1. Oral anticoagulant therapy : a look to the future Alexander G. G. Turpie Department of Medicine HHS-General Hospital Hamilton, Canada

2. Antithrombotics That Have Changed Clinical Practice Anticoagulants  Low-molecular-weight heparin Antiplatelet Drugs  Thienopyridines  Glycoprotein IIb/IIIa Inhibitors

3. But…………………….. for oral anticoagulation, Vitamin K antagonists (warfarin) remain the only available option for oral anticoagulation, Vitamin K antagonists (warfarin) remain the only available option

4. The ‘ideal’ oral anticoagulant  Oral, preferably once daily  Rapid onset and offset of action  Predictable PK and PD  Low propensity for food and drug interactions  Fixed doses  Wide therapeutic window   Easy to use with no need for monitoring

5. New Anticoagulants TFPI (tifacogin) Fondaparinux Idraparinux Rivaroxaban Apixaban LY517717 YM150 DU-176b Betrixaban TAK 442 Dabigatran ORALPARENTERAL DX-9065a Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz & Bates, J Thromb Haemost 2007 TTP889

6. VIIa Xa IXa XIa XIIa Direct Thrombin inhibition Tissue factor Factor IIa (thrombin) Dabigatran II ×

7. Dabigatran for prevention of VTE after major orthopaedic surgery: phase III studies  Dabigatran doses of 150 and 220 mg once daily (od) were investigated in all three studies TKR: total knee replacement; THR: total hip replacement Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007 Study Type of surgery Comparator Number of patients Time to 1st administration of dabigatran Treatment duration RE-MODELTKR Enoxaparin 40 mg od, starting evening before surgery 2010 1–4 hours post-surgery 6–10 days RE-MOBILIZETKR Enoxaparin 30 mg bid, starting 12–24 hours post- surgery 2615 6–12 hours post-surgery 12–15 days RE-NOVATETHR Enoxaparin 40 mg od, starting evening before surgery 3494 1–4 hours post-surgery 28–35 days

8. Dabigatran for prevention of VTE after major orthopaedic surgery: results Enoxaparin Dabigatran (150 mg) Dabigatran (220 mg) DVT, PE and all-cause mortality (%) RE-NOVATE6.7 8.6 p<0.0001* 6.0 p<0.0001* RE-MOBILIZE25.3 33.7 p=0.0009 † 31.1 p=0.02 † RE-MODEL37.7 40.5 p=0.0005* 36.4 p=0.0345* Major bleeding (%) RE-NOVATE1.61.32.0 RE-MOBILIZE1.40.60.6 RE-MODEL1.31.31.5 *Non-inferior to enoxaparin; † inferior to enoxaparin Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007

9. Dabigatran: phase III studies  RE-LY (stroke prevention in patients with AF) –Planned enrolment 15,000 patients –Dabigatran 110 and 150 mg bid compared with warfarin –Treatment duration up to 3 years  RE-SOLVE, RE-COVER and RE-MEDY –Ongoing studies in treatment and secondary prevention of VTE

10. New Anticoagulants TFPI (tifacogin) Fondaparinux Idraparinux Rivaroxaban Apixaban LY517717 YM150 DU-176b Betrixaban TAK 442 Dabigatran ORALPARENTERAL DX-9065a Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz & Bates, J Thromb Haemost 2007 TTP889

11. VIIa Xa IXa XIa XIIa Direct Factor Xa inhibition Tissue factor Fibrinogen Fibrin clot Factor II (prothrombin) Rivaroxaban Apixaban YM150 DU-176b LY517717 Betrixaban TAK 442 ×

12. Apixaban  Oral, direct, selective factor Xa inhibitor  Produces concentration-dependent anticoagulation  No formation of reactive intermediates  No organ toxicity or LFT abnormalities in chronic toxicology studies  Low likelihood of drug interactions or QTc prolongation  Good oral bioavailability  No food effect  Balanced elimination (~25% renal)  Half-life ~12 hrs He et al., ASH, 2006, Lassen, et al ASH, 2006

