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Hot Topics In Anticoagulation Deborah Zeitlin, Pharm.D. Assistant Professor of Pharmacy Practice Butler University College...
Disclosure Statement <ul><li>This individual has the following to disclose concerning possible financial or personal relat...
Objectives <ul><li>Discuss guidelines on bridging patients with heparin </li></ul><ul><li>Describe current guidelines for ...
LM is scheduled for a root canal.  What should be recommended regarding LM’s warfarin therapy? <ul><li>Continue warfarin t...
Decision Tree For Bridging Jaffer AK.  Cleve Clin J Med.  2009;76(4):S37-S44. 5 Surgery/Procedure Risk Factors  <ul><li>De...
Risk Of Thromboembolism 6 Douketis JD, et al.  Chest.  2008;133:S299-S339.  Thromboembolism Risk Mechanical Heart Valve At...
Thrombophilia Classifications <ul><li>Severe </li></ul><ul><li>Protein C deficiency </li></ul><ul><li>Protein S deficiency...
CHADS 2  Score <ul><li>Assess annual stroke risk in atrial fibrillation patients </li></ul><ul><li>Score range: 0 – 6 </li...
Warfarin Perioperative Recommendations <ul><li>For temporary interruption of warfarin requiring normal INR, stop warfarin ...
Treatment Based On Risk 10 Douketis JD, et al.  Chest.  2008;133:S299-S339.  Risk of Developing Thromboembolism Treatment ...
Heparin Bridging Recommendations <ul><li>Administer last SC LMWH dose 24 hours prior to surgery/procedure (1C) </li></ul><...
Restarting Heparin Bridge After Surgery/Procedure <ul><li>For minor procedures with therapeutic-dose LMWH, resume LMWH 24 ...
Minor Surgeries & Procedures <ul><li>Dental, dermatologic, ophthalmic and gastrointestinal </li></ul><ul><li>Patients usua...
Dental Procedures <ul><li>Continue Warfarin </li></ul><ul><li>Single/multiple tooth extractions (up to 3) </li></ul><ul><l...
Dermatologic Surgery <ul><li>Simple excisions and Mohs surgery </li></ul><ul><ul><li>Basal and squamous cell carcinomas </...
Ophthalmic Procedures <ul><li>Cataract surgery, trabeculectomy </li></ul><ul><li>Jamula et al. showed continuing warfarin ...
Bleeding Risk For Endoscopic Procedures <ul><li>Low </li></ul><ul><li>Diagnostic with biopsy </li></ul><ul><ul><li>EGD, co...
Cardiac Device Surgery <ul><li>Case reports demonstrate complications of periprocedural bridging including pocket hematoma...
BRUISE CONTROL Trial <ul><li>Randomized 1:1; moderate to high-risk patients of arterial thromboembolism or high-risk of VT...
LM is scheduled for a root canal.  What should be recommended regarding LM’s warfarin therapy? <ul><li>Continue warfarin t...
RD, a 40 year old female, finished trimethoprim/ sulfamethoxazole today for a current urinary tract infection.  Her warfar...
Causes Of Nontherapeutic INRs <ul><li>Inaccurate INR testing </li></ul><ul><li>Changes in vitamin K intake </li></ul><ul><...
Bleeding Risk With Elevated INR <ul><li>Absolute daily risk of bleeding is low </li></ul><ul><li>Assess bleeding risk </li...
Ansell J, et al.  Chest.  2008;133:160S-198S. Condition Intervention For Elevated INRs And Bleeding INR <5, but more than ...
Oral Vitamin K Versus Placebo <ul><li>Oral vitamin K use in over anticoagulated pts  </li></ul><ul><li>711 non-bleeding pa...
Results: Oral Vitamin K Versus Placebo <ul><li>No statistical significant difference  </li></ul><ul><ul><li>Bleeding, thro...
RD, a 40 year old female, finished trimethoprim/ sulfamethoxazole today for a current urinary tract infection.  Her warfar...
Low Molecular Weight Heparin <ul><li>Benefits </li></ul><ul><ul><li>Easy to use </li></ul></ul><ul><ul><li>Predictable res...
A 65 year old male [weight=320lbs, height=70in] with a serum creatinine of 2.8 is scheduled for hernia repair surgery.  He...
