KHRS 2013 2013-Jun-15 NOAC vs. Warfarin in AF Catheter Ablation Jin-Seok Kim, MD Department of Cardiology Sejong General Hospital Bucheon, Republic of Korea
Clinical Burden of AF Rhythm Disturbance Thromboembolic Risk Symptomatic AF due to rhythm disturbance Reduced Cardiac Output Tachycardia-mediated CMP Heart Failure Ischemic Stroke Embolization of Atrial Thrombi
Therapeutic Strategy for AF Control Rhythm Disturbance Thromboembolic Risk Rhythm Control Rate Control Antithrombotic Therapy
Anti-thrombotic Therapy for AF patients Novel Oral Anticoagulants: NOACs
Anti-thrombotic Therapy for AF patients 39% in ischemic stroke 2-5 the risks of bleeding (including ICH) Beneficial effects as getting older: Aspirin ( ) vs Warfarin( ) 28% in ischemic stroke >50% higher in major bleeding 1 29.8% in ischemic stroke Lower risk of major bleeding 6 1. ACTIVE Investigator et al. N Engl J Med. 2009;360:2066-2078. 2. Hart RG et al. Ann Intern Med. 2007;146:857-867. 3. Mant J et al. Lancet. 2007;370:493-503. 4. Rash A et al. Age Ageing. 2007;36:151-156. 5. van Walraven C et al. Stroke. 2009;40:1410-1416. 6. ACTIVE Writing Group of the ACTIVE Investigators et al. Lancet 2006:367:1903-1912
Rhythm Control: RF Catheter Ablation of AF AF Sinus Rhythm RF catheter ablation has become an effective treatment of drug-refractory AF * * Calkins H et al. Heart Rhythm 2012;9(4):632-696 e21.
RF Catheter Ablation of AF
Peri-procedural Complications Potential Risk of Peri-procedural Complications Bleeding Complications Thrombo-embolic Cx (+) (-) Peri-procedural anticoagulation
Optimal Peri-procedural anticoagulation Bleeding Complications Thrombo-embolic Cx
Peri-procedural Anticoagulation Strategies * Warfarin Warfarin, continuous UFH IV + Heparin(UFH or LMWH) Bridge or UFH: unfractionated heparin LMWH: low molecular weight heparin Pre-procedure Intra-procedure Post-procedure * Calkins H et al. Heart Rhythm 2012;9(4):632-696 e21.
Continuous Warfarins(CW) Strategy vs. Heparin Bridging(HB) Strategy Peri-procedural Risks of Thromboembolic and Bleeding Complications 1-4 1. Di Biase L et al. Circulation 2010;121:2550-2556 2. Husein AA et al. Heart Rhythm 2009;6:1425-1429. 3. Wazni OM et al. Circulation 2007;116:2531-2534 4. Cappato R et al. Circ Arrhythm Electrophysiol 2010;3:32-38
Warfarin : Optimal Anticoagulant for Stroke Prevention and AF Ablation in Patients with AF??
Clinical Barrier of Warfarin Use Ansell J et al. Chest 2008;133;160S 198S; Nutescu EA et al. Cardiol Clin 2008;26:169 87; Umer Ushman MH et al. J Interv Card Electrophysiol 2008;22:129 37
Clinical Barrier of Warfarin Use Approximately 55% of eligible, high-risk patients are not treated with OAC 1 Over 80% of patients aged 85 and higher are not started on warfarin 2 100 Proportion of eligible patients using warfarin (%) 80 60 40 20 44% 58% 61% 57% 35% Overall use = 55% (n= 11 082) 0 <55 55 64 65 74 75 84 85 Age (yrs) OAC=oral anticoagulation. 1. Adapted from Ogilvie IM et al. Am J Med. 2010;123(7):638-645. 2. Gallagher AM et al. J Thromb Haemost. 2008;6(9):1500-1506.
Clinical Barrier of Warfarin Use Warfarin are associated with High Discontinuation Rates Proportion Who Persisted on Warfarin 1.0 0.9 0.8 0.7 0.6 0.5 More than 25% of patients newly starting warfarin for NVAF discontinued therapy in the first year 0.4 0 1 2 3 4 5 6 Time to Warfarin Discontinuation (Years) Fang MC et al. Circ Cardiovasc Qual Outcomes. 2010;3(6):624-631.
