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Emerging Anticoagulants for VTE Prevention and Treatment: Is change upon us?

Emerging Anticoagulants for VTE Prevention and Treatment: Is change upon us?. Amanda C. Walker, PharmD Clinical Pharmacist University of Utah University Thrombosis Service. Objectives. Describe the pharmacology and mechanism of action for new and emerging anti-thrombotic agents

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Emerging Anticoagulants for VTE Prevention and Treatment: Is change upon us?

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  1. Emerging Anticoagulants for VTE Prevention and Treatment: Is change upon us? Amanda C. Walker, PharmD Clinical Pharmacist University of Utah University Thrombosis Service

  2. Objectives • Describe the pharmacology and mechanism of action for new and emerging anti-thrombotic agents • Discuss and review current randomized controlled trials for new and emerging anti-thrombotic agents for VTE prevention and treatment • Evaluate the adverse drug reactions and side effects associated with these new agents

  3. Current Limitations Lassen MR. Vasc Health Risk Manag. 2008;4(6):1373-86.

  4. Anti – Xa : direct Rivaroxaban (oral) Apixaban (oral) Betrixiban (oral) Edoxaban (oral) Otamixaban (parenteral) LY – 517717 (oral) DU – 176B (oral) DX – 9065a (parenteral) PRT054021 (oral) Anti – Xa : indirect Idraparinux biotinylated (parenteral) Anti – IIa Dabigatran (oral) Odiparcil (oral) Flovagatran (parenteral) Pegmusirudin (parenteral) Peg Hirudin Desiruidin New and Emerging Anticoagulants

  5. Indirect Xa Inhibitors “-parinux” AT Direct Thrombin Inhibitors “-gatran” warfarin Site of Action for New Anti-thrombotic Agents Extrinsic XII Intrinsic XI Tissue Factor IX VII VIII Direct Xa Inhibitors “-xaban” X V II Fibrinogen Fibrin Clot

  6. Factor Xa One Xa forms many IIa Limited role in diversity of action outside of coagulation cascade Clinical effectiveness Fondaparinux Factor IIa Supports feedback amplification through Factor V, Factor VIII, and Factor IX Has many cellular effects inflammation Clinical effectiveness Argatroban Hirudins Factor Xa vs. Factor IIa

  7. Direct Factor Xa Inhibitors XII Intrinsic Extrinsic XI TF IX VII VIII Direct Xa Inhibitors “-xaban” X V II Fibrinogen Fibrin Clot

  8. Oral tablet Bioavailability: 50% Peak Plasma Levels = 3 hrs Half-life ~ 12 hours Metabolized in liver via CYP3A4 and CYP independent mechanisms Eliminated via multiple pathways No laboratory monitoring required Manufactured by Bristol-Myers Squibb/Pfizer Plan to submit for U.S. approval in 2009-2010 Apixaban

  9. Apixaban Efficacy Outcomes in TKR (Phase II) Incidence of VTE and all-cause death (%) Duration = 10 -14 days 5 QDay 2.5 BID 10 QDay 5 BID 20 QDay 10 BID Enox 30mg BID (n=152) Warf (n=153) Apixaban (mg) (n = 933) Lassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.

  10. Apixaban Safety Outcomes in TKR (Phase II) Incidence of bleeding events (%) 5 QDay 2.5 BID 10 QDay 5 BID 20 QDay 10 BID Enox 30mg BID (n=152) Warf (n=153) Apixaban (mg) (n = 933)

  11. Apixaban Phase III Trials

  12. ADVANCE – 1: Results of Efficacy vs. Enoxaparin 30 mg BID RR: 1.02 (95% CI: 0.78 to 1.32) P=0.06 for non-inferiorityAbsolute Difference: 0.1% (95% CI: -2.22 to 2.44) P<0.001 for non-inferiority 8.99%N = 1157 8.85%N = 1130 Lassen MR, et al. NEJM 2009;361:594 – 604.

  13. ADVANCE – 2: Primary Efficacy Results RR: 0.62; 95% CI: 0.51 – 0.74p<0.0001* 24.5%n = 997 15.1%n = 975 *Composite of adjudicated asymptomatic DVT by venography; objectively confirmed symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority.

  14. Summary of ADVANCE – 2 Study • Apixaban 2.5mg BID vs. Enoxaparin 40mg QD • Superior for: • Primary endpoint of ANY DVT/PE/All-Cause Death • Secondary endpoint for Major VTE • Lower observed bleeding rates • Major • Clinically relevant non-major • Similar overall safety profile

  15. Brand name Xarelto®, Bayer Oral tablet High oral bioavailability (>80%) Onset of action 2-4 hours Half-life 9-12 hours No observed effects on agonist-induced platelet aggregation Primarily renal elimination No laboratory monitoring required No dosage adjustment for gender, age, extreme body weight Approved by Europe and Canadian agencies, and under FDA review currently Rivaroxaban

  16. RRR 49% RRR 62% Rivaroxaban in VTE Prevention:RECORD 3 - TKA 2531 patients % % No Difference

  17. Rivaroxaban in VTE Prevention:RECORD 4 - TKA Rivarox: RRR 31%; ARR 3.2% % % NotSignificant Turpie, et al. Lancet 2009;373:1673 – 80.

