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1933 Deer Park, Wisconsin

This educational review explores anticoagulation guidelines, pharmacology of new oral anticoagulants, data leading to their approval, advantages, disadvantages, and potential indications. It delves into various options including Warfarin, Dabigatran, Rivaroxaban, and Apixaban, discussing their efficacy, safety, pharmacokinetics, and clinical applications. The text evaluates post-op prophylaxis of VTE, stroke prophylaxis in atrial fibrillation, and the shift towards oral anticoagulation. A critical analysis of different anticoagulant options, their impact on thromboembolic diseases, and the evolving landscape of anticoagulation therapy is presented.

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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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