1. New Oral Anticoagulants in Peri-operative Medicine Teresa L. Carman, MD Director, Vascular Medicine University Hospitals Case Medical Center Associate Professor of Medicine Case Western Reserve University School of Medicine

2. Review the new anticoagulants and clinical indications Discuss the pharmacology of the drugs Review available surgical and trauma guidelines for reversing and monitoring the new anticoagulants Objectives

3. Historical Perspective 1916 Heparin 1950s 1990s2002 WarfarinLMWHs Indirect Factor Xa Inhibitors DTIs Lepirudin Argatroban Bivalirudin Desirudin Fondaparinux Enoxaparin Dalteparin Tinzaparin 2010 Dabigatran Rivaroxaban Apixaban 2012 Endoxaban Betrixaban

4. Ideal Anticoagulant Oral administration Rapid and predictable anticoagulant effect Broad therapeutic window Efficacious with a low bleeding risk No food-drug and drug-drug interactions No need for laboratory monitoring Easily reversible Affordable (acceptable cost-benefit ratio)

5. Mechanisms of Anticoagulation XIIa IIa Xa Intrinsic system (surface contact) XII XI XIa Tissue factor IX IXa VIIa VII VIIIVIIIa Extrinsic system (tissue damage) X Xa VVa II FibrinogenFibrin (Thrombin) IIa Factor Xa inhibitors Direct thrombin inhibitors Vitamin K antagonists Heparins

6. New Terminology DOAs – Direct oral anticoagulants NOAs – New oral anticoagulants TSOAs – Target specific oral anticoagulants

7. TSAs

8. Emerging Therapies Pentasacchaide anti-Xa –Idrabioptraparinux** Oral DTIs –Ximelagatran** –Dabigatran –AZD0837 –SB-424323 –TGN-167 Oral direct Anti-Xa –Rivaroxaban –Apixaban – Edoxaban –Betrixaban –Otamixaban FVIIa inhibitors –rNAP-c2 –TFPI

9. TSOAs DabigatranRivaroxabanApixaban VTE prevention RE-MODEL RE-NOVATE RE-MOBILIZE RE-SOLVE RECORD 1 RECORD 2 RECORD 3 RECORD 4 MAGELLAN ADVANCE I ADVANCE 2 ADVANCE 3 ADOPT VTE treatment RE-COVER RE-MEDY RE-SONATE EINSTEIN-DVT EINSTEIN-PE EINSTEIN-EXT AMPLIFY AMPLIFY-EXT Stroke prevention in AFRE-LYROCKET-AF ARISTOTLE AVERROES Prevention of secondary events in ACS —ATLAS 2APPRAISE 2

10. TSOA Phase III trials of new/emerging anticoagulants demonstrate promise –Ease of dosing –Bioeffective –Safe compared to conventional therapies –Monitoring and dose adjustments are typically not required Apply caution in renal insufficiency

11. Dabigatran Oral direct thrombin inhibitor (DTI) Rapidly converted from dabigatran etexilate to dabigatran Binds clot-bound and free thrombin with high affinity and specificity Predictable anticoagulant effect Low plasma protein binding No liver toxicity based on available clinical data

12. Dabigatran Onset is immediate with peak activity at 2-3 hrs Plasma t ½ 12-17 hours Excreted renally (80%); eliminated in bile No significant food-drug Few drug-drug interactions (amiodarone, quinidine, verapamil – dose once daily) Bottled product has a 4-month shelf life once opened Needs acidic environment for best absorption

13. Dabigatran Approved for NONVALVULAR AFIB –Fixed dose CrCl>30 ml/min - 150 mg BID Once daily dosing with verapamil, quinidine, and amiodarone Dose adjustment or avoidance with other strong P-gp agents –Caution with CrCl < 30 ml/min –CrCl 15-30 ml/min - 75 mg BID FDA recommended based on pharmacology (no trial data) No monitoring is required NOT for use in patients with valves Approved in Europe and Canada for orthopedic prophylaxis

14. Rivaroxaban Direct factor-Xa inhibitor Inhibits free factor-Xa as well as prothrombinase-bound and clot bound factor-Xa Circulates primarily bound to albumin 80-100% oral bioavailability Peak activity at 2-4 hours T ½ - 7 to 11 hours Hepatic metabolism with renal and fecal excretion Avoid with CrCl <15 ml/min; caution when CrCl 15- 30ml/min No food and few drug interactions

