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Dabigatran for Atrial Fibrillation: Cardioversion and Ablation July 18, 2013 Marti Larriva, PharmD Candidate

Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

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The presentation covers background information regarding atrial fibrillation (A-fib) and the use of oral anticoagulant dabigatran surrounding cardioversion and ablation for A-fib. The information surrounds a patient case in which the patient prefers dabigatran over warfarin. Available literature on the topic is analyzed to make a patient specific recommendation.

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Page 1: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Dabigatran for Atrial Fibrillation: Cardioversion and

AblationJuly 18, 2013

Marti Larriva, PharmD Candidate

Page 2: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Outline• Patient Case• Background• Literature• Summary• Patient Case

Page 3: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Patient Case• Medications:

o ASA 325 mg o Lisinopril 40 mg dailyo Sotalol 160mg PO BID (HELD)

• CHADS2 = 1• CrCl = 90mL/min• Cardiology consult

o Diltiazem and heparin drip started

o Plan for TEE and cardioversiono Patient does not want

warfarin, was offered dabigatran and wants it instead.

• Mr. W 64 y/o male admitted with a chief complaint of chest pain, heart palpitations, and DOE x 1 weeko EKG shows A. fib with RVR

• PMH: HTN, sleep apnea, paroxysmal A. fib., and obesity

Vitals

Temperature 98.06

Pulse 100

Respiration 18

Blood Pressure

120/82

Page 4: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Clinical Question• What is the role of dabigatran as an anticoagulant

during cardioversion or ablation for atrial fibrillation?

Page 5: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

BackgroundAtrial Fibrillation

Cardioversion/AblationDabigatran

Page 6: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Atrial Fibrillation

Page 7: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Atrial FibrillationPathophysiology Pulmonary vein reentry circuits

Reversible Causes Cardiac surgery, pericarditis, myocardial infarction, hyperthyroidism, pulmonary embolism, pulmonary disease, and excessive alcohol ingestion

Symptoms Common - palpitations, tachycardia, weakness, dizziness, lightheadedness, reduced exercise capacity, mild dyspnea

Severe - dyspnea at rest, angina, presyncope, syncope, embolic event, right sided heart failure

Classification Paroxysmal ≥ 2 episodes that terminates spontaneously in 7 days or less

PersistentAF that does NOT terminate after 7 days

Permanent AF for which cardioversion has failed or not been attemptedCheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013

Page 8: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Atrial FibrillationTreatment• General

o Treat any underlying reversible causeso Slow ventricular rate – beta blockers, non-DHP calcium channel

blockers o Convert to normal sinus rhythm – direct current, pharmacologico Prevent recurrences – ablation o Prevent stroke/improve survival – anticoagulation

• Congestive Heart Failure, Hypertension, Age > 75, Diabetes, StrokeCHADS2 Score Events per 100 patient years OR % per

year

0 0.49

1 1.52

2 2.50

3 5.27

4 6.02

5 or 6 6.88

Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013

Go AS,   Hylek  EM,   Chang Y,  et al.  JAMA. 2003;290(20):2685-2692

Page 9: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Cardioversion• Direct current or antiarrhythmic to return to NSR

• Stroke risk post-cardioversion is 1-5% over 1 montho Higher than baseline risk of 1-6% over 1 year

Reasons to Cardiovert Reasons NOT to Cardiovert

Unstable hemodynamics or worsening symptoms due to AF

Minimally symptomatic

First episode, irrespective of long term control strategy

Multiple comorbidities OR Overall poor prognosis

Duration of AF Pre-Cardioversion Post-Cardioversion

≤ 48 h LMWH/UFH at therapeutic doses on presentation

Oral Anticoagulation x 4 weeks Stop/Continue based on rhythm

> 48h TEE and/orOral Anticoagulation x 3 weeks

Oral Anticoagulation x 4 weeks Stop/Continue based on rhythm

Naccarelli G, Ganz L, Manning W. Restoration of sinus rhythm in atrial fibrillation.In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013

You JJ, Singer DE, Howard PA et al. Chest.2012;141(2 Suppl):e531S-75S.

