The New Oral Anticoagulants: When and When Not to Use Them Philip C. Comp, M.D., Ph.D. Professor of Medicine, University of Oklahoma Health Sciences

Transcription

1 The New Oral Anticoagulants: When and When Not to Use Them Philip C. Comp, M.D., Ph.D. Professor of Medicine, University of Oklahoma Health Sciences Center September 25, 2015

2 Question: With which of the new anticoagulants are you most familiar? 1. Rivaroxaban (Xarelto ) 2. Dabigatran (Pradaxa ) 3. Apixaban (Eliquis ) 4. Edoxaban (Savaysa ) 5. None of the above

3 Answer Rivaroxaban (Xarelto ) Just because

4 Question: Which commonly used anticoagulant does not require laboratory monitoring, has no antidote and the dose is influenced by renal function? 1.Warfarin (Coumadin ) 2.Aspirin 3.Enoxaparin (Lovenox )

5 Answer Enoxaparin (Lovenox )

6 Edoxaban

7 Question The blood clotting system is 1. Totally confusing 2. Hard to memorize 3. Is make up of individual enzymes.

8 Answer The clotting cascade make up of individual enzymes

9 Oral Xa and oral thrombin inhibitors Dabigatran EDOXABAN Rivaroxaban Apixaban

10 Question In what country does this race take place? 1. France 2. Canada 3. Italy 4. United States (New York)

11 Answer

12 Dabigatran (Pradaxa ) Apixaban (Eliquis ) Rivaroxaban (Xerelto ) Atrial Fibrillation Deep Vein Thrombosis/ Prevention of recurrence + +/+ (after initial enoxaparin) Hip/knee Postop Prophylaxis + +/ /+ + Edoxaban (Savaysa ) + (if CrCl <95 ml/min) + (after initial enoxaparin)

13 Question How many new oral anticoagulants are now on the market? 1. None 2. Four 3. There will soon be a bunch

14 Answer Four But a bunch more will soon arrive

15 Canine Model of Blood Coagulation CLOT Factor IX Factor X PROTHROMBIN

16 Canine Model of Blood Coagulation Effect of Warfarin Factor IXa Factor Xa THROMBIN

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

18 Canine Model of Blood Coagulation Oral Anti-thrombin Factor IXa Factor Xa THROMBIN rivaroxaban apixaban edoxaban dabigatran

19 Question Which dog looked the meanest? 1. Factor IX 2. Factor X 3. Thrombin

20 Answer? Factor X Typical Vitamin K-dependent clotting factor like protein C and prothrombin

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

22 The new anticoagulants: Oral Short half-lives Renal clearance No INRs No food interactions Few drug interactions

23 What should you not worry about concerning the new oral anticoagulants? 1. The risk of falls 2. Creatinine clearance 3. Patient compliance 4. The color of the pill

24 Answer The color of the pill Except

25 The major use: Prevention of Stroke Number needed to treat/1.8 years: 167 Granger et al. NEJM 3654: , 2011

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

27 STROKE Atrial Fibrillation- Dabigatran CHADS 2 Scores % 2 35% % ESTIMATE 5% risk/year In a non-treated group Warfarin Dabigatran Number needed to treat NT 88 v. warfarin Modified from Connolly et al. NEJM 361, 2009

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

29 Dabigatran reduced the risk of stroke in atrial fibrillation times better than warfarin 2. Less than warfarin 3. About the same as warfarin in many patients

30 Answer About the same in many patients But if patient is doing well on warfarin, little reason to switch

31 I M P O R T A N T D E F I N I T I O N STROKE = Ischemic Stroke and Hemorrhagic Stroke* *Subdural hematomas, epidural hematomas, subarachnoid hematomas and intracerebral hemorrhage Less hemorrhage than with warfarin.

