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Judicious Use of Anticoagulation: A Case-Based Approach

Judicious Use of Anticoagulation: A Case-Based Approach. Michael B. Streiff, MD, FACP Associate Professor of Medicine and Pathology Division of Hematology Medical Director, Johns Hopkins Anticoagulation Management Service and Outpatient Clinics. Research Funding Bristol-Myers Squibb

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Judicious Use of Anticoagulation: A Case-Based Approach

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  1. Judicious Use of Anticoagulation: A Case-Based Approach Michael B. Streiff, MD, FACP Associate Professor of Medicine and Pathology Division of Hematology Medical Director, Johns Hopkins Anticoagulation Management Service and Outpatient Clinics

  2. Research Funding Bristol-Myers Squibb NIH/NHLBI Consulting Sanofi-aventis Eisai, Inc. Daiichi-Sankyo Janssen Healthcare BiO2 Speaking Honoraria Sanofi-aventis Ortho-McNeil Educational Grants Sanofi-Aventis Covidien Disclosures

  3. Anticoagulation for pregnancy loss • 32 year old woman with 2 previous first trimester pregnancy losses asks about LMWH to prevent miscarriages. You advise her to • Start therapeutic dose LMWH • Start prophylactic dose LMWH • Start prophylactic dose LMWH + Aspirin 100 mg • Start no antenatal prophylaxis

  4. LMWH does not improve pregnancy outcomes: The ALIFE Study Placebo (N=121) Completed Study (N=103) 364 women with at least 2 pregnancy losses Aspirin 80 mg (N=120) Completed Study (N=97) Aspirin 80 mg + Nadroparin 2850 IU (N=123) Completed Study (N=99) Kaandorp S et al. NEJM 2010

  5. Baseline characteristics Kaandorp S et al. NEJM 2010

  6. LMWH did not increase the live birth rate Kaandorp S et al. NEJM 2010

  7. Thrombophilia did not affect live birth rate Kaandorp SP et al. NEJM 2010

  8. Anticoagulation does not prevent early pregnancy loss • Open-label RCT of enox 40 mg/d + ASA 75 mg vs. surveillance alone • PMHx ≥ 2 losses 24 weeks or less • Begin 7 weeks gestation or less • Conclusion- Prophylactic AC does not improve pregnancy outcomes N=294 Clark P et al. Blood 2010

  9. Heparin + Aspirin reduces pregnancy loss in Antiphospholipid Syndrome • Metanalysis of 5 RCTs of UFH/LMWH + aspirin versus aspirin • Regimens- UFH 5000-20000 units + aspirin 75-81 mg and LMWH 5000 + aspirin 75-81 mg • Conclusion- UFH/LMWH + ASA improves live birth rates RR 1.3 Mak A et al. Rheumatol 2010

  10. Anticoagulation- Less or More? • A 65 year old man with a St Jude aortic valve is scheduled to undergo a prostatectomy for cancer. When should he resume full-dose anticoagulation? • 12 hours post-op • 24 hours post-op • 36 hours post-op • 72 hours post-op

  11. Perioperative AC- Is less more? • Metanalysis of 34 studies of 12,278 patients • Outcomes- Thromboembolism and Bleeding • Limitation- Lack of RCT • Conclusion- Value of perioperative bridging unclear Siegal D et al. Circulation 2012

  12. Less is more for perioperative AC • Prospective Cohort of 1262 patients • Low risk- AVR w/o Afib-prophylactic LMWH • High risk- MVR, AVR w/Afib or stroke- Enox 0.7 mg/kg q12h • Post-op- resume AC day 1-3 based upon hemostasis Pengo V et al. Circulation 2009

  13. Thromboembolism Risk Stratification TE risk factors= A fib, Cardiac failure, HTN, DM, Age > 75, Stroke/TIA Douketis JD Blood 2011

  14. Bleeding Risk Assessment Spyropoulos AC and Douketis JD Blood 2012

  15. AC Management

  16. Anticoagulation for VTE • 65 year old man develops a right femoral-popliteal vein DVT 1 week after right knee replacement. A thrombophilia evaluation reveals he is heterozygous for the factor V Leiden mutation. How long should he be treated? • 6 weeks • 3 months • 12 months • Indefinite

