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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  • Mr. W admitted with cc of CP, palpitations, and DOE x 1 weekEKG on admitPMH significant for HTN paroxysmalFor his A. fib he takesCardiology was consultedStartedPlan forPt does not want warfarin
  • Difference between NSR and a. fib. is a change in the initiation of cardiac conductionNSR – SA node is pacemakerfib. – abnormal pulmonary veins in atria take over as the pacemaker, bypassing the SA nodeResult = atria to not depolarize and contract normally to fill the ventricles adequatelyStasis of blood in the atria can lead to thrombus and if pushed systemically can lead to stroke
  • Reversible causes are listed hereSome common symptoms our patient experienced palpitations, tachycardia, dyspnea, and angina.
  • General treatment strategies are listed here; today we will focus on conversion to NSR with cardioversion and ablation as well as anticoagulation.Patients with AF have baseline risk for strokeStratified by CHADS2 score – Increased score = increased risk of stroke over the next year
  • Cardioversion is the conversion of a patient from A. fib into NSREither DCC or antiarrhythmic medications like amiodarone can be usedSome patients make good candidates while others don’tReasons to cardiovert or not are listed hereBut the reason we are talking about this in relation to dabigatran has to do with increase risk of stroke in the post-cardioversion periodRisk of stroke is increased from baseline in patients undergoing cardioversion, therefore specific guidelines exist for anticoagulationDepending upon the duration of a. fib. and presence of atrial thrombus dabigatran could potentially be used in either the pre or post cardioversion period. Unstable hemodynamics (RVR, decreased CO) or worsening symptoms due to AFMultiple comorbidities (LVH or mitral valve disease) OR Overall poor prognosis (> 80 y/o)DCC – unstable patients OR first/rare episode patientsPharmacologic (Amiodarone, Dofetilide, Ibutilide) – longstanding AF patients in whom a rhythm approach is planned. If failed then DCC an option
  • Radiofrequency ablation is done to eliminate pulmonary veins that are ectopicSuccess is fairly high, but ablation is invasive and complications do occurEmbolism surrounding a. fib is as high as 2% although some studies quote higherUse of anticoagulation in the periablation period can reduce this complication and dabigatran could be used in this settingUnlike cardioversion, there is no clear method for anticoagulation surrounding ablation. Continuous warfarin therapy effective, unclear safety and efficacy of dabigatran
  • Dabigatran is a DTI with quick onsetAccording to it’s labeling it should be renally dosed; however dosing in renal dysfunction is not well studied Canadian labeling, the ACCP, and the VA avoid dabigatran in renal imparimentApproved fro non-valvular AF
  • RE-LY was a prospective, randomized, controlled, multi-center study A posthoc analysis of this study was done to look at dabigatran in patients who underwent cardioversion while on study medicationInclusion criteria was documented AF and at least 1 other factor that would make the patient a candidate for anticoagulationPatients were excluded if they had a heart valve disorder, recent or severe stroke or poor renal function
  • Patients were treated with one of 3 regimens Warfarin titrated to an INR of 2-3 or Dabigatran at one of two doses (discontinued <12h prior in 50% of patients)Outcomes included stroke, systemic embolism and major bleeding.Major bleeding was defined as a reduction in the hemoglobin level of at least 2, transfusion of at least 2 U blood, or symptomatic bleeding in a critical area or organ.
  • Results showed no difference in stroke and systemic embolism 30 days post NO difference in major bleeding except for in the group receiving D110 whose rate was higher6/11 of these patients happened to have been receiving ASA and clopidogrel while no other treatment arms were exposed to this
  • Study not powered to detect a difference in stroke/embolismIn order to power a study like this would need 15,000-40,000 patients due to low rate of strokesMajor bleeding rates were similar in all groups,except D110 likely due to use of DAPT in this group. Concluded both agents were comparable in this setting
  • Strengths of this study that improved its internal validity were it’s large randomized and controlled nature as well as intention to treatLimitations include the unplanned posthoc analysis which was not powered to detect differences in stroke/embolismStudy did not address the lack of a reversal agentSponsored by manufacturer
  • Lakkireddy et al performed a multicenter, prospective, matched observational study in patients undergoing ablation in 8 high volume US centersPatient had to have drug refractory symptomatic AF and be scheduled for an ablationPatients on warfarin were kept on continuous therapy during the procedure with a goal INR or 2-3.5Patients on dabigatran were told to hold their AM dose and resumed it 3h post procedureOutcomes included bleeding, both major [bleeding requiring blood transfusion, hematomas requiring surgical intervention, and pericardial effusions requiring drainage (tamponade)] and minor small hematomas and pericardial effusions not requiring an intervention (nontamponade). Thromboembolic complications included stroke and TIA
  • NNH = 20 for major bleeding complicationsNNH for composite bleeding and thromboembolic complications = 10Most of the results showed no difference between groups with the exception of major bleeding complications in the dabigatran group in which cardiac tamponade requiring drainage was the most common event.Additionally the composite bleeding and thromboembolic complications were also significantly different between the groups for which dabigatran use and age>75 were the predictors for these events.
