1. Warfarin and Direct-Acting Oral Anticoagulants for Primary and Secondary Stroke Prevention
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Emmanuel Markakis, Pharm.D., BCPS
Clinical Pharmacy Program Manager
PGY1 Residency Director
Boca Raton Regional Hospital

2. Objectives
Review the vitamin K and non-vitamin K depending anticoagulants
Identify patients at risk for stroke with atrial fibrillation
Compare and contrast the oral anticoagulants used in primary and secondary stroke prevention
Provide strategies in choosing the optimal anticoagulant in patients

3. Timeline and Approval of Oral Anticoagulants for NVAF
Edoxaban
2015
Apixaban
2012
Rivaroxaban 2011
Dabigatran 2010
Warfarin
1954

4. What’s in a Name? What will they be called next? Warfarin Warfarin
(VKA)
Warfarin
NOACS
(Novel Anticoagulants)
DOACS
(Direct-Acting Anticoagulants)
What will they be
called next?

5. Let’s Begin with a Poll
A 58 year old male patient with a PMH of atrial fibrillation is referred to your clinic by a PCP. The patient is deemed a candidate for anticoagulation. Which oral anticoagulant class would you recommend?
Factor Xa Inhibitors (rivaroxaban, edoxaban, apixaban)
Direct Thrombin Inhibitor (dabigatran)
Warfarin
I have no idea, I’ll text Dr. Espinosa

6. Oral Anticoagulants and the Clotting Cascade

7. The Oral Anticoagulants
Generic
Brand
Dose in Afib
Potential Clinical Benefits
Downside
Warfarin
Coumadin
Depends on INR
Defined INR Range
Defined INR range
Expensive to reverse
Physician Visits/Lab Draws
Not at true dose until 2 weeks
(Need to understand which factors are being inhibited)
Dabigatran
Pradaxa
150mg PO BID, if Cl 15-49ml/min, then 75mg PO daily
No lab monitoring
Cannot use Cl<15ml/min
BID dosing??
Rivaroxaban
Xarelto
20mg PO Daily with Food, if Cl 15-49ml/min, then 15mg PO daily, <15ml/min avoid use
Once a day dosing
MUST be given with food
Apixaban
Eliquis
5mg PO BID unless:
SCr>1.5: >80 OR <60kg
SCr <1.5: >80yo AND <60kg, then 2.5mg PO BID
Complex Dosing – needs creatinine level to be accurate
Edoxaban
Savaysa
60mg PO Daily, if Cl15-49ml/min, then 30mg PO daily, <15ml/min avoid use
Avoid if Cl>95ml/min
Lack of familiarity

8. Pre-Assessment Question
Which statement is true regarding how the DOACs compare to warfarin in primary prevention of stroke in literature in patients with NVAF?
Warfarin is superior to DOACs in ischemic stroke prevention
DOACs are superior to warfarin in preventing both ischemic strokes and hemorrhagic strokes
In independent trials vs warfarin, DOACs have shown both noninferiority and superiority in various end points compared to warfarin
I have no idea, I’ll text Dr. Espinosa

9. Primary Prevention

10. Primary Prevention
.Vasc Health Risk Management, 2015: 11;

11. DOACs In Primary Prevention

12. Assessment Question
Which statement is true regarding how the DOACs compare to warfarin in primary prevention of stroke in literature in patients with NVAF?
Warfarin is superior to DOACs in ischemic stroke prevention
DOACs are superior to warfarin in preventing both ischemic strokes and hemorrhagic strokes
In independent trials vs warfarin, DOACs have shown both noninferiority and superiority in various end points compared to warfarin
I have no idea, I’ll text Dr. Espinosa

13. Assess Primary Prevention CHA2DS2-VASc Score
Congestive heart failure
Hypertension
Age >75 years (2)
Diabetes mellitus
Stroke or transient ischemic attack (2)
Vascular disease
Age years
Sex category
Assign 1 point each for CHF, HTN, age years, diabetes, vascular disease, female sex
Assign 2 points for previous Stroke or TIA or Age ≥ 75 years
If total=0, no therapy
If total=1, give oral anticoagulant, aspirin, or no therapy
If total ≥ 2, give oral anticoagulant

14. Real World Primary Prevention in Medicare Patients

15. DOACs vs Warfarin for Primary Prevention in Medicare Registry
Amin et al; Current Medical Research and Opinion; June, 2017

16. DOACs vs DOACs in Insurance Registry Data
Noseworthy et al, CHEST, Vol 150, Dec 2016

17. Another Assessment
Which statement is true regarding how the DOACs compare to warfarin in primary prevention of ischemic and hemorrhagic stroke in literature in patients with NVAF?
Warfarin is superior to DOACs in ischemic stroke prevention
In Insurance registry patients, no DOAC has been shown more efficacious than another
In CMS registry patients, only apixaban has been shown superiority compared to warfarin
I have no idea, I’ll text Dr. Espinosa

18. Back to Our Question
Which statement is true regarding how the DOACs compare to warfarin in primary prevention of ischemic and hemorrhagic stroke in literature in patients with NVAF?
Warfarin is superior to DOACs in ischemic stroke prevention
In Insurance registry patients, no DOAC has been shown more efficacious than another
In CMS registry patients, only apixaban has been shown superiority compared to warfarin
I have no idea, I’ll text Dr. Espinosa

19. Accurate Dosing Matters in Primary Prevention!
Yao et al; Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients with A-Fib and Renal
Dysfunction; Journal of American Cardiology; Vol 69 (23) 2017

20. Secondary Prevention

21. 2018 Stroke Guidelines for Secondary Prevention
14 Days Only
AHA/ASA 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke; Stroke; March 2018

22. Secondary Prevention
Tsivgoulis et al; Ther Adv Neurol Disord; 2016, Vol. 9(5) 359–368
Abstract Printed in STROKE; 2016:47:A37, presented at the International Stroke Conference

23. Results: Secondary Prevention
The surface under the cumulative ranking curve (SUCRA) is a numeric presentation of the overall ranking and presents a single number associated with each treatment.SUCRA values range from 0 to 100%.
Tsivgoulis et al; Ther Adv Neurol Disord; 2016, Vol. 9(5) 359–368
Abstract Printed in STROKE; 2016:47:A37, presented at the International Stroke Conference

24. Take Home Points

25. Summary-Primary Prevention DOACs vs Warfarin
CMS Registry
Efficacy vs Warfarin
Combined Stroke/SE
Ischemic Stroke
Hemorrhagic Stroke
Dabigatran
No Difference
Superior
Rivaroxaban
Apixaban
CMS Registry
Efficacy vs Warfarin
Major Bleeding
GI Bleeding
Intracranial Bleeding
Dabigatran
Superior
No Difference
Rivaroxaban
Inferior
Apixaban

26. Summary-Primary Prevention DOACs vs DOACs
No randomized controlled trials….yet
Based on insurance report registry, none are more efficacious than the other
Apixaban has had less overall less MAJOR bleeding, but no better than the others in preventing ICH
Dosing is important!

27. Summary-Secondary Prevention
Little data published in literature
Meta-analysis shows dabigatran is best at preventing second hemorrhagic stroke, but worst at preventing second ischemic stroke
Rivaroxaban is right in the middle regarding safety and preventing second strokes/systemic embolism
Apixaban is more consistent preventing second stoke/systemic embolism and bleeding events

28. Poll Question
When a patient has a CHA2DS2-VASc Score of >2, which oral anticoagulant would you initiate a patient <65