Clinical Barrier of Warfarin Use The Risk for Thrombotic and Bleeding Events Increases Outside a Narrow Therapeutic Range of Warfarin * INR=international normalized ratio. 1. Haas S. J Thromb Thrombolysis. 2008;25:52-60. 2. Fuster V et al. Circulation. 2011;123:e269-e367. 3. Hylek EM, Singer DE. Ann Intern Med. 1994;120:897-902. 4. Oden A et al. Thromb Res. 2006;117:493-499.
Clinical Barrier of Warfarin Use AF Patients on VKAs Are Outside of Therapeutic Range About Half the Time * Error bars represent 95% CIs. The solid line extending upwards from 100% is the null value. None of these studies were randomized clinical trials. AC=anticoagulation; CI=confidence interval; TTR=time in therapeutic range. Adapted from Baker WL et al. J Manag Care Pharm. 2009;15(3):244-252.
Clinical Barrier of Warfarin Use as an Peri-procedural Anticoagulant Total N=1133 Logit (Pr[Y=1]) = α + βx + γ X2 + δc Kim JS et al. Circ Arrhythm Electrophysiol 2013
Requirements of new antithrombotic agents Adapted from Lip GY et al. EHJ Suppl 2005;7:E21 5
Emerging Novel Oral Anticoagulant
Target for Anti-thrombotic Agents in the Coagulation Cascade AT= antithrombin; Ph = Phase 1. Connolly SJ et al. N Engl J Med 2011;364:806 17; 2. Granger CB et al. N Engl J Med 2011;365:981 92; 3. Patel MR et al. N Engl J Med 2011;365:883 91; 4. NCT00781391; available at www.clinicaltrials.gov; accessed March 2012 5. Connolly SJ et al. N Engl J Med 2009;361:1139 51
Pharmacology of NOACs Dabigatran Rivaroxaban Apixaban Mechanism Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor Bioavailability 6% 60-80% 50% Time to peak level 3 H 3 H 3 H Half-life 12 17 H 5-13 H 9-14 H Excretion 80% renal 2/3 liver, 1/3 renal 25% renal, 75% faecal Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253
Phase III Trials with NOACs for Stroke Prevention in AF Trial acronym Dose Comparator N CHADS 2 score Expected completion date RE-LY 1 150mg BID 110mg BID Warfarin (INR 2.0 3.0) 18 000 1 Completed ARISTOTLE 2 5 mg* BID Warfarin (INR 2.0 3.0) 18 000 1 Completed AVERROES 3 5 mg* BID Aspirin (81 324 mg OD) 6000 1 Completed ROCKET-AF 4 20 mg OD Warfarin (INR 2.0 3.0) 14 000 2 Completed *2.5 mg BID for patients who met two of the following criteria: age 80 yrs, body weight 60 kg, serum creatinine 1.5 mg/dl; Adjusted based on renal function BID = twice daily; INR = international normalized ratio; OD = once daily 1. Connolly SJ et al. N ENG J Med 2009;361:1139-51 2. Granger CB et al. N Engl J Med 2011;365:981 92; 3. Connolly SJ et al. N Engl J Med 2011;364:806 17; 4. Patel MR et al. N Engl J Med 2011;365:883 91
2011 ACCF/AHA/HRS Focused Updates of Guidelines for NVAF Stroke Prevention ACCF=American College of Cardiology Foundation; AHA=American Heart Association; HRS=Heart Rhythm Society. 1. Fuster V et al. Circulation. 2011;123:e269-e367. 2. Wann SL et al. Heart Rhythm. 2011; 8(3):e1-e8.
2012 Focused Update of the ESC Guidelines for NVAF Camm AJ et al. Eur Heart J. 2012
NOACs vs. Warfarin in AF Ablation Can NOACs Be an Alternative Peri-procedural Anticoagulation for AF Ablation?