  • Concluded dabigatran increases risk of bleeding complications which they attributed to not enough time off dabigatran prior to ablation and overlapping dabigatran with UFH a practice that is not well studied.Overalll think a large randomized trial would be ideal to determine what regimen to use.
  • One of the strengths of this study was it’s multicenter nature which increases generalizability, However, it was limited by the fact that it was not randomized and had a matched control design limiting internal validity.
  • A study by Kim et al was also case-control for AF patients undergoing ablationPatients underwent a very similar protocol as the previous study, but dabigatran was held for a longer period prior to ablationOutcomes measured included thromboembolic complications and major and minor bleedingMajor bleeding complications included pericardial tamponade that requiring surgery, rehospitalization and/or longer hospital stay, or blood transfusion.Minor bleeding complications were defined as a small groin hematoma, any bleeding that did not require an intervention, or pericardial effusion without tamponade.
  • Results from this case control showed no difference in any of the measured outcomes; however, INR, clopidogrel use and CHADS-Vasc was associated with major bleeding in the warfarin groupNeither group had left atrial appendage thrombus on TEE
  • If withheld for 24 h dabigatran is as safe and effective as warfarin therapy in the periablation period, risk of thrombus is not increased during this holding period.
  • Although the data was collected prospectively the study was not randomized, had a case control design which limit internal validity. Also, the may not have powered their study adequately to detect a difference
  • Overall in cardioversionDabigatran was associated with increased bleeding in patients taking DAPTDifference in stroke rate will probably not be determined since the sample size needed is so highAblationKinetics matter, must give at least 24 hours between dabigatran and ablation procedure to maintain safety of dabigatran in the periablation periodNo study has looked at patients with severe renal impairment taking dabigatran.
  • Just a reminder of the patient case – Mr W is in A. fib. awaiting cardioversion and hoping to receive pradaxa afterwards
  • If we look at the data to support use of dabigatran in this patient we see that given the RE-LY data is is not clear if warfarin or dabigatran is better with regards to stroke risk. Additionally, this patient would be switched from ASA to warfarin or dabigatran meaning he would not be at the increased risk of bleeding seen when overlapping antiplatelets and dabigatran in the pericardioversion period. Generally this patient has no contraindications to either medication, but cost is an issue and a non-formulary consult just because the patient doesn’t want warfarin is not likely to get approved.
  • Per cardiology on discharge they were able to convince the patient to do warfarin for 4 weeks and then he could switch to dabigatran afterwards2 days after discharge the patient came to the ED with palpitations and a high pulseOn EKG he has A. fi and ventricular rate of 88The ED physician discussed the option of ablation with the patient who decided he would postpone this until after his planned vacationIf this were to happen per cardiology’s request he would be on dabigatran (assuming approval by pharmacy) prior to ablation. Based on the data we reviewed he would be okay to continue it as long as it was held 24h prior to the procedure.
  • Dabigatran for Atrial Fibrillation: Cardioversion and Ablation

    1. 1. Dabigatran for Atrial Fibrillation: Cardioversion and Ablation July 18, 2013 Marti Larriva, PharmD Candidate
    2. 2. Outline • • • • • Patient Case Background Literature Summary Patient Case
    3. 3. Patient Case • Mr. W 64 y/o male admitted with a chief complaint of chest pain, heart palpitations, and DOE x 1 week o EKG shows A. fib with RVR Vitals Temperature 98.06 Pulse 100 Respiration 18 Blood Pressure 120/82 • PMH: HTN, sleep apnea, paroxysmal A. fib., and obesity • Medications: o ASA 325 mg o Lisinopril 40 mg daily o Sotalol 160mg PO BID (HELD) • CHADS2 = 1 • CrCl = 90mL/min • Cardiology consult o Diltiazem and heparin drip started o Plan for TEE and cardioversion o Patient does not want warfarin, was offered dabigatran and wants it instead.
    4. 4. Clinical Question • What is the role of dabigatran as an anticoagulant during cardioversion or ablation for atrial fibrillation?
