New Oral Anticoagulant R 2 Patcharee Seesongsom R

New Oral Anticoagulant R 2 Patcharee Seesongsom R 2 Sirada Phojai Advisor AJ Tachawan Jiratiwanon

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

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

NEW FUNDAMENTALS IN HEMOSTASIS Physiol Rev 93: 327– 358, 2013 doi: 10. 1152/physrev. 00016. 2011

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 Rev 93: 327– 358, 2013 doi: 10. 1152/physrev. 00016. 2011

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

Do you know mechanism of action of warfarin?

Warfarin >> Vitamin K Antagonist

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

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

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/ajhp 070624

Rivaroxaban

Rivaroxaban Direct FXa inhibitor 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

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

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

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.

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

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

Patients 4433 Rivaroxaban 2209 Enoxaparin 2224 • 10 -mg oral rivaroxaban 6 -8 hr after wound closure • 40 mg enoxaparin SC 12 hr before surgery, 6 -8 hr after wound closure

RECORD 1 clinical trials .

RECORD 1 clinical trials .

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. RECORD 1 clinical trials.

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

Patients 2459 • 10 -mg oral rivaroxaban 6 -8 hr after wound closure Rivaroxaban 1220 Enoxaparin 1239 • 40 mg enoxaparin SC 12 hr before surgery, 6 -8 hr after wound closure

RECORD 3 clinical trials.

RECORD 3 clinical trials.

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. RECORD 3 clinical trials.

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

Patients 14264 • 20 -mg oral rivaroxaban daily or 15 mg (Cr. Cl 30 -49 ml/min ) Rivaroxaban Warfarin 7131 7133 • Adjusted-dose warfarin (target INR 2. 0 -3. 0)

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.

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.

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

Dabigatran

Dabigatran Direct thrombin inhibitor 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

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

Drug interaction • Ketoconazole • Quinidine • Amiodarone • Verapamil

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

Ecarin Clotting Time

RE-LY

Procedure >> 18, 113 patients Dabigatran 110 mg bid Dabigatran 150 mg bid Follow up visit 14 day , 1 mo 3 m 0 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 Warfarin INR 2 -3 INR every 1 mo

Stroke and systemic embolism RE-LY clinical trails.

Major bleeding

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.

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

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

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

Anesthetic Implication • Elective surgery • Emergency surgery

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

Recommended time intervals before and after puncture or catheter removal Time before Time after puncture/catheter manipulation or removal Rivaroxaban (for prophylaxis, 10 mg OD) 22– 26 h 4– 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

Emergency case

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

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.

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