Novel Oral Anticoagulants final (NOAC).pptx

NOAC

1. Novel Oral Anticoagulants (NOAC) Presenter: Dr. Kushal Ranjit Moderator: Dr. Ankit Rimal 1

2. Objective To know the types of NOAC To know the advantages/disadvantages over warfarin To know the perioperative management of patients under NOAC 2

3. Intoduction Non-Vitamin-K-antagonist Oral Anticoagulants/ Novel Oral Anticoagulants (NOACs) or Direct Oral Anticoagulants ( DOACs) are drugs developed as an alternative to warfarin due to various limitations of warfarin. F ocused update of the 2014 guideline by the AHA/ACC in 2019 recommended the use of NOACs as first-line agents over warfarin in eligible patients with non- valvular atrial fibrillation (i.e., except those with moderate-to-severe mitral stenosis or a mechanical heart valve ) P reference of NOACs over warfarin was also advocated by the European Heart Rhythm Association in 2018 Accordingly, increasing number of patients presenting for surgery are exposed to NOACs 3

4. Currently , there are 4 approved NOACs which can be divided in 2 types depending on their action mechanisms D irect thrombin inhibitor (Dabigatran ) D irect factor Xa inhibitors ( R ivaroxaban , A pixaban , and E doxaban ) 4

5. MOA of NOACs 5

6. Indication P revention of thromboembolism and stroke in AF (Acceptable in mild to moderate valvular disease, bioprosthetic valve/valve repair > 3months post operative, hypertrophic cardiomyopathy, transaortic valve implantation) T reatment or prevention of deep vein thrombosis and pulmonary embolism 6

7. contraindication S evere valvular heart disease or mechanical heart valve . CrCL <30ml/min for dabigatran, other NOACs used in reduced dose. Significant liver failure. Significant active bleeding or bleeding disorder. Organ lesions at risk of bleeding including ICH in previous 6 months. Indwelling spinal or epidural catheter and during the first 6 hours after removal. Pregnancy or breastfeeding. Known hypersensitivity . 7

8. Pharmacokinetics Dabigatran Apixaban Edoxaban Rivaroxaban Bioavailability 6.5% 52% 62% 80-100% (10mg) 66-11% (20 mg) Prodrug Yes No No No Tmax 3 h 3h 2h 2h T1/2 12-17h 12h 10-14h 5-9h 11-13 h (elderly) Elimination 80% renal 20% hepatic 27% renal 73% hepatic 50% renal 50% hepatic 35% renal 75% hepatic Distribution volume 60–70 l 21 l 107 l 50 l Absorption with food none none 6-22 % 39 % 8

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10. Drug Stroke prevention in AF and in AF post ACS/PCI Comment Apixaban 5mg BID 2.5 mg BID if two out of three fulfilled: weight <_60 kg, age >_80 years, serum creatinine >_133 mmol /L (1.5 mg/ dL ) (or single criterion: if CrCl 15–29 mL/min) Dabigatran 150 mg BID/110 mg BID No pre-specified dose-reduction criteria Edoxaban 60 mg QD 30 mg QD if: weight <_60 kg or CrCl 15–49 mL/min or concomitant therapy with strong P- Gp inhibitor Rivaroxaban 20 mg QD 15 mg QD if CrCl <_15–49 mL/min 10

11. DVT/PE treatment Drug Initial Remainder Apixaban 10 mg BID, 7 days 5mg BID, no dose reduction Dabigatran Heparin/LMWH 150 mg BID, no dose reduction Edoxaban Heparin/LMWH 60mg QD, same dose reduction as for SPAF Rivaroxaban 15 mg BID, 21 days 20 mg QD, no dose reduction 11

12. DVT prophylaxis Apixaban 2.5 mg BID Dabigatran 150 mg BID Edoxaban 60 mg QD Rivaroxaban 10 mg QD 12

13. Secondary prevention of atherothrombotic events post-ACS in patients without AF: Rivaroxaban : 2.5 mg BID In addition to aspirin ± P2Y12 inhibitor Secondary prevention of atherothrombotic events in patients with chronic coronary syndrome and/or symptomatic peripheral artery disease patients without AF: Rivaroxaban : 2.5 mg BID In addition to aspirin 13

14. Advantages over warfarin Pharmacokinetics are more predictable -> Fixed doses and no need for frequent blood tests Fast onset of action within 1-3 hours -> Don’t require bridging with heparin or LMWH ). Shorter elimination half life (5-15 hrs ) L ower predisposition to food and drug interaction -> do not require restriction on vitamin K-containing food Possibly lower incidence of life-threatening bleeding. 14

15. Disadvantages L acks empirical evidence on its proper use making clinicians less interested to switch over to NOACs Not suitable for prosthetic heart valves or in those with moderate-severe renal failure. Possible increase in incidence of GI bleeding . C osts are higher for NOACs compared to VKAs 15

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17. Coagulation tests Test Dabigatran Apixaban Edoxaban Rivaroxaban PT/INR - aPTT TT,ECT,DTT - - - Anti- FXa - 17