    5. 5. Background Atrial Fibrillation Cardioversion/Ablation Dabigatran
    6. 6. Atrial Fibrillation
    7. 7. Atrial Fibrillation Pathophysiology 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 Persistent AF that does NOT terminate after 7 days Permanent AF for which cardioversion has failed or not been attempted Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013
    8. 8. Atrial Fibrillation Treatment • General o o o o o • Treat any underlying reversible causes Slow ventricular rate – beta blockers, non-DHP calcium channel blockers Convert to normal sinus rhythm – direct current, pharmacologic Prevent recurrences – ablation Prevent stroke/improve survival – anticoagulation Congestive Heart Failure, Hypertension, Age > 75, Diabetes, Stroke CHADS2 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 Go AS, Hylek EM, Chang Y, et al. JAMA. 2003;290(20):2685-2692 Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013
    9. 9. Cardioversion • Direct current or antiarrhythmic to return to NSR 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 • Stroke risk post-cardioversion is 1-5% over 1 month o Higher than baseline risk of 1-6% over 1 year 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/or Oral Anticoagulation x 3 weeks Oral Anticoagulation x 4 weeks Stop/Continue based on rhythm You JJ, Singer DE, Howard PA et al. Chest.2012;141(2 Suppl):e531S-75S. Naccarelli G, Ganz L, Manning W. Restoration of sinus rhythm in atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013
    10. 10. 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 death o Pulmonary vein stenosis 1.0 - 3.0% • No clear anticoagulation strategy o Continuous warfarin therapy shown to be safe and effective o Unclear safety and efficacy of dabigatran Passman, R. Radiofrequency ablation to prevent recurrent atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013.
    11. 11. Dabigatran Mechanism Direct thrombin inhibitor Pharmacokinetics Time to peak – 1 hour Excreted 80% in urine Metabolized 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 valves Active 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.
    12. 12. Literature Pericardioversion – posthoc of 1 RCT Periablation – 2 case-control studies
    13. 13. RE-LY Design 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 disorder Stroke within 14 days OR severe stroke within last 6 months Conditions that increased the risk of hemorrhage CrCl < 30 mL/min Reversible cause of A. fib. Plan for ablation Nagarakanti R, Ezekowitz MD, Oldgren J et al. Circulation. 2011;123(2):131-6. Connolly SJ, Ezekowitz MD, Yusuf S et al. N Engl J Med. 2009;361(12):1139-51
    14. 14. RE-LY Treatment Warfarin titrated to an INR of 2.0-3.0 OR Dabigatran 110 mg BID OR Dabigatran 150 mg BID Major Outcomes Stroke, systemic embolism, and major bleeding within 30 days of cardioversion Nagarakanti R, Ezekowitz MD, Oldgren J et al. Circulation. 2011;123(2):131-6. Connolly SJ, Ezekowitz MD, Yusuf S et al. N Engl J Med. 2009;361(12):1139-51
    15. 15. Results Outcome Major Bleeding First 0.30% 0.60% (N = 672) (N = 664) 0.48% 0.48% 0.46% (N = 421) (N = 436) 1.7% 0.60% 0.60% (N = 647) All 0.77% (N = 413) First Warfarin (N = 647) All Dabigatran 150 mg (N = 672) (N = 664) 2.66% 0.48% 0.46% (N = 413) Stroke & systemic embolism 30 days post Cardioversion Dabigatran 110 mg (N = 421) P-value (N = 436) D110 vs. W D150 vs. W 0.71 0.45 0.96 0.97 _ _ 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.
    16. 16. 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.
    17. 17. Analysis Strengths 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
    18. 18. Lakkireddy et al. Design Multicenter, prospective, matched observational study Patient population Patients undergoing ablation for AF in 8 high volume US centers Inclusion Symptomatic AF Scheduled 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 procedure OR Dabigatran 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.
    19. 19. Results Outcome 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 9 (6) 0.009 Composite bleeding and 23 (16) thromboembolic complications Values 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.
    20. 20. 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 procedure o 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.
    21. 21. Analysis Strengths • Multicenter study at 8 high volume electrophysiology laboratories Limitations • Non-randomized • Matched control design
    22. 22. 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 post OR Dabigatran 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.
    23. 23. Results Outcome 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.
    24. 24. 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.
    25. 25. Analysis Strengths Limitations • Prospectively collected data • Non-randomized • Case-control design • Inadequate power to detect a difference in embolic and bleeding rates
    26. 26. Summary Cardioversion • 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
    27. 27. Patient Case • Mr. W 64 y/o male admitted with a chief complaint of chest pain, heart palpitations, and DOE x 1 week o EKG shows A. fib with RVR Vitals Temperature 98.06 Pulse 100 Respiration 18 Blood Pressure 120/82 • PMH: HTN, sleep apnea, paroxysmal A. fib., and obesity • Medications: o ASA 325 mg o Lisinopril 40 mg daily o Sotalol 160mg PO BID (HELD) • CHADS2 = 1 • CrCl = 90mL/min • Cardiology consult o Diltiazem and heparin drip started o Plan for TEE and cardioversion o Patient does not want warfarin, was offered dabigatran and wants it instead.
    28. 28. 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
    29. 29. 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 pulse o EKG showed A. fib with a ventricular rate of 88 o ED physician and patient discussed the option of ablation o 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 ablation o Should be okay if discontinued 24 hours prior to ablation o Pre-procedural TEE is recommended
    30. 30. References 1. Cheng A, Kumar K. Overview of atrial fibrillation. In: UpToDate, Baslo, DS (Ed), Waltham, MS, 2013 2. 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.
    31. 31. Questions?

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