15. Riveroxaban VTE prophylaxis in THA/TKA –10 mg daily (w/ or w/o food) Nonvalvular Afib –20 mg daily w/ evening meal –15 mg daily with CrCl 15-50 mg/ml w/ evening meal VTE dosing –15 mg BID x 21 days then 20 mg daily with food VTE extended prophylaxis –20 mg daily with food Approved in European Union for VTE prophylaxis after TKA/THA, nonvalvular afib, and VTE Approved in Canada for VTE prophylaxis after TKA/THA

16. Apixaban Direct factor-Xa inhibitor Inhibits free factor Xa as well as clot bound Xa and activated prothrombinase bound Xa Peak activity at 3 hours T ½ - 8 to 11 hours Non-renal metabolism with renal (25-30%) and fecal (65%) excretion Reduce dosing with ketoconazole, itraconazole, ritonair, clarithromycin

17. Apixaban Dosing Nonvalvular Afib –5 mg BID –With 2 or more risk factors – dose 2.5 mg BID age >80 Cr > 1.5 wt < 60 kg

18. TSOAs J Thromb Thrombolysis 2013;36:133-140.

19. New Anticoagulants Benefits –Efficacy similar in to present therapy in many clinical settings –Large trials support relative safety compared to VKA –Wide therapeutic window Problems –Inability to accurately monitor the agents –NO antidotes –Short t ½ may leave patients unprotected with missed doses –No clear indication of patients that may benefit most from the new therapies –$$$

20. Special Clinical Situations Peri-procedural management –Determining the need for bridging Acute reversal for surgery or bleeding

21. Pre-procedural Interruption J Thromb Thrombolysis 2013;36:212-222.

22. Pre-procedural Interruption Cleve Clin J Med 2013;80:443-451.

23. Bridging algorithm for vitamin K antagonists and new oral anticoagulants. Gallego P et al. Circulation 2012;126:1573-1576 Copyright © American Heart Association

24. Pre-op Management If surgery cannot be delayed, there is an increased risk of bleeding in patients receiving anticoagulants. Risk of bleeding should be weighed against the urgency of intervention. Discontinue drugs minimum 1 to 2 days (CrCl ≥ 50 mL/min) Patients with the highest risk of bleeding hold for 2-4 days –major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required CrCl< 50 mL/min hold 2 to 5 days before elective invasive or surgical procedures van Ryn et al. Thromb Haemost 2010;103:1116-1127.

25. Need for Bridging Estimated that >250,000 patients interrupt AC annually for procedures >10% risk 5-10% risk < 5% risk

26. Bridging Therapy Bridging -- transitioning warfarin to a short-acting anticoagulant for a temporary interruption of anticoagulation, especially for surgery or a potential invasive procedure (colonic polyp removal). Pro –avoid thromboembolism –avoid prolonged hospitalization Con –May increase bleeding complications –Creates miscommunications, logistical nightmares –Prolongs the hospital stay in some cases –Lack of evidence (no RCTs) –Published reports are cohort studies, without tight protocols

27. Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates Circulation 2012; 126:1630 Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall (OR 5.4) and major bleeding (OR 3.6) and at similar risk of thromboembolic events compared to nonbridged patients (0.9% vs. 0.6%).

28. Bridging Decisions Does AC need interrupted? Is bridging required (risk assessment)? “Bridge in”– Preop strategy “Bridge out”– Postop strategy Anticoagulation Intensity –(risk/bleeding assessment) “full” or “therapeutic” (e.g., Enoxaparin 1 mg/kg BID or UFH gtt) “prophylactic” (e.g., Enoxaparin 40 mg/day or SQ UFH)

29. Bridging Protocol Arch Cardiovasc Dis 2011;104:669-676.

30. Basic Recommendations 1.“Bridging” is becoming more selective because of the high bleeding risks, logistical problems, and communication mishaps. 2.The higher the risk the tighter the management. 3.Don’t forget about the option of “bridging- in” with LMWH (OP) or IV UFH in- hospital when necessary. 4.“Bridging-out” may be unnecessary in many patients.

