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Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy

Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy. David Stewart, PharmD , BCPS Associate Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy stewardw@etsu.edu . Disclosures. Speaker’s Bureau for: Boehringer-Ingelheim Pharmaceuticals

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Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy

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  1. Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy David Stewart, PharmD, BCPS Associate Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy stewardw@etsu.edu

  2. Disclosures Speaker’s Bureau for: Boehringer-Ingelheim Pharmaceuticals Janssen Pharmaceuticals

  3. At the conclusion of this program, the audience should be able to: • List the new oral anticoagulant medications currently approved or in the approval process by the United States Food and Drug Administration • Communicate basic principles of pharmacokinetics to other healthcare providers • Identify appropriate indications for the use of new oral anticoagulant medications • Develop patient specific plans utilizing newly approved oral anticoagulant agents for the treatment and prevention of venous thromboembolic events in various patient populations

  4. Anticoagulant Timeline

  5. Coagulation Cascade Intrinsic Pathway (PTT) Extrinsic Pathway (PT) XII XIIa XI XIa VII VIIa IX IXa VIII XIII Warfarin Va X Xa Rivaroxaban & Apixaban II IIa XIIIa Dabigatran Fibrinogen Fibrin

  6. Summary Table 1Indication Specific. For VTE no adjustment and avoid use < 30 ml/min.

  7. Measuring Dabigatran ThrombHaemost 2010;103:1116-27.

  8. Measuring Rivaroxaban & Apixaban • Role of aPTT & PT/INR • Anti-Xa Assays • Chromagenic anti-Xa assays may be useful • Different assays vary in sensitivity • Must calibrate standard curve based on drug concentration • HepTest® accurate when modified for rivaroxaban (and likely apixaban) • Incubation period too long • Modified HepTest® may be useful Ther Drug Monit 2010;32:673-9.

  9. Measuring Rivaroxaban PT is sensitive (Don’t rely on INR) aPTT not sensitive Highlights peak concentrations J ThrombHaemost 2011;9:133-9.

  10. Reversal of New Anticoagulants • Universal Xa antidote (PRT4445) in Phase 2 trials • FFP • No data, unclear/unknown benefit • 3 factor PCC • Unknown • 4 factor PCC • Reverse rivaroxaban but not dabigatran (not available in US) • aPCC • Baboon data showed transient reversal of rivaroxaban • Recombinant Factor VIIa • Case reports only • Risk of arterial thrombosis • All PCC’s and RFVIIa increase the risk of arterial thrombotic events in non-hemophiliac patients • Must weigh potential risks with potential benefits • These effects may all be only transient Portola Pharmaceuticals. Press Release: 10 December 2012. Am J Hematol. 2012;84:S141-5. Am J Health-Syst Pharm. 2012;69:1473-84. Circulation. 2011;124:1573-79.

  11. Issues with New Anticoagulants

  12. Summary of Afib Data 1Dabigatran 150 mg BID group. 2Major bleeding per study design. New Engl J Med 2009;DOI:10.1056/NEJMoa0905561. New Engl J Med 2011;DOI:10.1056/NEJMoa1009638. New Engl J Med 2011;DOI:10.1056/NEJMoa1107039.

  13. Treatment of VTE N Engl J Med 2012;DOI:10.1056/NEJMoa1113572. N Engl J Med 2010;DOI:10.1056/NEJMoa1007903. N Engl J Med 2009;DOI:10.1056/NEJMoa0906598. N Engl J Med 2013;368:699-708. N Engl J Med 2013;368:709-18.

  14. Summary of Acute VTE Treatment Data 1Initial therapy in study group, both studies “bridged” control group. New Engl J Med 2012;DOI:10.1056/NEJMoa1113572. New Engl J Med 2010;DOI:10.1056/NEJMoa1007903. New Engl J Med 2009;DOI:10.1056/NEJMoa0906598.

  15. Summary of Orthopedic VTE Data1 1Includes patients undergoing both TKA and THA. Most studies excluded patients with CrCl < 30 ml/min. Summary of these data available in: Pharmacother 2011;31:1175-91.

  16. Additional Therapeutic Uses • VTE Prophylaxis in Medical Patients • Only evaluated in extended durations vs. enoxaparin • No benefit for extended prophylaxis • Acute Coronary Syndrome • Apixaban significantly increased risk of bleeding • Rivaroxaban (evaluated 2.5 mg and 5 mg BID) • Primary Endpoint (CV Death, MI or CVA) showed benefit • TIMI Major Bleeding higher with rivaroxaban • Intracranial Hemorrhage higher with rivaroxaban New Engl J Med 2011;365:2167-77. New Engl J Med 2012;366:9-19. New Engl J Med 2011 Online;DOI:10.1056/NEJMoa1110899.

