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 1943 Heparin 1954 Warfarin 2010 D abigatran 2011 Riv aroxaban 2012 Apixaban

5. Rivaroxaban & Apixaban Coagulation Cascade XIIXIIa XIXIa IX IXa VIIa Intrinsic Pathway (PTT)Extrinsic Pathway (PT) XaX VIII II IIa XIII FibrinogenFibrin XIIIa Warfarin Dabigatran Va VII

6. Summary Table ParameterApixabanDabigatranRivaroxaban Target ProteinFactor XaThrombin (IIa)Factor Xa Pro-DrugNoYes (etexilate)No 1˚ EliminationCYP3A4/P-gpRenalCYP3A4/P-gp Renal AdjustmentAvoid < 15 ml/min↓ 15-30 ml/min Avoid < 15 ml/min ↓ 15-50 ml/min Avoid < 15 ml/min 1 Drug-Drug Interact.CYP3A4/P-gpP-gpCYP3A4/P-gp Onset of activity3-4 hrs1-2 hrs2-4 hrs t½8-15 hrs12-18 hrs5-9 hrs Dosing intervalTwice daily Daily Measuring testsPT/Anti-factor XaECT, TT, +/- aPTTPT/Anti-factor Xa 1 Indication Specific. For VTE no adjustment and avoid use < 30 ml/min.

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

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 Apixaban (ARISTOTLE) Dabigatran (RE-LY) Rivaroxaban (ROCKET – AF) # Patients> 18,000 > 14,000 Mean CHADS 2 ≈ 2 ≈ 3.5 TTR62%64%55% Efficacy vs. VKASuperiorSuperior 1 Non-Inferior Bleeding 2 vs. VKADecreasedSimilar 1 Dabigatran 150 mg BID group. 2 Major 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 ApixabanDabigatranRivaroxaban Comparator(s) PlaceboWarfarin/Placebo Treatment Type ChronicAcute/Chronic Acute Results N/A≈ warfarin Chronic Results > Placebo (both doses) ≈ warfarin & > placebo Follow-Up 12 monthsUp to 36 monthsUp to 24 months Bleeding Outcomes (Acute) N/A≈ warfarin Bleeding Outcomes (Chronic) ≈ or > placebo (dose dependent) < warfarin & > placebo 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 Dabigatran (RE-COVER) Rivaroxaban (EINSTEIN) # Patients> 2,500> 3,400 Treatment Duration6 months Initial Therapy 1 LMWHRivaroxaban TTR60%58% Efficacy vs. VKANon-Inferior Bleeding vs. VKASimilar VTE TypeDVT & PE 1 Initial 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 Data 1 ComparatorApixaban (2.5 mg q12h) Dabigatran (150 or 220mg/day) Edoxaban (30 mg/day) Rivaroxaban (10 mg/day) Enoxaparin 40 mg daily SuperiorNon-Inferior---Superior Enoxaparin 20 mg q12h --- Superior--- Enoxaparin 30 mg q12h Non-InferiorInferior---Superior Bleeding vs. Enoxaparin Similar 1 Includes 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 Antiplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-AF (Rivaroxaban) ASA< 165 mg/dayYes< 100 mg/day ClopidogrelYes CombinationNoYesNo Aspirin Use (%)31%40%36% New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92. Trials for other indications were similar.

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 ParameterDabigatranRivaroxabanApixaban Dosing Non-valvular Atrial fibrillation 150 mg BID (CrCl > 30 ml/min) 75 mg BID (CrCl 15-30 ml/min) 20 mg QD (CrCl > 50 ml/min) 15 mg QD (CrCl 15-50 ml/min) 5 mg BID (2.5 mg BID if age ≥ 80, weight ≤ 60 kg, or SCr ≥ 1.5 mg/dl) Orthopedic VTE Px N/A10 mg QDN/A Treatment DVT/PE N/A 20 mg QD X 21 days, then 15 mg QD (CrCl ≥ 30 ml/min) N/A Timing of Dose Anytime (With or Without Food) 15, 20 mg Dose – With Food 10 mg Dose – Anytime Anytime (With or Without Food)

