1. Advancements In Anticoagulation John Devlin, Pharm D Feb 4, 2009

2. Agenda 1.Unmet needs in anticoagulation 2.Niche for new anticoagulants 3.Dabigatran Etexilate 4.Evidence for efficacy and safety from phase 3 randomized trials 5.Implications for clinical practice 6.Comparing agents 7.Future developments

3. Currently available anticoagulants Parenteral Agents Heparins UFH LMWH (3 agents) Heparinoids Anti-Xa Fondaparinux DTIs Bivalirudin / hirudin Argatroban Oral Agents VKA’s –Warfarin –Acenocoumarol

4. Place in therapy Venous thrombosis Prevention –In-hospital –Out-of-hospital Treatment – Initial – Long term Arterial thrombosis Treatment – ACS Prevention – Stroke (AF, CHF, Prosthetic valves) – Post MI – PCI / HD

5. The “Magic Bullet” Oral Dosage Form Little or no monitoring required Equally efficacious and safe to current treatments Consistent dosing regimen (wide therapeutic window) Predictable PK and PD Free from alcohol and food interactions Free from drug interactions Un phased by genetic factors (VKOR, CYP2C9) Un phased by organ dysfunction Reversibility Rapid onset and offset Inexpensive

6. Urgent Need to Replace Warfarin!

7. Where Can We Improve? Venous thrombosis Prevention –In-hospital –Out-of-hospital Treatment – Initial – Long term Arterial thrombosis Treatment – ACS Prevention – Stroke (AF, CHF, Prothestic heart valves) – Post MI – PCI / HD

8. VTE Prevention “Call to Action” on DVT and PE September 15, 2008 (Washington, DC) - The Office of the Surgeon General called today for a coordinated, multifaceted plan to reduce the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the us. The “call to action” is intended to increase awareness about these silent conditions and emphasize the importance of evidence based practices in the management of DVT.

9. Out of Hospital Underuse of Extended Prophylaxis after major Orthopedic Surgery ACCP guidelines for extended prophylaxis: Hip fracture 1A Hip arthroplasty 1A Knee arthroplasty 2B Reasons for underuse Need for subcut injection Need for monitoring and dose adjustment of VKA therapy Coordinating drug coverage

10. VTE Prevention Non Traditional Prophylaxis Medical patients (EXCLAIM trial) 4000 patients 6-14 days vs 1 month with LMWH > 14 days? Knee arthroscopy (KANT trial) 1800 patients Nadroparin 3800 units vs elastic stockings for 7 days 0.9% vs 3.2 % Thalidomide associated VTE

11. Long Term Secondary VTE Prophylaxis Duration of anticoagulation for first unprovoked VTE Proximal DVT or PE, no bleeding risk factors, and good monitoring is available Those with permanent risk factors (ie Cancer) Unprovoked VTE with strong preference for less frequent monitoring.

12. Aterial Thrombosis Underuse of Warfarin in AF

13. New Oral Agents

14. FeatureDabigatran EtexilateRivaroxabanApixiban TargetThrombinFactor XaFactor Xa ProdrugYes NoNo DosingFixed, b.i.d. Fixed, o.d. Fixed, b.i.d Bioavailability6% 80% 50% MonitoringNo No No Half-life (h)12-175-9 12 Renal clearance80% 65% 25% InteractionsP-gp inhibitor Combined P-gpPotent CYP3A4 and CYP3A4 inhibitors inhibitors IndicationsVTE prevention VTE prevention None Trials ongoingAF, ACS, VTEAF, ACS, VTE AF, ACS, VTE treatment treatment prevent/treat Pradax Product Monograph 2008; Xarelto Product Monograph 2008; Turpie Eur Heart J 2008; Gross, Weitz. Arterioscler Thromb Vasc Biol 2008

15. New Oral Anticoagulant Targets Common Pathway IX X VIII Xa Thrombin Fibrin Thrombin Activity Initiation Phase Amplification Propagation Phase Platelet Surface XII XI Contact Fibrinogen Rivaroxaban Apixaban Dabigatran Etexilate TF/VII

