perioperative management of anticoagulant and antiplatelet agents

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1. PERIOPERATIVE MANAGEMENT OF ANTICOAGULANT AND ANTIPLATELET AGENTS Presenter Dr. Shailendra Maharjan Lecturer Department of Anaesthesiology KIST MCTH

2. Objectives 1) Introduction 2) Pre-procedural assessment 3) Perioperative management of anticoagulant and antiplatelet agents 4) Reversal of anticoagulant therapy for urgent surgery

3. Introduction - management of patients on anticoagulants and antiplatelet therapy is a challenge for physicians - interruption of therapy increases the risk of thrombosis - non interruption of medications heightens the risk of bleeding - optimal management is achieved through balance between thromboembolic and bleeding risks

4. Several case-based considerations affect the decision of whether or not to interrupt anticoagulation or anti-aggregation therapy before surgery Includes evaluation of an individual's underlying bleeding risk, the risk of bleeding associated with the surgical procedure, the timing of interruption and resumption of anticoagulation therapy, and whether bridging required or not

5. Etiology Anticoagulation therapy indications : - atrial fibrillation - deep venous thrombosis - pulmonary embolism - prosthetic heart valves Antithrombotic therapy : - Patient undergone PCI - stroke - coronary artery bypass graft - essential thrombocytosis

6. Classification of anticoagulants I Anticoagulants Factor Xa inhibitors Oral Thrombin inhibitors UFH Direct Direct Indirect Indirect Parenteral Thrombin inhibitors Factor Xa inhibitors LMWH

7. Classification of antiplatelet drugs Cyclooxygenase/TX2 synthase inhibitors: Aspirin Adenosine diphosphate receptor inhibitors(P2Y12): irreversible: Clopidogrel , Ticlopidine reversible: Prasugrel , Ticagrelor Phoshpodiesterase inhibiors : Dipyridamole PDE 3 inhibitor: Cilostazol 4) Glycoprotein IIb / IIIa inhibitors: Abciximab , Tirofiban

8. Coagulation cascade Intrinsic surface contact XII XIIa Extrinsic XI XIa VIIa Tissue damage IX IXa X Xa X Prothrombin Thrombin VIII Fibrinogen Fibrin VIIIa Fibrin(Insoluble) Stable fibrin clot

9. Pre-procedure assessment Determine the thromboembolic risk of the patient other medications including those with an antiplatelet action other patient related bleeding factors, for example, platelet count, hemoglobin level, previous medical history

10. Estimating procedural bleeding risk Minimal bleeding risk procedure Low bleeding risk procedure High bleeding risk procedure Minor dermatological procedures(excision of basal and squamous cell skin cancer, premalignant or cancerous malignant skin nevi) Cataract procedure Minor dental procedure(dental extraction, restoration, prosthesis, endodontics, dental cleaning and filling) Arthroscopy Cutaneous/ lymph node biopsy Shoulder/foot/hand surgery Coronary angiogram Gastrointestinal endoscopy/biopsy Abdominal hysterectomy Lap cholecystectomy Abdominal hernia repair Haemorrhoidal surgery Bronchoscopy±biopsy Epidural injection with INR<1.2 Major surgery with extensive tissue injury Cancer surgery Major orthopedic surgery Reconstructive plastic surgery Urology or gastrointestinal surgery TURP, bladder resection Nephrectomy, kidney biopsy Bowel resection Surgery in highly vascular organs Cardiac, spinal, intracranial surgery any major procedures>45 minutes

11. Perioperative management of anticoagulant and antiplatelets WARFARIN: Bridging therapy - administration of therapeutic dose of short acting anticoagulant, during interruption of long acting anticoagulant 1) Whom warfarin can be continued? 2) Whom bridging therapy is not required? 3) Bridging of warfarin: - bridging with intravenous unfractionated heparin infusion - bridging with therapeutic dose LMWH

12. 6 days prior to surgery 5 days prior to surgery 4 days prior to surgery 3 days prior to surgery 2 days prior to surgery 1 day prior to surgery Morning of surgery Warfarin Take last dose of warfarin No warfarin No warfarin No warfarin No warfarin No warfarin No warfarin INR test × × Check INR Either 1 day prior or morning of surgery Check INR< 1.5 Enoxaparin × × Commence enoxaparin when INR≤2 Cease enoxaparin 24 hours before procedure

