Management of Antithrombotic Medication in surgical patient Joint hospital Grand round April 2019 Lau Siu Ting, Ruby North district hospital

Types of antithrombotic agent Aspirin Other antiplatelet agent e.g clopidogrel, prasugrel, ticagrelor, etc Warfarin New oral anticoagulant (NOAC) Dabigtran Rivarxaban Apixaban Edoxaban

Mechanism of action Warfarin Dabigatran Vitamin K antagonist preventing synthesis of factors II (prothrombin), VII, IX, and X Dabigatran direct thrombin inhibitor Reversibly blocks the enzymatic function of thrombin in converting fibrinogen to fibrin (factor IIa) Rivaroxaban / apixaban / edoxaban direct factor Xa inhibitor Reversibly blocks the enzymatic function of factor Xa in converting prothrombin to thrombin

Challenge in surgical patient Thromboembolic risk DVT PE ACS CVS Bleeding risk

Steps to face this challenge Step 1 : assessing thrombotic risk of patient Individualization !!! Step 2 : Determinate the bleeding risk of procedure and individual patient Step 3 Determine need to withhold antithrombotic agent +/- need of bridging therapy

Assessing thromboembolic risk

Assessing Thromboembolic risk To estimate the risk of thromboembolic event occurrence if thromboembotic agent is discontinued American college of surgeon’s guideline 2018: Thromboembolic risk stratification High (>10% annual risk of thromboembolism) Moderate (5% - 10% annual risk) Low (<5% annual risk) Indication of antithrombotic agent Non valvular AF Mechanical heart valve History of venous thromboembolism Coronary artery disease Cerebrovascular disease

Non valvular AF High risk Moderate risk Low risk CHA2DS2-VASc score >= 6; stroke or TIA within previous 3 month Rheumatic valvular heart disease Moderate risk CHADS-VASc score 4-5 Previous stroke or TIA >3 months ago Low risk CHADS-VASc score 2-3 CHA2DS2-VASc Score Adjusted Stroke Risk, (% per year)* 1 1.3 2 2.2 3 3.2 4 4.0 5 6.7 6 9.8 7 9.6 8 9 15.2 *Lane DA, Lip GY. Use of the CHA2DS2VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atria fibrillation. Circulation 2012 aug 14.126 (7):860-5

Mechanical heart valve Prosthetic heart valves Type, number, location of valve Any presence of additional cardiac risk factor High risk : Mitral valve prosthesis; caged-ball or tilting disc aortic prosthesis; Low risk : Bi leaflet aortic valve prosthesis

Venous thromboembolism High risk : recent thromboembolic event within 3 months Severe thrombophilia (protein C, protein S or antithrombin deficiency etc) Moderate risk: thromboembolic event within 3-12 months Recurrent thromboembolic event Low risk : thromboembolic event >12 months ago

Coronary artery disease Dual agent antiplatelet (DAPT) is needed for patient with coronary stent placement American College of Cardiology (ACC) and American Heart Association (AHA) clinical practice guidelines : DAPT is currently recommended for at least 6 to 12 months after placement of bare-metal stents and drug-eluting stents. Elective surgery should be deferred at least >14 days after balloon angioplasty 30 days after bare-metal stent placement 1 year after drug-eluting stent placement. Elective surgery can be considered 180 days after drug-eluting stent placement if surgical delay outweighs the potential harms of stent thrombosis. If a patient absolutely requires surgery less than 30 days out from drug-eluting stent placement DAPT should be continued if possible, and if not, aspirin should be continued and dual antiplatelet therapy should be resumed as soon as possible after Surgery Discuss with cardiologist and document patient’s will Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2014;64:e77e137

Stroke Recent history of ischemic stroke was significantly associated with major cardiovascular events after elective non-cardiac surgery The elevated risk for cardiac events plateaued at 9 months after ischemic stroke. American college of surgeon’s guideline 2018 recommendation : Elective surgery should be deferred, if possible, for at least 9 months after ischemic stroke. *Jorgensen ME, Torp-Pedersen C, Gislason GH, et al. Time elapsed after ischemic stroke and risk of adverse cardiovascular events and mortality following elective noncardiac surgery. JAMA 2014;312:269e277

Estimation of bleeding risk

Individual Bleeding risk HAS-BLED score Score >= 3 indicate high bleeding risk (5.8% yearly risk)

Procedure bleeding risk Stratify surgery into high / low bleeding risk Largely a subjective decision on behalf of the operating surgeon

Recommendation of withholding antithrombotic medication Antithrombotic agent Timing to withhold Low molecular weight heparin 24 hour before operation Aspirin 7-10 days before high bleeding risk operation Other antiplatelet e.g plavix 5-8 days before operation Warfarin 5 days before operation Dabigratan Normal renal function Impaired renal function 2 days before high risk OT; 1 day before low risk OT 4 days before high risk OT; 2 day before low risk OT Rivaroxaban, apixaban, edoxaban 2 days before high risk OT. 1 day before low risk OT

Perioperative bridging Heparin bridging Substitution of long-acting anticoagulants with short-acting agents in preparation for an invasive procedure