  17. Anticoagulation for VTE • 48 year old man presents with progressive dyspnea over 1 week and left leg discomfort. CT angiogram identifies bilateral PE. Duplex study finds a left leg DVT. No VTE risk factors are identified. How long should he be treated? • 3 months • 6 months • 12 months • Indefinite

  18. Do the Results of Thrombophilia Tests Help to Determine Duration of Therapy? HR 2.0 (1.5-2.7) HR 1.8 (1-3.1) HR 1.4 (0.9-2.2) Recurrent VTE (%) HR 1.5 (0.8-2.8) (N= 570) 24 mos. (N=474) 84 mos. (N=267) 46 mos. (N=1626) 50 mos.

  19. Thrombophilia-Assessing the risk • High risk thrombophilia • Antithrombin deficiency - 1.8 % per year (95% CI 1.1-2.6%) • Protein C deficiency - 1.5% per year (1.1-2.1%) • Protein S deficiency - 1.9% per year (1.3-2.6%) • Moderate risk thrombophilia • Factor V Leiden - 0.5% per year (0.4-0.6%) • Prothrombin gene mutation - 0.3% per year (0.2-0.5%) • Factor VIII - 0.5% per year (0.4-0.5%) • Low risk thrombophilia • Factor IX - 0.1% per year (0.02-0.2%) • Factor XI - 0.2% per year (0.06-0.6%) • Hyperhomocysteinemia – 0.1% per year (0.05-0.3%) Lijfering WM et al. Blood 2009

  20. Antiphospholipid syndrome is associated with recurrent thromboembolism P=0.0013 Recurrent VTE (%) Months Schulman S , et al. Am J Med 1998; 104: 332-338

  21. VTE recurrence rate varies depending upon initial trigger for the event N = 570 Cumulative recurrent VTE (%) Time after cessation of therapy (months) Baglin T et al., Lancet 2003

  22. VTE Setting influences recurrence risk • Systematic review of prospective cohort studies and RCTs • 15 Studies • 5159 Subjects • Follow up- 3-96 months • Conclusion- Setting of thrombosis strongly influences recurrence rate Iorio A et al. Arch Intern Med 2010

  23. D dimer and recurrent VTE • D dimer- an indirect marker of activated coagulation • PROLONG study (Palareti G et al. NEJM 2006) • F/U 1.4 years • Systematic Review (Verhovsek M et al. Ann Intern Med 2008) • 7 studies, 1888 patients • Recurrent VTE- Abnl vs. nl DD (8.9% vs. 3.5% per year) N=608

  24. How do we identify the low risk patient with idiopathic VTE? • Prospective cohort study of 665 patients with idiopathic VTE • Enrolled at 12 centers, 4 countries prior to DC of warfarin after 5-7 months of therapy • Information of 76 laboratory and clinical variables associated with VTE were collected • Multivariate analysis used to develop clinical prediction rule for recurrent VTE • Results • F/U population 600/665 (90%) • Mean F/U -18 months (1-47 mos.) • Annual risk of recurrent VTE 9.3% per year (7.7%-11.3%) • Men 13.7% (10.8%-17%) • Women 5.5% (3.7%-7.8%) Rodger MA, et al. CMAJ 2008;179(5):417-26

  25. Clinical prediction rule for recurrent VTE in women Rodger MA, et al. CMAJ 2008;179(5):417-26

  26. Risk stratification for idiopathic VTE: The Vienna Risk Model http://www.meduniwien.ac.at/user/georg.heinze/zipfile/ViennaPredictionModel.html Eichinger S et al. Circulation 2010

  27. Thrombosis Bleeding Indefinite Anticoagulation: Weighing the risks

  28. Assessing Bleeding Risk: The HAS-BLED Score • HASBLED • Hypertension (uncontrolled SBP>160) = 1 point • Abnormal renal/liver function = 1 or 2 points • Stroke = 1 point • Bleeding (or anemia) = 1 point • Labile INRs (TTR<60%)= 1 point • Elderly (Age > 65 years)= 1 point • Drugs or alcohol= 1 or 2 points Pisters R et al. Chest 2010; Olesen JB, et al. JTH 2011