13. Apixaban :Phase II Apropos – orthopaedic surgery Apropos – orthopaedic surgery Botticelli – treatment Botticelli – treatment Adapt – advanced cancer Adapt – advanced cancer Appraise 1 – ACS Appraise 1 – ACS

14. Lassen et al. Blood 2006 Total VTE and All-Cause Mortality (%) Major Bleeding (%) Enoxaparin (30mg bid) Apixaban for Prevention of VTE After Major Orthopaedic Surgery  Apixaban od and bid (total daily doses 5-20mg) were assessed relative to enoxaparin and warfarin, in 1,217 patients 20mg Apixaban (Total Daily Dose) 10mg5mg Warfarin (INR 1.8-3.0) Enoxaparin (30mg bid) 20mg Apixaban (Total Daily Dose) 10mg5mg Warfarin (INR 1.8-3.0) Percent

15. Büller, Eur Heart J 2006 Composite of Symptomatic Recurrent VTE and Deterioration of Thrombotic Burden (%) Major Bleeding (%) Apixaban for the Treatment of DVT: The Botticelli-DVT Study  Apixaban bid (5 and 10mg) and od (20mg) were assessed relative to low molecular weight heparin (LMWH) or fondaparinux followed by VKA, in 520 patients 20mg bid Apixaban 10mg bid 5mg bid LMWH/ fondaparinux + VKA 20mg bid Apixaban 10mg bid 5mg bid LMWH/ fondaparinux + VKA Percent

16. Apixaban : Phase III Advance 1,2,3 – orthopaedic surgery Advance 1,2,3 – orthopaedic surgery Adopt – medically ill Adopt – medically ill Aristotle -atrial fibrillation Aristotle -atrial fibrillation Appraise 2 - ACS Appraise 2 - ACS

17. Rivaroxaban: oral direct Factor Xa inhibitor  Predictable pharmacology  High bioavailability  Low risk of drug–drug interactions  Fixed dose  No requirement for monitoring Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005 Rivaroxaban ® – rivaroxaban

18. Rivaroxaban  Specific, competitive, direct FXa inhibitor  Inhibits free and clot- associated FXa activity, and prothrombinase activity  Inhibits thrombin generation via inhibition of FXa activity –Prolongs time to thrombin generation –Inhibits peak thrombin generation –Reduces the total amount of thrombin generated  Does not require a cofactor Perzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther 2005; Br J Clin Pharmacol, 2007; Graff et al. In press

19. Rivaroxaban 10 mg once daily is the optimum dose 05102040Enoxaparin30 0 10 20 40 30 0 10 20 30 Incidence – efficacy (%) Incidence – safety (%) Rivaroxaban (mg total daily dose) DVT, PE and all-cause mortality Major post-operative bleeding p=0.0852 p=0.039 Efficacy, n=618; safety, n=845 Eriksson et al. Circulation 2006

20. Rivaroxaban: VTE Treatment Trials Deep Vein Thrombosis Pulmonary Embolism Treatment

21.  Two large, phase II studies of rivaroxaban for 3 months for the treatment and long­term secondary prevention of VTE: – ODIXa-DVT : Rivaroxaban 10–30 mg bid and 40 mg od and 40 mg od –EINSTEIN DVT : Rivaroxaban 20–40 mg od –LMWH followed by a VKA comparator in both studies Agnelli et al. Circulation 2007; Büller. Eur Heart J 2006 Rivaroxaban for the treatment and secondary prevention of VTE

22. Phase III RECORD programme in VTE prevention  Oral rivaroxaban 10 mg od is being compared with subcutaneous enoxaparin in >11,000 patients worldwide Study Duration of rivaroxaban therapy Duration of enoxaparin therapy RECORD1THR 5 weeks RECORD2THR 10–14 days, followed by placebo RECORD3TKR 10–14 days RECORD4TKR

23. Efficacy endpoints Primary  Total venous thromboembolism (VTE): any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality Secondary  Major VTE: proximal DVT, non-fatal PE, and VTE-related death  DVT: any, proximal, distal  Symptomatic VTE All endpoints were adjudicated centrally by independent, blinded committees