Is bridging needed for all patient on warfarin? BRIDGE trial Double blinding RCT Inclusion criteria : patient with AF on warfarin Exclusion criteria: mechanical heart valve Stroke / systemic embolism /TIA within the previous 12 weeks major bleeding within the previous 6 weeks creatinine clearance < 30ml/min platelet count <100 planned cardiac, intracranial, or intraspinal surgery Conclusion : No bridging was non-inferior to perioperative bridging with LMWH for the prevention of arterial thromboembolism and decreased the risk of major bleeding

Is bridging needed in NOAC Relatively short half life Several prospective studies done and showed bridging is not necessary for short term interruption of NOAC

Latest trial PAUSE trial (Perioperative Anticoagulant Use for Surgery Evaluation Study ) 3007 patients on NOAC recruited Prospective cohort study No bridging for interruption of NOAC low rates of perioperative Massive Bleeding (<2%) and Acute Thromboembolic event (<1%). https://bjaed.org/article/S2058-5349(18)30071-4/pdf

Who need bridging? American College of Chest Physicians (ACCP) 9th Edition guidelines Patient who is on warfarin with : Mechanical heart valve Mitral-valve replacement 2 mechanical valves non-bi-leaflet aortic-valve replacement Aortic-valve replacement with previous stroke, TIA, intracardiac thrombus, or cardioembolic event. CHA2DS2-VASc score of 7 or 8 VTE occurrence within the past 3 months Patients who have had VTE while on therapeutic anticoagulation

How to bridge American College of Chest Physicians (ACCP) 9th Edition guidelines Stop warfarin 5 days before procedure Start LMWH when INR fall below patient’s therapeutic range In patients with renal insufficiency (creatinine clearance [CrCl] < 30 mL/min), unfractionated heparin is preferred over LMWH, which is renally eliminated.

Emergency surgery!!!!

Emergency setting Estimate thrombotic risk Estimate bleeding risk Need to withhold anticoagulant +/- reversing agent

Reversal of anticoagulants No bleeding/minor bleeding : Discontinue anticoagulant. Spontaneous resolution over time is an option with all anticoagulants. Vitamin K for warfarin. The approach to reversal of both warfarin and NOACs depends on the degree of bleeding and if this bleeding is life threatening Severe bleeding Discontinue anticoagulant. Supportive care (i.v. fluids and blood products). Activated charcoal (if within 3 h of ingestion). Consider dialysis (dabigatran only). Consider NOAC reversal agent. Consider prothrombin complex concentrate (PCC) Consider recombinant factor VIIa. Consider tranexamic acid. Fresh frozen plasma is not recommended for the reversal of the effects of warfarin. PCC has a relatively short duration of action (half-life of 6 h), so vitamin K is essential tomaintain the corrected coagulation profile if haemostasis is desired after this 6 h window.

Reversing agent Idarucizumab Andexanet binds dabigatran prevent it binding to thrombin Andexanet Recombinent factor Xa that binds to rivaroxaban and apixaban Available in mid-2018 (registed in USA FDA)

Anticoagulant Reversal agent Advantage disadvantage Warfarin Vitamin K Onset in 2 hours Small volume 24-48 hours for full effect Fresh frozen plasma Rapid effect Need crossmatch Must be thawed before use Large volume, risk of fluid overload Risk of transfusion reaction Cannot fully normalize INR Promthrombin complex concentrate No need crossmatch Risk of arterial or venous thrombosis High cost Recombinant activated factor VII Risk of thromboembolism Dabigatran Idaruzicumab Drug specific Risk of thrombosis High cost Apixaban Rivaroxaban Andexanet alfa Rapid effect Risk of thrombosis High cost Prothrombin complex concentrate No need crossmatch Uncertain efficacy Edoxaban

New drugs coming … Ciraparantag (PER977) synthetic molecule that forms hydrogen bonds to its intended targets Pre-clinical studies shows it can reverse the effects of heparin, the factor Xa inhibitors (edoxaban, rivaroxaban, and apixaban), and dabigatran PER977 normalized the whole blood clotting time within 10 minutes

Step 1 : assessing thrombotic risk of patient Summary Step 1 : assessing thrombotic risk of patient Individualization !!! Step 2 : Determinate the bleeding risk of procedure and individual patient Step 3 Determine need to withhold antithrombotic agent +/- need of bridging therapy +/- reversal agent

THE END

Other than bridging … Placement of a temporary inferior vena caval (IVC) filter indicated : Recent (within the prior three to four weeks) acute VTE & interruption of anticoagulation for a surgery or major procedure in which it is anticipated that therapeutic- dose anticoagulation will need to be delayed for more than 12 hours postoperatively.

Emergency reversal of anticoagulant

When to resume

More studies on warfarin bridging Upcoming trial PERIOP 2 - A Safety and Effectiveness of LMWH vs Placebo Bridging Therapy for Patients on Long Term Warfarin Requiring Temporary Interruption of Warfarin Double blinded RCT Aim: determine the effectiveness and safety of LMWH postoperative bridging therapy (standard of care) versus postoperative placebo bridging therapy (experimental arm)for patients with mechanical heart valves or atrial fibrillation or atrial flutter who are at high risk for stroke when warfarin is temporarily interrupted for a procedure Estimated study completion time : September 2019