1. The New Oral Anticoagulants: Handle with Care Philip C. Comp, M.D., Ph.D. October 18, 2013

2. Speaker for dabigatran (Pradaxa®) and rivaroxaban (Xarelto®)

3. Anticoagulant Quiz Which commonly used anticoagulant does not require laboratory monitoring? Which anticoagulant has no antidote? The dose of which anticoagulant depends on renal function? ( Enoxaparin, Lovenox® )

4. Edoxaban

5. The New Oral Anticoagulants Dabigatran (Pradaxa®) Inhibits thrombin Twice a day Atrial fibrillation Apixaban (Eliquis®) Inhibits factor Xa Twice a day Atrial fibrillation Rivaroxaban (Xarelto®) Inhibits factor Xa Once a day Atrial fibrillation; DVT/PE treatment; Reduction in risk of DVT/PE (after 6 mn Tx); Hip/Knee prophylaxis;

6. Canine Model of Blood Coagulation Factor IX Factor X PROTHROMBIN

7. Canine Model of Blood Coagulation Effect of Warfarin Factor IXa Factor Xa THROMBIN

8. Canine Model of Blood Coagulation Oral Anti-Xa Factor IXa Factor Xa THROMBIN

9. Canine Model of Blood Coagulation Oral Anti-thrombin Factor IXa Factor Xa THROMBIN rivaroxaban apixaban

10. There is no free lunch The effectiveness of an anticoagulant must be weighed against the risk of bleeding Bleeding Thrombosis

11. Apixaban, Dabigatran and Rivaroxaban Oral Short half-lives Renal clearance No INRs No food interactions Few drug interactions

12. Prevention of Stroke-Apixaban Granger et al. NEJM 3654: 981-92, 2011Number needed to treat/1.8 years: 167

13. Atrial Fibrillation- Dabigatran Connolly et al. NEJM 361, 2009 35% RRR ! Number needed to treat/ 2 years: 88

14. Atrial Fibrillation- Rivaroxaban C Patel et al. NEJM 365: 883-91, 2011 Number needed to treat/1.6 years: 135

15. Atrial Fibrillation- Dabigatran Modified from Connolly et al. NEJM 361, 2009 STROKE No Treatment Warfarin Dabigatran Number needed to treat NT 88 v. warfarin No Treatment CHADS 2 Scores 0-1 33% 2 35% 3-6 33% ESTIMATE 5% risk/year In a non-treated group

16. Percentage of AF patients with stroke per year No treatment 5.0% Warfarin 1.6% Dabigatran 1.0% ~ Modified from Connolly et al. NEJM 361, 2009 3.4% 0.6% 68% of strokes gone; 32 occur 80% of strokes gone; 20 occur 100 strokes occur

17. STROKE = Ischemic Stroke and Hemorrhagic Stroke* * Subdural hematomas, epidural hematomas, subarachnoid hematomas and intracerebral hemorrhage

18. Stroke rates (percent/year) All Stroke Hemorrhagic Stroke Time INR in 2-3 range Dabigatran/ Warfarin 1.44/1.570.10/0.3864 Rivaroxaban/ Warfarin (as treated) 2.61/3.120.5/0.755 Apixaban/ Warfarin 1.19/1.510.24/0.4762

19. Bleeding and death rates (percent/year) Major Bleeding Death Dabigatran/ Warfarin 3.11/3.363.64 /4.13 Rivaroxaban/ Warfarin (as treated) 3.60/3.401.90/2.20 Apixaban/ Warfarin 2.13/3.093.52/3.94

20. Bleeding Event Rate (%/year) IntracranialGastrointestinal Apixaban 0.330.76 Warfarin 0.800.86 Dabigatran 0.301.51 Warfarin 0.741.02 Rivaroxaban 0.773.15 Warfarin 1.182.16 N Engl J Med 2011;365:981-92 N Engl J Med 2009;361:1139-51. N Engl J Med 2011;365:883-91.