16. Anti-Xa or Anti-IIa? Anti-IIa Anti-Xa Hirudin Bivalirudin Argatroban Ximelagatran Dabigatran Etexilate Fondaparinux Idraparinux Rivaroxaban Apixaban Unfractionated Heparin Dalteparin Enoxaparin Nadroparin Reviparin

17. Anti-Xa or Anti-IIa? Pharmacologic Considerations Anti-XaAnti-IIa “Gatekeeper of the coagulation cascade” “Final Common Pathway” Block thrombin generationBlock thrombin activity Selective “targeted” effectBlock Contact Activation Maintain -ve feedbackBlock +ve feedback Platelet Inhibition

18. Dabigitran Etixilate

19. The Molecule

20. Key Characteristics Indicated for prevention of VTE post THR & TKR Dose 110 mg 1-4 hours post surgery followed by 220 mg daily

21. Dabigatran Pharmacokinetics Absorption Oral Bioavailability: ~ 6.5% Time to peak: 0.5-2 hours, delayed 2 hours by food Distribution Linear kinetics ~35% protein bound Vd = 60-70L

22. Dabigatran Pharmacokinetics Metabolism Hepatic glucuronidation to active metabolite Elimination Excreted in urine (85%, primarily as unchanged drug); fecal (6% of total dose) t 1/2 = 12-17 hours

23. Drug Interactions Avoid concomitant use with p-glycoprotein inhibitors & inducers Verapamil, Clarithromycin, *Quinidine Rifampicin, St. Jonh’s Wort, Tenofovir) Antacids diminished clinical effect; avoid within 24 hours after surgery Amiodarone Adjust dosing to 150 mg daily dabigatran with amiodarone Pantoprazole Co-administration with Dabigatran may diminish clinical effect

24. Special Considerations Contraindications Severe renal impairment (CrCl < 30 mL/min) Concomitant treatment with strong P-Glycoprotein inhibitors (Quinidine) Antidote Switching agents Special Patient Populations Age Pregnancy Weight End organ dysfunction

25. Dabigatran Etixilate & Phase 3 Trials REVOLUTION

26. Dabigatran Phase III Studies: REVOLUTION Start evening before surgery* OR 12-24 hours post-operatively # Start 1-4 hours* OR 6-12 hours # post-operatively Enoxaparin 40 mg QD* OR 30 mg BID # Dabigatran etexilate 75 / 150 mg QD Venography Within 12 hours of last dose Follow-up 12–14 weeks Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132 *RE-MODEL and RE-NOVATE # RE-MOBILIZE Design:Non-Inferiority in Modified Intention-To-Treat Population R R Dabigatran etexilate 110 / 220 mg QD Study Therapy Duration Enoxaparin Dose (mg) RE-MODELKnee6-10 days40 QD RE-NOVATEHip28-35 days40 QD RE-MOBILIZEKnee12-15 days30 BID

27. Methods - Procedures Primary efficacy outcome: Composite of total venous thromboembolic events (VTE) (symptomatic or venographic DVT and/or pulmonary embolism [PE]), and all-cause mortality during treatment Secondary efficacy outcomes: Composite of major VTE (proximal DVT and PE) and VTE-related mortality Proximal DVT Incidence of total VTE and all-cause mortality during follow-up Individual components of the primary outcome TrialCountries# SitesSample Size RE-MODEL Europe, Australia, South Africa 105 2101 RE-NOVATE 115 3494 RE-MOBILIZE US, Canada, Mexico, UK58 2615 Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

28. Methods - Procedures Primary safety outcome: – Major bleeding events – Associated with ≥2 g/dL drop in haemoglobin or required transfusion of ≥2 units blood – Fatal, retroperitoneal, intracranial, intraocular, or intraspinal – Warranted treatment cessation or re-operation – Clinically relevant non-major bleeding events – Minor bleeding events Events were classified by an independent, expert adjudication committee Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132