13. Pre-procedure warfarin management Patient taking warfarin undergoing an elective procedure Cease warfarin 5 days prior to surgery Bridging therapy is required Prescribing physician estimates risk of thromboembolism Cease warfarin 5 days prior to surgery Bridging therapy is not required Continue warfarin and monitor for bleeding Minimal bleeding risk procedure and INR is within theraupeutic range Require interruption to warfarin therapy prior to surgery Low and high bleeding risk procedure Risk of thromboembolism is low/moderate Risk of thromboembolism is high Surgeon/ proceduralist assesses whether warfarin can be continued Proceduralist or surgeon estimates the bleeding risk Consults with physician YES NO

14. Post procedure : - The treating surgeon and treating physician should advise when anticoagulant therapy can be recommenced - Following high bleeding risk procedures, therapeutic LMWH should be delayed for 48 to 72 hours or substituted with prophylactic dose LMWH - Warfarin can be restarted on the evening of surgery at the previous maintenance dose if there is adequate surgical haemostasis - Continue LMWH or intravenous unfractionated heparin infusion until the target INR is reached

15. Reversal of warfarin for urgent surgery Prothrombinex Fresh frozen plasma Vitamin K Initial INR 1.5-2.5 Initial INR 3.6-3.5 Initial INR 3.6-10 Initial INR>10 Target INR:0.9-1.3 30 units/kg 35 units/kg 50 units/kg 50 units/kg Target INR: 1.4-2 15 units/kg 25 units/kg 30 units/kg 40 units/kg

16. Patient on warfarin requires urgent surgery Check INR INR > 3 INR < 1.5 INR 1.5-3 Consult with haematology specialist Reverse warfarin with: Vitamin k1 AND Prothrombinex – VF OR Fresh frozen plasma (if Prothrombinex – VF is contraindicated or not available) Proceed with surgery Minimal or selected low bleeding risk procedure (see Table 1) High bleeding risk procedure

17. Perioperative management of Dabigatran, Apixaban and Rivaroxaban Timing of ceasing Dabigatran prior to surgery Dabigatran (110 or 150 mg BD) Low bleeding risk surgery High bleeding risk surgery Normal renal function (CrCl≥80mL/min) Last dose 24 hour before surgery Last dose 48 hours before surgery Mild impaired renal function(50-80mL/min) Last dose 24-48 hours before surgery Last dose 48-72 hours before surgery Moderately impaired renal function(30-49m L/min) Last dose 48-72 hours before surgery Last dose 96 hours before surgery CrCl <30mL/min Seek specialist advice. Dagibatran contraindicated. Stop 5 edays before high risk surgery

18. Dagibatran reversal: Idarucizumab : - recommended dose 5 g (2 x 2.5 g/ 50 mL ). - Administer intravenously as two consecutive infusions over 5 to 10 minutes each or as a bolus injection -No dose adjustment is required for renal impairment Resuming Dagibatran : - as soon as medically appropriate - specialist should be sought - treatment can be stared 24 hours after administration of Idarucizumab

19. Timing of ceasing Apixaban prior to surgery Apixaban (2.5 mg or 5 mg BD) Low bleeding risk surgery High bleeding risk surgery Normal/mildly impaired renal function( CrCl >50mL/min) Last dose 24 hours before surgery Last dose 48-72 hours before surgery Moderately impaired renal function ( CrCl 30-50mL/min) Last dose 48 hours before surgery Last dose 72 hours before surgery CrCl <30 mL/min Seek specialist advice

20. Timing of ceasing Rivaroxaban prior to surgery Rivaroxaban (15 or 20 mg OD) Low bleeding risk surgery High bleeding risk surgery Normal/mildly impaired renal function ( CrCl >50mL/min) Last dose 24 hours before surgery Last dose 48-72 hours before surgery Moderately impaired renal function ( CrCl 30-50mL/min) Last dose 48 hours before surgery Last dose 72 hours before surgery CrCl < 30mL/min) Seek specialist advice

21. Perioperative management of antiplatelet agent Patient with a moderate or high risk of cardiovascular event Patient with low risk of cardiovascular event Discontinuation of antiplatelet agent prior to surgery Antiplatelet agent When to cease antiplatelet therapy Aspirin 5 days prior Clopodogrel 7 days prior Prasugrel 7 days prior Ticagrelor 7 days prior Ticlopidine 14 days prior

