1. New Oral Anticoagulant R2 Patcharee Seesongsom R2 Sirada Phojai Advisor AJ Tachawan Jiratiwanon

2. Scope Overview Introduction of NOACs Rivaroxaban ( Xarelto ) Dabigatran ( Pradaxa ) Anesthetic implication

3. Hemostasis http://www.thrombosisadviser.com/en/understanding-thrombosis/haemostasis/ Primary hemostasis Secondary hemostasis

5. NEW FUNDAMENTALS IN HEMOSTASIS Physiol Rev93: 327–358, 2013doi:10.1152/physrev.00016.2011

6. NEW FUNDAMENTALS IN HEMOSTASIS Physiol Rev93: 327–358, 2013doi:10.1152/physrev.00016.2011

7. Various Phases of Coagulation Initiation phase Extrinsic pathway of coagulation. Disrupted vasculature. FVII, TF ( Tissue factor ). Amplification phase Thrombin. Propagation phase NEW FUNDAMENTALS IN HEMOSTASIS Physiol Rev93: 327–358, 2013doi:10.1152/physrev.00016.2011

9. Oral Anticoagulant Drug Current anticoagulants Vitamin K antagonists : warfarin Novel anticoagulants Direct Factor Xa inhibitors : rivaroxaban, apixaban Direct thrombin inhibitors : Ximelagatran, Melagatran, dabigatran

10. Do you know mechanism of action of warfarin?

11. Warfarin >> Vitamin K Antagonist

12. Disadvantage of Warfarin Narrow therapeutic range. Slow onset of action. Slow offset of action (long duration of action,long elimination half life) Multiple drug and dietary interactions. Monitoring required to maintain in therapeutic range. Thromb Haemost 2010;103:34-39

13. Oral Anticoagulant drug Novel anticoagulants Direct Factor Xa inhibitors : rivaroxaban ( Xarelto ) Direct thrombin inhibitors : dabigatran ( Pradaxa )

14. Action of Anticoagulant Drug Rivaroxaban Dabigatran Rivaroxaban: An oral direct inhibitor of factor Xa,American Society of Health-System Pharma-cists, Inc. All rights reserved. 1079-2082/08/0802-1520$06.00.DOI 10.2146/ajhp070624

15. Rivaroxaban

16. Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74 Direct FXa inhibitor

17. Pharmacokinetic of Rivaroxaban Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74

18. Drug Interaction “ azole” antifungal (eg. ketoconazole) HIV protease inhibitors (eg. Ritonavir) Increase effect Rifampicin, Phenytoin, carbamazepine, St. John’s wort Decrease effect New Drug Review Rivaroxaban: An Oral Factor Xa Inhibitor (Clin Ther.2013;35:427) © 2013 Published by Elsevier HS Journals, Inc.

19. Not Recommended Avoid in patients with mod-severe hepatic impairment Avoid in pregnancy women New Drug Review Rivaroxaban: An Oral Factor Xa Inhibitor Clin Ther.2013;35:427.

20. Monitoring Rivaroxaban prolongs the prothrombin time (PT) and this might be used as a rough estimate of an anticoagulation effect. A better estimate for an anticoagulant effect for the oral Factor Xa inhibitors is an anti-Xa assay. Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74

21. n engl j med 358;26 www.nejm.org june 26, 2008

22. Patients 4433 Rivaroxaban 2209 Enoxaparin 2224

23. RECORD1 clinical trials.

25. Conclusion Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total hip arthroplasty, with similar rates of bleeding. 10-mg oral of rivaroxaban VS 40-mg SC of enoxaparin. RECORD1 clinical trials.

26. n engl j med 358;26 www.nejm.org june 26, 2008

27. Patients 2459 Rivaroxaban 1220 Enoxaparin 1239

28. RECORD3 clinical trials.

30. Conclusion Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding. 10-mg oral of rivaroxaban VS 40-mg SC of enoxaparin. RECORD3 clinical trials.

31. n engl j med 365;10 nejm.org september 8, 2011

32. Patients 14264 Rivaroxaban 7131 Warfarin 7133

35. Conclusion In patients with AF, rivaroxaban was equal to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. ROCKET AF Clinical Trials.

