1. Presented at Grand Rounds Department of Neurology Loyola University Health System Maywood, Illinois 60153 September 30, 2011

2. Dabigatran and other New Oral Anticoagulants Jeanine M. Walenga, PhD Professor, Thoracic-CV Surgery and Pathology Co-Director, Hemostasis and Thrombosis Research Laboratories Loyola University Chicago LOYOLA UNIVERSITY HEALTH SYSTEM

3. Currently Available Anticoagulants DRUG CLINICAL USE WarfarinLong-term AC, stroke prevention in AF HeparinVTE, ACS, CPB, PCI LMW heparinsVTE prevention Lepirudin (DTI)HIT Bivalirudin (DTI)HIT, PCI Argatroban (DTI)HIT, PCI

4. Some of the New Anticoagulants Anti-FXa –Rivaroxaban (o) –Apixaban (o) –Edoxaban (o) –Otamixaban (p) –LY-517717 (o) –DX-9065a (p) –Betrixiban (o) –TK-442 (o) Anti-Flla (anti-thrombin) –Dabigatran (o) –Odiparcil (o) –Flovagatran (p) –Pegmusirudin (p) –Peg-hirudin (p) –Desirudin (p) O:Oral, P:Parenteral

5. Oral Anticoagulant Target Sites Antithrombin Fibrinogen Factor II (Prothrombin) Fibrin Factor IIa (Thrombin) Factor X Factor IX Factor VII Anti-FXa drugs Apixaban Betrixaban Edoxaban Rivaroxaban LY 517717 TAK 442 YM 150 Anti-FXa drugs Apixaban Betrixaban Edoxaban Rivaroxaban LY 517717 TAK 442 YM 150 Anti-FIIa drugs Dabigatran Ximelagatran AZD 0837 Anti-FIIa drugs Dabigatran Ximelagatran AZD 0837 Factor Xa VKA drugs Tecarfarin Warfarin VKA drugs Tecarfarin Warfarin FVIIa FIXa

6. Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed IndicationsSame Same Food effect Yes No Drug interactions Yes Yes Monitoring Yes No Half-life Long Short Antidote Yes No Comparison of NEW ORAL ANTICOAGULANTS with WARFARIN

7. Rivaroxaban Direct, specific, competitive factor Xa inhibitor Rapid onset within 2-4 hours High bioavailability of >80% Metabolized via the CYP3A4, CYP211, and P-gp transport mechanisms See interactions with drugs using the same metabolic pathways Renal and fecal elimination Perzborn et al., J Thromb Haemost 2005. Kubitza et al., J Clin Pharmacol 2007. Xarelto ®

8. Rivaroxaban: Clinical Development Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF ACS ODIXa-KNEEEINSTEIN-DVTROCKET-AF ATLAS ACS-TIMI 46 ODIXa-HIPEINSTEIN-EXTROCKET-J ATLAS ACS-TIMI 51 RECORD-1EINSTEIN-PE RECORD-2 RECORD-3 RECORD-4

9. RECORD 1-4 Summary Total Treatment Duration Pool Symptomatic VTE and all-cause mortality Major bleeding 1.3% 0.6% 0.2% 0.4% ARD=–0.8% p<0.001 ARD=0.2% p=0.076 13/6,20024/6,18382/6,200 35/6,183 p-values analyzed using a Cox regression model; safety population, n=12,383 0 0.5 1.0 1.5 2.0 Incidence (%) Enoxaparin regimens Rivaroxaban regimens Primary population for analysis Turpie AGG, et al. Presented at ASH 2008

10. ROCKET-AF: Stroke, Non-CNS Embolism Study Outcome: Rivaroxaban vs Warfarin On Treatment N = 14,143 1.70% vs 2.15% stroke rate 21% reduction in stroke rate w/ rivaroxaban p = 0.015 ITT N = 14,171 2.12% vs 2.42% stroke rate 12% reduction in stroke rate w/ rivaroxaban p = 0.117

11. ROCKET-AF: Clinical Trial Outcomes Efficacy –Rivaroxaban: non-inferior to warfarin for SPAF –Rivaroxaban: superior to warfarin while patients were taking study drug Safety –Similar rates of bleeding and adverse events –Less ICH and fatal bleeding with rivaroxaban Conclusion –Rivaroxaban is a potential alternative to warfarin for moderate or high risk AF patients

