1. Nathan P. Clark, Pharm D, FCCP, BCPS Clinical Pharmacy Supervisor Clinical Pharmacy Anticoagulation and Anemia Service Kaiser Permanente Colorado Aurora, CO

2. Disclosures  I have no financial conflict of interest related to this talk

3. Use of any “bridging” anticoagulant is off label) Objectives (Use of any “bridging” anticoagulant is off label) 1. Discuss the rationale for bridge therapy and the historical perspective 2. Summarize the state of the evidence for bridge therapy for the 3 major anticoagulation indications 3. Explain unknowns and gaps in bridge therapy literature 4. Apply evidence-based guidance for anticoagulation management around invasive procedures

4. Rationale for Bridge Therapy  1 in 10 anticoagulated patients requires an invasive diagnostic or surgical procedure annually ~ 175,000 procedures in patients with atrial fibrillation (AF) alone  Warfarin pharmacokinetics are not ideal in the perioperative setting: Long half-life ○ Requires interruption several days prior to high bleeding risk procedures Delayed onset ○ 5 or more days to achieve a therapeutic antithrombotic effect after reinitiation

5. Hypothetical Models of Perioperative Thrombotic Risk Warfarin

6. Hypothetical Models of Perioperative Thrombotic Risk

7. Rationale for Bridge Therapy “squeeze” the window The advent of low-molecular-weight heparins (LMWHs) provided an opportunity to “squeeze” the window of thromboembolic (TE) risk Two critical assumptions: 1. LMWH prevents the TE outcome of interest (stroke, systemic embolism, DVT/PE, valve thrombosis) 2. Any excess bleeding (anticipated) related to LMWH will be sufficiently offset by TE reduction and result in a net benefit to the patient

8. New Hypothetical Model of Perioperative Thrombosis Risk

9. Early Bridge Therapy Research  Case series and cohort studies published in early 2000’s No randomized, controlled trials  Guideline recommendations for perioperative warfarin management appear in 2008 American College of Chest Physicians (ACCP) 8 th edition

10. ACCP Guidelines 8 th Edition recommend bridging  We recommend bridging with therapeutic LMWH…over no bridging for patients at high risk of thrombosis (1C) suggest bridging  We suggest bridging with therapeutic LMWH… over no bridging for patients at moderate risk of thrombosis (2C) suggest bridging  We suggest bridging with prophylactic doses of LMWH or no bridging for low risk patients (2C) CHEST 2008; 133(6_suppl):299S-339S PMID: 18574269

11. Meta-analysis of Cohort Studies  Evaluated adult patients interrupting vitamin K antagonist therapy for an elective invasive procedure or surgery  Some patients received LWMH bridging, others did not ○ Analyzed TE and bleeding outcomes Circulation. 2012;126:1630-1639. PMID: 22912386

12. Thromboembolism Circulation. 2012;126:1630-1639. PMID: 22912386

13. Major Bleeding Circulation. 2012;126:1630-1639. PMID: 22912386

14. ACCP Guidelines 9 th Edition highrisk In patients at high risk for thromboembolism, we suggest Bridging (Grade 2C) Bridging anticoagulation instead of no bridging during interruption of VKA therapy (Grade 2C) lowrisk In patients at low risk for thromboembolism, we suggest No bridging No bridging instead of bridging anticoagulation during interruption of VKA therapy (Grade 2C) moderaterisk In patients at moderate risk for thromboembolism: individual patient- and surgery-related factors The bridging or no-bridging approach chosen is, as in the higher- and lower risk patients, based on an assessment of individual patient- and surgery-related factors Chest. 2012 Feb;141(2 Suppl):e326S-50S. PMID: 22315266 We make no suggestion!