36. Approval Approved by FDA, EMA ( European Medicines Agency ) & ACCP ( American College of Chest Physicians ) VTE prophylaxis after hip or knee replacement surgery. Stroke prevention in patients with non-valvular AF.

37. Dosing Guidelines Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74

38. Dabigatran

39. Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74 Direct thrombin inhibitor

40. Pharmacokinetic of Dabigatran Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74

41. Drug interaction Ketoconazole Quinidine Amiodarone Verapamil

42. Monitoring Prolong aPTT ( exclude if normal value) Prolong thrombin time Prolong of ECT ( ecarin clotting time ) is directly and linearly to the plasmatic levels of dabigatran.

43. Ecarin Clotting Time

44. RE-LY

45. Procedure >> 18,113 patients Dabigatran 110 mg bid Follow up visit 14 day,1 mo 3 m0 Every 3 mo in 1 year, then 4 mo until 2 yrs Follow up LFT montly in 1 yr then if normal performed only regular visit Dabigatran 150 mg bid Warfarin INR 2-3 INR every 1 mo

46. RE-LY clinical trails. Stroke and systemic embolism

47. RE-LY clinical trails.

48. Major bleeding

49. Stroke or Systemic embolism Dabigatran 110 mg VS warfarin (Relative risk) Dabigatran 150 mg VS warfarin (Relative risk) Stroke or Systemic embolism 0.91 (0.74-1.11) P-value < 0.001 0.66 (0.53-0.82) P-value < 0.001 Major bleeding 0.80(0.69– 0.93) P-value 0.003 0.93(0.81-1.07) P-value 0.31

50. Conclusion Patients with AF, dabigatran 110 mg oral bid VS warfarin treatment Similar rate of stroke and systemic embolism lower rates of major hemorrhage. Patients with AF, dabigatran 150 mg oral bid VS warfarin treatment lower rate of stroke and systemic embolism similar rates of major hemorrhage.

54. Conclusion Meta-analysis of RE-MODEL and RE-NOVATE and RE-MOBILIZE Dabigatran etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. No significant difference between dabigatran and enoxaparin in any of the end-points analysed Total VTE All cause of mortality

55. Approval Stroke prevention in patients with non-valvular AF. Approved by FDA & EMA ( European Medicines Agency ),Canada,Japan and United states VTE prophylaxis after hip or knee replacement surgery. Approved in Europe and Canada Not approved,yet in United states

56. Dosing Guidelines Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74

57. Anesthetic Implication Elective surgery Emergency surgery

58. Preoperative Discontinuation of Dabigatran Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Anesthesiology 2013; 118:1466-74

59. Interruption of Target-Specific Oral Anticoagulant Therapy for Invasive Procedures and Surgery Oral anticoagulant therapies: Balancing the risks, Am J Health-Syst Pharm—Vol 70 May 15, 2013

60. Recommended time intervals before and after puncture or catheter removal Time before puncture/catheter manipulation or removal Time after puncture/catheter manipulation or removal Rivaroxaban (for prophylaxis, 10 mg OD) 22–26 h4–6 h Dabigatran (for prophylaxis, 150–220 mg) Contraindicated according to the manufacturer 6 h Guideline Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology, Eur J Anaesthesiol 2010;27:999–1015

61. Emergency case

62. Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74

63. Managing New Oral Anticoagulants in the Perioperative and Intensive Care Unit Setting, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1466-74

64. Take Home Message New oral anticoagulants have approved for thromboprophylaxis after hip & knee arthroplasty and stroke prevention in non-valvular AF patient. Rivaroxaban > Direct Fxa inhibitor. Dabigatran > Direct thrombin inhibitor. No antidote available now. If abnormal bleeding >> Supportive & symptomatic treatment.

65. THANK YOU

66. new England Jounal med 361;24 nejm.org december 10, 2009

68. Conclusion A fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin for treatment of venous thromboembolism.

69. Recommended time intervals before and after puncture or catheter removal

70. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation, European Heart Journal (2012)33, 2719–2747 doi:10.1093/eurheartj/ehs253

71. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation,European Heart Journal (2012)33, 2719–2747 doi:10.1093/eurheartj/ehs253