Obesity And LMWH  <ul><li>Maximum recommended dose in obesity </li></ul><ul><ul><li>Tinzaparin and enoxaparin: none </li><...
LMWH and VTE Prophylaxis <ul><li>A study with surgical patients demonstrated negative correlation of body weight & anti-fa...
Target Anti-Factor Xa Levels Nutescu EA, et al.  Ann Pharmacother.  2009;43:1064-1083. 33 Indication LMWH Dosing Peak Rang...
Sample Enoxaparin Treatment Dosing Nomogram Nutescu EA, et al.  Ann Pharmacother.  2009;43:1064-1083. 34 Anti-Factor Xa Le...
Definition Of Renal Function Nutescu EA, et al.  Ann Pharmacother.  2009;43:1064-1083. 35 Creatinine Clearance by Cockcrof...
Renal Insufficiency & LMWH <ul><li>If CrCl <30ml/min with therapeutic doses, use UFH instead of LMWH (2C) </li></ul><ul><l...
LMWH Dosing with Renal Insufficiency <ul><li>Prophylaxis </li></ul><ul><li>30-90ml/min: dose adjustment not needed </li></...
A 65 year old male [weight=320lbs, height=70in] with a serum creatinine of 2.8 is scheduled for hernia repair surgery.  He...
Hot Topics In Anticoagulation Deborah Zeitlin, Pharm.D. Assistant Professor of Pharmacy Practice Butler University College...
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  • Deborah Zeitlin, Pharm.D. Hot Topics in Anticoagulation
  • Deborah Zeitlin, Pharm.D. Hot Topics in Anticoagulation
  • Deborah Zeitlin, Pharm.D. Hot Topics in Anticoagulation
  • 1B = Strong recommendation; moderate quality of evidence Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • 20% of all surgical and nonsurgical procedures Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Local measures such as gelatin sponges, tranexamic acid mouthrinces or fibrin glue with gelatin and stutures Speak with dentist prior to procedure Check INR prior to procedure Prefer to have INR on lower end of range 1B recommendation: who have minor dental procedures and on warfarin continue warfarin and provide local measures Douketis JD. Chest. 2008;133:S299-S339. Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • May need further monitoring and treatment with skin grafts and flaps with plastic surgery due to more invasive procedure. Risk of thromboembolism when stopping warfarin causes a greater risk of morbidity and mortality Educate the patient on what to expect. More concern about risk of thromboembolism Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Trabeculectomy: surgery to help treat glaucoma Review study by jamula et al. with 11 studies looking at caract surgery and assessing bleeding risk when patients were continued on warfarin which showed thatet al shows that there is a three-fold greater risk for bleeding than patient who were anticoagulted, but the bleeds were not clinically significant (self-limited without clinical consequences) difference can be based on surgerical and anesthetic techniques that were not consistent. Remove trabeculom to reduce pressure Continue warfarin rather than stop in intravitreal injections or intraocular surgery Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • These guidelines come from the american society for gastrointestinal endoscopy 2009 esophagogastroduodenoscopy Endoscopic retrograde cholangiopancreatography Patients in low category continue with warfarin Discontinue warfarin and patients with high thrombotic risk consider bridge therapy for either elective or urgernt endoscopic procedures Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Information based on case reports Pocket hematomas risk ranges from 8-77%; cause prolonged cessation of anticoagulation with increased risk of arterial thrombosis and reoperation requred. Increased length of hospitalization Also increased risk of arterial thromboembolism due to normal coagulability and when able to restart bridging. Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Conventional bridgine with unintertupted anticoagulation. Target INR for patients remaining on warfarin will be INR &lt; 3 Patient excluded will be poor compliance, renal failure, HIT, active device infection or not want to participate Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Especially if patient has no risk factor. Also need to assess risk of Thromboembolism with oral surgeon or dentist performing procedure Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • SC vitamin K is less predictable and more risk of hematoma Do not give to high a dose of vitamin K since you do not want to overcorrect and put patient at sub-therapeutic level for too long. Factor VIIa not currently approved has been shown to be effective in health volunteers; also has an increased risk of thromboembolic complications Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Further Adjustment of warfarin based on INR FFP=fresh frozen plasma; PCC=prothrombin complex concentrate; rFVIIa=recombinant factor VIIa Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • To treat an excessive anticoagulation in patients on warfarin and clinical outcomes Secondary outcomes includeed frequency of major bleeding events, confirmed venous or