Strategies for Reversing Warfarin Anticoagulation

1. Strategies for Reversing Warfarin Anticoagulation W. Cederquist, MD, Anesthesiology PGY-V Mentor: Paul Picton, MD Case Discussion – Practical Updates in Anesthesiology 2014 Tues, February 4th, 2014

2. Disclosures • No conflicts of interest to report

3. Case Presentation (1) • HPI: 70 y.o. ASA 3 man presenting to ED with 12 hours of vomiting, loose stools and RLQ abdominal pain. • PMH: HTN and atrial fibrillation on warfarin • VS: T 39°C; BP 108/63; HR 74 regular; RR 16; SpO2 96% RA. • Exam: 72 in, 100kg, BMI 30. Neurologic, HEENT, cardiopulmonary, GU, MSK and skin wnl. Tenderness at McBurney’s point, Rosving’s sign.

4. Case Presentation (2) • Labs: WBC 14.3 (4-10 K/mm3) 80% PMNs Hct 46.8 (40-50 %) Plt 173 (150-400 K/mm3) COMP Within normal limits aPTT 31.6   (22.0-32.0 s) PT 28.4   (9.8-12.5 s) INR 2.8

5. Case Presentation (3) • CT abdomen/pelvis with IV/PO contrast • Surgical plan: Laparoscopic appendectomy

6. Case Presentation (4) Surgery Note: “The patient will be transfused 3 units of FFP to correct his INR to less than 1.5. The patient will have immediate INR check and will be continued to be transfused with FFP should he remain therapeutic... Once his INR is reversed, the patient will be taken to the operating room...”

7. Perioperative Course (1) 1349 Arrival to ED 1425 INR 2.8 1624 CT abdomen/pelvis 1745 Ciprofloxacin/Metronidazole Administered 2040 1st FFP 2125 2nd FFP 2136 Arrived in Pre-Op Area 2212 INR 2.2 2230 3rd FFP and 4th FFP 0146 INR 1.7 0200 5th FFP 0300 Facial edema and urticaria noted

8. Perioperative Course (2) 0412 Patient In Room 0421 Anesthesia Induction End 0431 Urology Consult for Difficult Foley Placement 0502 Surgical Incision 0545 Converted to Open Ileocecetomy 0611 INR 1.7 0845 EBL 300cc 0851 Surgical Dressing Complete 0858 Extubated Awake 0901 Transported to PACU 0942 INR 1.8 1325 Admitted to Surgical Ward

9. Perioperative Course (3) • Post Op Course • - complicated by paroxysmal atrial fibrillation • Outcome • - warfarin restarted at discharge to home on postoperative day #4

10. Goals and Objectives Identify the hemostatic defect in warfarin therapy Evaluate the safety and efficacy of three methods to correct warfarin anticoagulation Critically appraise the association between an elevated prothrombin time and bleeding risk Introduce prothrombin complex concentrate as an alternative to FFP for warfarin reversal

11. Classical Coagulation Pathway aPTT PT/INR

12. Differential Diagnosis

13. Warfarin Factors II VII IX X ACCP Guidelines 8th Edition (2008)

14. Coagulation Factor Activity vs INR Gulati et al. Archives of Pathology & Laboratory Medicine ( 2011)

15. Classical Coagulation Pathway

16. Question • What three general strategies are available for the correction of warfarin-induced coagulopathy? • - discontinue warfarin (days) • - supplement vitamin K (12 - 24 hours) • - replace clotting factors (immediate)

17. Vitamin K Supplementation • Phytonadione ACCP Guidelines 8th Ed

18. Intravenous Vitamin K - 178 patients on warfarin - vitamin K 3 mg IV - PT/PTT checked on day of procedure Burbury et al. Br J Haematology (2011)

19. Intravenous Vitamin K Normal Range Burbury et al. Br J Haematology (2011)

20. Added to Chest Guidelines Recommendations: “Anticoagulation reversal for non-major bleeding should be with 1-3 mg intravenous vitamin K (Grade 1B).”

21. Question • What three general strategies are available for the correction of warfarin-induced coagulopathy? • - discontinue warfarin (days) • - supplement vitamin K (12 - 24 hours) • - replace clotting factors (immediate)

22. Replacement of clotting factors Blood Product (FFP) Multiple factor replacement (Prothrombin Complex Concentrate) Single factor replacement (Recombinant Factor VIIa)

23. What’s in it? Stanworth. Hematology (2007)

24. Professional Guidelines • ASA Practice Guideline for Perioperative Blood Transfusion (2006): • “FFP should be given … to achieve a minimum of 30% plasma factor concentration (usually achieved with administration of 10-15 ml/kg FFP), except for urgent reversal of warfarin anticoagulation, for which 5-8 ml/kg FFP usually will suffice.” American Society of Anesthesiology. Anesthesiology (2006)

25. Making Assumptions Surgery Note: “The patient will be transfused 3 units of FFP to correct his INR to less than 1.5…and will be continued to be transfused with FFP should he remain therapeutic... ” Assumptions: 1) FFP will decrease the bleeding risk

26. Will FFP decrease the bleeding risk? • - review of FFP • - multiple clinical endpoints • - evidence supporting FFP is weak Stanworth. Hematology (2007)

27. Making Assumptions Surgery Note: “The patient will be transfused 3 units of FFP to correct his INR to less than 1.5…and will be continued to be transfused with FFP should he remain therapeutic... ” Assumptions: 1) FFP will decrease the bleeding risk 2) FFP will correct the INR to < 1.5

28. Change in INR per unit FFP Holland LL, Brooks JP. Am J Clin Path (2006)

29. Will FFP decrease the INR to 1.5? Starting INR 1.5-1.8 Median INR change = 0.07 Less than 1% achieve normalization of the INR. Abdel-Wahab et al. Transfusion (2006).

30. Where did that number come from?

31. Where did that number come from? Holland LL, Brooks JP. Am J Clin Path (2006)

32. Replacement of clotting factors Blood Product (FFP, whole blood) Multiple factor replacement (Prothrombin Complex Concentrate) Single factor replacement (Recombinant Factor VIIa)

33. Prothrombin Complex Concentrate PCC II VII IX X Hemophilia B

34. How is it made? Ion exchange chromatography II VII IX X Pasteurize Adult dose: 25-50 U/kg

35. Effect of PCC on clotting factors Pabinger et al. J. Thromb Haemost (2008).

36. PCC vs FFP

37. Added to Chest Guidelines Recommendation: “For patients with warfarin-associated major bleeding, we suggest rapid reversal of anticoagulation with four-factor PCC rather than with plasma (Grade 2C).” ACCP Guidelines 9th Edition (2012)

38. Coming soon to a pharmacy near you PCC PCC II IX X II IX X 3 factor PCC 3 factor PCC

39. Clinical Trials • - 202 patients taking warfarin • - equal in terms of “effective hemostasis” • - possibly fewer adverse events Sarode et al. Circulation (2013)

40. New Oral Anticoagulants • - direct thrombin inhibitors (dabigatran) • - factor Xa inhibitors (-xabans) • - consider PCC if all else fails Heidbuchel et al. Europace (2013)

41. Conclusions • Identify the hemostatic defect in the coagulopathic patient presenting for emergency surgery. • Use vitamin K for procedures that can be delayed 12 hours, otherwise use FFP. • Minor elevations in INR are unlikely to be corrected by plasma transfusion. • Prothrombin complex concentrate is a promising alternative but further studies are needed.