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1933 Deer Park, Wisconsin

1933 Deer Park, Wisconsin. Br J Haematol. 2008 Jun;141(6):757-63. Anticoagulation. A review of guidelines and update in emerging therapies. Brian Spoelhof, PharmD April 19, 2012. Disclosure. The presenter has no actual or potential conflicts to disclose. Objectives.

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1933 Deer Park, Wisconsin

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  1. 1933 Deer Park, Wisconsin Br J Haematol. 2008 Jun;141(6):757-63

  2. Anticoagulation A review of guidelines and update in emerging therapies Brian Spoelhof, PharmD April 19, 2012

  3. Disclosure • The presenter has no actual or potential conflicts to disclose

  4. Objectives • Summarize the indications for anticoagulation • Describe the pharmacology of new oral anticoagulants • Evaluate the data that led to the approval of the new oral anticoagulants • Discuss the advantages and disadvantages of new anticoagulants; • Examine new potential indications for the new anticoagulants.

  5. Roadmap • Anticoagulation Guidelines • Atrial Fibrillation • Post-op Orthopedic Surgery • Pharmacology of current options • Dabigatran • Rivaroxaban • Apixiban • Summary • Questions

  6. What is the perfect anticoagulant? Safe Effective Oral Easy Reversible

  7. Pathophysiology of Thromboembolic Disease

  8. Tissue Damage Surface Contact Common Pathway Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

  9. Current Options Warfarin • Vitamin K Antagonist • Unfractionated Heparin (UFH) • Low Molecular Weight Heparin (LMWH) • Direct Thrombin Inhibitors • Factor Xa Inhibitors Heparin Enoxaparin Bivalirudin Argatroban Dabigatran Fondaparinux Rivaroxaban Apixiban

  10. Warfarin • Vitamin K Antagonist • Narrow Therapeutic • Genetic variation • Drug interactions • Food interactions • Required monitoring • Slow onset of action Is this the perfect anticoagulant? Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

  11. Review of Guidelines

  12. Post-Op Prophylaxis of VTE • AAOS – American Academy of Orthopedic Surgeons • Updated September 2011 • Recommends no specific agent • ACCP – American College of Chest Physicians • Updated February 2012 • Hip Fracture Surgery • Total Hip Replacement • Total Knee Replacement LMWH (preferred), Fondaparinux, Warfarin (INR 2-3), Dabigatran*, Rivaroxaban*, Apixaban* * Not recommend in hip fracture surgery Chest. 2008 Jun;133 AAOS VTE Prevention Guidelines

  13. Thromboembolic Stroke Prophylaxis in Atrial Fibrillation • ACCP and ACCF/AHA /HRS guidelines fairly similar • Risk Stratification • C – Congestive heart failure • H - Hypertension • A – Age ≥ 75 • D - Diabetes • Sx2 – Prior stroke or TIA x 2 J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7 Chest. 2008 Jun;133

  14. Thromboembolic Stroke Prophylaxis in Atrial Fibrillation • CHADS2score of 0 • Aspirin 81 to 325 mg daily • CHADS2 score of 1 • Aspirin 81 to 325 mg daily plus clopidogrel or • Dabigatran or warfarin titrated to INR of 2.0-3.0 • CHADS2 score 2 or greater • Dabigatran or warfarin titrated to INR of 2.0-3.0 J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7 Chest. 2008 Jun;133

  15. Thromboembolic Stroke Prophylaxis in Atrial Fibrillation • Oral anticoagulation preferred over dual antiplatelet therapy • Dabigatran preferred over warfarin, except • Mitral valve stenosis • Stable coronary artery disease • Intracoronary stents

  16. A new era in the world of Anticoagulation?

  17. New Options • Dabigatran – Pradaxa • Direct Thrombin Inhibitor • Approved to prevent stroke and systemic embolism nonvalvular atrial fibrillation • Rivaroxaban – Xarelto • Factor Xa Inhibitor • Approved to prevent stroke and systemic embolism nonvalvular atrial fibrillation and Postoperative thromboprophylaxis • Apixaban • Factor Xa Inhibitor • Not currently approved Rivaroxaban, Package Insert Dabigatran, Package Insert

  18. Eriksson BI et al. Annu Rev Med. 2011 Feb 18;62:41-57.

  19. Dabigatran • Indication: • Prevent stroke and systemic embolism nonvalvular atrial fibrillation • Dosage: • CrCl > 30 mL/min: 150 mg Twice Daily • Renal: Next slide • Dyspepsia Dabigatran, Package Insert

  20. Recent FDA Label Changes • CrCl 15 – 30 mL/min: 75 mg Twice Daily • November 2011 • Consider reduced dose (75 md twice daily) in patients with moderate renal impairment (30-50 mL/min) and concurrently taking ketoconazole or dronedarone. • Assess renal function prior to starting and in patients • ≥ 75 years old • CrCl or < 50 mL/min • Use with extreme caution in patient greater than 80 Dabigatran, Package Insert

  21. Coagulation Cascade Dabigatran Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

  22. Pharmacokinetics and Monitoring Monitoring: • aPTT • Qualitative not Quantitative • TT (Thrombin Time) • Linear dose relationship • Not as readily available Pharmacokinetics • Prodrug • Rapid absorption • Time to peak: 1-2 hours • Half-Life: 12-17 hours • Longer in renal impairment Dabigatran, Package Insert

  23. RE-LY Trial • Randomized, Dose blinded/regimen unblinded, noninferiority trial • Dabigatran 110 mg twice daily vs. Dabigatran 150 mg twice daily vs . Warfarin titrated to INR • n = 18,113 N Engl J Med. 2009 Sep 17;361(12):1139-51