arterial thromboembolism and death Warfarin was reinistuted by clinic when INR was within therapeutic range after study drug Baseline characteristics were similar Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Study was underpowered to find difference in major bleeding Does not improve clinical outcomes. The study was not powered to detect small differences in frequency of major bleeds Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Do more frequent monitoring of INR results. Should hold 1-2 doses and recheck value with 48 hours Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • BMI is 45kg/m 2 CrCl = 27ml/min Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • 196kg studied in enoxaparin patient with acute coronary syndrome 190 in dalteparin; 165 in tinzaparin and 159 in enoxaparin Total body witht or adjusted body weight correnated better with dalteparin clearance than lean body weight. In enoxaparin using bid dosing instead of daily dosing is also better Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • In bariatric surgical patients: mean BMI was 50kg/m 2; 30mg BID versus 40mg BID 703 * weight (lb)/ height (in) 2 Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Treatment nomogram for LMWH: only in complicated or unstable patients Peak levels drawn at 4 hours post SC dose Anti-Xa activity is chromogenic mehtod There is no set recommended way to actual monitor thes patients Can use to treat obesity and severe renal impairment but also pregnancy and childredn Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • BMI is 46kg/m 2 CrCl = 27ml/min Weight in kg is 145 kg Need to increase VTE prophylaxis dose by about 30% and since on for only 7 days due not need to monitor Hot Topics in Anticoagulation Deborah Zeitlin, Pharm.D.
  • Transcript of "Hot Topics In Anticoagulation Deborah Zeitlin, Pharm.D."

    1. 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. 2. Disclosure Statement <ul><li>This individual has the following to disclose concerning possible financial or personal relationships with commercial entities that may be referenced in this presentation. </li></ul><ul><ul><li>Deborah Zeitlin, Pharm.D.: Roche </li></ul></ul>2
    3. 3. Objectives <ul><li>Discuss guidelines on bridging patients with heparin </li></ul><ul><li>Describe current guidelines for vitamin K </li></ul><ul><li>Define appropriate dosing recommendations for use of low molecular weight heparin (LMWH) with obesity and renal insufficiency </li></ul>3
    4. 4. LM is scheduled for a root canal. What should be recommended regarding LM’s warfarin therapy? <ul><li>Continue warfarin therapy </li></ul><ul><li>Stop warfarin 5 days prior to procedure </li></ul><ul><li>Stop warfarin 5 days prior and bridge with low molecular weight heparin therapy </li></ul><ul><li>Stop warfarin one day prior </li></ul><ul><li>Check INR and confirm result is < 1.5 </li></ul>4
    5. 5. Decision Tree For Bridging Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44. 5 Surgery/Procedure Risk Factors <ul><li>Determine anticoagulation diagnosis </li></ul><ul><ul><li>Mechanical heart valve </li></ul></ul><ul><ul><li>Atrial fibrillation </li></ul></ul><ul><ul><li>Thromboembolism </li></ul></ul><ul><li>Risks for thromboembolism </li></ul><ul><li>Type of surgery </li></ul><ul><li>Bleeding risk </li></ul><ul><li>Risk of thromboembolism </li></ul><ul><li>Time off anticoagulation </li></ul>Risk of thromboembolism versus bleeding Preference of physician and patient Need for bridging therapy Patient Risk Factors
    6. 6. Risk Of Thromboembolism 6 Douketis JD, et al. Chest. 2008;133:S299-S339. Thromboembolism Risk Mechanical Heart Valve Atrial Fibrillation Venous Thromboembolism High <ul><li>Mitral mechanical valve </li></ul><ul><li>Older aortic valve </li></ul><ul><li>Stroke or TIA in last 6 months </li></ul><ul><li>CHADS 2 score 5-6 </li></ul><ul><li>Stroke or TIA in last 3 months </li></ul><ul><li>Rheumatic valvular heart disease </li></ul><ul><li>Venous thromboembolism (VTE) in last 3 months </li></ul><ul><li>Severe thrombophilia </li></ul>Moderate Bileaflet aortic valve & atrial fibrillation, prior TIA /stroke, diabetes, hypertension, heart failure, > 75 years CHADS 2 score 3-4 <ul><li>VTE in last 3-12 months </li></ul><ul><li>Recurrent VTE </li></ul><ul><li>Nonsevere thrombophilia </li></ul><ul><li>Active cancer </li></ul>Low Bileaflet aortic valves without atrial fibrillation and no risks of stroke CHADS 2 score 0-2 (no history of stroke or transient ischemic attack (TIA)) Single VTE within past 12 months and no other risk factors
    7. 7. Thrombophilia Classifications <ul><li>Severe </li></ul><ul><li>Protein C deficiency </li></ul><ul><li>Protein S deficiency </li></ul><ul><li>Antithrombin deficiency </li></ul><ul><li>Antiphospholipid syndrome </li></ul><ul><li>Multiple thrombophilia </li></ul><ul><li>Nonsevere </li></ul><ul><li>Heterozygous Factor V Leiden mutation </li></ul><ul><li>Heterozygous Factor II mutation </li></ul>7 Douketis JD, et al. Chest. 2008;133:S299-S339.