  17. Dabigatran and Myocardial Infarction • Meta-analysis (January 2012) • 30,514 patients included • Multiple indications/populations • Dabigatran vs. Warfarin • MI • RR: 1.33 (1.03-1.71); AR: 0.40% • Mortality • RR: 0.89 (0.80-0.99); AR: 0.19% • Long-term VTE Treatment • Dabigatran vs. Warfarin • RR: 4.5 (13 events vs. 3 events); p = 0.02 Arch Intern Med. Online Jan 9, 2012;DOI:10.101/archinternmed.2011.1666. N Engl J Med 2013;368:709-18.

  18. Use of Concomitant Antiplatelet Agents in Afib Studies Trials for other indications were similar. New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.

  19. Warfarin + ASA + Clopidogrel • Triple therapy • Assumed appropriate for many patients post PCI • Lack of data to support use or non-use • Until now – the WOEST Study • Clopidogrel + Warfarin vs. Clopidogrel + Warfarin + ASA • Patients on warfarin undergoing PCI • ≈ 65% DES • Primary Endpoint – Any bleeding event • Any bleeding Event – HR (95% CI): 0.36 (0.26-0.50) • TIMI Major – HR (95% CI): 0.56 (0.25-1.27) • TIMI Major and minor – HR (95% CI): 0.40 (0.27-0.58) • Secondary Endpoint – Composite of death, MI, CVA, Target-vessel revascularization, and stent thrombosis • Lower event rate in DOUBLE therapy group (p = 0.025) • All-cause mortality individually lower • Cardiac death, Any MI, STEMI, NSTEMI, CVA all numerically lower in DOUBLE therapy group • Main limitation is open-label design Lancet online early February 13, 2013 – DOI: 10.1016/S0140-6736(13)60054-9.

  20. Take Home Points for Providers • Several new options currently or will exist to replace warfarin • Current approved indications include: • Prophylaxis of VTE in orthopedic patients • Prevention of stroke in patients with Afib • Acute and chronic treatment of VTE • Adverse event rates are high when not used/dosed appopriately • Agents vary based on various pharmacologic and pharmacokinetic parameters • None of the new agents require monitoring • Would base choice of agent on patient specific factors • All of them can be “measured” if needed • Best technique for reversal is unknown for most at this time but likely is either expensive, locally unavailable, or both • Cost will be a limitation if not covered by insurance

  21. FDA Approved Dosing

  22. Patient Education • Dabigatran • Store in original container • Discard opened product after 4 months • Dyspepsia most common side effect (up to 30%) • Do not open capsule • Comprehensive Patient Guide Available Online1 • Rivaroxaban • Take with food 1Circ 2011;124:e209-e211. (DOI: 10.1161/CIRCULATIONAHA.111.019786)

  23. Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy David Stewart, PharmD, BCPS Associate Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy stewardw@etsu.edu

  24. Summary Table 1Orthopedic VTE prophylaxis doses (10 mg daily) do not require renal adjustment; do not use if CrCl < 30 ml/min.

  25. Use of Concomitant Antiplatelet Agents New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.

  26. RE-LY - Results *Non-inferiority margin = 1.46 New Engl J Med 2009;361:1139-51. New Engl J Med 2010;363:1875-76.

  27. RE-LYSummary • Dabigatran 110 mg BID vs. warfarin • Non-Inferior Efficacy • Lower major and overall bleeding rates • Similar GI bleeding rates • Dabigatran 150 mg BID vs. warfarin • Superior efficacy • Lower overall bleeding rates • Similar major bleeding rates • Elevated rates of GI bleeding • Both doses showed decreased ICH compared to warfarin (60-70% RRR)

  28. ROCKET-AFResults *Non-inferiority margin = 1.46 New Engl J Med 2011;365:883-91.

  29. ROCKET-AFSummary • Rivaroxaban vs. warfarin • Non-Inferior Efficacy • Similar bleeding rates • Lower ICH rates • High risk patient population (Mean CHADS2 score > 3) • TTR 55% New Engl J Med 2011;365:883-91.

  30. ARISTOTLEResults *Non-inferiority margin = 1.38 New Engl J Med 2011;365:981-92.

  31. ARISTOTLE Summary • Apixaban vs. warfarin • Superior efficacy with apixaban • ↓ overall mortality with apixaban (NNT = 238) • Lower bleeding rates with apixaban • Lower ICH rates • Apixaban vs. Aspirin • 6,000 high-risk patients (mean CHADS2 = 2) • Not candidates for warfarin • 1 year follow-up • Superior efficacy to aspirin • Similar bleeding (including ICH) rates New Engl J Med 2011;365:981-92. New Engl J Med 2011;364:806-17.

  32. Summary of Afib Data 1Dabigatran 150 mg BID group. 2Major bleeding per study design.

  33. Use of Concomitant Antiplatelet Agents New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.

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