – Before ablation

• 12-24 hours before procedure: • Stop NOAC

– During ablation• Administer heparin• Achieve an ACT > 300 s

– After ablation• Stop heparin• Consider protamine • Remove sheath when ACT is < 250 s• Resume NOAC 6-8 hours after sheath removal• Reevaluate at 3 months

Weitz JI, et al. Circulation. 2014;129:1688-94.

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Dabigatran: AF Ablation*Minimally Interrupted (Winkle) Interrupted (Bassiouny )

Primary Outcome

TE events, bleeding, side effects over 30-day follow-up

Safety

N 123 376 on dabigatran623 on uninterrupted warfarin344 in each group propensity matched

Pre-Ablation Anticoagulation

45.5% warfarin (discontinued 5 days PP with LMWH bridge started 3 days PP)27.6% dabigatran (discontinued 36-60 hrs PP depending on renal function; no bridge)21.1% aspirin (no bridge)5.7% no anticoagulant (no bridge)

Dabigatran held 1-2 doses before protocol

During Ablation Heparin (target ACT = 225 s) Heparin (target ACT = 350-450 s

Post Ablation 2 doses of enoxaparin (immediately post ablation and 12 hours); dabigatran started 22 hours after the procedure

Dabigatran restarted at the conclusion of procedure

Results No TE or hemorrhagic events3 patients discontinued dabigatran for dyspepsia, diarrhea, or rash

Hemorrhagic/TE complications: 3.2% vs 4.1% (P = 0.53) Major hemorrhage: 1.2% vs. 1.5% (P = 0.74), in dabigatran vs warfarin group, respectivelyTEE: 1 in each arm

Despite higher levels of intraprocedural heparin, the mean ACT was lower in dabigatran patients

Winkle R. J Cardiovasc Electrophysiol. 2012;23:264-8; Bassiouny M, et al. Circulation. 2013;6:460-6.*Off-label use; not FDA approved in this setting.

• Multicenter, observational study from a prospective registry including all consecutive patients undergoing AF ablation in 8 high-volume centers in the US

• 145 patients on uninterrupted warfarin (INR 2.0-3.0)

• 145 patients on dabigatran (taken the night before, held on morning of ablation, resumed within 3 hrs after hemostasis)

• Intraprocedural ACT of 300-400 seconds• Dabigatran was an independent multivariate predictor of bleeding or thromboembolic

complications (OR, 2.76; P = 0.01)

Uninterrupted Dabigatran* vs Warfarin in AF Ablation

Lakkireddy D, et al. J Am Coll Cardiol. 2012;59:1168-74.

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P = 0.009P = 0.03

Thromboembolism Major Bleeding

TotalBleeding

Composite of Total Bleeding and TE

P = 0.02

DabigatranWarfarin

*Off-label use; not FDA approved in this setting.

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Meta Analysis: Warfarin, Rivaroxaban, and Dabigatran (N = 3,575)

Warfarin Rivaroxaban Dabigatran

TEE 0.4% 0.4% 0.4%

MajorHemorrhage

2.3% 1.2% 1.6%

Raj Aryal M, et al. Am J Cardiol. 2014;114:577-82.

Is It All About Timing?

Lakkireddy, et al.

• Dabigatran 150 mg held morning of PVI

• Resumed 3 hours after sheath pull

Winkle, et al.

• Dabigatran stopped 36 hours pre-ablation (if normal renal function)

• Enoxaparin 0.5 mg/kg Q12 hours x 2 doses

• Dabigatran restarted 22 hours post-PVI (renally dosed)

Courtesy of J Piccini.Lakkireddy D, et al. J Am Coll Cardiol. 2012;59:1168-74; Winkle RA, et al. J Cardiovasc Electrophysiol. 2012;23:264-8.

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Case Study

• During the procedure, JW is given 10,000 units IV heparin before transeptal puncture, and her heparin boluses are given to achieve an ACT > 300 seconds; ACT is measured every 20 minutes during the procedure

• Utilizing ICE, fluoroscopy, intracardiac electrogram, and mapping system guidance, all 4 pulmonary veins are electrically isolated using radiofrequency catheter ablation

Case Study

• After completion of the procedure, no further doses of heparin are given; IV protamine is given, and her ACT is monitored

• Sheaths are pulled when her ACT < 200 seconds• JW is placed on bedrest with IV fluids for 6 hours• A postprocedure ECG is obtained, and JW is

monitored in the postprocedure telemetry unit

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VENTURE-AF: Uninterrupted Rivaroxaban* vs Warfarin

• Primary endpoint was the number of major bleeding events measured by the occurrence of at least 1 of 3 adjudicated definitions: GUSTO, ISTH, or TIMI

• Secondary endpoints included the composite of stroke, SE, MI, and vascular death events, as well as other complications

• If pre-ablation anticoagulation duration was < 4 weeks, a planned TEE or ICE were required to exclude intracardiac thrombus

Naccarelli GV, et al. J Interv Card Electrophysiol. 2014;41:107-16;Cappato R, et al. Eur Heart J. 2015;36:1805-11.