Page 10: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Ablation• Radiofrequency catheter ablation is applied to

pulmonary veins suspected of initiating AF. o Success ranges from 50-80%

• Complications:o Periprocedural Embolism (CVA/TIA) – 0.5 - 2.0% o Cardiac tamponade > 1%

• Most frequent cause of deatho Pulmonary vein stenosis 1.0 - 3.0%

• No clear anticoagulation strategy

o Continuous warfarin therapy shown to be safe and effectiveo Unclear safety and efficacy of dabigatran

Passman, R. Radiofrequency ablation to prevent recurrent atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.

Page 11: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

DabigatranMechanism Direct thrombin inhibitor

Pharmacokinetics Time to peak – 1 hourExcreted 80% in urineMetabolized to active form by plasma/hepatic esterases

Dosage forms 75mg, 150mg

Renal dose adjustment

> 50 mL/min: no dose adjustment 30-50 mL/min adjust dose in concomitant

interacting medication that increases dabigatran concentrations

15-30 mL/min: 75 mg PO BID < 15mL/min: avoid use

FDA-approved uses Nonvalvular atrial fibrillation

Non FDA-approved uses

Postoperative thomboprophylaxis (knee/hip replacement)

Contraindications Mechanical prosthetic heart valvesActive bleeding*Severe renal impairment (CrCl <30 mL/min)*Both Canadian labeling and ACCP list CrCl <30mL/min as a contraindication to

dabigatran use. Dabigatran: Lexicomp Drug information. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.

Page 12: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

LiteraturePericardioversion – posthoc of 1 RCTPeriablation – 2 case-control studies

Page 13: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

RE-LYDesign Post-hoc analysis of a prospective, randomized, controlled,

multi - center study

Inclusion • Documented AF (paroxysmal or persistent) PLUS one of the following:• History of previous stroke, TIA, or systemic embolism• EF < 40%• Symptomatic heart failure (≥ NYHA class II)• Age 75 years• Age 65 years and DM (on treatment), CAD, or HTN (on

treatment) AND• Underwent cardioversion during the RCT

Exclusion Severe heart valve disorderStroke within 14 days OR severe stroke within last 6 monthsConditions that increased the risk of hemorrhageCrCl < 30 mL/minReversible cause of A. fib.Plan for ablation

Connolly SJ, Ezekowitz MD, Yusuf S et al.  N Engl J Med. 2009;361(12):1139-51

Nagarakanti R, Ezekowitz MD, Oldgren J et al.  Circulation. 2011;123(2):131-6.

Page 14: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

RE-LYTreatment Warfarin titrated to an INR of 2.0-3.0

ORDabigatran 110 mg BID ORDabigatran 150 mg BID

Major Outcomes Stroke, systemic embolism, and major bleeding within 30 days of cardioversion

Connolly SJ, Ezekowitz MD, Yusuf S et al.  N Engl J Med. 2009;361(12):1139-51

Nagarakanti R, Ezekowitz MD, Oldgren J et al.  Circulation. 2011;123(2):131-6.

Page 15: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

ResultsOutcom

eCardioversi

on Dabigatran 110

mg

Dabigatran 150

mg

Warfarin

P-value

D110 vs. W

D150 vs. W

Stroke & systemic embolism 30 days post

All 0.77%(N = 647)

0.30%(N = 672)

0.60%(N = 664)

0.71 0.45

First 0.48%(N = 413)

0.48%(N = 421)

0.46%(N = 436)

0.96 0.97

Major Bleeding

All 1.7%(N = 647)

0.60%(N = 672)

0.60%(N = 664)

_ _

First 2.66%(N = 413)

0.48%(N = 421)

0.46%(N = 436)

0.009 0.97*6/11 (54%) of patients with major bleeding in the dabigatran 110 mg group were taking concomitant aspirin and clopidogrel, no other groups has patients taking both.

Nagarakanti R, Ezekowitz MD, Oldgren J et al.  Circulation. 2011;123(2):131-6.

Page 16: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Author’s Conclusions• RE-LY was not powered to detect a difference in

stroke and systemic embolism among groups undergoing cardioversion.o At 80% power and 0.05 significance 15,000 – 40,000 cardioversions

assuming stroke and embolism rates of 0.6% in the warfarin arm and between 0.3% and 0.4% in the D150 arm.

• Major bleeding rates were similar among all groups, but highest in the D110 group.

