Bridge Therapy: Peri-operative Anticoagulation Management Amjad AlMahameed, MD, MPH Division of Cardiology Beth Israel

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

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

3. BENEFITSSupporting 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 Must Answer three basic questions 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)

5. SAFE SURGERYWhat is the Risk of pei-operative Thrombosis? DEFICIENCIES IN CURRENT EVIDENCE • 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

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

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

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

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

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

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

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

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

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