21. NNT with dabigatran for 1 year to prevent one adverse event compared to warfarin NNT Stroke or systemic embolus 172 Intracranial bleeding227 Major bleeding154 Life-threatening bleeding 286 Nature Reviews Cardiology 7, 10-11 (January 2010)

22. Can atrial fibrillation studies be directly compared? Mean Age and CHADS 2 Score Apixaban 70y 2.1 ± 1.1 Rivaroxaban 73y 3.5 ± 0.94 Dabigatran 72y 2.1 ± 1.1 Direct comparison of strokes and bleeding between studies is difficult. CHF 1 Hypertension 1 Age > 75 1 Diabetes 1 Prior stroke 2

23. New oral agents in atrial fibrillation Apixaban superior to warfarin Rivaroxaban not inferior to warfarin Dabigatran superior to warfarin Davis, N Engl J Med 2012;366:1914-22.

24. No food interactions Compare to WARFARIN AND FOOD

25. Dietitians

26. CHLOROPHOBIA (fear of the color green)

27. Green Tea

28. 333 liters of green tea contain 1 mg vitamin K

29. Iceberg Lettuce

30. How do you test a new anticoagulant? Hip or knee joint replacement → Venogram Deep vein thrombosis → Prevent recurrence Atrial fibrillation → Prevent stroke $ $ $$$$$$$$

31. New anticoagulants have short half- lives (9-17 hours)

32. Forgetfulness 30% Other priorities 16% Decision to omit doses 11% Lack of information 9% Osterberg l et al. NEJM 353: 487-97 2005

33. 1,800,000 patients prescribed a statin: Patients filled prescriptions for a mean of 11.4 medications/3 month 10% of patients filled prescriptions for 23 or more medications. 10% had prescriptions written by 4 or more prescribers. Choudhry NK The Implications of Therapeutic Complexity on Adherence to Cardiovascular Medications. Archives of Internal Medicine 171:814-822, 2011

34. Retrospective Study of Medication Prescription in Oklahoma City, n=3 64 year old man: 14 medications daily; 31 pills 61 year old woman: 15 medications; 39 pills 90 year old man: 15 medications; 27 pills

35. Drugs don’t work in patients who don’t take them C. Everett Koop, M.D. 1916-2013

36. Typical Clinical Trial Patient

37. Who is the ideal patient? Does not like INRs Reliable Well insured

38. Who will have a bleed? Frail (<60 kg) Reduced creatinine clearance Over 80 years of age Harper. Bleeding Risk with Dabigatran in the Frail Elderly N Engl J Med 2012; 366:864-866

39. Proper prescriber behavior At each visit – Are your taking drug X? At every visit – Why are you taking drug X? At each visit – Are you taking X every day?

40. KIDNEY FUNCTION IS IMPORTANT! CHECK THE CREATININE CLEARANCE

41. What is the effect of no more INRs? No more anticoagulation clinics and fewer office visits. Will that reduce compliance? BOUNCING BEN in a BAD candidate! INR

42. Who to switch from warfarin Not a cure for the bouncing INR Stroke risk: Least benefit to well controlled warfarin patients Fewer potential drug interactions in polypharmacy patients?

43. Warfarin > new anticoagulant Patients angst: Miss INRs Miss food restrictions

44. If bleeding occurs Little data available a. Factor VIIa b. Factor VIII Inhibitor Bypassing Activity (FEIBA) c. Hydration Fresh frozen plasma and Vitamin K are not the way to go!

45. Everyone is developing an antidote Oral anticoagulant inhibits factor Xa Xa Inhibitor

46. Everyone is developing an antidote A recombinant antidote (DU-176b) Xa

47. Surgery while on medication Dabigatran (100% renal) Rivaroxaban (65% renal clearance) Apixaban (25% renal clearance) When to stop the medication preoperatively depends on the medication and renal function. Look it up!

48. What is the cost per day* Dabigatran = $9.50 Rivaroxaban= $9.46 Apixaban = $9.40 *Sam's Club, Northwest Highway, OKC 10/10/13

49. Advising patients Explain they are taking lots of medications – stroke preventers critical Avoid friendly little black dogs and get someone else to clean the gutters!

51. Summary of New Anticoagulants Marginally better than warfarin for atrial fibrillation No food interactions; few drug interactions No need for INRs Short-half life – take regularly Check creatinine clearance yearly