New Oral Anticoagulant

R2 Patcharee SeesongsomR2 Sirada Phojai

Advisor AJ Tachawan Jiratiwanon

Scope

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

Hemostasis

http://www.thrombosisadviser.com/en/understanding-thrombosis/haemostasis/

Primary hemostasis Secondary hemostasis

NEW FUNDAMENTALS IN HEMOSTASIS Physiol Rev93: 327–358, 2013doi: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 Rev93: 327–358, 2013doi: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/ajhp070624

Rivaroxaban

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

Direct FXa inhibitor

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 wortNew 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 InhibitorClin 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

• 10-mg oral rivaroxaban 6-8 hr after wound closure

• 40 mg enoxaparin SC 12 hr before surgery, 6-8 hr after wound closure

Patients4433

Rivaroxaban

2209

Enoxaparin

2224

RECORD1 clinical trials.

RECORD1 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.

RECORD1 clinical trials.

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

• 10-mg oral rivaroxaban 6-8 hr after wound closure

• 40 mg enoxaparin SC 12 hr before surgery, 6-8 hr after wound closure

Patients2459

Rivaroxaban

1220

Enoxaparin

1239

RECORD3 clinical trials.

RECORD3 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.

RECORD3 clinical trials.

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

• 20-mg oral rivaroxaban daily or 15 mg (CrCl 30-49 ml/min )

• Adjusted-dose warfarin (target INR 2.0-3.0)

Patients14264

Rivaroxaban

7131Warfarin

7133

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

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

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 aPTT ( 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

Dabigatran110 mg bid

Follow up visit 14 day ,1 mo 3 m0Every 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

RE-LY clinical trails.

Stroke and systemic embolism

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

removalTime before

puncture/cathetermanipulation or removal

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 accordingto 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.

THANK YOU