• Warfarin and dabigatran are comparable in this setting.

Nagarakanti R, Ezekowitz MD, Oldgren J et al.  Circulation. 2011;123(2):131-6.

Page 17: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

AnalysisStrengths Limitations

• Large, randomized, controlled trial

• Intention to treat analysis

• Posthoc analysis• Not powered to find

difference in stroke and embolism

• Did not address lack of reversal agent for dabigatran

• Sponsored by manufacturer

Page 18: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Lakkireddy et al. Design Multicenter, prospective, matched observational study

Patient population

Patients undergoing ablation for AF in 8 high volume US centers

Inclusion Symptomatic AFScheduled AF ablation Drug refractory

Exclusion INR not between 2.0-3.5 on warfarin

Treatment Warfarin titrated to an INR of 2.0-3.5 x at least 3 weeks prior then continued uninterrupted throughout the procedureORDabigatran 150 mg BID x at least 3 weeks, held morning of, and resumed 3 h post

Outcomes Bleeding (Major and Minor)Thromboembolic complications (CVA and TIA)

Lakkireddy D, Reddy YM, Di Biase L et al.  J Am Coll Cardiol. 2012;59(13):1168-74.

Page 19: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

ResultsOutcome Dabigatran

(N= 145)Warfarin (N = 145)

P-value

Major Bleeding Complications

9 (6) 1 (1) 0.019

Periprocedural pericardial tamponade

6 (4) 1 (1) 0.12

Late pericardial tamponade 3 (2) 0 (0) 0.25

Minor Bleeding Complications

12 (8) 8 (6) 0.35

Groin hematoma 6 (4) 5 (3) 0.76

Pericardial hematoma without tamponade

6 (4) 4 (3) 0.76

Embolic Complications (CVA/TIA)

3 (2) 0 (0) 0.25

Composite bleeding and thromboembolic complications

23 (16) 9 (6) 0.009Values are n (%)Note: Dabigatran use and age > 75 were the only univariable predictors of composite bleeding and thromboembolic complications.

Lakkireddy D, Reddy YM, Di Biase L et al.  J Am Coll Cardiol. 2012;59(13):1168-74.

Page 20: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Author’s Conclusions• Use of dabigatran periprocedurally for AF ablation

was associated with an increased risk of bleeding.o Discontinued dabigatran only the morning prior to the procedureo Overlapped of dabigatran with UFH required during the procedure.

• Large randomized controlled trials are required to confirm results and identify an optimal periprocedural anticoagulation protocol.

Lakkireddy D, Reddy YM, Di Biase L et al.  J Am Coll Cardiol. 2012;59(13):1168-74.

Page 21: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

AnalysisStrengths Limitations

• Multicenter study at 8 high volume electrophysiology laboratories

• Non-randomized• Matched control

design

Page 22: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Kim et al.Design Case-control study

Inclusion Symptomatic AF Scheduled for ablation

Exclusion Not specifically stated

Treatment Warfarin titrated to an INR of 2.0-3.0 ≥ 4 weeks and continued during ablation and continued ≥ 3 months postORDabigatran 110 mg BID ≥ 4 weeks, held 24-30 hours prior, resumed 4 h post hemostasis and continued ≥ 3 months post

Outcomes Thromboembolic complications (CVA, TIA, systemic embolism)Major and minor bleeding

Kim JS, She F, Jongnarangsin K et al.  Heart Rhythm. 2013;10(4):483-9.

Page 23: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

ResultsOutcome Dabigatran

(N= 191)Warfarin (N = 572)

P-value

Major Bleeding 4 (2.1) 12 (2.1)* 1.0

Pericardial tamponade 2 (1.0) 7 (1.2) 1.0

Vascular complications 2 (1.0) 5 (0.9) 1.0

Minor Bleeding 5 (2.6) 19 (3.3) 0.81

Groin hematoma 4 (2.1) 19 (3.3) 0.47

Pericardial effusion without tamponade

1 (0.5) 0 (0) 0.25

Embolic Complications (CVA/TIA)

0 (0) 0 (0) 1.0

Values are n (%)*INR, clopidogrel use, and CHADS2-VASc were the only things associated with major bleeding in the warfarin group.+Warfarin group had a higher number of patients with previous stroke and a higher number of patients on statin medications.#TEE performed in all dabigatran patients and at risk warfarin patients, no LAA thrombus in any patients

Kim JS, She F, Jongnarangsin K et al.  Heart Rhythm. 2013;10(4):483-9.