    8. 8. CHADS 2 Score <ul><li>Assess annual stroke risk in atrial fibrillation patients </li></ul><ul><li>Score range: 0 – 6 </li></ul><ul><li>One point for each factor </li></ul><ul><ul><li>C ongestive heart failure (recent) </li></ul></ul><ul><ul><li>H ypertension </li></ul></ul><ul><ul><li>A ge > 75 </li></ul></ul><ul><ul><li>D iabetes </li></ul></ul><ul><li>Two points: history of s troke or TIA </li></ul>Gage BF, et al. JAMA. 2001;285:2864-2870. 8 CHADS 2 Score Stroke Adjusted Rate per 100 Patient-Years 0 1.9 1 2.8 2 4 3 5.9 4 8.5 5 12.5 6 18.2
    9. 9. Warfarin Perioperative Recommendations <ul><li>For temporary interruption of warfarin requiring normal INR, stop warfarin 5 days prior to surgery/procedure (1B) </li></ul><ul><li>Resume warfarin 12 to 24 hours after surgery/ procedure when adequate hemostasis exists (1C) </li></ul><ul><li>May administer 1-2mg of oral vitamin K to normalize INR if INR is > 1.5 1-2 days prior to surgery/procedure (2C) </li></ul>9 Douketis JD, et al. Chest. 2008;133:S299-S339.
    10. 10. Treatment Based On Risk 10 Douketis JD, et al. Chest. 2008;133:S299-S339. Risk of Developing Thromboembolism Treatment Based on Risk Strength of Recommendation High Bridge anticoagulation with therapeutic -dose SC LMWH or IV UFH SC LMWH preferred versus IV UFH 1C 2C Moderate Bridge anticoagulation with therapeutic- dose SC LMWH, therapeutic-dose IV UFH or low-dose SC LMWH Therapeutic-dose SC LMWH preferred 2C Low Bridge anticoagulation with low-dose SC LMWH or no bridging 2C
    11. 11. Heparin Bridging Recommendations <ul><li>Administer last SC LMWH dose 24 hours prior to surgery/procedure (1C) </li></ul><ul><li>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) </li></ul><ul><li>When bridging with IV UFH, stop UFH 4 hours prior to surgery </li></ul><ul><li>Do not monitor anti-factor Xa levels when bridging </li></ul>Douketis JD, et al. Chest. 2008;133:S299-S339.
    12. 12. Restarting Heparin Bridge After Surgery/Procedure <ul><li>For minor procedures with therapeutic-dose LMWH, resume LMWH 24 hours later (1C) </li></ul><ul><li>For major surgery or high risk of bleeding surgery/procedure with therapeutic-dose UFH or LMWH (1C) </li></ul><ul><ul><li>Delay initiation for 48-72 hours </li></ul></ul><ul><ul><li>Use low-dose UFH or LMWH </li></ul></ul><ul><ul><li>Completely avoid UFH or LMWH </li></ul></ul><ul><li>Assess anticipated bleeding risk and hemostasis post surgery/procedure; do not resume at fixed time </li></ul>Douketis JD, et al. Chest. 2008;133:S299-S339.
