1. Warfarin, Your Days are Numbered!
Linda R. Kelly PharmD PhC CACP
Pharmacy Anticoagulation Specialist
Presbyterian Healthcare System

2. Objectives Identify and classify the available oral anticoagulants
Evaluate patient characteristics that would suggest using one product over another
Design a plan for switching from one oral anticoagulant to another
Manage oral anticoagulants in the peri- procedural period

3. Terminology VKA-Vitamin K Antagonist (warfarin)
DOAC-Direct Oral Anticoagulant
TSOAC-Target Specific Oral Anticoagulant
NOAC-Novel (or New or Non-vitamin K) Oral Anticoagulant

4. Resources

5. Available Direct Acting Oral Anticoagulants (DOACs)
Dabigatran
Rivaroxaban
Apixaban
Edoxaban

6. DOAC Mechanism of Action
Inhibits Factor Xa
Rivaroxaban
Apixaban
Edoxaban
Direct Thrombin Inhibitor
Dabigatran

7. DOAC Indications and Dosing
Focus on Venous Thromboembolism and Non-valvular Atrial Fibrillation

8. Meet Marge
Marge is a 72 year old female with non-valvular atrial fibrillation (NVAF). She has been taking warfarin for stroke prevention. Her history also includes hypertension. What is her CHA2DS2- VASc score?

9. CHA2DS2-VASc Score

10. Marge
Marge comes to see you about starting a new product, bringing you a souvenir from her latest excursion.
What factors should be considered when planning to start or switch a patient to a DOAC?

12. DOAC Indications and Dosing
Rivaroxaban
Apixaban
20 mg once daily with evening meal
5mg twice daily
NVAF
Rivaroxaban
Apixaban
15 mg twice daily x 21 days
10 mg twice daily x 7 days
20 mg once daily with evening meal
5 mg twice daily
DVT PE

13. DOAC Indications and Dosing
Dabigatran
Edoxaban
150 mg twice daily
60 mg daily
NVAF
Dabigatran
Edoxaban
LMWH lead in x 5-10 days
150 mg twice daily
60 mg daily
DVT PE

14. 2.5 mg Apixaban twice daily**
DOAC Renal Dosing
Rivaroxaban
NVAF
CrCl mL/min
15 mg once daily
CrCl < 15 mL/min
Use warfarin
DVT/PE
CrCl < 30 mL/min
2.5 mg Apixaban twice daily**
NVAF
Must meet 2 of the following
Age 80 years or older
Actual body weight 60 kg or less
Serum Creatinine 1.5 mg/dL or greater
**No dose reduction in DVT/PE patients. However, patients with SCr > 2.5 or CrCl < 25 mL/min not studied

15. DOAC Renal Dosing Dabigatran NVAF CrCl 15-30 mL/min 75mg bid
Use warfarin
DVT/PE
CrCl < 30 mL/min
Edoxaban
NVAF
CrCl >95 mL/min
DO NOT USE
CrCl mL/min
30mg daily
CrCl < 15mL/min
Use warfarin
DVT/PE

16. Use with caution- limited clinical experience
DOAC Hepatic Dosing
Child- Pugh Class
Rivaroxaban
Apixaban A
No Adjustment B
Use warfarin
Use with caution- limited clinical experience C
Child- Pugh Score calculator can be found at PresNet Anticoagulation Oral Anticoagulants Rivaroxaban (Xarelto) Child-Pugh Classification Score

17. DOAC Hepatic Dosing Child- Pugh Class Dabigatran Edoxaban A
No Adjustment B
Use Warfarin C
Use warfarin
Child- Pugh Score calculator can be found at PresNet Anticoagulation Oral Anticoagulants Rivaroxaban (Xarelto) Child-Pugh Classification Score

18. Drug Interactions Dabigatran: Rivaroxaban: Apixaban: Edoxaban
Substrate for p-glycoprotein
Rivaroxaban:
51% CYP 3A4 metabolism
Apixaban:
25% CYP 3A4 metabolism
Edoxaban
Minimal CYP 3A4 metabolism

19. Drug Interactions Common Interacting Classes
Anticonvulsants including barbiturates
Antiretrovirals
Antifungals
Antiplatelet drugs and NSAIDS
Your favorite drug interaction program is your best friend

20. Oral Anticoagulant Product Selection
Focus on Venous Thromboembolism and Non-valvular Atrial Fibrillation

21. Is a DOAC a Good Choice For Marge?
What should we consider before prescribing a DOAC?

22. DOAC Selection DVT of leg or PE with active cancer Pregnant
DVT of leg or PE without active cancer

23. Anticoagulant Selection
Valvular atrial fibrillation
Valve replacement
Myocardial infarction requiring dual antiplatelet therapy
Breast feeding

