Debate: New Generation Anti-Coagulation Agents are a Better Choice than Warfarin in the Management of AF Bradley P. Knight, MD Director of Cardiac Electrophysiology Bluhm Cardiovascular Institute Northwestern University bknight@nmff.org
Stroke Rate (%) CHADS 2 Stroke Risk Stratification Scheme for Patients With Nonvalvular AF Risk factors Score C Recent congestive heart failure 1 H Hypertension 1 A Age 75 yrs 1 D Diabetes mellitus 1 S 2 History of stroke or transient ischemic attack 2 20 15 10 5 0 18.2 12.5 5.9 8.5 4.0 1.9 2.8 0 1 2 3 4 5 6 Relationship between CHADS 2 score and annual risk of stroke Adapted from Hersi A, et al. Curr Probl Cardiol. 2005;30:175 234.
Narrow therapeutic window Requires INR monitoring Many food and drug interactions Slow onset of action/need for bridging
Within the first year, 26% of patients 80 years of age stopped taking warfarin
Use of Warfarin in a Primary Care Population* No Warfarin 6% Supratherapeutic INR 65% 15% Therapeutic INR 13% Subtherapeutic INR *All patients appropriate candidates for warfarin, according to guidelines; no contraindications to warfarin. Samsa GP, et al. Arch Intern Med. 2000;160(7):967-973.
Inhibition of Coagulation Cascade by New ACs Intrinsic XII Pentasaccharide Xa Inhibitors XI IX VIII AT Thrombin X V IIa VII TF Extrinsic Rivaroxaban Apixaban Dabigatran Oral and Injectable DTIs Fibrinogen Fibrin Clot AT = antithrombin. Weitz JI, et al. Chest. 2001;119(1 Suppl):95S-107S. Gulseth MP, et al. Am J Health Syst Pharm. 2008;65(16):1520-1529.
RE-LY Study Design AF 1 risk factor Absence of contraindications 951 centers in 44 countries Blinded event adjudication R Primary outcome: all strokes and systemic emboli Open Blinded Warfarin adjusted (INR 2.0-3.0) N = 6022 Dabigatran Etexilate 110 mg BID N = 6015 Dabigatran Etexilate 150 mg BID N = 6076 RE-LY = Randomized Evaluation of Long-term Anticoagulation Therapy; R= randomization; BID = twice daily. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.
Cumulative Hazard Rate RE-LY Study Results: Stroke and Systemic Emboli 0.05 Noninferiority vs warfarin: P <.001 for both Dabigatran 110 mg and 150 mg 0.04 0.03 Dabigatran 110 mg Warfarin RR, 0.66; 95% CI (0.53-0.82) P <.001 0.02 Dabigatran 150 mg 0.01 0.00 0 6 12 18 24 30 Months Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.
RE-LY Study: Results Efficacy Outcomes, According to Treatment Group Dabigatran Dabigatran Event 110 mg (n = 6015) 150 mg (n = 6076) Warfarin (n = 6022) 110 mg, vs Warfarin 150 mg, vs Warfarin 150 mg vs 110mg %/year %/year %/year P P P Stroke or systemic embolism 1.53 1.11 1.69 <.001 for NI,.34 <.001 for NI, <001.005 Stroke 1.44 1.01 1.57.41 <.001.003 Hemorrhagic 0.12 0.10 0.38 <.001 <.001.67 Ischemic or unspecified 1.34 0.92 1.20.35.03.002 Nondisabling stroke 0.50 0.37 0.58.40.01.10 Disabling or fatal stroke 0.94 0.66 1.00.65.005.02 MI 0.72 0.74 0.53 0.07.048.88 NI = noninferiority. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.
RE-LY: Safety Results Safety Outcomes, According to Treatment Group Dabigatran Dabigatran Event 110 mg (n = 6015) 150 mg (n = 6076) Warfarin (n = 6022) 110 mg, vs Warfarin 150 mg, vs Warfarin 150 mg vs 110mg %/year %/year %/year P P P Major bleeding Life-threatening Non life-threatening Gastrointestinal Minor bleeding Major or minor bleeding Intracranial bleeding Extracranial bleeding Net clinical benefit outcome 2.71 3.11 3.36.003.31.052 1.22 1.45 1.80 <.001.04.11 1.66 1.88 1.76.56.47.17 1.12 1.51 1.02.43 <.001.007 13.16 14.84 16.37 <.001.005 <.001 14.62 16.42 18.15 <.001.002 <.001 0.23 0.30 0.74 <.001 <.001.28 2.51 2.84 2.67.45.38.11 7.09 6.91 7.64.10.04.66 Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.
RE-LY Conclusions High dose dabigatran prevented more strokes than warfarin, but had more major bleeds than low dose dabigatran High dose dabigatran prevented more fatal or disabling strokes than warfarin Dabigatran was associated with higher rates of MI RELY proved that dabigatran is not inferior to warfarin, and high dose dabigatran was superior to warfarin for stroke prevention
March 2011
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP: Evidence-Based Practice Guidelines For patients with AF, for recommendations in favor of oral anticoagulation (excluding recommendations for patients with mitral stenosis, stable ACS, stents, and ACS), we suggest dabigatran 150 mg twice daily rather than adjusted-dose vitamin K antagonist (VKA) therapy (target INR range, 2.0-3.0) (Grade 2B).
FDA alert March 30, 2011? shelf life once bottle opened Tablets must stay in manufacturer s container Label: discard product 30 days after opening container
Dabigatran compared to control (warfarin, enoxaparin, placebo) Increased absolute risk of MI or ACS 0.27% Increased relative risk of MI or ACS 33%
Rivaroxaban Once daily As effective or better than warfarin Less hemorrhagic stroke than warfarin Similar reduction in ischemic stroke Less bleeding than warfarin No routine lab testing No reversal Half life 5-9 hours Coagulation testing: aptt Discontinuation : increased stroke
Apixaban Twice daily As effective or better than warfarin Less hemorrhagic stroke than warfarin Similar reduction in ischemic stroke Less bleeding than warfarin Lower overall mortality No routine lab testing No reversal Half life 8-15 hours Coagulation testing: PT, aptt
Pharmacodynamics of New Anticoagulants Dabigatran Apixaban Rivaroxaban Target IIa (thrombin) Hours to Cmax 2 1-3 2-4 Xa Xa CYP Metabolism None 15% 32% Half-Life 12-14h 8-15h 9-13h Renal Elimination 80% 40% 33% Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14 Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22 Ruff CR et al. Am Heart J 2010; 160:635-41
Approaches to Peri-procedural Anticoagulation for Catheter Ablation of AF Knight BP, JACC 2012
Warfarin with INR 2-3 vs. Dabigatran Held on morning of procedure Restarted 3 hours after hemostasis Lakkireddy, D JACC 2012
Uninterrupted Warfarin vs. Nearly Uninterrupted Dabigatran Lakkireddy, D JACC 2012
Uninterrupted Warfarin vs. Nearly Uninterrupted Dabigatran At first this paper appears to suggest that dabigatran has no role peri-procedurally in patients undergoing AF ablation. However, it is important to note that dabigatran may still have a role around the time of an AF ablation. Knight BP, JACC 2012