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