The New Oral Anticoagulants: Rivaroxaban, Dabigatran and Apixaban

1. The New Oral Anticoagulants: Rivaroxaban, Dabigatranand Apixaban Michael J. Cox, MD, FCCM Associate Program Director Critical Care Medicine Training Program Saint Louis University School of Medicine Mercy Hospital St. Louis Medical Director Physician Assistant Program Doisy College of Health Sciences Saint Louis University Health Sciences Center

2. Objectives • Briefly review the coagulation cascade • Discuss limitations of the traditional anticoagulants • Review the new anticoagulants, including medications currently available and those in late trial development • Discuss the advantages as well as limitations of the new anticoagulants • Outline the management of bleeding caused by the new medications

3. The Coagulation Cascade “Tissue Factor Pathway” “Contact Activation Pathway” “Common Pathway” Stein, PD. Pulmonary Embolism, 2nd ed. 2007

4. The “Perfect” Anticoagulant • excellent efficacy • minimal risk of bleeding • half-life sufficient to allow once daily dosing but not too excessive if bleeding develops • reversibility possible should bleeding occur • no monitoring required but available for special situations (obesity and low weight, renal or • hepatic dysfunction) • one dose for all patients • no dependence on renal or hepatic clearance • oral or subcutaneous route available for self-administration to allow home use • no or minimal risk of thrombocytopenia • no or minimal interaction with other drugs or food • reasonable cost with adequate insurance coverage

5. Anticoagulants “Old” • Warfarin • Heparin • LMWH “New” • Fondaparinux • Idraparinux • Rivaroxaban • Apixaban • Desirudin • Bivalirudin • Argatroban • Dabigatran Factor Xa inhibitors Factor IIa inhibitors Circulation, 2011; 123:1436-1450.

6. Indirect Factor Xa Inhibitors Stein, PD. Pulmonary Embolism, 2nd ed. 2007

7. Indirect Factor Xa Inhibitors (cont.) • synthetic pentasaccharides that reversibly bind to AT and inhibit Factor Xa • both have long half-lives allowing less frequent dosing • no monitoring is required • do not react with platelets thus eliminating risk of HIT • clearance is through kidneys and accumulation has been seen in pts < 50 kg • Fondaparinux is approved for VTE prophylaxis following abdominal and orthopedic surgery and VTE treatment • Idraparinux has a longer half-life and has not received FDA approval Fondaparinux Idraparinux

8. Fondaparinux – VTE Prophylaxis P < 0.05

9. Fondaparinux – VTE Treatment

10. Idraparinux – VTE Treatment

11. Direct Factor Xa Inhibitors Apixaban Edoxaban ddnnn Rivaroxaban Stein, PD. Pulmonary Embolism, 2nd ed. 2007

12. Direct Factor Xa Inhibitors (cont.) • do not require AT to inhibit Factor Xa • no effect on platelets • no monitoring required • Rivaroxaban is well absorbed orally, 80% bioavailability, 5-9 hr half-life which permits once-daily dosing and potent inhibitor of CYP3A4 and P-glycoprotein • Apixaban is also well absorbed orally, >50% bioavailability, 9-14 hr half-life, is dosed twice daily and potent inhibitor of CYP3A4 and P-glycoprotein Rivaroxaban Apixaban

13. Rivaroxaban – VTE Prophylaxis Direct Thrombin (IIa) Inhibitors (cont.) Am J Health-Syst Pharm. 2008; 65:1520-9.

14. Direct Thrombin (IIa) Inhibitors (cont.) Rivaroxaban – VTE Treatment

15. Direct Thrombin (IIa) Inhibitors (cont.) Rivaroxaban – Atrial Fibrillation

16. Apixaban – VTE Prophylaxis Direct Thrombin (IIa) Inhibitors (cont.)

17. Direct Thrombin (IIa) Inhibitors (cont.) Apixaban – VTE Treatment

18. Direct Thrombin (IIa) Inhibitors (cont.) Apixaban – Atrial Fibrillation

19. Direct Thrombin (IIa) Inhibitors Desirudin Lepirudin - IV/SQ - PO Dabigatran Stein, PD. Pulmonary Embolism, 2nd ed. 2007

20. Direct Thrombin (IIa) Inhibitors (cont.) Direct Thrombin (IIa) Inhibitors (cont.) • binds directly to thrombin (Factor IIa) which inactivates it • binds fluid phase and bound thrombin (unlike UFH) which results in less thrombus growth • do not interact with platelets or plasma proteins • Hirudin (medicinal leeches) irreversibly binds thrombin and has no antidote if bleeding develops. Not commercially available • Lepirudin (recombinant hirudin) is indicated for anticoagulation in HIT, monitored with aPTT and renally excreted • Desirudin (another recombinant hirudin)has been shown to be superior to UFH and LMWH in VTE prevention after orthopedic surgery with a similar safety profile, is monitored with aPTT and is renally excreted

21. Direct Thrombin (IIa) Inhibitors (cont.) Direct Thrombin (IIa) Inhibitors (cont.) • Bivalirudin (PCI trials) binds thrombin less avidly, has shorter half-life, less renal excretion and thus better safety profile than Lepirudin and Desirudin. Monitored with aPTT or ACT • Argatroban (HIT approval) has similar thrombin binding affinity as Bivalirudin, intermediate half-life, monitored with aPTT or ACT and is metabolized hepatically • Ximelagatran has good oral bioavailability but was removed from the market in 2006 due to liver toxicity • Dabigatran is available orally, requires no monitoring , is renally excreted and is dosed either once or twice daily. It exists as a prodrug which requires an acidic environment for absorption thus potential interaction with PPI’s and similar meds Dabigatran

22. Dabigatran – VTE Prophylaxis Direct Thrombin (IIa) Inhibitors (cont.)

23. Direct Thrombin (IIa) Inhibitors (cont.) Dabigatran – VTE Treatment

24. Dabigatran – Atrial Fibrillation

25. Direct Thrombin (IIa) Inhibitors - Bleeding Circulation, 2011; 123:1436-1450.

26. Crowther, MA et. al. Blood 2008;111:4871-4879

27. Summary WarfarinFondaparinuxRivaroxabanApixabanDabigatran • MOA • Route • FrequencyOnce DailyOnce DailyOnce Daily Twice Daily Once Daily (VTEP) Twice Daily (VTET, AF) • MonitoringINR Anti-Xa Uncertain Uncertain Uncertain • Bridging Required Not Required Not Required Not RequiredNot Required • Renal No Yes Yes No Yes Dosing • Drug Many/Food Few Many Many Acid Suppresion Interactions • Reversal None PCC? None None • Approval II, VII, IX and X inhibitor Indirect Xa Inhibitor Direct Xa Inhibitor Direct Xa Inhibitor Direct IIa Inhibitor Oral and IV Subcut Oral Oral Oral FFP, PCC, Vit K VTEP VTET AF VTEP VTET VTEP AF(CHADS2 = 3.5 ////////////////TTR = 55%) None AF(CHADS2 = 2.1 TTR = 66%) AF(CHADS2 = 2.1 TTR = 64%)