N = 248 Adults With

Nonvalvular AF Undergoing

Catheter Ablation

Randomization(1:1)

Catheter AblationACT 300-400 s

(300-325 recommended)

End of Study

Uninterrupted Rivaroxaban20 mg once daily

(with evening meal recommended)

Uninterrupted VKADose-adjusted

(INR 2.0-3.0 recommended)

Next dose at ≥ 6 hrs after establishing hemostasis

Next dose administered as per usual care

Up to 5 Weeks Approximately 4 Weeks

*Off-label use; not FDA approved in this setting.

VENTURE-AF: Results

• 248 patients randomized (124 on rivaroxaban, 124 on VKA)• Major complication rates

– The incidence of primary safety events was low and similar (0.4%; 1 event in VKA group and 0 in rivaroxaban group)

– The incidence of composite TEs was low and similar (0.8%; 2 events in VKA group and 0 in rivaroxaban group)

• The overall complication rate was 20.6%• The rivaroxaban group required a mean of 13,871 units of heparin to

achieve a mean ACT of 302 seconds vs the warfarin arm, which used a mean of 10,964 units of heparin to achieve a mean ACT of 332 seconds (P < 0.001 for both)

• The number of bleeding and thromboembolic complications in nonvalvular AF patients using uninterrupted rivaroxaban was low and similar to warfarin; the use of uninterrupted rivaroxaban in nonvalvular AF patients undergoing catheter ablation is feasible and medically practical

Cappato R, et al. Eur Heart J. 2015;36:1805-11.

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Uninterrupted Apixaban* vs Warfarin: Safety

• 400 patients (200 on apixaban, 200 on warfarin)• No bridging with LMWH• No statistical differences regarding major and minor complications or total bleeding

between apixaban and warfarin groups– Major bleeding complications (n = 2 [1.0%] apixaban vs n = 1 [0.5%] warfarin; P =

1.00)– Early pericardial effusion (n = 1 [0.5%] apixaban vs n = 1 [0.5%] warfarin; P = 1.00)– Delayed pericardial effusion (n = 1 [0.5%] apixaban vs n = 0 [0%] warfarin; P = 1.00)– Minor bleeding complications (n = 7 [3.5%] apixaban vs n = 5 [2.5%] warfarin; P =

0.56)– Pericardial effusion without tamponade and no clinical relevance (n = 3 [1.5%]

apixaban vs n = 2 [1.0%] warfarin; P = 1.00)– Groin hematoma (n = 3 [1.5%] apixaban vs n = 2 [1.0%] warfarin; P = 1.00)– Total bleeding complications (n = 9 [4.5%] apixaban vs n = 6 [3.0%] warfarin; P =

0.43)– Thromboembolic complications (n = 0 [0%] apixaban vs n = 0 [0%] warfarin)– Composite of bleeding and embolic complications (n = 9 [4.5%] apixaban vs n = 6

[3.0%] warfarin; P = 0.43)

Di Biase L, et al. Heart Rhythm. 2015;12:1162-8.*Off-label use; not FDA approved in this setting.

Ongoing Trials Assessing Safety of NOACs for AF Ablation

• AXAFA (apixaban) (NCT02227550): 650 patients in a PROBE design– Composite of all-cause death, stroke, and

major bleeding events • RE-CIRCUIT (dabigatran) (NCT02348723): 724

patients randomized to uninterrupted dabigatran 150 mg twice daily vs warfarin– Major bleeding events (ISTH) and TEs during

ablation and 2 months of follow-up

Clinicaltrials.gov: NCT02227550; Clinicaltrials.gov: NCT02348723.

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Anticoagulation for AF Ablation

• Uninterrupted warfarin remains the standard in clinical practice; however, no powered prospective RCT totally supports this approach

• Interrupted dabigatran and uninterrupted Xainhibition show promise

• There are “moving parts” surrounding an AF ablation procedure in addition to which anticoagulant is used

• Current RCTs for NOACs are not powered for an approved indication

Case Study: Conclusion

• JW is given her evening dose of rivaroxaban with dinner the night of the procedure, and her metoprolol is also started

• She ambulates without difficulty or groin bleeding within 6-8 hours after the procedure

• She is discharged the next morning on rivaroxaban and metoprolol succinate

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To receive credit, read the introductory CME material, participate in the Audiocast, and complete the evaluation, attestation, and post-test, answering at least 70% of the post-test questions correctly.

The evaluation, attestation, and post-test will be accessible by clicking the “Get Credit” tab at the bottom of the Audiocast at the conclusion of the activity.

Call (toll-free) 866 858 7434E-mail info@med-iq.com

Please visit us online at www.Med-IQ.com for additional activities sponsored by Med-IQ.

Instructions to Receive Credit

Contact Information

© 2015

Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors.