1. Anticoagulant Review Morning Report – April 25, 2018
Sydney N. Kutter, Pharm.D.
PGY1 Pharmacy Practice Resident
Central Texas Veterans Health Care System

2. Rivaroxaban (Xarelto)
Anticoagulants
Warfarin (Coumadin)
Edoxaban (Savaysa)
Dabigatran (Pradaxa)
Rivaroxaban (Xarelto)
Apixaban (Eliquis)

3. Warfarin Review

4. Warfarin - Dosing
Highly individualized – tailored based on bleeding risk, indication, goal range, interactions, etc.
Initiation between mg daily
Lower doses for elderly age, genetic polymorphism, alcohol or tobacco usage, change in diet, interacting medications, sickness, etc.
Adjusted based on INR result

5. Warfarin Initial Dosing – VA PBM Algorithm

6. Warfarin Maintenance Dosing – VA PBM Algorithm

7. Drug Interactions Increase INR Decrease INR Alcohol Drugs
Certain juices
Sickness
Vitamin K
Nutritional shakes
Liver
Green tea

8. Drug/Drug Interactions
Increase INR
Decrease INR
Antibiotics
Amiodarone
Prednisone
Acetaminophen/NSAIDs
Statins
Phenytoin
Omeprazole
Herbals/OTCs
Antibiotics
Carbamazepine
Rifampin
Butalbital

9. Drug/Drug Interactions - Antibiotics
Increase INR
Decrease INR
Metronidazole
Bactrim
Doxycycline
Fluoroquinolones
Macrolides
B-lactams
Cloxacillin
Dicloxacillin
Nafcillin

10. DOAC Review
Direct Oral Anticoagulants

11. DOAC Review Drug VTE Dose AF Dose Notes Apixaban (Eliquis)
Factor Xa Inhibitor
10mg BID x 7 days,
then 5mg BID
5mg BID
Preferred in those with history of GI bleeding
Rivaroxaban (Xarelto)
15mg BID x 21 days,
then 20 mg daily
20mg daily
Take doses > 10mg with meal
Edoxaban (Savaysa)
60mg daily
After 5-10 days of parenteral anticoagulation
Cheapest
Dabigatran (Pradaxa)
Thrombin Inhibitor
150mg BID
Store in original container, discard after 4 months
HOKUSAI-VTE Investigators. N Engl J Med. 2013;369:
ENGAGE AF-TIMI 48 Investigators. N Engl J Med. 2013; 369:
RE-COVER Investigators. N Engl J Med. 2009; 361:
RE-LY Investigators. N Engl J Med. 2009; 361:
AMPLIFY Investigators. N Engl J Med. 2013;369(9):
ARISTOTLE Investigators. N Engl J Med. 2011;365:
EINSTEIN Investigators. N Engl J Med. 2010;363:
ROCKET AF Investigators. N Engl J Med. 2011;365:

12. DOAC Renal Elimination
Apixaban
~27%
Rivaroxaban
~35%
Edoxaban
~50%
Dabigatran
~80%
ESC Scientific Document Group. Europace. 2017;19(11):

13. Edoxaban Contraindicated in patients with AF if CrCl > 95 ml/min

14. Dabigatran Dyspepsia AUC decreases by ~30% in patients taking a PPI
No impact on clinical outcomes?
Compliance issues – must store in original container
Reversal agent

15. Rivaroxaban Take doses > 10 mg with evening meal
Increased absorption

16. Apixaban Recommended in patients at increased risk for bleeding
Prior history of GIB
On DAPT
Age > 75
Clinical judgement

17. DOAC Effect on INR INR not monitored if on DOAC therapy
Can increase INR, though not a safety or efficacy measure

18. General DOAC Considerations - Reversal
Reversal agent
Dabigatran – Idarucizumab (Praxbind)
Rivaroxaban
Apixaban
Edoxaban
Under development
Andexanet alfa – reversal agent for all Factor Xa inhibitors
Ciraparantag – universal antidote
No specific antidote, suggest using
4F-PCC, FFP
Pollack, et al. N Engl J Med. 2015;373(6):
ANNEXA-4 Investigators. N Engl J Med. 2016;375(12):
Ansell, et al. Thromb Haemost. 2017;117(2):

19. General DOAC Considerations - Obesity
Not recommended
The ISTH 2016 guideline suggests avoiding the use of direct oral anticoagulants in patients with a BMI > 40 kg/m2 or weight > 120 kg due to the lack of clinical data in this population.
Subgroup analysis of obese patients from the pivotal phase 3 DOAC trials suggests that DOACs generally appear to be safe and effective; however, data are limited.
Martin, et al. J Thromb Haemost. 2016;14(6):

20. General DOAC Considerations - Obesity
VA PBM recommends that when a DOAC is being considered in such patients:
“A shared decision making approach should be utilized with information provided on the
limited data regarding the efficacy and safety
of these agents in extremes of body weight
and recommendations of some groups
against use in this situation."

21. General DOAC Considerations - Valves
Mechanical valves excluded from all landmark trials
Bioprosthetic valves
Minimally included in apixaban and edoxaban AF trials
ARISTOTLE (apixaban)
N = 82 (1.7%)
ENGAGE-AF (edoxaban)
N = 191 (6.8%)
No significant difference between groups with or without valvular heart disease
ESC Scientific Document Group. Europace. 2017;19(11):

22. General DOAC Considerations - Cancer
Minimally studied in DOACs
Subgroups included in landmark trials
Studied edoxaban in HOKUSAI VTE Cancer trial (2018)
LMWH versus edoxaban (n=1046)
Primary outcome – composite of recurrent VTE or major bleeding 12 months after randomization
Edoxaban
Primary Outcome: 12.8%
VTE: 7.9%
Bleeding: 6.9%
LMWH
Primary Outcome: 13.5%
VTE: 11.3%
Bleeding: 4%
HOKUSAI VTE Cancer Investigators. N Engl J Med. 2018;378(7):

23. RE-VERSE AD Study
IDARUCIZUMAB (PRAXBIND)

24. RE-VERSE AD Multicenter, prospective, observational trial
Sponsored by the Boehringer Ingelheim
Objective
Examine the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects of dabigatran
Idarucizumab is a monoclonal antibody fragment that binds dabigatran with an affinity that is 350 times as high as that observed with thrombin
Pollack, et al. N Engl J Med. 2015;373(6):

25. RE-VERSE AD Group B Group A N = 39 N = 51
Uncontrollable or life-threatening bleeding
Group B
N = 39
Surgical or invasive procedure that couldn’t be delayed 8 hours
Pollack, et al. N Engl J Med. 2015;373(6):

26. RE-VERSE AD - Treatment
5 grams of idarucizumab
Two 50ml boluses (each containing 2.5 grams)
No more than 15 minutes apart
Could repeat if necessary
Primary outcome
Maximum percentage reversal of dabigatran
Dilute thrombin time or ecarin clotting time
5 grams Calculated to reverse the total body load of dabigatran that was associated with the 99th percentile of the dabigatran levels measured in the RE-LY trial
DTT or ECT chosen because they are highly correlated with the concentrations of unbound dabigatran
Pollack, et al. N Engl J Med. 2015;373(6):

27. RE-VERSE AD - Results Median maximum percentage reversal was 100%
95% CI (100 to 100)
Concentrations of dabigatran remained below 20ng/ml at 24 hours in 79% of patients
Hemostasis restored at 11.4 hours in Group A
Pollack, et al. N Engl J Med. 2015;373(6):

28. RE-VERSE AD - Limitations
No control group
Mortality can’t be extrapolated
Adverse events?
Primary outcome – lab versus clinical ?
22 patients had DTT that were WNL at initiation of study?
Lack of flow diagram
Pollack, et al. N Engl J Med. 2015;373(6):

29. Bottom Line DOACs can be complicated Don’t take studies at face value
Perform thorough histories to determine appropriate agents
Utilize pharmacy staff