  18. Rivaroxaban Ongoing Phase III Clinical Trials DVT Einstein-DVT Rivarox 15mg BID x 3 wks then 20mg Qday vs Enox/VKA PE Einstein-PE Rivarox 15mg BID x 3 wks then 20mg Qday vs Enox/VKA DVT/PE Einstein-Extension Rivarox 20mg Qday vs Placebo AF Rivarox 20 mg Qday vs Warfarin Medically Ill Rivarox 10mg Qday x 35 days vs Enox 40mg Qday x 10 days

  19. Indirect Xa Inhibitors “-parinux” AT Indirect Factor Xa Inhibitors XII Intrinsic Extrinsic XI TF IX VII VIII X V II Fibrinogen Fibrin Clot

  20. Idraparinux • Once weekly SC injection • 100% SC bioavailability • Half-life ~ 96-130 hours • Renal elimination • No monitoring required • Manufactured by Sanofi-Aventis • Plan to file for U.S. approval in 2009

  21. Van Gogh Trials Idraparinux 2.5 mg SC qweek vs standard therapy (heparin/LMWH + VKA) DVT Study PE Study VTE Extended Study Idraparinux vs placebo 2904 patients 2215 patients 1215 patients ↔ 3- and 6-month recurrence ↓ bleeding at 3 mo ↔ bleeding at 6 mo ↔ mortality ↑3- and 6-month recurrence ↓ bleeding at 3 and 6 mo ↑ mortality ↓ recurrent events ↑ bleeding ↔ mortality

  22. Amadeus Trial 4576 patients • Non-valvular atrial fibrillation • Idraparinux 2.5 mg SC qweek vs VKA • Trial stopped early due to excess clinically relevant bleeding with idraparinux

  23. Idraparinux Biotinylated Idraparinux sodium Idraparinux Biotinylated Avidin Biotin arm with spacer • No pharmacological effect • IV injection • Short half-life (10-16 min)

  24. E Q U I N O X C SSIO EA Phase III Clinical Trials with Idraparinux Biotinylated Idraparinux biotinylated 3 mg weekly vs warfarin in 6-month PE treatment (3200 patients) Idraparinux biotinylated 3 mg weekly vs idraparinux 2.5 mg weekly in 6-month DVT tx (700 patients) BOREALIS-AF Idraparinux biotinylated 3 mg weekly vs warfarin in AF (9600 patients)

  25. Direct Thrombin Inhibitors “-gatran” Direct Thrombin Inhibitors XII Intrinsic Extrinsic XI TF IX VII VIII X V II Fibrinogen Fibrin Clot

  26. COMPANY NEWS; F.D.A. PANEL VOTES AGAINST BACKING DRUG BY ASTRAZENECA COMPANY NEWS; F.D.A. REJECTS ASTRAZENECA'S ANTI-CLOTTING DRUG Published: September 11, 2004 Published: October 9, 2004 AstraZeneca failed to win backing from a federal government panel for its Exanta blood thinner, a possible first alternative to the drug Coumadin in more than 50 years. AstraZeneca said yesterday that federal regulators did not approve its anti-clotting drug, Exanta.

  27. No dietary/food interactions Brand name Rendix™ or Pradaxa®, Boehringer-Ingelheim Approved in Europe March 2008; plans are to obtain U.S. FDA approval by 2010 Oral capsule Rapid onset of action Half-life 12-17 hours Renal elimination No routine monitoring required P-gp substrate—use with caution when administered concomitantly with P-gp inhibitors Dabigatran

  28. Dabigatran Dabigatran in TKR:RE-MODEL (Phase II) % Total VTE & Death % Adverse Events n=1541 patients treated 6-10 days, followed for 3 months post-surgery Dabigatran

  29. Dabigatran Dabigatran Dabigatran in THR:RE-NOVATE (Phase II) % Total VTE & Mortality % Adverse Events n=2651 patients treated 28-35 days, followed for 3 months post-surgery Eriksson BI et al. Lancet 2007;370:949-56.

  30. Dabigatran: RE-VOLUTION Trial Program (Phase III)

  31. Summary Time to Market for New Anti-Thrombotic Agents Apixaban Dabigatran Otomaxiban Idraparinuxbiotinylated Rivaroxaban 2010 2011 2012 2013

  32. Adapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:380-386.

  33. Potential Limitations of New Anticoagulants • Antidotes • None of the newer agents has a specific antidote • Monitoring • Adverse Drug Events • Compliance • Cost • Clinical Trials vs. Actual Clinical Practice • Patient populations not even studied (i.e. Cancer)

  34. Conclusion • Several oral and parenteral Anti Xa and Anti IIa drugs are under development at this time • Rivaroxaban and Dabigatran are approved in the European Union and Canada for the prophylaxis of DVT and awaiting FDA review/approval • Safety issues are of prime importance in the development of these drugs and will be strongly scrutinized upon review

  35. What about RE-LY? Dabigatran versus Warfarin in Patients with Atrial Fibrillation • Non-inferiority trial • Over 18,000 patients • Followup = 2 years Dabigatran 110 mg and 150mg vs. Adjusted dose warfarin

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