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

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

3. 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

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

5. 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

6. Assessing thromboembolic risk

7. 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

8. 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 (7):860-5

9. 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

10. 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

11. 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 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

12. 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 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

13. Estimation of bleeding risk

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

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

16. 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

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

18. 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

19. 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

20. 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%).

21. 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

22. 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.

23. Emergency surgery!!!!

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

25. 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.

26. 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)

27. 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

28. 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

29. 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

30. THE END

31. 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.

32. Emergency reversal of anticoagulant

34. When to resume

36. 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