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Br J Haematol. 2008 Jun;141(6):757-63. A review of guidelines and update in emerging therapies Brian Spoelhof, PharmD April 19, 2012.

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Presentation on theme: "Br J Haematol. 2008 Jun;141(6):757-63. A review of guidelines and update in emerging therapies Brian Spoelhof, PharmD April 19, 2012."— Presentation transcript:

1 Br J Haematol. 2008 Jun;141(6):757-63

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

3  The presenter has no actual or potential conflicts to disclose

4  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  Anticoagulation Guidelines  Atrial Fibrillation  Post-op Orthopedic Surgery  Pharmacology of current options  Dabigatran  Rivaroxaban  Apixiban  Summary  Questions

6 Oral Safe Effective Easy Reversible

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

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

10  Vitamin K Antagonist  Narrow Therapeutic  Genetic variation  Drug interactions  Food interactions  Required monitoring  Slow onset of action ProteinHalf Life (Hours) Prothrombin (II) 60-100 Factor VII6-8 Factor IX20-30 Factor X24-40 Protein C8-10 Protein S40-60 Is this the perfect anticoagulant? Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

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12  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  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  CHADS 2 score of 0  Aspirin 81 to 325 mg daily  CHADS 2 score of 1  Aspirin 81 to 325 mg daily plus clopidogrel or  Dabigatran or warfarin titrated to INR of 2.0-3.0  CHADS 2 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  Oral anticoagulation preferred over dual antiplatelet therapy  Dabigatran preferred over warfarin, except  Mitral valve stenosis  Stable coronary artery disease  Intracoronary stents

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17  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

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19  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  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 Dabigatran Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008

22 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  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

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26 Increased efficacy noninferior bleeding Noninferior efficacy lower bleeding

27  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  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  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 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 Rivaroxaban Dipiro: Pharmacotherapy: a Pathophysiologic Approach, 2008 J Thromb Haemost. 2006 Jan;4(1):121-8 Rivaroxaban directly inhibits Factor Xa

32 Eikelboom JS and Weitz JI. Lancet 2008. TrialSettingEnoxaparin regimen Rivaroxaban regimen DVT/PE/ death (%) RRR (%) Symptomatic VTE (%) RRR (%) RECORD1 n=4541 THA40 mg daily x 35 days 10 mg daily x 35 days 3.7 vs 1.170—— RECORD2 n=2509 THA40 mg daily x 10–14 days 10 mg daily x 31–39 days 9.3 vs 2.0791.2 vs 0.280 RECORD3 n=2531 TKA40 mg daily x 10–14 days 10 mg daily x 10–14 days 18.9 vs 9.6492.0 vs 0.766 RECORD4 n=3148 TKA30 mg BID x 10–14 days 10 mg daily x 10–14 days 10.1 vs 6.9311.2 vs 0.7NS

33 Turpie AG et al. 2008 International Congress on Thrombosis; June 27, 2008; Athens, Greece. Abstract O5. Outcome Enoxaparin (%) Rivaroxaban (%) p Symptomatic VTE/all-cause mortality 1.30.5<0.001 Major bleed0.20.30.305

34  Comparison of rivaroxaban to warfarin in patients with atrial fibrillation  Randomized, Double Blinded, Double Dummy, Noninferiority  Consideration  Time in Therapeutic Range

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

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38  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  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  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  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  Apixaban vs warfarin for atrial fibrillation  Randomized, double blind, double dummy, noninferiority trial  n= 18,201patient

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45  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

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

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51  DiPiro, Joseph T. Pharmacotherapy: a Pathophysiologic Approach. New York: McGraw-Hill Medical, 2008. Print.  Katzung, Bertram G. Basic and Clinical Pharmacology. New York: McGraw Hill Medical, 2007. Print.  Jacobs, J; Mont, M; Bozic, K; et al, Guideline on Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty. Rosemont, IL AAOS September 24, 2011  http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_mea sures/ - Specifications Manual for National Hospital Inpatient Quality Measure; The Joint Commission Surgical Care Improvement  Dabigatran [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, November, 2011 http://bidocs.boehringer- ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Informati on/PIs/Pradaxa/Pradaxa.pdf  Rivaroxaban [package insert Janssen Pharmaceuticals, Inc. Titusville, NJ 2011 http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf  Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011 Feb 18;62:41-57.  Turpie AG, Lassen MR, Kakkar AK, et al. A meta-analysis of three pivotal studies of rivaroxaban—a novel, oral, direct factor XA inhibitor—for thromboprophylaxis after orthopaedic surgery. 2008 International Congress on Thrombosis; June 27, 2008; Athens, Greece. Abstract O56.  Eikelboom JW and Weitz JI. Selective factor Xa inhibition for thromboprophylaxis. Lancet 2008; DOI:10.1016/S0140-6736(08)60879-X. Available at: http://www.thelancet.com.

52  Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, Misselwitz F, Kälebo P; ODIXa-HIP Study Investigators. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost. 2006 Jan;4(1):121-8. PubMed PMID: 16409461.  Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol. 2008 Jun;141(6):757-63. Epub 2008 Mar 18. Review. PubMed PMID: 18355382.  Hirsh J, Guyatt G, Albers GW, Harrington R, Schünemann HJ, American College of Chest Physician.Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):110S-112S. Erratum in: Chest. 2008 Aug;134(2):473. PubMed PMID: 18574260.  Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. Epub 2009 Aug 30. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. PubMed PMID: 19717844.  Barry M. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Dec 31;361(27):2674; author reply 2675. PubMed PMID: 20050385.  Samama MM, Martinoli JL, LeFlem L, Guinet C, Plu-Bureau G, Depasse F, Perzborn E. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost. 2010 Apr;103(4):815-25. Epub 2010 Feb 2. PubMed PMID: 20135059.  Wann LS, Curtis AB, Ellenbogen KA, Estes NA 3rd, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7. Epub 2011 Feb 14. PubMed PMID: 21324629.  Kazmi RS, Lwaleed BA. New anticoagulants: how to deal with treatment failure and bleeding complications. Br J Clin Pharmacol. 2011 Oct;72(4):593-603. doi: 10.1111/j.1365-2125.2011.04060.x. PubMed PMID: 21752066; PubMed Central PMCID: PMC3195736.  Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9. Epub 2011 Sep 6. PubMed PMID: 21900088.

53  Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. Epub 2011 Aug 10. PubMed PMID: 21830957.  Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002 Sep 26;347(13):969-74


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