15. Perioperative Anticoagulation Recommendations 2012  Based upon weak evidence Event rates were likely influenced by underlying risk factors directing bridge therapy to higher risk populations  Still no randomized, controlled trial data

16. Case 1 A 78 yo female anticoagulated for AF requires warfarin interruption for an upcoming total knee arthroplasty. Past medical history:  Stroke (prior to anticoagulation)  Hypertension (controlled)  No history of valvular heart disease or CKD  No history of HIT or medication allergy

17. Case 1 In addition to stopping warfarin for 5 days prior to surgery, which of the following do you recommend: ○ Therapeutic enoxaparin bridge therapy ○ Prophylactic dalteparin bridge therapy ○ Rivaroxaban bridge therapy ○ No bridging A B C D

18. ACCP AF Risk Stratification Chest. 2012 Feb;141(2 Suppl):e326S-50S. PMID: 22315266 CHADS 2 = congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, and stroke or transient ischemic attack

19. The BRIDGE Trial  Randomized, double blind, placebo controlled elective invasive procedure  AF patients requiring warfarin interruption for elective invasive procedure were randomized: LMWH bridging (dalteparin 100IU/kg BID) No bridging (placebo injections)  Warfarin was stopped 5 days prior to the procedure for all patients N Engl J Med 2015; 373(9):823-833 PMID: 26095867

21. Selected Baseline Characteristics CharacteristicNo Bridging (N=950) Bridging (N=934) Age - years71.8 (+/- 8.74)71.6 (+/- 8.88) Male – no. (%)696 (73.3)686 (73.4) CHADS 2 score (mean)2.3 (+/- 1.03)2.4 (+/- 1.07) Stroke – no. (%)79 (8.3%)99 (10.6%) TIA – no. (%)79 (8.3%)77 (8.2%) Mitral valve disease – no. (%)165 (17.4%)142 (15.2%) N Engl J Med 2015; 373(9):823-833 PMID: 26095867

22. N Engl J Med 2015; 373(9):823-833 PMID: 26095867

23. Critiques of BRIDGE appropriate  Non-inferiority design appropriate? How about the 1% non-inferiority margin for arterial TE?  Few  Few high risk patients: 14% had CHADS 2 ≥ 4 8-10% had history of CVA high risk  Can we apply these results to high risk AF patients?

24. Acute Stroke in AF Stroke. 2015;46:2175-2182. PMID: 26130094

25. Lancet 2000; 355: 1205-1210. PMID: 10770301

26. Two Critical Assumptions 1. LMWH prevents the TE outcome of interest (stroke, systemic embolism) 2. Any excess bleeding related to LMWH will be sufficiently offset by TE reduction and result in a net benefit to the patient

27. Case 1 In addition to stopping warfarin for 5 days prior to surgery, which of the following do you recommend: ○ Therapeutic enoxaparin bridge therapy ○ Prophylactic dalteparin bridge therapy ○ Rivaroxaban bridge therapy ○ No bridging A B C D

28. Case 2 69 you with is receiving warfarin for recurrent idiopathic PE (last PE was 2 years ago) has been scheduled for a hemicolectomy for metastatic colon cancer. Past medical history:  Colon cancer  Diabetes  No history of congenital thrombophilia, CKD, or medication allergy

29. Case 2 In addition to holding warfarin for 5 days, which of the following is recommended? ○ Therapeutic enoxaparin bridge therapy ○ Prophylactic dalteparin bridge therapy after surgery ○ Dabigatran bridge therapy ○ No bridging A B C D

30. ACCP VTE Risk Stratification Chest. 2012 Feb;141(2 Suppl):e326S-50S. PMID: 22315266

31. The ANTI-RIOT Study  Retrospective cohort of 1812 procedures in 1178 patients on warfarin for DVT/PE  Bridge therapy (75% therapeutic/ 25% prophylactic) was compared to no bridging  30-day rates of clinically-relevant bleeding, recurrent VTE, and death were compared JAMA Intern Med 2015; 175(7): 1163-8. PMID: 26010033

32. JAMA Intern Med 2015; 175(7): 1163-8. PMID: 26010033

33. Bridge therapy was associated with excess clinically- relevant bleeding HR=17.2 (95% CI 3.9-75.1) No difference in recurrent VTE JAMA Intern Med 2015; 175(7): 1163-8. PMID: 26010033

34. Two Critical Assumptions 1. LMWH prevents the TE outcome of interest (DVT, PE) 2. Any excess bleeding related to LMWH will be sufficiently offset by TE reduction and result in a net benefit to the patient

35. Case 2 In addition to holding warfarin for 5 days, which of the following is recommended? ○ Therapeutic enoxaparin bridge therapy ○ Prophylactic dalteparin bridge therapy after surgery ○ Dabigatran bridge therapy ○ No bridging A B C D