    13. 13. Minor Surgeries & Procedures <ul><li>Dental, dermatologic, ophthalmic and gastrointestinal </li></ul><ul><li>Patients usually discharged home </li></ul><ul><li>Patients need to be informed of expectations </li></ul><ul><ul><li>Prolonged bleeding </li></ul></ul><ul><ul><li>Major bleeding </li></ul></ul><ul><ul><li>Medical attention required </li></ul></ul><ul><li>Obtain PT/INR prior ideally 24 hours before </li></ul><ul><li>Greater risk of thromboembolism than bleeding </li></ul>Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44. Douketis JD, et al. Chest. 2008;133:S299-S339.
    14. 14. Dental Procedures <ul><li>Continue Warfarin </li></ul><ul><li>Single/multiple tooth extractions (up to 3) </li></ul><ul><li>Endodontics (root canal) </li></ul><ul><li>Dental hygiene </li></ul><ul><li>Restorative surgery; supragingival </li></ul><ul><li>Dental scaling </li></ul><ul><li>Prosthetics </li></ul><ul><li>Crowns and bridges </li></ul><ul><li>Consider Other Options </li></ul><ul><li>Full-mouth extractions </li></ul><ul><li>Multiple implant placements </li></ul><ul><li>Extractions of multiple bony impactions </li></ul><ul><li>Gingivectomy </li></ul><ul><li>Orthognathic surgery </li></ul>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. 15. Dermatologic Surgery <ul><li>Simple excisions and Mohs surgery </li></ul><ul><ul><li>Basal and squamous cell carcinomas </li></ul></ul><ul><ul><li>Actinic keratoses </li></ul></ul><ul><ul><li>Malignant or premalignant nevi </li></ul></ul><ul><ul><li>Continue warfarin therapy (1C) </li></ul></ul><ul><li>Benefits include shorter hospitalization, fewer blood tests and monitoring, and reduced cost </li></ul><ul><li>Make sure INRs are within therapeutic range and stable; not greater than 4 </li></ul>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. 16. Ophthalmic Procedures <ul><li>Cataract surgery, trabeculectomy </li></ul><ul><li>Jamula et al. showed continuing warfarin increases bleeding risk by 3 fold in cataract surgery, but bleeding not clinically significant </li></ul><ul><li>Chest only makes recommendation for cataract removal and recommends continuing warfarin (1C) </li></ul><ul><li>Charles et al. states risk of ocular hemorrhage is less significant than risk of thromboembolism with intravitreal injections or intraocular surgery </li></ul>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. 17. Bleeding Risk For Endoscopic Procedures <ul><li>Low </li></ul><ul><li>Diagnostic with biopsy </li></ul><ul><ul><li>EGD, colonoscopy, flexible sigmoidoscopy </li></ul></ul><ul><li>ERCP without sphinecterotomy </li></ul><ul><li>Endoscopic ultrasound without fine needle aspiration </li></ul><ul><li>Capsule endoscopy </li></ul><ul><li>Enteral stent deployment without dilation </li></ul><ul><li>Enteroscopy & diagnostic balloon-assisted enteroscopy </li></ul><ul><li>High </li></ul><ul><li>Polypectomy </li></ul><ul><li>Biliary/pancreatic sphincterotomy </li></ul><ul><li>Pneumatic or bougie dilation </li></ul><ul><li>PEG placement </li></ul><ul><li>Endoscopic hemostasis </li></ul><ul><li>Treatment of varices </li></ul><ul><li>Cystogastrostomy </li></ul><ul><li>Tumor ablation </li></ul><ul><li>Therapeutic balloon-assisted enteroscopy </li></ul>Anderson MA, et al. Gastrointest Endosc. 2009;70(6):1060-1068.
    18. 18. Cardiac Device Surgery <ul><li>Case reports demonstrate complications of periprocedural bridging including pocket hematomas, arterial thromboembolism and increased cost </li></ul><ul><ul><li>Pacemakers </li></ul></ul><ul><ul><li>Implantable cardioverter defibrillators </li></ul></ul><ul><ul><li>Cardiac resynchronization therapy </li></ul></ul><ul><li>BRUISE CONTROL trial </li></ul><ul><ul><li>Bridge or continue coumadin for device surgery randomized control trial </li></ul></ul>Birnie D, et al. Curr Opin Cardiol. 2008;24:82-87.
