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Hot Topics In Anticoagulation

Hot Topics In Anticoagulation. Deborah Zeitlin, Pharm.D. Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacist Specialist, Clarian Health. Disclosure Statement.

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Hot Topics In Anticoagulation

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  1. Hot Topics In Anticoagulation Deborah Zeitlin, Pharm.D. Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacist Specialist, Clarian Health

  2. Disclosure Statement This individual has the following to disclose concerning possible financial or personal relationships with commercial entities that may be referenced in this presentation. • Deborah Zeitlin, Pharm.D.: Roche

  3. Objectives • Discuss guidelines on bridging patients with heparin • Describe current guidelines for vitamin K • Define appropriate dosing recommendations for use of low molecular weight heparin (LMWH) with obesity and renal insufficiency

  4. LM is scheduled for a root canal. What should be recommended regarding LM’s warfarin therapy? • Continue warfarin therapy • Stop warfarin 5 days prior to procedure • Stop warfarin 5 days prior and bridge with low molecular weight heparin therapy • Stop warfarin one day prior • Check INR and confirm result is < 1.5

  5. Decision Tree For Bridging Patient Risk Factors Surgery/Procedure Risk Factors • Determine anticoagulation diagnosis • Mechanical heart valve • Atrial fibrillation • Thromboembolism • Risks for thromboembolism • Type of surgery • Bleeding risk • Risk of thromboembolism • Time off anticoagulation Risk of thromboembolism versus bleeding Preference of physician and patient Need for bridging therapy Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44.

  6. Risk Of Thromboembolism Douketis JD, et al. Chest. 2008;133:S299-S339.

  7. Thrombophilia Classifications Severe Nonsevere Heterozygous Factor V Leiden mutation Heterozygous Factor II mutation • Protein C deficiency • Protein S deficiency • Antithrombin deficiency • Antiphospholipid syndrome • Multiple thrombophilia Douketis JD, et al. Chest. 2008;133:S299-S339.

  8. CHADS2 Score • Assess annual stroke risk in atrial fibrillation patients • Score range: 0 – 6 • One point for each factor • Congestive heart failure (recent) • Hypertension • Age > 75 • Diabetes • Two points: history of stroke or TIA Gage BF, et al. JAMA. 2001;285:2864-2870.

  9. Warfarin Perioperative Recommendations • For temporary interruption of warfarin requiring normal INR, stop warfarin 5 days prior to surgery/procedure (1B) • Resume warfarin 12 to 24 hours after surgery/ procedure when adequate hemostasis exists (1C) • May administer 1-2mg of oral vitamin K to normalize INR if INR is > 1.5 1-2 days prior to surgery/procedure (2C) Douketis JD, et al. Chest. 2008;133:S299-S339.

  10. Treatment Based On Risk Douketis JD, et al. Chest. 2008;133:S299-S339.

  11. Heparin Bridging Recommendations • Administer last SC LMWH dose 24 hours prior to surgery/procedure (1C) • For major surgery or spinal/epidural anesthesia, only administer morning dose of LMWH if BID dosing or 50% of once daily dosing to decrease residual anticoagulant effect (1C) • When bridging with IV UFH, stop UFH 4 hours prior to surgery • Do not monitor anti-factor Xa levels when bridging Douketis JD, et al. Chest. 2008;133:S299-S339.

  12. Restarting Heparin Bridge After Surgery/Procedure • For minor procedures with therapeutic-dose LMWH, resume LMWH 24 hours later (1C) • For major surgery or high risk of bleeding surgery/procedure with therapeutic-dose UFH or LMWH (1C) • Delay initiation for 48-72 hours • Use low-dose UFH or LMWH • Completely avoid UFH or LMWH • Assess anticipated bleeding risk and hemostasis post surgery/procedure; do not resume at fixed time Douketis JD, et al. Chest. 2008;133:S299-S339.

  13. Minor Surgeries & Procedures • Dental, dermatologic, ophthalmic and gastrointestinal • Patients usually discharged home • Patients need to be informed of expectations • Prolonged bleeding • Major bleeding • Medical attention required • Obtain PT/INR prior ideally 24 hours before • Greater risk of thromboembolism than bleeding Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44. Douketis JD, et al. Chest. 2008;133:S299-S339.

  14. Dental Procedures Continue Warfarin Consider Other Options Full-mouth extractions Multiple implant placements Extractions of multiple bony impactions Gingivectomy Orthognathic surgery • Single/multiple tooth extractions (up to 3) • Endodontics (root canal) • Dental hygiene • Restorative surgery; supragingival • Dental scaling • Prosthetics • Crowns and bridges Douketis JD, et al. Chest. 2008;133:S299-S339. Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44. Herman WW et al. J Am Dent Assoc. 1997;128:327-335.