29. Baseline characteristics RE-MOBILIZERE-MODELRE-NOVATE Patient Characteristics Age (mean) - years 666864 Females - % 586656 Weight (mean) – kg 888379 Anesthetic Details General - % 533831 Study Drug Administration Time to first oral dose* (mean) – h 9.53.53.4 Treatment duration (median) – d 13833

30. P=0.0003 for non-inferiority RE-MODELRE-MOBILIZE † RE-NOVATE P=0.017 for non-inferiority P<0.0001 for non-inferiority Primary Efficacy Outcome: Total VTE or All-Cause Mortality (Hip) (Knee) Dabigatran Enoxaparin Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007 P=0.02 * * P-value that the margin of 9.2% as the upper limit of the 95% CI for ARD was exceeded P=0.0009 * † Confidence intervals not reported

31. RE-MODELRE-MOBILIZE*RE-NOVATE No significant differences between either dose of dabigatran etexilate and enoxaparin. Safety Outcome: Major Bleeding Events * Confidence intervals not reported Dabigatran Enoxaparin Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007

32. Interpretational Considerations Failure to demonstrate non-inferiority of dabigatran in Re-Mobilize Factors that may have contributed Higher dose of enoxaparin (30 mg BID vs 40 mg QD in RE-MODEL) Comparator event rate was lower than anticipated (25.3% versus 37.7% in RE-MODEL) Different median duration of treatment Delayed initiation of dabigatran dosing

33. Efficacy by Timing of Initiation of Dabigatran (70/498)(121/539) Total VTE Rate (%) P = 0.0005 Eriksson et al. J Thromb Haemost 2005 A post-hoc analysis from BISTRO II (THR & TKR patients)

34. Meta-Analysis of RE-MODEL, RE-MOBILIZE, RE-NOVATE: Total VTE & All-Cause Mortality Wolowacz et al. Thromb Haemost 2009 0.1 0.2 0.5 1 2 5 10 Favours Enoxaparin Favours Dabigatran Etexilate RE-MOBILIZE188/604163/643 RE-MODEL183/503193/512 RE-NOVATE 53/880 60/897 Study or sub- category Dabigatran etexilate 220 mg QD n/N Enoxaparin n/N RR [95% CI] 1.23 [1.03, 1.47] 0.97 [0.82, 1.13] 0.90 [0.63, 1.29] Total events: 424 (dabigatran etexilate), 416 (enoxaparin) Test for heterogeneity: Chi 2 = 4.73, df = 2 (P=0.09), I 2 = 57.7% Random Effects Analysis Total (95% CI)1987 2052 Test for overall effect: Z = 0.47 (P = 0.64) 1.05 [0.87, 1.26] RR Analysis is based on the 220 mg QD dose of dabigatran etexilate.

35. The “Magic Bullet”……. Oral Dosage Form Little or no monitoring required Equally efficacious and safe to current treatments Consistent dosing regimen Predictable PK and PD Free from alcohol and food interactions Free from drug interactions Un phased by genetic factors (VKOR, CYP2C9) Un phased by organ dysfunction Reversibility Rapid onset and offset Inexpensive

36. …..Not entirely yet much better! Oral Dosage Form  Little or no monitoring required  Equally efficacious and safe to current treatments  Consistent dosing regimen  Predictable PK and PD  Free from alcohol and food interactions  Free from drug interactions X Un phased by genetic factors (VKOR, CYP2C9)  Un phased by organ dysfunction X Reversibility X Rapid onset and offset  Inexpensive 

37. Implications for Clinical Practice Dabigatran etexilate is safe and effective for prevention of VTE in patients undergoing hip or knee arthroplasty Potential to replace LMWH or fondaparinux Major unmet need is out of hospital prophylaxis Potential to improve guideline adherence and reduce VTE disease burden

38. Summary Massive unmet need for new oral anticoagulant Dabigatran etexilate Simple Convenient, unmonitored Safe Effective First in AF (September 2009) Closing the care gap – more patients treated appropriately with improved quality of life. Excellent replacement for warfarin

39. Questions?