    19. 19. BRUISE CONTROL Trial <ul><li>Randomized 1:1; moderate to high-risk patients of arterial thromboembolism or high-risk of VTE </li></ul><ul><li>Primary outcome </li></ul><ul><ul><li>Clinically significant hematoma that requires reoperation and/or transfusion and/or unplanned/ prolonged hospitalization and/or interruption of LMWH, IV UFH or anticoagulation </li></ul></ul><ul><li>Secondary outcomes </li></ul><ul><ul><li>Thromboembolic events, components of primary outcomes and major perioperative bleeding </li></ul></ul><ul><li>Goal of 984 patients recruited by July 2010 </li></ul>Birnie D, et al. Curr Opin Cardiol. 2008;24:82-87.
    20. 20. LM is scheduled for a root canal. What should be recommended regarding LM’s warfarin therapy? <ul><li>Continue warfarin therapy </li></ul><ul><li>Stop warfarin 5 days prior to procedure </li></ul><ul><li>Stop warfarin 5 days prior and bridge with low molecular weight heparin therapy </li></ul><ul><li>Stop warfarin one day prior </li></ul><ul><li>Check INR and confirm result is < 1.5 </li></ul>
    21. 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? <ul><li>A. Stop warfarin </li></ul><ul><li>B. Send to emergency room </li></ul><ul><li>C. Give vitamin K 5 mg orally </li></ul><ul><li>D. Give vitamin K 5 mg IV </li></ul><ul><li>E. Make no changes </li></ul>
    22. 22. Causes Of Nontherapeutic INRs <ul><li>Inaccurate INR testing </li></ul><ul><li>Changes in vitamin K intake </li></ul><ul><li>Changes in warfarin or vitamin K absorption </li></ul><ul><li>Changes in warfarin metabolism </li></ul><ul><li>Changes in vitamin K-dependent coagulation factor synthesis or metabolism </li></ul><ul><li>Concomitant drug use </li></ul><ul><li>Patient noncompliance </li></ul>Ansell J, et al. Chest. 2008;133:160S-198S.
    23. 23. Bleeding Risk With Elevated INR <ul><li>Absolute daily risk of bleeding is low </li></ul><ul><li>Assess bleeding risk </li></ul><ul><ul><li>Potential risk of bleeding </li></ul></ul><ul><ul><li>Active bleed </li></ul></ul><ul><ul><li>INR level </li></ul></ul><ul><li>Treatment </li></ul><ul><ul><li>Hold warfarin dose or decrease </li></ul></ul><ul><ul><li>Use oral or IV vitamin K </li></ul></ul><ul><ul><li>Life-threatening bleeds </li></ul></ul><ul><ul><ul><li>Fresh frozen plasma </li></ul></ul></ul><ul><ul><ul><li>Prothrombin complex concentrate </li></ul></ul></ul><ul><ul><ul><li>Recombinant factor VIIa </li></ul></ul></ul>Ansell J, et al. Chest. 2008;133:160S-198S.
    24. 24. Ansell J, et al. Chest. 2008;133:160S-198S. Condition Intervention For Elevated INRs And Bleeding INR <5, but more than goal Lower or omit dose, monitor more often & restart at lower dose when INR in range; if minimally above range, no dose change needed. INR > 5 but <9, no significant bleed Omit 1-2 doses, monitor more often & restart at lower dose when INR in range OR omit dose, give vitamin K 1-2.5mg po, if ↑ bleeding risk OR rapid reversal (urgent surgery) vitamin K < 5mg po to reduce INR within 24 hours. If INR still high, may give vitamin K 1-2.5mg po. INR > 9, no significant bleed Hold warfarin & give vitamin K 2.5-5mg po with INR expected to decrease in 24-48 hours. Monitor more frequently. Use more vitamin K if needed. Restart warfarin at appropriate adjusted dose when INR within goal. Serious bleed with elevated INR Hold warfarin. Given vitamin K 10mg by slow IV infusion, supplement with FFP, PCC or rVIIa, depending upon urgency, vitamin K may be repeated at 12 hours. Life-threatening bleed Hold warfarin & give FFP, PCC or rVIIa supplemented with vitamin K 10mg slow IV infusion. Repeat if needed based on INR. Administration of vitamin K With mild to moderate elevated INR without major bleed, give vitamin K orally not subcutaneously.