36. Case 3 76 yo female with atrial fibrillation and a bileaflet mechanical heart valve is scheduled for Mohs procedure to remove skin cancer from her face. What would you recommend? ○ Therapeutic enoxaparin bridge therapy ○ Continue warfarin with tight INR monitoring ○ Stop warfarin but no bridge therapy ○ Stop warfarin and use aspirin A B C D

37. ACCP Guidelines dermatologic  In patients who require minor dermatologic procedures and are receiving VKA therapy, we suggest (Grade 2C) Continuing VKAs around the time of the procedure and optimizing local hemostasis instead of other strategies (Grade 2C) cataract  In patients who require cataract surgery and are receiving VKA therapy, we suggest (Grade 2C) Continuing VKAs around the time of the surgery instead of other strategies (Grade 2C) Chest. 2012 Feb;141(2 Suppl):e326S-50S. PMID: 22315266

38. Prosthetic Heart Valves a.Starr Edwards – Ball in Cage b.Medtronic Hall – Single tilting disc c.St. Jude – Bileaflet tilting disc d.Carpentier Edwards – Bioprosthetic e.Hancock - Bioprosthetic

39. ACCP MHV Risk Stratification Chest. 2012 Feb;141(2 Suppl):e326S-50S. PMID: 22315266

40. Observational MHV Data Thromboembolism detail – No Heparin: myocardial infarction (1); LMWH Only: cerebral ischemia (1), unstable angina (1); Any UFH: cerebral ischemia (2) Thrombosis Research. 2009. 124: 300-305. PMID: 19232682

41. Bridging Data for MHV  Very limited Unable Unable to assess the critical assumptions skeptical  Reason to be skeptical Enoxaparin treatment failure in pregnancy with MHV ○ Formerly a boxed warning in the Lovenox® package label to avoid use in MHV

42. Bottom Line “evidence-based”  There is no “evidence-based” application of bridge therapy during warfarin interruption greatest risk  No tools reliably identify which patients are at greatest risk for perioperative thrombosis Need to target patients with absolute TE risk > 2-3% no bridge therapy  Default position for AF and DVT/PE patients should be no bridge therapy

43. Who do I still bridge? history of TE during a previous interruption  Patients with a history of TE during a previous interruption or low INR acute thrombosis  Patients with acute thrombosis within the past month DVT/PE Mural thrombus Left atrial appendage thrombus high VTE risk surgery  High risk DVT/PE patients ALSO having a high VTE risk surgery (e.g. ortho, cancer surgery) Prefer prophylactic dose LMWH  High risk patients with MHV or AF and mitral stenosis

44. Other Bleeding Risk Factors Abstract # 305. Thrombosis Hemostasis Summit of North America. April 14, 2016. Chicago, IL LMWH bridge therapy should not be restarted until 48 to 72 hours after major surgery or high bleeding risk procedures

45. Other Bleeding Risk Factors Abstract # 305. Thrombosis Hemostasis Summit of North America. April 14, 2016. Chicago, IL

46. DOAC Management Around Procedures  No bridge therapy  Timing of resumption according to bleeding risk High risk: 48 -72 hours Not high risk: 24 hours BMJ 2015; 351:h2391 PMID: 26174061

47. DOAC Management Around Procedures 30-day event rates (%) Trial RE-LYROCKET-AFARISTOTLE dabigatranwarfarinrivaroxabanwarfarinapixabanwarfarin Stroke or Systemic Embolism 0.5 0.30.4 0.6 Major Bleeding 5.14.60.990.791.61.9 Circulation. 2012; 126(3): 343-8. PMID: 22700854 Circulation. 2014; 129(18): 1850-9. PMID: 24552831 Blood 2014; 124(25): 3692-8. PMID: 25320240

48. Bridging in the Future?  Draft bridge therapy guidelines for AF from the American College of Cardiology  The Peri-Op 2 study is ongoing adequately powered No study will be adequately powered with high risk patients major bleeding  Bridge therapy NNH (major bleeding): 50 for low bleeding risk procedures 22 for high risk procedures thrombosis  Bridge therapy NNT (thrombosis): ?? ? ? ? ? ??

49. LMWH bridging is dead (according to the evidence) but somehow it lives on…