  24. RE-LY: Efficacy N Engl J Med. 2009 Sep 17;361(12):1139-51

  25. RE-LY: Safety N Engl J Med. 2009 Sep 17;361(12):1139-51

  26. RE-LY Summary Dabigatran 150 mg Increased efficacy noninferior bleeding Dabigatran 110 mg Noninferior efficacy lower bleeding

  27. “RE-versal” • No known reversal agent • Study of 12 healthy individuals • Prothrombin Complex Concentrate • No effect on aPTT or TT • Supportive care • Blood • Fluid (to support kidney function) • Possible dialysis  Circulation. 2011 Oct 4;124(14):1573-9

  28. “RE-view” • Oral direct thrombin inhibitor • Requires renal adjustments • More effective than warfarin • Same risk of bleeding • Twice daily dosing • Dyspepsia • Limited available monitoring • No reversal

  29. Rivaroxaban • Indications: • Approved to prevent stroke and systemic embolism nonvalvular atrial fibrillation • Postoperative thromboprophylaxis (Knee and Hip) • Dosage • Afib: • CrCl>50 mL/min: 20 mg once daily • CrCl 15 - 50 mL/min: 15 mg once daily • Post-op VTE prophylaxis • Knee replacement: 10 mg once daily x 12-14 days • Hip replacement: 10mg once daily x 35 days Rivaroxaban Package Insert

  30. Pharmacokinetics and Monitoring Pharmacodynamics • Peak 2.5-4 hours • Half Life: 3.2 – 22 hours • Metabolized via 3A4 Monitoring • PT • More sensitive • Varies with different reagents • Cannot be standardized • aPTT • Anti-Xa • Modified Anti-Xa being developed Br J Clin Pharmacol. 2011 Oct;72(4):593-603 Thromb Haemost. 2010 Apr;103(4):815-25

  31. MOA and Coagulation Cascade Rivaroxaban directly inhibits Factor Xa Rivaroxaban Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008 J Thromb Haemost. 2006 Jan;4(1):121-8

  32. RECORD 1-4 Main Endpoints Eikelboom JS and Weitz JI. Lancet 2008.

  33. Pooled Safety Analysis Turpie AG et al. 2008 International Congress on Thrombosis; June 27, 2008; Athens, Greece. Abstract O5.

  34. ROCKET-AF • Comparison of rivaroxaban to warfarin in patients with atrial fibrillation • Randomized, Double Blinded, Double Dummy, Noninferiority • Consideration • Time in Therapeutic Range

  35. ROCKET-AF: Efficacy  N Engl J Med. 2011 Sep 8;365(10):883-91

  36. ROCKET-AF: Safety  N Engl J Med. 2011 Sep 8;365(10):883-91

  37. ROCKET-AF: Discontinuation  N Engl J Med. 2011 Sep 8;365(10):883-91

  38. Reversal • Prothrombin Complex Concentrate potentially reverses rivaroxaban • Study in 12 healthy males • Returned to nearly normally levels within 15 minutes  Circulation. 2011 Oct 4;124(14):1573-9

  39. Review • Oral direct Factor Xa inhibitor • Post-op thromboprophylaxis • Superior to enoxaparin • Similar rates of major bleeds • Stroke prophylaxis in atrial fibrillation • Non-inferior to warfarin • Less risk of major bleeding • Discontinuation increases risk of thromboembolism

  40. Summary • Anticoagulation rapidly evolving • New option provide potential but haven’t eradicated the need for warfarin • When choosing an agent must balance compliance, risk, renal function

  41. Apixaban • Oral Factor Xa inhibitor • Not yet approved, no indications • Approval expected 6/28/12 • Dosing: • 5 mg twice daily • 2.5 mg twice daily with two of the following: • Age > 80 years • Weight < 60 kg • SCr > 1.5 mg/dL

  42. ARISTOTLE • Apixaban vs warfarin for atrial fibrillation • Randomized, double blind, double dummy, noninferiority trial • n= 18,201patient

  43. ARISTOTLE: Efficacy

  44. ARISTOTLE: Safety

  45. Review • Apixaban awaiting FDA review • Approval expected • Apixaban reduced occurrence of stroke and systemic embolism compared to warfarin • Apixaban associated with lower risk of bleeding compared to warfarin

  46. The Future

  47. Anticoagulants for ACS • Warfarin has reduced secondary endpoints but risk of bleeding has not outweighed benefit • APPRAISE-2 • Apixaban 5 mg BID vs Placebo post- MI • No benefit • ATLAS-ACS2 TIMI 51 • Rivaroxaban 2.5 mg daily or 5 mg daily vsplacebo post-MI • Rivaroxaban 2.5 mg = Benefit • Rivaroxaban 5 mg = No benefit Hurlen M, et al. N Engl J Med. 2002 Sep 26;347(13):969-74

  48. ATLAS-ACS2 TIMI 51 • Rivaroxaban 2.5 mg daily • Decreased primary endpoint • Cardiovascular Death, MI, or stroke • 9.1% vs 10.7% (HR 0.84, P=0.0.02) • NNT = 63 • Decreased all cause mortality • 2.9 % vs 4.5 % (HR 0.68, P=0.002) • NNT = 63 • Increased major bleeding (HR 3.46, P=0.001) • 1.8% vs 0.6%(HR 3.46, P=0.001) • NNH = 83

  49. Summary • Dabigatran • Best stroke reduction data • Twice daily dosing • Dyspepsia/ GI Bleed • No reversal • Rivaroxaban • Reversible • Once daily dosing • Afib data not as strong • Early discontinuation increases events • Apixaban • Better efficacy and safety • Theoretically reversible • Twice daily dosing • Not yet approved

  50. Questions

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