18. European Society of Cardiology classified surgical procedure in three categories: I nterventions not requiring discontinuation of anticoagulation (dental, ophthalmology procedures) Intervention with low bleeding risk (prostate or bladder biopsy, angiography, pacemaker insertion) High bleeding risk procedures (spinal, epidural anaesthesia , cardiothoracic surgery, abdominal surgery, major orthopaedic surgery, liver biopsy, transurethral resection of the prostate and kidney biopsy). 18

19. Perioperative management Two major questions arise: When to discontinue NOACs before surgery Need for bridge-anticoagulation therapy D iscontinuing NOACs for 2 days before surgery with high bleeding risk would allow negligible residual drug concentration (usually < 10% corresponding to discontinuation for 3 to 4 half-lives ) Discontinuation for 1 day would suffice for surgeries or procedures with low bleeding risk (15 to 25% residual activity)  19

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21. RFT must be assessed If under dronedarone , amiodarone or verapamil, discontinuation for an additional 1 day when the thromboembolic risk is not high Bridging therapy for NOACs in the preoperative period is currently not recommended, but it should be restarted after surgery as soon as possible 21

22. For low bleeding risk surgery resume NOAC 24 hrs after surgery For high bleeding risk surgery, resume NOAC 48-72 hr after surgery According to ASRA guideline, NOAC can be started 6 hr after removal of catheter/ neuraxial block Restarting therapy is not recommended with catheter insitu In unanticipated administration, hold rivaroxaban (22-26 hr ), edoxaban (20-28 hr ), apixaban (26-39 hr ) , dabigatran ( 34-36 hr ) or assess anti factor Xa assay for riviroxaban , apixaban , edoxaban or ECT for dabigatran before catheter removal 22

23. Emergency surgery NOACs should be immediately stopped F ollowing detailed knowledge should be acquired : 1) Type of NOAC used 2) Last time of intake 3) Renal function 4) C oagulation tests (prothrombin time [PT], activated partial thromboplastin time [ aPTT ], and possibly chromogenic anti-factor Xa assay, or diluted thrombin time [ dTT ]/ ecarin -based assays [ECA]) 23

24. A dministration of specific reversal agents should be considered Idarucizumab for dabigatran reversal and Andexanet alfa for rivaroxaban and apixaban reversal Ciraparantag : Universal reversal agent for all NOAC 24

25. Reversal agents Idarucizumab Andexanet alfa Non-vitamin K antagonists Dabigatran Rivaroxaban , apixaban , edoxaban Mode of action Humanized monoclonal antibody fragment Binds to dabigatran with 350-fold higher affinity than thrombin Binds to factor Xa inhibitors with similar affinity to native factor Xa Also binds to heparin- antithrombin III complex Dosage   IV bolus of 5 g (2.5 g over 5–10 min × 2)   IV bolus over 15–30 min + 2 h of continuous infusion: 400 mg bolus, 480 mg infusion ( rivaroxaban intake > 7 h or apixaban ) 800 mg bolus, 960 mg infusion ( rivaroxaban intake within 7 h [or unknown] or edoxaban ) Alternative options Hemodialysis for 4 h Hemodialysis not applicable PCC, 2 doses of 4-factor PCC or bolus of 50 IU/kg (+ 25 IU/kg as necessary ) Tranexamic acid, bolus 10–30 mg/kg (10–20 min) + continuous infusion 3–5 mg/kg/h 25

26. Ciraparantag Universal reversal of NOAC Synthetic cationic molecule developed to reverse the anticoagulation effect of UFH/LMWH via non-covalent hydrogen linkage and charge-charge interaction. D irectly binds to Xa inhibitors and thrombin inhibitors in a similar manner 26

27. Limitations Increased incidence of thromboembolic events to 18% after administration of the reversal agents, compared to less than 1% in case of planned interruption of NOACs H igh cost 27

28. If specific reversal agents are not accessible, PCC may be given ( clinical evidence is limited and controversial  ) Suggested regimens of PCC include 2 doses of 4-factor PCC or an initial bolus of 50 IU/kg followed by an additional 25 IU/kg if necessary 28

29. In urgent cases, consider delaying the surgery for at least 12 h (preferably 24 h) after the last NOAC administration After delay, the coagulation tests should be performed again . Normal dTT or aPTT most likely excludes high therapeutic levels of dabigatran N ormal PT would rule out high levels of rivaroxaban S pecific tests to measure the activity of NOACs should be performed to guide the need for reversal agents. ECA for dabigatran A nti-factor Xa assays for rivaroxaban , apixaban , or edoxaban 29

30. In case of dabigatran, hemodialysis may be considered (approximately 50 to 60% of the drug removed after 4 h of hemodialysis) A ctivated charcoal (30 to 50 g), reduces the absorption of recently overdosed NOACs C onsidered in patients who ingested NOAC within 2 to 4 h before urgent surgery E fficacy in patients who received a prescribed dose of NOAC, and not accidental overdosed, remains questionable 30

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33. Take home message Dabigatran: Direct thrombin inhibitor Apixaban . Edoxaban , rivaroxaban : Factor Xa inhibitor PT more sensitive towards rivaroxaban Anti Factor Xa for rivaroxaban , apixaban , edoxaban aPTT , TT, ECA sensitive for the monitoring of dabigatran Reversal agents: Idarucizumab : Dabigatran Andexanet alpha: Apixaban , Edoxaban , Rivaroxaban Ciraparantag : Universal reversal agent 33

34. THANK YOU! 34