Dabigatran vs. Warfarin in AF Ablation J Cardiovasc Electrophysiol 2012;23:264-268 123 patients who received dabigatran immediately after AF ablation. Retrospective study
Dabigatran vs. Warfarin in AF Ablation Total 123 patients 56 (45.5%) 34 (27.6%) 33 (26.8%) Mean intraprocedural ACT : 229 ± 20 s Mean highest ACT : 237 ± 32 s No peri-procedural thromboembolic events No procedure-related bleeding complications FU 30-day post-procedure No stroke, TIA, systemic thromboembolism, or bleeding complications. No vascular complications J Cardiovasc Electrophysiol 2012;23:264-268
Dabigatran vs. Warfarin in AF Ablation Lakkireddy, D., et al., J Am Coll Cardiol, 2012. 59(13): 1168-74 A total of 290 patients, including 145 taking periprocedural dabigatran and an equal number of matched patients taking uninterrupted periprocedural warfarin, were included; a matched-control design A multicenter, observational study from a prospective registry
Dabigatran vs. Warfarin in AF Ablation Total 290 patients Warfarin (145) Therapeutic anticoagulation 30 days prior to AF ablation (INR 2 to 3.5). Uninterrupted warfarin therapy during peri-procedural periods. Dabigatran (145) Peri-procedural dabigatran therapy (150mg bid) 30 days prior to AF ablation The dose held on the morning of the procedure. Intraprocedural Anticoagulation using UFH Target ACT 300-400 s Dabigatran was resumed within 3 hours after hemostasis Lakkireddy, D., et al., J Am Coll Cardiol, 2012. 59(13): 1168-74
Dabigatran vs. Warfarin in AF Ablation Total 290 patients Warfarin (145) Dabigatran (145) Lakkireddy, D., et al., J Am Coll Cardiol, 2012. 59(13): 1168-74
Dabigatran vs. Warfarin in AF Ablation Total 290 patients Warfarin (145) Dabigatran (145) Lakkireddy, D., et al., J Am Coll Cardiol, 2012. 59(13): 1168-74
Dabigatran vs. Warfarin in AF Ablation Heart Rhythm 2013;10:483 489 763 patients underwent AF ablation using dabigatran (N=191) or uninterrupted warfarin (N=572) for periprocedural anticoagulation. Retrospective Case-Control study
Dabigatran vs. Warfarin in AF Ablation Kim JS et al. Heart Rhythm 2013;10:483 489
Dabigatran vs. Warfarin in AF Ablation Complications Dabigatran (n = 191) Warfarin (n = 572) P Hemorrhagic complications 9 (4.7) 31 (5.4) 0.85 Major bleeding complications 4 (2.1) 12 (2.1) 1 Cardiac tamponade 2 (1) 7 (1.2) 1 Vascular complications 2 (1) 5 (0.9) 1 Minor bleeding complications 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 0.25 Thromboembolic complications Stroke or TIA 0 0 1 Values are n (%). TIA = transient ischemic attack Kim JS et al. Heart Rhythm 2013;10:483 489
Dabigatran vs. Warfarin in AF Ablation Kim JS et al. Heart Rhythm 2013;10:483 489
Dabigatran vs. Warfarin in AF Ablation Circ J 2012;76: 2337 A total of 221 patients, including 110 taking periprocedural dabigatran (110mg bid) and 101 taking uninterrupted periprocedural warfarin, were included.
Dabigatran vs. Warfarin in AF Ablation Kaseno et al. Circ J 2012;76: 2337
Dabigatran vs. Warfarin in AF Ablation Kaseno et al. Circ J 2012;76: 2337
Dabigatran vs. Warfarin in AF Ablation Kim JS et al* dabigatran ACT 300-350 (hemostasis+4h) Kim JS et al. Heart Rhythm 2013;10:483 489
NOACs as an Peri-procedural Anticoagulant Bassiouny et al. Circ Arrhythm Electrophysiol 2013 Total 999 patients (376 dabigatran vs. 623 warfarin with INR2-3) Dabigatran 150mg bid. Prior AF ablation, dabigatran was held 1 to 2 doses/ warfarin continued during peri-procedural period. Total bleeding and thromboembolic complications were similar in both groups. Maddox et al. JCE 2013 Total 463 patients (212 patients on dabigatran vs. 251 on warfarin) Uninterrupted warfarin and dabigatran as periprocedural anticoagulation. Total bleeding and thromboembolic complications were similar in both groups.
NOACs as an Peri-procedural Anticoagulant Pros Rapid onset of action with shorter time to therapeutic anticoagulation No concern of a sub- or supratherapeutic INR on the day of procedure No need for postprocedural bridging Cons Lack of specific antidote Need for dose adjustments in patients with renal dysfunction Much higher cost The absence of a routine clinical coagulation test to confirm patient compliance
Summary The timing of discontinuation and re-initiation of anticoagulants in the peri-procedural time frame seem to be an important consideration in order to minimize the risk of stroke and procedure-related bleeding. Although some small studies have shown the safety and efficacy of the use of diabigatran in the periprocedural period for AF ablation, compared with warfarin, the use of NOACs in AF ablation as periprocedural anticoagulation has been still challenging and its experiences limited. Large randomized studies will be needed to confirm the results of those studies.
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