1. Bridge Therapy: Peri-operative Anticoagulation Management Amjad AlMahameed, MD, MPH Division of Cardiology Beth Israel Deaconess Medical Center Boston

2. Cross Coverage to Therapeutic INR Requiring AC but have not achieved Therapeutic INR Peri-procedural: RATIONALE FOR BRIDGING Already Rxed w chronic AC and now documented drop in INR mechanical heart valves A Fib w risk factors for emboli recent VTE (< 3 months) hypercoaguable states

3. BENEFITS Supporting Need for Bridge Therapy high daily risk estimate for thrombosis when patients remain unprotected for several days peri-procedure Subtherapeutic INR offers little or no protection Possible rebound hypercoaguable state, especially when warfarin reinitiated leading to thrombosis Bleeding complications can be controlled while CVA or PE may have lasting effect New drugs and new data offer increased ease of therapy

4. SAFE SURGERY : Choosing the Best Approach 1- What is the risk of bleeding with AC based upon the type of procedure and patient’s history? 2- What is the risk of thrombosis if AC reduced or stopped? 3- Which is the best bridging strategy (bridging medication, timing, outpatient vs. inpatient) Must Answer three basic questions

5. SAFE SURGERY What is the Risk of pei-operative Thrombosis? From descriptive studies and clinical experience Does not account for: - the added risk of thrombosis during surgery - the rebound theory - the heterogeneity in patients’ characteristics - the post-operative clinical course DEFICIENCIES IN CURRENT EVIDENCE

6. SAFE SURGERY What is the Optimal Upper INR Level? Type of Surgery Patients’ Characteristics Integrity of the hemostasis/coagulation system Technical/intraoperative factor

7. Current Standard in Bridge Therapy Prospective Randomized Controlled Trials Expert Opinion/Consensus

8. Prospective Randomized Trials (Bridge Therapy) None available, but some in progress and others in the planning phase

9. Expert Opinion on Bridge Therapy British Society of Hematology American College of Chest Physicians (ACCP) Kearon and Hirsh article; NEJM, May, 1997 Pregnancy and Prosthetic Valve Clinical Consensus (PPCR) Douketis article

10. Procedure 3 2 1.3 1 INR Pre-Op Day 3 2 1 Stop Warfarin +/- Vit K UFH when INR < 2 British Society of Haematology Normal INR Range 1-1.3 Therapeutic INR range Procedure

11. 3 2 1.3 1 INR Pre-Op Day 5 4 3 1 Stop Warfarin +/- Vit K Low or full dose UFH or LMWH when INR < 2 American College of Chest Physicians Normal INR Range 1-1.3 Therapeutic INR range Procedure

12. Kearon C, Hirsh J. NEJM 1997336:1506-1511 Kearom and Hirsh Recommendations NEJM, May, 1997 Indication Before After VTE 1 monthIV UFH IV UFH Month 2-3No Heparin IV Heparin RecurrentNo Heparin SC Heparin Arterial 1 month IV Heparin IV Heparin Mechanical Valve No Heparin SC Heparin A Fib No Heparin No Heparin

13. Limitations of Kearon and Hirsh Recommendations Discounts rebound phenomena Estimate 100-fold  in VTE risk but no  in ATE risk [versus Wahl’s review (5 of 493 patients had ATE, 4 died)] Low estimate ATE risk off warfarin (4.5 %/ year A fib, 8% /year mechanical valve) Estimate heparin bleeding risk of 3% per 2 days Recommends SC vitamin K, does not utilize LMWH Does not focus on patients’ characteristics (type of valve, risk factors for ATE in A Fib) SC (or no) heparin in A fib and mechanical valves??!!