  15. Dermatologic Surgery • Simple excisions and Mohs surgery • Basal and squamous cell carcinomas • Actinic keratoses • Malignant or premalignant nevi • Continue warfarin therapy (1C) • Benefits include shorter hospitalization, fewer blood tests and monitoring, and reduced cost • Make sure INRs are within therapeutic range and stable; not greater than 4 Lam J, et al. BJPS. 2001;54(4): 372-373. Jaffer AK. Cleve Clin J Med. 2009;76 (4):S37-S44. Sugden P, et al. Surgeon. 2008;6(3):148-150. Douketis JD, et al. Chest. 2008;133:S299-S339. Kirkorian AY, et al. Dermatol Surg. 2007;33:1189-1197.

  16. Ophthalmic Procedures • Cataract surgery, trabeculectomy • Jamula et al. showed continuing warfarin increases bleeding risk by 3 fold in cataract surgery, but bleeding not clinically significant • Chest only makes recommendation for cataract removal and recommends continuing warfarin (1C) • Charles et al. states risk of ocular hemorrhage is less significant than risk of thromboembolism with intravitreal injections or intraocular surgery Jamula E, et al. Thromb Res. 2009;124:292-299. Jaffer AK. Cleve Clin J Med. 2009;74(4):S37-S44. Douketis et al. Chest. 2008;133:S299-S339. Charles S, et al. Retina. 2007;27(7):813-815.

  17. Bleeding Risk For Endoscopic Procedures Low High Polypectomy Biliary/pancreatic sphincterotomy Pneumatic or bougie dilation PEG placement Endoscopic hemostasis Treatment of varices Cystogastrostomy Tumor ablation Therapeutic balloon-assisted enteroscopy • Diagnostic with biopsy • EGD, colonoscopy, flexible sigmoidoscopy • ERCP without sphinecterotomy • Endoscopic ultrasound without fine needle aspiration • Capsule endoscopy • Enteral stent deployment without dilation • Enteroscopy & diagnostic balloon-assisted enteroscopy Anderson MA, et al. Gastrointest Endosc. 2009;70(6):1060-1068.

  18. Cardiac Device Surgery • Case reports demonstrate complications of periprocedural bridging including pocket hematomas, arterial thromboembolism and increased cost • Pacemakers • Implantable cardioverter defibrillators • Cardiac resynchronization therapy • BRUISE CONTROL trial • Bridge or continue coumadin for device surgery randomized control trial Birnie D, et al. Curr Opin Cardiol. 2008;24:82-87.

  19. BRUISE CONTROL Trial • Randomized 1:1; moderate to high-risk patients of arterial thromboembolism or high-risk of VTE • Primary outcome • Clinically significant hematoma that requires reoperation and/or transfusion and/or unplanned/ prolonged hospitalization and/or interruption of LMWH, IV UFH or anticoagulation • Secondary outcomes • Thromboembolic events, components of primary outcomes and major perioperative bleeding • Goal of 984 patients recruited by July 2010 Birnie D, et al. Curr Opin Cardiol. 2008;24:82-87.

  20. LM is scheduled for a root canal. What should be recommended regarding LM’s warfarin therapy? • Continue warfarin therapy • Stop warfarin 5 days prior to procedure • Stop warfarin 5 days prior and bridge with low molecular weight heparin therapy • Stop warfarin one day prior • Check INR and confirm result is < 1.5

  21. RD, a 40 year old female, finished trimethoprim/ sulfamethoxazole today for a current urinary tract infection. Her warfarin indication is Factor V Leiden Mutation, and normally her INR is 2.5 (Goal 2-3). Her INR today is 6.1 with no active bleed. What is the appropriate recommendation? • A. Stop warfarin • B. Send to emergency room • C. Give vitamin K 5 mg orally • D. Give vitamin K 5 mg IV • E. Make no changes

  22. Causes Of Nontherapeutic INRs • Inaccurate INR testing • Changes in vitamin K intake • Changes in warfarin or vitamin K absorption • Changes in warfarin metabolism • Changes in vitamin K-dependent coagulation factor synthesis or metabolism • Concomitant drug use • Patient noncompliance Ansell J, et al. Chest. 2008;133:160S-198S.

  23. Bleeding Risk With Elevated INR • Absolute daily risk of bleeding is low • Assess bleeding risk • Potential risk of bleeding • Active bleed • INR level • Treatment • Hold warfarin dose or decrease • Use oral or IV vitamin K • Life-threatening bleeds • Fresh frozen plasma • Prothrombin complex concentrate • Recombinant factor VIIa Ansell J, et al. Chest. 2008;133:160S-198S.

  24. Ansell J, et al. Chest. 2008;133:160S-198S.

  25. Oral Vitamin K Versus Placebo • Oral vitamin K use in over anticoagulated pts • 711 non-bleeding patients with INR 4.5 – 10 • INRs: 8.1-10 (72); 6.1-8 (185); 4.5-6 (487) • Held 1 warfarin dose & randomized to vitamin K 1.25 mg (347) or placebo (365) • Outcome of bleeding events within 90 days • Major (fatal, > 2 units pack red blood cells, therapeutic intervention or confirmed bleeding in enclosed space) • Minor (medical assessment) • Trivial (no medical assessment) Crowther MA, et al. Ann Intern Med. 2009;150:293-300.