24. Anticoagulant Selection
Valvular atrial fibrillation
Valve replacement
Myocardial infarction requiring dual antiplatelet therapy
Pregnant or breast feeding
Will the patient have trouble paying for a DOAC?
Yes No
Non-valvular atrial fibrillation
Secondary VTE prevention
VTE prophylaxis following knee/hip replacement surgery
Does patient have
CrCl < 30, mechanical heart valve, moderate to severe hepatic impairment (Child-Pugh B or C), significant drug-drug interactions6?
Yes No

25. Anticoagulant Selection
Does patient have
CrCl < 30, mechanical heart valve, moderate to severe hepatic impairment (Child-Pugh B or C), significant drug-drug interactions6?
Patient/ Family Preference No
Yes
Patient Characteristics Favoring DOAC
Highly like to be adherent with DOAC therapy and follow up plan
Reliable to notify health care provider about changes to health and pertinent medical issues
Confirmed ability to obtain DOAC on a longitudinal basis from a financial, insurance coverage and retail availability standpoint
Unstable diet or malnutrition
Frequent illness or health status changes
Frequent medicine changes or need for medications that interact with warfarin but not with DOAC
Frequent medical procedures with bleeding risk

26. Anticoagulant Selection
Patient/ Family Preference
Drug 1
Older, more established
Strong interaction with diet and other medications
Reversible and easily monitored
Frequent monitoring and dose changes often required
Bridging may be required around procedures
Higher risk of intracranial hemorrhage
Drug 2
Newer, less familiar
No diet interaction and fewer interactions with other medications
Cannot easily monitor level of anticoagulation and reversal agent may not be readily available
Frequent monitoring and dose changes not required
Bridging NOT required around procedures
Lower risk of intracranial hemorrhage

27. Drug affordability Warfarin $
Rivaroxaban, Apixaban, Dabigatran, Edoxaban $$$$
Commercial plans (not Medicare/ Medicaid)
Patient copay
Medicare
Consider coverage gap
TrOOP vs. Drug spend
Use sample card and/or coupon Sample clinic Patient pay

28. Drug affordability- Medicare
Medicare coverage gap or “Donut Hole”
Must pay deductible (PHS plan deductible= $0)
Copay ~$45 per month
Gap starts at $3700 total cost or “drug spend”
This is copay + balance insurance pays
In 2017, when in the gap patient pays ~51% cost for generic, ~40% for brand.
Out of gap at $4,950 paid in out of pocket expenses
True out of pocket cost= “TrOOP”
Cost the patient sees, copay, coinsurance, spending during the coverage gap

29. Drug Affordability- Medicare
Example- Rivaroxaban alone
Rivaroxaban total cost= $431.4
Rivaroxaban copay = $45
Will meet gap in 8.6 months ($3700)
After gap, drugs cost = $ per month
TrOOP ($4950 to get out of gap)
$360 (on copays) before gap with no deductible
$ (4 months in gap)
Drug spend for catastrophic = $4950
After gap $21.57 (5%) (if patient is on other medications)

30. Drug Affordability- Medicare
Example – Warfarin alone
Warfarin total cost $6 (5 mg per day x 30 days. )
Warfarin copay= $4
Will not meet gap with warfarin
In the gap, warfarin cost approx $3
After gap will pay $1.60 per month

31. Patient Assistance Utilize patient savings cards Sample Cards
1st month free! Regardless of insurance plan.
Copy Card
$0 copay for commercial insurance
Samples may be available

32. Patient selections takeaway
LMWH preferred in patients with active cancer
DOAC preferred in patients with DVT/ PE
NVAF European and Canadian guidelines recommend DOAC over warfarin, AHA/ACC/HRS guidelines do not recommend one over the other
Must consider patient co-morbidities and ability to afford therapy

33. Is a DOAC a Good Choice For Marge?

34. Questions?

35. Oral Anticoagulant Switching

36. Enoxaparin TO/FROM DOAC
Stop old medication and start new medication when the next dose is due
Abo-Salem J Thromb Thrombolysis (2014)

37. DOAC TO DOAC Stop DOAC 1 and start DOAC 2 when the next dose is due
Abo-Salem J Thromb Thrombolysis (2014)

38. DOAC to Warfarin/Warfarin to DOAC
Abo-Salem J Thromb Thrombolysis (2014)

39. Warfarin to DOAC Discontinue warfarin
Begin rivaroxaban when INR below 3.0
Begin dabigatran or apixaban when INR below 2.0

40. DOAC to warfarin Need overlap therapy until INR equal or above 2.0
May interfere with INR reading
Must use DOAC trough for INR draw
Make clear to the patient that they MUST go in for an INR draw right before next DOAC dose is due. OR
LMWH
Transition like normal LMWH bridge per PMG policy.
Start LMWH when next DOAC dose due.

41. Anticoagulant Transitions
Warfarin to DOAC, DOAC to Warfarin
** INR < 3.0 for Rivaroxaban

42. How Does Marge Switch from Warfarin to Rivaroxaban?

43. Peri-Procedural Anticoagulation

44. Peri-procedural bridging
Avoid overlapping LMWH and DOACS
Can the procedure be delayed until patient is not on anticoagulation therapy?
Is the bleeding risk of procedure high enough to warrant DOAC interruption?
Consult bleed risk tables.
Can we delay procedure to increase time for elimination?
DOAC elimination based on renal function.
Resume DOAC after hemostasis is achieved
Low bleed risk: 24 hours
High bleed risk: hours.