12. Rivaroxaban: FDA Status Xarelto  trade name For the prevention of DVT/PE after orthopedic surgery: –Rivaroxaban 10 mg OD is FDA approved (July 2011) –Approved in the EU and Canada For the prevention of stroke in patients with atrial fibrillation: –FDA advisory committee voted to approve (Sept. 2011) Yes=9, No=2, Abstain=1 –Recommended approval in the EU (Sept. 23, 2011)

13. Apixaban Direct, reversible FXa inhibitor Rapid onset, peak within 3 hrs Bioavailability of 51-85% Long half life, slightly longer in elderly (15 hrs) Multiple elimination pathways –25% renal –75% biliary Metabolism via CYP3A4, SULT1AA pathways Perzborn et al., J Thromb Haemost 2005. Kubitza et al., J Clin Pharmacol 2007. Eliquis 

14. Apixaban: Clinical Development Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF ACS APROPOSBotticelli DVT dose-ranging study ARISTOTLEAPPRAISE-1 ADVANCE-1AMPLIFY (ongoing) AVERROESAPPRAISE-2 (study terminated because of bleeding) ADVANCE-2AMPLIFY-EXT (ongoing) APPRAISE Japan (study terminated) ADVANCE-3

15. ADVANCE-2: Primary Efficacy Results Lassen MR, et al. Presented at ISTH, Boston, MA. July 2009. *Composite of adjudicated asymptomatic DVT by venography; objectively confirmed symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority. Apixaban 2.5mg BID (n=976) Enoxaparin 40mg QD (n=997) 15.1 % 24.4 % 0% 5% 10% 15% 20% 25% RR: 0.62; 95% CI: 0.51-0.74 p < 0.0001* Primary Endpoint* (%) 95%CI:13.0-17.5%95%CI:21.8-27.1%

16. ARISTOTLE: Study Outcomes Treatment with apixaban as compared to warfarin in patients with AF (n>18,000) and at least one additional risk factor for stroke: –Reduces stroke and systemic embolism by 21% (p=0.01) –Reduces major bleeding by 31% (p<0.001) –Reduces mortality by 11% (p=0.047) –Consistent effects across all major subgroups –Fewer drug discontinuations on apixaban than on warfarin, consistent with good tolerability Granger CB, et al. NEJM 2011;365: Aug 28

17. Apixaban: FDA Status Eliquis  trade name For the prevention of DVT/PE after orthopedic surgery: –No FDA approval yet –Apixaban approved in the EU For the prevention of stroke in patients with atrial fibrillation: –No approvals yet

18. Edoxaban: Clinical Development Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF Oral direct FXa inhibition with E for thrombophylaxis after elective THR: a randomized double-blind dose-response study The Edoxaban Hokusai-VTE Study (ongoing) Randomized, parallel-group, multicenter, multinational Phase II study comparing E, an oral factor Xa inhibitor, with warfarin for SPAF STARS J-1 ENGAGE AF-TIMI 48 STARS J-2 (completed June 2011; unpublished) Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with NVAF STARS E-3 (completed Feb. 2010; unpublished) STARS J-4 (completed Feb. 2010; unpublished) STARS J-5 (completed March 2010; unpublished)

19. Edoxaban: FDA Status Lixiana  trade name For the prevention of DVT/PE after orthopedic surgery: –No FDA approval yet –Edoxaban approved in Japan For the prevention of stroke in patients with atrial fibrillation: –No approvals

20. Dabigatran Etexilate Specific, competitive, reversible univalent thrombin inhibitor Pro-drug converted to active form Rapid onset within 2 hours Low bioavailability, 3.5-5% Low protein binding Half life 12-17 hours Renal clearance as glucuronic acid conjugate: 85% Metabolized by esterase catalyzed hydrolysis and P-gp transport mechanisms Perzborn et al., J Thromb Haemost 2005. Kubitza et al., J Clin Pharmacol 2007. Pradaxa ®

21. Dabigatran: Clinical Development Postsurgical prophylaxis of DVT DVT Treatment Stroke Prevention in AF ACS RE-MODELRE-COVERRE-LY RE-DEEM (unpublished) RE-MOBILIZE RE-MEDY (ongoing) RE-NOVATE RE-SONATE (unpublished) RE-NOVATE 2 (unpublished)