22. Perioperative management of anticoagulants and antiplatelets for patients requiring neuraxial procedures Before catheter insertion While epidural catheter in place Prior to catheter removal After catheter removal IV unfractionated heparin infusion Withhold iv UFH infusion at least for 6 hours prior to catheter insertion Check aPTT should be within normal range Do not administer IV UFH until 1 hour after epidural catheter insertion Do not administer IV UFH at least for 6 hours prior to catheter removal Check aPTT within normal range Do not administer IV UFH 1 hour after catheter removal Theuraptic dose LMWH Withhold theurapeutic dose of LMWH atleast 24 hours prior to catheter insertion Do not administer atleast 12 hours after epidural catheter insertion Withhold theurapeutic dose of LMWH atleast 24 hours prior to catheter removal Recommence LMWH atleast 4 hours following catheter removal

23. Before catheter insertion While epidural catheter in situ Prior to catheter removal After catheter removal Warfarin Warfarin should be withheld or reversed to achieve INR<1.5 prior to procedure Contraindicated Ensure INR<15 Do not administer until 4 hours after catheter removal May need another anticoagulation following procedure

24. Before catheter insertion While catheter in place Prior to catheter removal After catheter removal Subcutaneous UFH Withold UFH 6 hours prior to catheter insertion Do not administer S/C UFH 1hour after catheter insertion Withhold S/C UFH 4-6 hours prior to catheter removal Recommences S/C UFH after 6 hours following catheter removal LMWH Withhold LMWH atleast 12 hours prior to catheter insertion Do not administer LMWH until 12 hours after catheter insertion Withhold LMWH 12 hours prior to catheter removal Recommencce LMWH atleast 4 hours following catheter removal

25. Discontinuation of factor Xa and direct thrombin inhibitors prior to neuraxial procedure Timing of VTE prophylactic dose Dabigatran 220 mg or 150 mg daily Apixaban 2.5mg BD Rivaroxaban 10 mg daily Last prophylaxis dose prior to spinal or epidural catheter insertion 48 hours 24 hours 24-48 hours Last prophylaxis dose prior to spinal or epidural catheter removal 48 hours 24 hours 24-48 hours Next prophylaxis dose after epidural catheter removal At least 6 hours At least 6 hours At least 6 hours

26. Newer anticoagulants Edoxaban : - belonging to DOACs - factor Xa inhibitor - as compared to Warfarin requires fewer monitoring, low risk of substantial bleeding and less drug interaction - trials ENGAGE AF-TIMI48 - half life: 10 to 14 hours, rapid onset, peak within 1-2 hours - 50% eliminated unchanged through the kidneys and excreted in urine - dose: 60 mg OD with Cr. Cl>50 and >95ml/min

27. Abelacimab : - monoclonal antibody that inhibits factor XI and activated factor Xia - binds to catalytic domain of facto XI and locks it in the Zymogen - potential antithrombotic activity - phase I study S/C upto dose of 240 mg was safe and well tolerated - new and attractive anticoagulation for management of CAT - trial of Abelacimab - Abelacimab reduces the risk of postoperative thromboembolism to a greater extent than conventional anticoagulants

28. Fondaparinux : - synthetic anticoagulant derived from pentasacchride sequence - indicated in treatment and prophylaxis of VTE, ACS and alternative to heparin in patient diagnosed with HIT - half life 5-17 hour - does not require frequent monitoring in majority of cases - anti Xa can be used in certain cases in which level must be accurately determined e.g. renal insufficency

29. Other drugs in clinical trial Fesomersen Osocimav Milvexian Asundexian Xosomab Andexanet alfa : reversal of Rivaroxaban and Apixaban

30. DOAC monitoring 2 tests : 1) screening test for determination of presence or absence of anticoagulation 2) quantification assay for detection of abnormal absorption/clearance/metabolism because of their limited sensitivities, PT and aPTT are not suitable for quantification of the anticoagulant effect indicated by the International Society for Laboratory Hematology (ISLH), the aPTT and PT are unpredictable in assessing DOAC activity Mass spectrometry, when calibrated with each drug individually, to be measured, is considered the gold-standard method for quantification of DOAC level  More rapid methods including dTT , ecarin methods, and chromogenic anti- Xa assays are potentially suitable means to measure DOACs

31. References updates in Anticoagulation therapy monitoring: Hannah L. McRae ,  Leah Militello , and  Majed A. Refaai 2021 Development in new anticoagulant in 2023: prime time for factor XI and Xia inhibitors: Nun K. Bentounis , sophie melicine , Anne celine Martin, David M.smadja Miller’s Anesthesia 9 th edition ASRA guidelines 4 th edition , April 2018 Marino’s ICU book, 4 th edition G uidelines on perioperative management of anticoagulant and antiplatelet agents: Clinical Excellence commission. December 2018 Perioperative anticoagulant medicine: Statpearls : Jan 23 2023 , , , ,  , , , , 

32. Thank you