  29. Central Venous Catheter Prophylaxis • 67 year old man has just had a right subclavian Hickman CVC placed for chemotherapy for recently diagnosed NHL. What should be used for CVC thrombosis prophylaxis? • Warfarin 1 mg daily • Enoxaparin 40 mg daily • Dalteparin 5000 units daily • No prophylaxis necessary

  30. CVC Prophylaxis • Open RCT of low dose warfarin 1 mg vs. no warfarin • Start 3 days before CVC insertion • Outcome-Venogram with symptoms or at 90 days • Conclusion- Low dose warfarin prevents CVC thrombosis P<0.001 Bern MM et al. Ann Intern Med 1990

  31. Catheter Prophylaxis

  32. Adjusted dose warfarin prevents CVC thrombosis: WARP study • A multicenter (N=68) open label study of warfarin CVC prophylaxis (N=1590) • Study Arms- • No warfarin (404) vs. warfarin 1 mg (408) • Warfarin 1 mg (471) vs. warfarin (INR1.5-2.0) ( 473) • Conclusion- Dose-adjusted warfarin is required to prevent CVC DVT P=0.002 Young AM, et al. Lancet 2009

  33. Elevated INR- Less vitamin K is more • 70 year old man taking warfarin for atrial fibrillation has an INR of 7. He does not have any signs of bleeding. What should you do? • Hold warfarin and administer vitamin K 2.5 mg po • Hold warfarin and administer vitamin K 2.5 mg IV • Hold warfarin and recheck INR in 1-2 days • Hold warfarin and administer Vitamin K 2.5 mg and 3 units of FFP

  34. Less vitamin K is more safe • RCT of vitamin K 1.25 mg or placebo for pts. with INR 4.5-10 • Setting- 14 AC clinics in US, Canada, Italy • Outcomes- Symptomatic bleeding or thromboembolism within 90 days • Conclusion- Oral Vit K does not improve outcomes with INR 4.5-10 Crowther MA et al. Ann Intern Med 2009

  35. Is less is more? • 72 year old man with atrial fibrillation who has been on warfarin 5 mg daily for 3 months. Today his INR is 1.8. No reason identified. What should you do with his warfarin dose? • Increase his dose to 7.5 mg MWF, 5 mg ROW (21% dose increase), recheck 1 week • Increase his dose to 7.5 mg daily (50% dose increase), recheck 1 week • Increase his dose to 7.5 mg W, 5 mg ROW (7% dose increase, recheck 1 week • Continue same dose, recheck 1 week

  36. Less dose adjustment=more time in range • Observational study of warfarin management • Setting- 94 AC clinics, 3961 patients • Outcome- Time in therapeutic range • Conclusion- Excessive warfarin dose changes lead to poorer INR control Rose AJ et al. J ThrombHaemost 2009

  37. Is less LMWH more? • A 65 year old man with an atrial fibrillation (CHADS2 score 3) who has been on warfarin for 4 months has an INR of 1.5. Your nurse asks you for advice. You suggest… • LMWH + warfarin dose increase • Warfarin dose increase only

  38. Less LMWH is safe • Retrospective study of patients in Kaiser CO AC clinics • Low INR and therapeutic INR groups • Only 13 patients received LMWH • Outcomes- Bleeding and TE at 90 days • Conclusion- LMWH not necessary for most patients with low INR Clark NP et al. Pharmacother 2008

  39. Conclusions • Anticoagulation is not indicated for recurrent early pregnancy loss except perhaps APS • Therapeutic AC should be used sparingly in the post-operative period • Setting rather than presence of thrombophilia dictates duration of therapy • Risk stratification models can help determine the risk of recurrent VTE and bleeding in patients with idiopathic VTE • Central venous catheter prophylaxis remains of unproven benefit • Studies continue to optimize warfarin management

  40. Questions ?

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