45. MAPPP Online and App

46. Bleeding Risk

47. Peri-Operative Management
Drug
Renal Function
Low Bleeding Risk Surgery
High Bleeding Risk Surgery
Resumption of Therapy
Low Bleeding Risk
High Bleeding Risk
Rivaroxaban
T ½ = 8-9 hrs
CrCl >50 mL/min
Last dose: 2 days before procedure
*Skip 2 doses
Last dose: 3 days before procedure
*Skip 3 doses
Resume on day after procedure
(24 h postop)
Resume 2-3 days after procedure
(48-72 h postop)
T ½ = 9 hrs
CrCl mL/min
T ½ = 9-10 hrs
CrCl mL/min
Last dose: 4 days before procedure
*Skip 4 doses

48. Peri-Operative Management
Drug
Renal Function
Low Bleeding Risk Surgery
High Bleeding Risk Surgery
Resumption of Therapy
Low Bleeding Risk
High Bleeding Risk
Apixaban
T ½ = 7-8 hrs
CrCl >50 mL/min
Last dose: 2 days before procedure
*Skip 4 doses
Last dose: 3 days before procedure
*Skip 6 doses
Resume on day after procedure
(24h postop)
Resume 2-3 days after procedure
(48–72h postop)
T ½ = hrs
CrCl mL/min
Last dose: 4 days before procedure
*Skip 8 doses

49. Peri-Operative Management
Drug
Renal Function
Low Bleeding Risk Surgery
High Bleeding Risk Surgery
Resumption of Therapy
Low Bleeding Risk
High Bleeding Risk
Dabigatran
T ½ = hrs
CrCl >50 mL/min
Last dose: 2 days before procedure
*Skip 4 doses
Last dose: 3 days before procedure
*Skip 6 doses
Resume on day after procedure
(24h postop)
Resume 2-3 days after procedure
(48-72h postop)
T ½ = hrs
CrCl mL/min
Last dose: 4–5 days before procedure
*Skip 8-10 doses

50. Peri-Operative Management
Drug
Renal Function
Low Bleeding Risk Surgery
High Bleeding Risk Surgery
Resumption of Therapy
Low Bleeding Risk
High Bleeding Risk
Edoxaban
T ½ = 6-11 hrs
CrCl >50 mL/min
Last dose: 2 days before procedure
*Skip 2 doses
Last dose: 3 days before procedure
*Skip 3 doses
Resume on day after procedure
(24h postop)
Resume 2-3 days after procedure
(48-72h postop)

51. DOAC temporary interruption
Allow for 95% drug elimination prior to procedure (~5 drug half lives)
Resume DOAC hours post procedure based on bleeding risk

52. Case Study: MR. JF
Creatinine Clearance is about 60ml/min

53. Case Study: Mr. JF

54. Bleeding Risk

55. Peri-Operative Management
Drug
Renal Function
Low Bleeding Risk Surgery
High Bleeding Risk Surgery
Resumption of Therapy
Low Bleeding Risk
High Bleeding Risk
Dabigatran
T ½ = hrs
CrCl >50 mL/min
Last dose: 2 days before procedure
*Skip 4 doses
Last dose: 3 days before procedure
*Skip 6 doses
Resume on day after procedure
(24h postop)
Resume 2-3 days after procedure
(48-72h postop)
T ½ = hrs
CrCl mL/min
Last dose: 4–5 days before procedure
*Skip 8-10 doses

56. Overview DOACS used for DVT/PE and NVAF
Double check dosing for drug/ indication
DOACS may not be the best option for everyone
Consider your patient and their preferences
DOACS come with added cost, but help is available
We can transition between drug classes with monitoring
DOAC temporary interruption AKA “peri-procedural bridging” is possible.
Be aware of procedure bleeding risk and patient risk factors.
Do not overlap LMWH with DOACS

57. Questions?

58. References www.xarelto.com
Antithrombotic Therapy For Vte Disease: Chest Guideline And Expert Panel ReportKearon C, Akl EA, Ornelas J, et al.Chest. 2016;149(2): doi: /j.chest
Abo-salem E, Becker R. Transitioning to and from the novel oral anticoagulants: a management strategy for clinicians. J Thromb Thrombolysis. 2014;37(3):
Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med ;375(12):
Burnett AE, Mahan CE, Vazquez SR, Oertel LB, Garcia DA, Ansell J. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41(1):
Rechenmacher SJ, Fang JC. Bridging Anticoagulation: Primum Non Nocere. J Am Coll Cardiol. 2015;66(12):
Management of Anticoagulation in the Peri-Procedural Period
Thrombosis Canada. New/ Novel oral anticoagulants (NOACS): Peri-Operative Management