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Oral anticoagulant therapy : a look to the future

Oral anticoagulant therapy : a look to the future. Alexander G. G. Turpie Department of Medicine HHS-General Hospital Hamilton, Canada . Antithrombotics That Have Changed Clinical Practice. Anticoagulants Low-molecular-weight heparin Antiplatelet Drugs Thienopyridines

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Oral anticoagulant therapy : a look to the future

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  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

  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 ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) RivaroxabanApixaban LY517717 YM150 DU-176b Betrixaban TAK 442 IXa VIIIa Va AT Xa FondaparinuxIdraparinux II DX-9065a IIa Dabigatran Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007

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

  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

  8. Dabigatran for prevention of VTE after major orthopaedic surgery: results *Non-inferior to enoxaparin; †inferior to enoxaparinEriksson 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 ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecogin alfa) sTM (ART-123) RivaroxabanApixaban LY517717 YM150 DU-176b Betrixaban TAK 442 IXa VIIIa Va AT Xa FondaparinuxIdraparinux II DX-9065a IIa Dabigatran Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007

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

  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 Botticelli – treatment Adapt – advanced cancer Appraise 1 – ACS

  14. 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 Total VTE and All-Cause Mortality (%) Major Bleeding (%) Percent Percent 5mg 10mg 20mg Warfarin (INR 1.8-3.0) Enoxaparin(30mg bid) 5mg 10mg 20mg Warfarin (INR 1.8-3.0) Enoxaparin(30mg bid) Apixaban (Total Daily Dose) Apixaban (Total Daily Dose) Lassen et al. Blood 2006

  15. 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 Composite of Symptomatic Recurrent VTE and Deterioration of Thrombotic Burden (%) Major Bleeding (%) Percent Percent LMWH/ fondaparinux + VKA LMWH/ fondaparinux + VKA 5mg bid 10mg bid 20mg bid 5mg bid 10mg bid 20mg bid Apixaban Apixaban Büller, Eur Heart J 2006

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

  17. Rivaroxaban® – rivaroxaban 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

  18. 100 80 60 Inhibition of Factor Xa activity (%) 40 20 Free FXa Prothrombinase activity Clot-associated FXa 0 0.01 0.1 1 10 100 1000 Rivaroxaban (nM) 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 30 40 DVT, PE and all-cause mortality Major post-operative bleeding 30 20 Incidence – efficacy (%) Incidence – safety (%) 20 p=0.0852 10 10 p=0.039 0 0 0 5 10 20 30 40 Enoxaparin Rivaroxaban (mg total daily dose) Efficacy, n=618; safety, n=845 Eriksson et al. Circulation 2006

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

  21. Rivaroxaban for the treatment and secondary prevention of VTE • 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 • 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

  22. Phase III RECORD programme in VTE prevention • Oral rivaroxaban 10 mg od is being compared with subcutaneous enoxaparin in >11,000 patients worldwide

  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. F S S O U U L R R L G G O E E W R R U Y Y P RECORD3: study design Double blind Rivaroxaban 10 mg od Mandatory bilateral venography 6–8 hours post-surgery R R 6–8 hours post-surgery Enoxaparin 40 mg od Evening before surgery Day 1 Day 42+5 Day 13±2 Last dose, 1 daybefore 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 Inclusion criteria • Patients aged ≥18 years, scheduled to undergo elective, total knee replacement (TKR) surgery

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

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

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

  30. F S O U L R L G O E W R U Y P RECORD1 study design Double blind Mandatory bilateral venography Rivaroxaban 10 mg od 6–8 hours post-surgery R 6–8 hours post-surgery Enoxaparin 40 mg od Evening before surgery Up to Day 65 Day 36±4 Day 1 Last dose, daybefore 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 Inclusion criteria • Patients aged ≥18 years, scheduled to undergo elective THR

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

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

  33. F S O U L R L G O E W R U Y P RECORD2: study design Double blind Rivaroxaban 10 mg od Mandatory bilateral venography 6–8 hours post-surgery R 6–8 hours post-surgery Enoxaparin40 mg od Oral placebo Evening before surgery Day 1 Day 36±4 Day 65+5 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

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

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

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