14. Douketis Article Thrombosis Research, 108 (2003) 3-13 Better risk stratification of: - risk of post-procedural bleed - risk of peri procedure thrombotic complications Advocates normal or near normal INR at the time of surgery (earlier withdrawal of warfarin) Includes practical algorithms that guide perioperative management of AC

15. Bleeding Risk Classification and Postoperative AC J.D. Douketis, Thrombosis Research; 108 (2003) 3-13 Low-dose LMWH: POD 1-2 Warfarin: evening POD 1-2 Full dose LMWH: POD 2-3 h NSG, Prostate/bladder, OHS, major vascular, renal Bx, polypectomy, major CA surgery Post-op ACType of ProcedureBleeding Risk Catarct, cutaneous, laparascopic choly/hernia repai, cardiac cath Low-dose LMWH & warfarin evening of OR day Full dose LMWH: POD 1 Low-dose LMWH & warfarin evening of OR day Full dose LMWH: POD 1-2 Major abd, thoracic, and orthopedic PPM insertion High Risk Low Risk Moderate Risk

16. Bridging strongly recommended Stroke or TIA < 1 mo Any MV Caged-ball or single leaflet tilting disc AV Perioperative AC Rx in Patients With Mechanical Valves J.D. Douketis, Thrombosis Research; 108 (2003) 3-13 High Low Bileaflet tilting disc AV and < 2 stroke RF Bridging is optional Bridging should be considered Bileaflet tilting disc AV and > 2 stroke RF Moderate Star-Edwards Bjork-Shiley Medtronic-Hall Omnicarbon St. Jude Carbomedics Thromboembolism Risk Category Patient Characteristics Suggested Management A Fib, CVA, TIA, emboli, LV dysfxn, >75 y/o, HTN, DM

17. Bridging strongly recommended Stroke or TIA < 1 mo Any MV Rheumatic MV Disease Perioperative AC Rx in Patients With Chronic A Fib J.D. Douketis, Thrombosis Research; 108 (2003) 3-13 High Low Chronic A Fib and < 2 stroke RF Bridging is optional Bridging should be considered Chronic A Fib and > 2 stroke RF Moderate Thromboembolism Risk Category Patient Characteristics Suggested Management A Fib, CVA, TIA, emboli, LV dysfxn, >75 y/o, HTN, DM

18. Bridging strongly recommended J.D. Douketis, Thrombosis Research; 108 (2003) 3-13  A Fib  CVA  TIA  arterial emboli  LV dysfxn  >75 y/o  HTN  DM Regardless of thromboembolism risk category, patient’s characteristics take precedent!

19. Bridging strongly recommended Recent VTE (< 3 wks) Active CA APL Ab or LA Major comorbid disease Perioperative AC Rx in Patients With VTE J.D. Douketis, Thrombosis Research; 108 (2003) 3-13 High Low None of the above Bridging is optional Bridging should be considered VTE < 6 months VTE with previous AC interruption Moderate VTE Recurrence Risk Patient Characteristics Suggested Management

20. Emergency Surgery in the Anticoagulated Patient D/C all anticoagulants If INR >2.5: plasma or factor concentrate (+/- Vit k) Prepare PRBC, platelet, and FFP Consider PRBC transfusion to “augment hematocrit” especially in pts with cardiac disease Watch for volume overload, dilutional thrombocytopenia and coagulaopathy

21. Available Anticoagulants UFH: Discovered 1916, clinical use 1935 Vitamin K antagonists: discovered 1940, clinical use 1960s, clinical trials 1990s LMWHs: Discovered 1976, clinical trials started in 1980s and ongoing … Parenteral DTIs: Lepirudin (recombinant Hirudin) and Argatroban approved for Rx of HIT/HIT-T (3/1998 and 6/2000). Bivalirudin (modified Hirudin), for patients with ACS undergoing PCI

22. New Anticoagulants Oral Small-Molecule DTIs: Ximelagatran. No FDA approval Pentasaccharide: Fondaparinux (anti Xa activity), FDA approval for VTE prophylaxis in orthopaedic surgery 12/2001. Idraparinux: Being evaluated for chronic treatment of VTE

23. Choosing the Best Bridging Medication Depends on patient characteristics: - Recent bleed - Renal function - Actual body weight - Pre-op INR - Baseline coagulation tests - History of Heparin-Induced Thrombocytopenia Available data, clinical experience, and Douketis advocate bridging with LMWH if possible

24. Day -7 -5 -3 -1 +1 +2 +3 +5 Surgery √ INR √ CBC √ INR Hold Coumadin J.D. Douketis, Thrombosis Research; 108 (2003) 3-13 √ INR Coumadin “BRIDGING” STRATEGY # Days pre-op # Days post-op Resume Coumadin Start full Dose LMWH Resume full dose LMWH Prophylactic Dose LMWH