31. Regional Anesthesia Anesthesiology 2013;118:1466-1474.

32. Why Monitor?

33. Monitoring Requires understanding of the available coagulation tests Should not be done “routinely” but limited to clinical situations a specific goal in mind –Urgent pre-op assessment –Active bleeding assessment Presently – do not quantitatively assess the degree of anticoagulation but can make a qualitative assessment

34. Cautions - Monitoring Do not have reliable laboratory monitoring –150 mg BID dose Peak - 184 ng/ml Trough - 90 ng/ml –PT is insensitive to dabigatran INR rarely exceeds 1.2 –aPTT is more sensitive with less variability –Very high dabigatran levels are underestimated by aPTT values van Ryn et al. Thromb Haemost 2010;103:1116-1127.

35. Cautions - Monitoring Thromb Haemost 2010;105 (epub) PT/INR and aPTT are variable based on the coagulometer and the reagent

36. Cautions - Monitoring For DTIs - ECT is the best lab monitor – not widely available/not FDA approved Chromogenic anti- factor II – FDA approved but not for monitoring DTIs Thrombin time is too sensitive van Ryn et al. Thromb Haemost 2010;103:1116-1127.

37. Cautions - Monitoring Limited data a best are available for rivaroxaban and apixaban for monitoring or reversal Rivaroxaban and Apixaban influences prothrombin time (PT) > aPTT Rivaroxaban and apixaban should be able to be monitored by chromogenic Anti-Xa assays Standards have not been set/reported

38. Monitoring Guidelines J Thromb Thrombolysis 2013;36:187-194.

39. Dabigatran Arch Cardiovasc Dis 2013;106:382-393.

40. Riveroxaban Arch Cardiovasc Dis 2013;106:382-393.

41. Managing Bleeding Hold the drug Local hemostatic measures Supportive PRBC/PLT transfusions FFP unlikely to be useful Initiate a hematology consult early Institutional protocols are recommended*

42. Managing Bleeding Specific reversal agents (“antidotes”) not yet available Protamine sulfate and vitamin K should not be expected to affect the anticoagulant activity With overdose – when given within 1-2 hours of ingestion activated charcoal can adsorb dabigatran (in vitro data) Maintain adequate diuresis given renal elimination Dabigatran can be dialyzed with removal of about 60% of drug over 2-3 hrs. Rivaroxaban is not expected to be dialyzable (high plasma protein binding). Consider transfusion of fresh frozen plasma, platelets or red blood cells for supportive management

43. Erenberg ES et al. Circ 2011:124:1573-9 Effect of PCC infusion (vs placebo) on the Protime after administration of Rivaroxaban 20 mg BID x 2.5 days Effect of PCC infusion (vs placebo) on the Ecarin Clotting Time after administration of Dabigatran 150 mg BID x 2.5 days Note: PCC infusion also reversed the effect of rivaroxaban on new thrombin generation as measured by the endogenous thrombin potential Note: PCC infusion did NOT reverse the anticoagulant effect of dabigatran on aPTT or Thrombin Time Reversal Agents

44. Managing Bleeding Some evidence supports use of activated prothrombin complex concentrates (FEIBA) for rivaroxaban, recombinant factor VIIa (Novoseven) for dabigatran or concentrates of coagulation factors II, IX, or X (PCC) but data are limited. 4-factor PCC recently approved in the US. –Best data available for the DTIs Always concerns about the “potentially” prothrombotic state created with bypassing agents. Xa recombinant reversing agent is under investigation. Phase II data was encouraging –Phase III in development

45. Conclusions Available anticoagulants successfully inhibit thrombin formation and the interactions of thrombin within the coagulation cascade There is no antidote yet available. Mechanisms to bypass the anticoagulant effect are available. In the appropriate patient the half-life is typically short. Withholding therapy may be sufficient

46. Conclusions Reversibility still need to be addressed Monitoring is problematic –Common/familiar coagulation assays are helpful but not the most accurate Be wary in high risk clinical settings Advise the use of Med-alert devices for patients using the drugs

47. Ongoing Clinical Challenges No validated tests to measure anticoagulation effect No established therapeutic range No true antidote for most agents Assessment of compliance more difficult than with vitamin K antagonists Potential for unknown long-term adverse events Balancing cost against efficacy Lack of head-to-head studies comparing new agents

48. Questions