Page 24: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Author’s Conclusions• When held 24 hours prior to ablation and

resumed 4 hours post, dabigatran appears to be as safe and effective as uninterrupted warfarin therapy

• There seems to be no risk of left atrial appendage thrombus after holding dabigatran for 24-30 h prior to ablation

Kim JS, She F, Jongnarangsin K et al.  Heart Rhythm. 2013;10(4):483-9.

Page 25: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

AnalysisStrengths Limitations

• Prospectively collected data

• Non-randomized• Case-control design• Inadequate power to

detect a difference in embolic and bleeding rates

Page 26: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

SummaryCardioversion• Dabigatran 110 mg was associated with a higher

incidence of bleeding in patients taking dual antiplatelet therapy

• Difference in stroke rate between warfarin and dabigatran in this setting will likely never be determined

Ablation• Discontinuation period prior to ablation can effect

bleeding rates, ideally discontinue at least 24 h prior to ablation

Page 27: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Patient Case• Medications:

o ASA 325 mg o Lisinopril 40 mg dailyo Sotalol 160mg PO BID (HELD)

• CHADS2 = 1• CrCl = 90mL/min• Cardiology consult

o Diltiazem and heparin drip started

o Plan for TEE and cardioversiono Patient does not want

warfarin, was offered dabigatran and wants it instead.

• Mr. W 64 y/o male admitted with a chief complaint of chest pain, heart palpitations, and DOE x 1 weeko EKG shows A. fib with RVR

• PMH: HTN, sleep apnea, paroxysmal A. fib., and obesity

Vitals

Temperature 98.06

Pulse 100

Respiration 18

Blood Pressure

120/82

Page 28: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Patient Case• Given the RE-LY data we cannot be sure about the

difference in stroke or embolism rate of warfarin vs. dabigatran in our patient

• The patient would be switched from ASA to warfarin or dabigatran and is on no other antiplatelet agents o Only difference in bleeding rates shown by RE-LY in patients on dual

antiplatelet therapy and dabigatran.

• No contraindications to use of warfarin or dabigatran exist for this patient

• Cost is an issue and patient desire not sufficient indication for dabigatran

Page 29: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Patient Update• Per cardiology note:

o Patient was discharged on enoxaparin and warfarin for a total of 4 weeks

o After 4 weeks patient can switch to dabigatran for prevention of stroke

• 2 days after discharge patient was seen in the ED complaining of pounding in his chest and a high pulseo EKG showed A. fib with a ventricular rate of 88o ED physician and patient discussed the option of ablationo Patient wants to postpone this until he returns from a 2 month vacation.

• If follows cardiology plan, he will be on dabigatran at the time of ablationo Should be okay if discontinued 24 hours prior to ablationo Pre-procedural TEE is recommended

Page 30: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

References1. Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 20132. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial

fibrillation. N Engl J Med. 2009;361(12):1139-51.3. Dabigatran: Lexicomp Drug information. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.4. Go AS,   Hylek  EM,   Chang Y,  et al.  Anticoagulation Therapy for Stroke Prevention in Atrial

Fibrillation: How Well Do Randomized Trials Translate Into Clinical Practice?  JAMA. 2003;290(20):2685-2692

5. Kim JS, She F, Jongnarangsin K et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm. 2013;10(4):483-9.

6. Lakkireddy D, Reddy YM, 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. J Am Coll Cardiol. 2012;59(13):1168-74.

7. Naccarelli G, Ganz L, Manning W. Restoration of sinus rhythm in atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013

8. Nagarakanti R, Ezekowitz MD, Oldgren J et al. Dabigatran versus warfarin in patients with atrial fibrillation: An analysis of patients undergoing cardioversion. Circulation. 2011;123(2):131-6.

9. Passman, R. Radiofrequency ablation to prevent recurrent atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.

10.You JJ, Singer DE, Howard PA et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest.2012;141(2 Suppl):e531S-75S.

Page 31: Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

Questions?