    25. 25. Oral Vitamin K Versus Placebo <ul><li>Oral vitamin K use in over anticoagulated pts </li></ul><ul><li>711 non-bleeding patients with INR 4.5 – 10 </li></ul><ul><ul><li>INRs: 8.1-10 (72); 6.1-8 (185); 4.5-6 (487) </li></ul></ul><ul><li>Held 1 warfarin dose & randomized to vitamin K 1.25 mg (347) or placebo (365) </li></ul><ul><li>Outcome of bleeding events within 90 days </li></ul><ul><ul><li>Major (fatal, > 2 units pack red blood cells, therapeutic intervention or confirmed bleeding in enclosed space) </li></ul></ul><ul><ul><li>Minor (medical assessment) </li></ul></ul><ul><ul><li>Trivial (no medical assessment) </li></ul></ul>Crowther MA, et al. Ann Intern Med. 2009;150:293-300. 26
    26. 26. Results: Oral Vitamin K Versus Placebo <ul><li>No statistical significant difference </li></ul><ul><ul><li>Bleeding, thromboembolism or death </li></ul></ul><ul><li>INR decreased more rapidly with vitamin K </li></ul><ul><ul><li>INR average decrease vitamin K: 2.8 </li></ul></ul><ul><ul><li>INR average decrease placebo: 1.4 </li></ul></ul><ul><li>Major bleeding events occurred more often in patients older than 70 years (10/13 events) </li></ul><ul><li>Vitamin K safe to correct INR, prevent death & thromboembolism, but does not minimize risk of bleeding </li></ul>Crowther MA, et al. Ann Intern Med. 2009;150:293-300. 27
    27. 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? <ul><li>A. Stop warfarin </li></ul><ul><li>B. Send to emergency room </li></ul><ul><li>C. Give vitamin K 5 mg orally </li></ul><ul><li>D. Give vitamin K 5 mg IV </li></ul><ul><li>E. Make no changes </li></ul>28
    28. 28. Low Molecular Weight Heparin <ul><li>Benefits </li></ul><ul><ul><li>Easy to use </li></ul></ul><ul><ul><li>Predictable response </li></ul></ul><ul><ul><li>Less monitoring </li></ul></ul><ul><ul><li>Less heparin induced thrombocytopenia (HIT) </li></ul></ul><ul><ul><li>Less risk of osteoporosis </li></ul></ul><ul><li>Concerns </li></ul><ul><ul><li>Less reversibility </li></ul></ul><ul><ul><li>Accumulates in renal insufficiency </li></ul></ul><ul><ul><li>Less experience in obesity </li></ul></ul><ul><ul><li>Expensive </li></ul></ul><ul><ul><li>Agents not interchangeable </li></ul></ul>Chawla LS, et al. Obes Surg. 2004;14:695-698. Hirsh J, et al. Chest. 2008;133:141S-159S. 29 Enoxaparin, Dalteparin, Tinzaparin
    29. 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? <ul><li>A. 30mg twice daily </li></ul><ul><li>B. 40mg twice daily </li></ul><ul><li>C. 30mg daily </li></ul><ul><li>D. 40mg daily </li></ul><ul><li>E. Avoid enoxaparin </li></ul>30
    30. 30. Obesity And LMWH <ul><li>Maximum recommended dose in obesity </li></ul><ul><ul><li>Tinzaparin and enoxaparin: none </li></ul></ul><ul><ul><li>Dalteparin 18,000 units daily (VTE treatment) & 20,000 units daily (acute coronary syndrome) </li></ul></ul><ul><ul><li>LMWH studied up to 190 kg for VTE treatment </li></ul></ul><ul><li>Treatment doses use actual body weight (2C) </li></ul><ul><ul><li>Does not cause more bleeding or thromboembolic events </li></ul></ul><ul><ul><li>BMI > 27 kg/m 2 : use enoxaparin 1mg/kg twice daily </li></ul></ul><ul><ul><li>Dalteparin 200 units/kg & tinzaparin 175 units/kg daily </li></ul></ul>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