22. RE-LY A Non-Inferiority Trial Atrial fibrillation with ≥ 1 Risk Factor Absence of contraindications 951 centers in 44 countries Atrial fibrillation with ≥ 1 Risk Factor Absence of contraindications 951 centers in 44 countries R Warfarin Adjusted INR 2.0 – 3.0 N=6,000 Blinded Event Adjudication Open Dabigatran 110 mg BID N=6,000Dabigatran 150 mg BID N=6,000 Blinded Connolly SJ, et al. NEJM 2009; 361:1139-1151

23. RE-LY: Stroke Prevention 150 mg - 34% Fewer Strokes 0.500.751.001.251.50 Dabigatran 110 vs. Warfarin Dabigatran 150 vs. warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 <0.001 Margin = 1.46 HR (95% CI) Warfarin betterDabigatran better Connolly SJ, et al. NEJM 2009;361:1139-51

24. RE-LY: Study Outcomes Efficacy Both doses of dabigatran were non-inferior to warfarin on the primary endpoint –reduction of the incidence of stroke including hemorrhagic and systemic embolism; p<0.001 Dabigatran 150 mg BID was superior to warfarin on the primary endpoint by 34% –RR 0.66, 95% CI, 0.53-0.82; p<0.001 Safety No significant difference in the rate of major bleeding for dabigatran 150 mg BID compared to warfarin –3.11 vs 3.36 %/yr; p=0.31 Rate of major bleeding with dabigatran 110 mg BID (2.71%/yr) was 20% lower compared to warfarin; p=0.003

25. RE-LY: MORTALITY REDUCTION DABIGATRAN VS WARFARIN Lower death rate with dabigatran: –Vascular death 2.69% vs 2.43 and 2.28%* (p=0.04 for 150 mg) –All cause death 4.13% vs 3.75 and 3.64% (p=0.05 for 150 mg) *Dabigatran 110 mg and 150 mg Connolly SJ, et al. NEJM 2009;361: 1139-1151

26. RE-LY: BLEEDING DABIGATRAN VS WARFARIN More bleeding with warfarin: –Life-threatening bleeding 1.8% vs 1.2 and 1.5%* (p<0.001, 0.04) –Intracranial bleeding 0.7% vs 0.2 and 0.3% (p<0.001, <0.001) –Major plus minor bleeding 18.2% vs 14.6 and 16.4% (p<0.001, 0.002) *Dabigatran 110 mg and 150 mg Connolly SJ, et al. NEJM 2009; 361:1139-1151

27. Dabigatran: FDA Status Pradaxa  trade name For the prevention of DVT/PE after orthopedic surgery: –FDA approval pending –Pradaxa approved in EU and Canada For the prevention of stroke in patients with non-valvular atrial fibrillation (SPAF): –Pradaxa 150 mg BID FDA approved (Oct. 2010) –Pradaxa approved in EU, Canada and Japan

28. Dabigatran: FDA Approved Dosing 150 mg BID for SPAF –150 mg for CrCl >30 mL / min – 75 mg for CrCl 15-30 mL / min

29. Stroke from Atrial Fibrillation AF is the most preventable cause of stroke: –12-16 million will be on warfarin treatment by 2050 in the US –Clinical trials have shown stroke can be reduced: Placebo vs ASA = 19%  ASA vs warfarin = 30%  Placebo vs warfarin = 62%  Dabigatran vs warfarin = 34% 

30. Dabigatran: Not Without Issues 1.No anticoagulant effect if missed dose 2% discontinuation rate due to GI distress Cost of drug ($240/mo vs $4/mo for warfarin) 2.No test to assess anticoagulation 3.Difficult to modulate dose 4.Bleeding in the elderly and renal impaired patients (5 dabigatran related deaths in Japan) 5.‘Real world’ untested populations 6.Drug interactions 7.Limited data on bridging between anticoagulants 8.No specific antidote 9.0.2% increase in myocardial infarction 10.Off-label use

31. New OACs: Immediate Practical Issues Is there a specific antidote for dabigatran associated bleeding? –No, still in development How do we manage bleeding complications associated with dabigatran? How can we test a patient for the presence of dabigatran? Are there drug interactions with dabigatran? –tPA (stroke, AMI) –Heparins (ACS, stroke) –Antiplatelet drugs

32. New OACs: ‘Real Life’ Experience Populations not studied in the clinical trials: –Elderly, pediatrics, pregnant –Heparin compromised (e.g., HIT) –Acute vs non-acute VTE –Chronically ill Common patient characteristics that influence the drug PKs and safety/efficacy of NOACs: –Co-morbid illnesses –Reduce renal function –Reduced hepatic function –Altered metabolism, gastric pH, intestinal motility, protein binding –Extremes in body weight –Co-administered R x drugs, dietary supplements, herbs