32 Stroke rates (percent/year) Dabigatran/ Warfarin All Stroke Hemorrhagic Stroke 1.44/ / Time INR in 2-3 range Rivaroxaban/ Warfarin (as treated) Apixaban/ Warfarin 2.61/ / / /

33 Bleeding and death rates Dabigatran/ Warfarin (percent/year) Major Bleeding Death 3.11/ /4.13 Rivaroxaban/ Warfarin 3.60/ /2.20 Apixaban/ Warfarin 2.13/ /3.94

34 Bleeding Event Rate (%/year) Intracranial Gastrointestinal Apixaban Warfarin Dabigatran Warfarin Rivaroxaban Warfarin N Engl J Med 2011;365: N Engl J Med 2009;361: N Engl J Med 2011;365:

35 Comparing fibrillation studies Mean Age and CHADS 2 Score Apixaban 70y 2.1 ± 1.1 Rivaroxaban 73y 3.5 ± 0.94 Dabigatran 72y 2.1 ± 1.1 Edoxaban 72y 2.8 ± 1.0 Hypertension 1 CHF 1 Age > 75 1 Diabetes 1 Prior stroke 2 Direct comparison of strokes and bleeding between studies is difficult.

36 Atrial fibrillation patients are 1. Are at risk of falls 2. Are on multiple medications 3. Are often older than me 4. All of the above

37 Answer All of the above Are at risk of falls poor eyes, out of shape, CHF, etc. Are on multiple medications - yep Are often older than me 72+

38 No food interactions Compare to WARFARIN AND FOOD

39 Dietitians and warfarin

40 What is in the bag? 1.Marijuana 2.Tea 3.Powered Camellia sinensis 4.Who knows

41 Answer Tea But Camellia sinensis is also correct

42 An old story Warfarin and CHLOROPHOBIA

43 Fear of the color green

44 Green Tea

45 Green Tea 333 liters of green tea contain 1 mg vitamin K

46 Iceberg Lettuce

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

48 Forgetfulness 30% Other priorities 16% Decision to omit doses 11% Lack of information 9% Osterberg l et al. NEJM 353:

49 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: , 2011

50 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

51 Who said this? Drugs don t work in patients who don t take them 1. Dr. Mehmet Oz 2. Dr. J. Everett Koop 3. Dr. Marcus Welby

52 Answer Dr. J. Everett Koop

53 Typical Clinical Trial Patient

54 Who is the ideal patient? 1. Does not like INRs 2. Reliable 3. Well insured or not well insured 4. All of the above

55 Answer All of the above: 1. Does not like INRs 2. Reliable 3. Well insured or not well insured

56 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:

57 Question What should you ask your patients at each visit? 1. Are your taking drug X? 2. Why are you taking drug X? 3. Are you taking X every day? 4. Have you fallen since I saw you last? 5. All of the above

58 Answer All of the above Are your taking drug X? TO PREVENT STOKE, DVT,PULMONARY EMBOLISM, DYING Why are you taking drug X? (Unless you tell me I won t know) Are you taking X every day? Because it does not stick around Have you fallen the forgotten question

59 KIDNEY FUNCTION IS IMPORTANT! CHECK THE CREATININE CLEARANCE

60 INR 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! Aug 2-Sep 2-Oct 2-Nov

61 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?

62 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!

63 Everyone wants an antidote New oral anticoagulants inhibits factor Xa Inhibitor Xa

64 Everyone is developing an antidote A recombinant antidote (Andexanet ) Xa Gold AM, et al. J Am Coll Cardiol. Abstract, 2015

65 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.

66 Question What do I do before my patient goes to surgery? 1. Call Comp 2. Look it up 3. Ask the drug rep 4. Ask my physician

67 Answer Look it up! Call Comp I will just look it up Ask the drug rep he or she will look it up Ask my physician he or she better look it up

68 What is the cost per day* Dabigatran = $11.03 Rivaroxaban= $11.00 Apixaban = $11.03 Edoxaban = $9.75 *Sam's Club, OKC 8/26/2015

69 Question What is the most dangerous thing in many households?

70 Answer The wall socket, because

71

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

73 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 Get familiar with one drug.