    31. 31. LMWH and VTE Prophylaxis <ul><li>A study with surgical patients demonstrated negative correlation of body weight & anti-factor Xa levels for VTE prophylaxis </li></ul><ul><li>Bariatric surgery patients showed higher prophylaxis dose with less incidence of VTE and no change in bleeding risk </li></ul><ul><li>Consider increasing VTE prophylactic doses by 30% with BMI > 40kg/m 2 </li></ul><ul><li>Monitor anti-factor Xa levels in patients >190kg </li></ul>Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083. 32
    32. 32. Target Anti-Factor Xa Levels Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083. 33 Indication LMWH Dosing Peak Range (units/ml) Mean at 4 hrs (units/ml) VTE Prophylaxis Dalteparin Enoxaparin 2500 units daily 5000 units daily 30mg q 12hr 40mg daily Moderate risk : 0.01 - 0.25 High risk : 0.2 - 0.5 Highest risk : 0.5 - 1.2 VTE Treatment Dalteparin Enoxaparin Tinzaparin 1mg/kg q12hr 1.5mg/kg daily 175units/kg/day 0.6 - 1 1 - 2 1.05 0.85
    33. 33. Sample Enoxaparin Treatment Dosing Nomogram Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083. 34 Anti-Factor Xa Level (units/ml) Hold Next Dose Dosage Change Next Anti-Xa Level < 0.35 No ↑ 25% 4 hrs after next dose 0.35 – 0.49 No ↑ 10% 4 hrs after next dose 0.5 – 1 No None Next day, then 1 week, then monthly 1.1 – 1.5 No ↓ 20% Before next dose 1.6 – 2 3 hours ↓ 30% Before next dose and 4 hours after next dose > 2 until anti-factor Xa <0.5units/ml ↓ 40% Before next dose & q12hr until anti-factor Xa < 0.5
    34. 34. Definition Of Renal Function Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083. 35 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 Description of Renal Function Glomerular Filtration Rate (ml/min) Normal > 90 Mildly decreased 60 – 89 Moderately decreased 30 – 59 Severely decreased 15 – 29 End-stage renal disease < 15 or on dialysis
    35. 35. Renal Insufficiency & LMWH <ul><li>If CrCl <30ml/min with therapeutic doses, use UFH instead of LMWH (2C) </li></ul><ul><li>LMWH use with severe renal insufficiency and therapeutic doses, decrease dose by 50% (2C) </li></ul><ul><li>More accumulation with enoxaparin than others </li></ul><ul><li>Watch for signs and symptoms of bleeding </li></ul><ul><li>Consider monitoring anti-factor Xa levels for use >10 days if CrCl 30–60 ml/min & risk of accumulation </li></ul>Hirsch J, et al. Chest. 2008;133:141S-159S. Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083. 36
    36. 36. LMWH Dosing with Renal Insufficiency <ul><li>Prophylaxis </li></ul><ul><li>30-90ml/min: dose adjustment not needed </li></ul><ul><li>CrCl <30ml/min </li></ul><ul><ul><li>Enoxaparin: 30mg daily </li></ul></ul><ul><ul><li>Dalteparin & tinzaparin adjustment not needed if used < 10 days </li></ul></ul><ul><li>Treatment </li></ul><ul><li>CrCl <20ml/min use weight-based adjusted-dose IV UFH and monitor aPTT due to limited studies in LMWH </li></ul><ul><li>CrCl <30ml/min </li></ul><ul><ul><li>Dalteparin: use caution </li></ul></ul><ul><ul><li>Enoxaparin: 1mg/kg daily </li></ul></ul><ul><ul><li>Tinzaparin: use caution </li></ul></ul>Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083. 37
    37. 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? <ul><li>A. 30mg twice daily </li></ul><ul><li>B. 40mg twice daily </li></ul><ul><li>C. 30mg daily </li></ul><ul><li>D. 40mg daily </li></ul><ul><li>E. Avoid enoxaparin </li></ul>38
    38. 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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