33. New OACs: ‘Real Life’ Experience Drug interactions with NOACs: –Potential adverse effects Alter the pharmacokinetics of the NOAC Increase or decrease exposure to the NOAC Increase bleeding risk –Known ‘cautioned’ drugs Proton pump inhibitors Inhibitors or inducers of the CYP3A4 or P-gp transport mechanisms NSAIDs, ASA, anti-platelet drugs –At risk patients Cardiovascular disease Depression Pain Epilepsy Requiring antibiotics, anti-fungals, anti-malaria drugs

34. Dabigatran: Bleeding Management Short half-life Maintain adequate diuresis Usual supportive measures: compression, surgical hemostasis Dialysis (low protein binding) 1 Activated charcoal w/ subsequent charcoal filtration (in vitro data) 1 Blood products –May not be effective: replace factor deficiency (warfarin) vs overcome an inhibitor (dabigatran) PCC not effective (effective against rivaroxaban) 2 rFVIIa 1 vanRyn J, et al. Thromb Haemost 2010;103(6):1116-27 2 Eerenberg ES, et al. Circulation 2011;124:Sept 6

35. Dabigatran: Laboratory Testing Monitoring vs anticoagulant assessment –PT and aPTT Differing reagent sensitivities Not a linear association between assay values and drug level Not validated for association to bleeding aPTT may be applicable for qualitative assessment –INR: not sensitive; not validated –TT: Super-sensitive; can identify if any drug onboard –Ecarin clotting time: results can vary depending on plasma factors; research use only (RUO) –PiCT: RUO –Chromogenic anti-FIIa –Hemoclot: quantitative using dabigatran calibrators; FDA approved yet?

37. 2 case reports of inaccurate INR values w/ dabigatran. Baruch L, Sherman O. Ann Pharmacother 2011 Jun 28

43. (Stangier et al. ISTH 2009, Boston) Dabigatran Calibration Curve Hemoclot Assay for Dabigatran Dabigatran Treated Patients

44. The New Oral Anticoagulants: Similar Yet Different Thrombin Inhibitors: 1. Dabigatran: pro-drug, renal clearance - twice daily FXa Inhibitors: 1. Rivaroxaban: renal clearance - once daily 2. Apixaban: hepatic clearance - twice daily 3. Edoxaban: hepatic clearance - once daily Circulation 2010;121:1523-1532

45. The New Oral Anticoagulants: Similar Yet Different FeaturesRivaroxabanApixaban Dabigatran Etexilate TargetXa IIa Molecular Weight 436460628 ProdrugNo Yes Bioavailability (%) 80506 Time to peak (h) 332 Half-life (h) 99-1412-17 Renal excretion (%) 652580 AntidoteNone Each drug has its own effect in lab tests. The metabolic mechanisms of each drug differ; see drug interactions. Each drug has to be managed individually.

46. The Future of Warfarin 1.Excellent efficacy 2.Low cost ($0.75 per day!) 3.Long track record (since 1954) 4.Centralized Anticoagulation Clinics that maintain TTRs > 60% 5.PT assay available: fast TAT, inexpensive 6.INR validated for warfarin relation to bleeding risk 7.Point-of-care testing 8.Rapid turnaround genetic testing

47. Conclusions 1.New anticoagulants are now clinically available and additional drugs are being developed. 2.The new oral anticoagulants rivaroxaban, dabigatran and apixaban, though costly, will provide more options for the management of VTE; however, these drugs are not superior to the standard of care. 3.For VTE prevention, heparins and warfarin will remain the standard of care for some time, especially in medical patients.

48. Conclusions 4.For atrial fibrillation (SPAF) the new oral anticoagulants appear to have a superior safety and efficacy profile. 5.Additional clinical trials are needed to determine the merit of these drugs beyond the ‘clinical trial’ populations, and to address unanswered questions. 6.Warfarin’s low cost, efficacy, and track record will prolong its life. Its use may decrease but it will remain a for years to come.

50. Regulatory Approvals Orthopedic surgery (THR/TKR/Hip fracture): –Dabigatran: EU, Canada –Rivaroxaban: EU, Canada, US –Apixaban: EU –Edoxaban: Japan Non-ortho surgery, medical patients: –No approvals SPAF: –Dabigatran: US, EU, Canada, Japan –Rivaroxaban: US and EU approval recommended