  26. Results: Oral Vitamin K Versus Placebo • No statistical significant difference • Bleeding, thromboembolism or death • INR decreased more rapidly with vitamin K • INR average decrease vitamin K: 2.8 • INR average decrease placebo: 1.4 • Major bleeding events occurred more often in patients older than 70 years (10/13 events) • Vitamin K safe to correct INR, prevent death & thromboembolism, but does not minimize risk of bleeding Crowther MA, et al. Ann Intern Med. 2009;150:293-300.

  27. RD, a 40 year old female, finished trimethoprim/ sulfamethoxazole today for a current urinary tract infection. Her warfarin indication is Factor V Leiden Mutation, and normally her INR is 2.5 (Goal 2-3). Her INR today is 6.1 with no active bleed. What is the appropriate recommendation? • A. Stop warfarin • B. Send to emergency room • C. Give vitamin K 5 mg orally • D. Give vitamin K 5 mg IV • E. Make no changes

  28. Low Molecular Weight Heparin • Benefits • Easy to use • Predictable response • Less monitoring • Less heparin induced thrombocytopenia (HIT) • Less risk of osteoporosis • Concerns • Less reversibility • Accumulates in renal insufficiency • Less experience in obesity • Expensive • Agents not interchangeable Enoxaparin, Dalteparin, Tinzaparin Chawla LS, et al. Obes Surg. 2004;14:695-698. Hirsh J, et al. Chest. 2008;133:141S-159S.

  29. A 65 year old male [weight=320lbs, height=70in] with a serum creatinine of 2.8 is scheduled for hernia repair surgery. He will be bedridden for one week. What is the recommended dose of subcutaneous enoxaparin for him for VTE prophylaxis? • A. 30mg twice daily • B. 40mg twice daily • C. 30mg daily • D. 40mg daily • E. Avoid enoxaparin

  30. Obesity And LMWH • Maximum recommended dose in obesity • Tinzaparin and enoxaparin: none • Dalteparin 18,000 units daily (VTE treatment) & 20,000 units daily (acute coronary syndrome) • LMWH studied up to 190 kg for VTE treatment • Treatment doses use actual body weight (2C) • Does not cause more bleeding or thromboembolic events • BMI > 27 kg/m2: use enoxaparin 1mg/kg twice daily • Dalteparin 200 units/kg & tinzaparin 175 units/kg daily Clark NP. Thromb Res. 2008;123:S58-S61. Hirsch J, et al. Chest. 2008;133:141S-159S. Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

  31. LMWH and VTE Prophylaxis • A study with surgical patients demonstrated negative correlation of body weight & anti-factor Xa levels for VTE prophylaxis • Bariatric surgery patients showed higher prophylaxis dose with less incidence of VTE and no change in bleeding risk • Consider increasing VTE prophylactic doses by 30% with BMI > 40kg/m2 • Monitor anti-factor Xa levels in patients >190kg Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

  32. Target Anti-Factor Xa Levels Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

  33. Sample Enoxaparin Treatment Dosing Nomogram Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

  34. Definition Of Renal Function Creatinine Clearance by Cockcroft Gault Equation (ml/min) CrCl = [(140 – age)* (IBW)]/72 * SrCr (multiple by 0.85 if female) Ideal Body Weight Male IBW: 50 kg + 2.3 kg for each inch > 5 feet Female IBW: 45.5kg + 2.3 kg for each inch > 5 feet Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

  35. Renal Insufficiency & LMWH • If CrCl <30ml/min with therapeutic doses, use UFH instead of LMWH (2C) • LMWH use with severe renal insufficiency and therapeutic doses, decrease dose by 50% (2C) • More accumulation with enoxaparin than others • Watch for signs and symptoms of bleeding • Consider monitoring anti-factor Xa levels for use >10 days if CrCl 30–60 ml/min & risk of accumulation Hirsch J, et al. Chest. 2008;133:141S-159S. Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

  36. LMWH Dosing with Renal Insufficiency Prophylaxis Treatment CrCl <20ml/min use weight-based adjusted-dose IV UFH and monitor aPTT due to limited studies in LMWH CrCl <30ml/min Dalteparin: use caution Enoxaparin: 1mg/kg daily Tinzaparin: use caution • 30-90ml/min: dose adjustment not needed • CrCl <30ml/min • Enoxaparin: 30mg daily • Dalteparin & tinzaparin adjustment not needed if used < 10 days Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

  37. A 65 year old male [weight=320lbs, height=70in] with a serum creatinine of 2.8 is scheduled for hernia repair surgery. He will be bedridden for one week. What is the recommended dose of subcutaneous enoxaparin for him for VTE prophylaxis? • A. 30mg twice daily • B. 40mg twice daily • C. 30mg daily • D. 40mg daily • E. Avoid enoxaparin

  38. Hot Topics In Anticoagulation Deborah Zeitlin, Pharm.D. Assistant Professor of Pharmacy Practice Butler University College of Pharmacy and Health Sciences Clinical Pharmacist Specialist, Clarian Health

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