24. Safety endpoints Main  Major bleeding starting after the first blinded dose and ≤2 days after last dose –Bleeding that was fatal, into a critical organ or required re-operation –Extra-surgical-site bleeding associated with a drop in hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units blood Other  Any bleeding on treatment*  Non-major bleeding*  Hemorrhagic wound complications*  Cardiovascular adverse events  Liver enzyme levels All endpoints were adjudicated centrally by independent, blinded committees *Up to 2 days after last dose of study medication

25. Rivaroxaban – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in total knee arthroplasty surgery

26. Enoxaparin 40 mg od Rivaroxaban 10 mg od Mandatory bilateral venography RECORD3: study design Inclusion criteria  Patients aged ≥18 years, scheduled to undergo elective, total knee replacement (TKR) surgery Day 42+5 R S U R G E R Y F O L L O W U P Evening before surgery 6–8 hours post-surgery Day 1 Day 13±2 Double blind Last dose, 1 day before venography Major exclusion criteria  Active bleeding or high risk of bleeding  Significant liver disease  Anticoagulant therapy that could not be stopped  Use of HIV-protease inhibitors R S U R G E R Y

27. RECORD3: summary Total VTE Major bleeding 20 Incidence (%) 0 Major VTE 5 10 15 NS RRR 49% RRR 62% Symptomatic VTE Rivaroxaban 10 mg od Enoxaparin 40 mg od RRR 65% 0.5%0.6%18.9%9.6%2.6% 1.0% 2.0%0.7%

28. Study background  ACCP guidelines: grade 1A recommendation for up to 35 days’ prophylaxis after elective hip replacement surgery Geerts et al., 2004 2004

29. Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty

30. Enoxaparin 40 mg od Rivaroxaban 10 mg od RECORD1 study design Mandatory bilateral venography R S U R G E R Y F O L L O W U P Evening before surgery 6–8 hours post-surgery Day 1 Day 36±4 Double blind Last dose, day before venography Up to Day 65 Inclusion criteria  Patients aged ≥18 years, scheduled to undergo elective THR Major exclusion criteria  Active bleeding or high risk of bleeding  Significant liver disease  Anticoagulant therapy that could not be stopped  Use of HIV-protease inhibitors

31. RECORD1: summary Incidence (%) Total VTE Major bleeding Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily 0 1 2 3 4 5 0.5% 0.3% 0.1% 0.3% Symptomatic VTE RRR 70% 2.0% 0.2% Major VTE RRR 88% 1.1%3.7%

32. Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with low molecular weight heparin after total hip arthroplasty

33. Rivaroxaban 10 mg od Mandatory bilateral venography RECORD2: study design Inclusion criteria  Patients aged ≥18 years, scheduled to undergo elective THR Day 65+5 R S U R G E R Y F O L L O W U P Evening before surgery 6–8 hours post-surgery Day 1 Double blind Major exclusion criteria  Active bleeding or high risk of bleeding  Significant liver disease  Anticoagulant therapy that could not be stopped  Use of HIV-protease inhibitors Day 36±4 Enoxaparin 40 mg od Oral placebo

34. RECORD2: summary Total VTE Major bleeding Major VTE Incidence (%) 0 2 4 6 10 8 9.3% RRR 78.9% 2.0% 5.1%0.1% 0.6% RRR 87.8% RRR 80.1% 1.2% 0.2% Symptomatic VTE Enoxaparin 40 mg once daily Rivaroxaban 10 mg once daily

35. Clinical programme overview: 50,000 patients to be enrolled VTE prevention in hospitalized medically ill patients Secondary prevention of acute coronary syndromes Japanese Phase III study Stroke prevention in atrial fibrillation  EINSTEIN-DVT  EINSTEIN-PE  EINSTEIN-EXT  ODIXa-DVT  EINSTEIN-DVT VTE treatment  RECORD1  RECORD2  RECORD3  RECORD4  ODIXa-HIP1  ODIXa-HIP2  ODIXa-KNEE  ODIXa-OD-HIP VTE prevention after major orthopaedic surgery Phase III Phase II >42,000 ~8,000