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 Online 1 Rivaroxaban – Take with food 1 Circ 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 ParameterApixabanDabigatranRivaroxaban Target ProteinFactor XaThrombin (IIa)Factor Xa Pro-DrugNoYes (etexilate)No 1˚ EliminationCYP3A4/P-gpRenalCYP3A4/P-gp Renal AdjustmentAvoid < 15 ml/min↓ 15-29ml/min Avoid < 15 ml/min Adjust < 50 ml/min Avoid < 15 ml/min 1 Drug-Drug Interact.CYP3A4/P-gpRifampin (P-gp)CYP3A4/P-gp Onset of activity3-4 hrs1-2 hrs2-4 hrs t½8-15 hrs12-18 hrs5-9 hrs Dosing intervalTwice daily Daily Monitoring testsAnti-factor XaECT, TT, +/- aPTTAnti-factor Xa FDA IndicationsNoneNon-valvular Afib.Non-valvular Afib. Ortho VTE Proph. Clinical UsesAfib Ortho VTE Proph Afib, VTEAfib, Ortho VTE Proph, VTE 1 Orthopedic 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 Antiplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-AF (Rivaroxaban) ASA< 165 mg/dayYes< 100 mg/day ClopidogrelYes CombinationNoYesNo Aspirin Use (%)31%40%36% 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 EventDabi 110 vs Warf HR (95% CI) Dabi 150 vs Warf HR (95% CI) Dabi 150 vs Dabi 110 HR (95% CI) Efficacy 1˚ Endpoint*0.91 (0.74-1.11)0.66 (0.53-0.82)0.73 (0.58-0.91) All stroke0.92 (0.74-1.13)0.64 (0.51-0.81)0.70 (0.56-0.89) Ischemic Stroke1.11 (0.89-1.40)0.76 (0.60-0.98)0.69 (0.54-0.88) Hemorrhagic Stroke0.31 (0.17-0.56)0.26 (0.14-0.49)0.85 (0.39-1.83) MI published1.35 (0.98-1.87)1.38 (1.00-1.91)1.02 (0.76-1.38) MI revised1.29 (0.96-1.75)1.27 (0.94-1.71)Not available All cause mortality0.91 (0.80-1.03)0.88 (0.77-1.00)0.97 (0.85-1.11) Safety Major bleeding0.80 (0.69-0.93)0.93 (0.81-1.07)1.16 (1.00-1.34) GI bleeding1.10 (0.86-1.41)1.50 (1.19-1.89)1.36 (1.09-1.70) All bleeding0.78 (0.74-0.83)0.91 (0.86-0.97)1.16 (1.09-1.23) IC bleeding0.31 (0.20-0.47)0.40 (0.27-0.60)1.32 (0.80-2.17) New Engl J Med 2009;361:1139-51. New Engl J Med 2010;363:1875-76. *Non-inferiority margin = 1.46

27. RE-LY Summary 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-AF Results EventRivaroxaban (% per year) Warfarin (% per year) HR (95% CI) Efficacy 1˚ Endpoint*2.12.40.88 (0.75-1.03) All stroke1.651.960.85 (0.70-1.03) Ischemic Stroke1.341.420.94 (0.75-1.17) Hemorrhagic Stroke0.260.440.59 (0.37-0.93) MI0.911.120.81 (0.63-1.06) All-cause mortality1.872.210.85 (0.70-1.02) Safety Major bleeding3.63.41.04 (0.90-1.20) All bleeding14.914.51.03 (0.96-1.11) Major GI bleeding3.2 (% overall)2.2 (% overall)p < 0.001 IC bleeding0.50.70.67 (0.47-0.93) New Engl J Med 2011;365:883-91. *Non-inferiority margin = 1.46

29. ROCKET-AF Summary Rivaroxaban vs. warfarin – Non-Inferior Efficacy – Similar bleeding rates – Lower ICH rates High risk patient population (Mean CHADS 2 score > 3) TTR 55% New Engl J Med 2011;365:883-91.

30. ARISTOTLE Results EventApixaban (% per year) Warfarin (% per year) HR (95% CI) Efficacy 1˚ Endpoint*1.271.600.79 (0.66-0.95) All stroke1.191.510.79 (0.65-0.95) Ischemic Stroke0.971.050.92 (0.74-1.13) Hemorrhagic Stroke0.240.470.51 (0.35-0.75) MI0.530.610.88 (0.66-1.17) All-cause mortality3.523.940.89 (0.80-0.998) Safety Major bleeding4.076.010.68 (0.61-0.75) All bleeding18.125.80.71 (0.68-0.75) IC bleeding0.330.800.42 (0.30-0.58) New Engl J Med 2011;365:981-92. *Non-inferiority margin = 1.38

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 CHADS 2 = 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 Apixaban (ARISTOTLE) Dabigatran (RE-LY) Rivaroxaban (ROCKET – AF) # Patients> 18,000 > 14,000 Mean CHADS 2 ≈ 2 ≈ 3.5 TTR62%64%55% Efficacy vs. VKASuperiorSuperior 1 Non-Inferior Bleeding 2 vs. VKADecreasedSimilar EliminationCYP3A4/P-gpRenalCYP3A4/P-gp/Renal 1 Dabigatran 150 mg BID group. 2 Major bleeding per study design.

33. Use of Concomitant Antiplatelet Agents Antiplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-AF (Rivaroxaban) ASA< 165 mg/dayYes< 100 mg/day ClopidogrelYes CombinationNoYesNo Aspirin Use (%)31%40%36% New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.