1. Prevention
of Atrial Fibrillation Related
Strokes and the Role of the
New Oral Anticoagulants
Matt Dickinson, PharmD/MBA Candidate
Idaho State University

2. Objectives
• Define the risk factors, pathophysiology, and treatment of
atrial fibrillation (AFib)
• Describe benefits of anticoagulation for stroke prevention in
atrial fibrillation and identify the population of patients at the
greatest risk
• Compare the benefits and risks of the new oral
anticoagulant therapies as well as their safety, efficacy,
pharmacology, cost, and convenience
• Utilize available decision making tools to stratify the
challenges and benefits of using new oral anticoagulants in
patients with atrial fibrillation

3. Etiology and Risk Factors1-4
• Hypertension
• Heart failure
• Coronary artery
disease
• Advanced age
• Diabetes
• Electrolyte
Imbalances
• Medications
• Hyperthyroidism
• COPD
• Alcohol

4. Pathophysiology1-4
• Structural and/or electrophysiological
abnormalities  cellular hypertrophy and/or
tissue fibrosis  alterations in function &
structure
• Ultimately leads to changes in the automaticity
of the SA node
• Atria beat chaotically and out of coordination
with ventricles

5. Clinical Presentation1-4
• Most commonly
o palpitations, tachycardia, dizziness, shortness of
breath, & weakness
o chest pain & worsening of heart failure
• Some patients are asymptomatic
• 5x more likely to have a stroke
o 15% of all strokes are due to AFib
o New oral anticoagulants may have better stroke
reduction & less of a bleed risk than warfarin

6. Treatment1-5
• Rate control
o beta-blockers, non-DHP Ca2+ channel blockers, digoxin,
amiodarone
• Rhythm control
o Acute Conversion
• ibutilide, flecainide, dofetilide, propafenone, amiodarone
o Maintenance
• amiodarone, propafenone, flecainide, sotalol, dofetilide
• Nonpharmacologic
o Ablation, pacemaker
• Prevention of thromboembolism
o ASA, clopidogrel, warfarin, NOACs

7. Estimating Risk: CHADS2
score1-5
• Estimates stroke risk in patients with AFib
o C = Congestive Heart Failure: 1pt
o H = Hypertension or treated for hypertension: 1pt
o A = Age >75 y/o: 1 pt
o D = Diabetes: 1 pt
o S2 = Prior stroke or TIA or thromboembolism: 2 pts

8. CHA2DS2-VASc Score1,5
• Supersedes CHA2D2 and provides better
stratification of low risk patients
o C = CHF: 1 pt
o H = Hypertension: 1 pt
• BP > 140/90 or treated: 1 pt
o A2 = Age >75 years: 2 pts
o D = Diabetes: 1 pt
o S2 = Prior stroke or TIA or thromboembolism: 2 pts
o V = Vascular disease: 1 pt – e.g., PAD, MI
o A = Age 65-74 years: 1 pt
o Sc = Female gender: 1 pt

9. Estimating Risk of Stroke:
CHA2DS2-VASc1, 5
Score Risk Anticoagulation Therapy Considerations
0 Low No antithrombotic therapy
or aspirin
Class IIa
recommendation
1 Moderate Antithrombotic therapy is
not necessary but an oral
anticoagulant or aspirin
may be considered
Class IIb
recommendation
2 or
higher
High Oral anticoagulant or
warfarin at INR target of 2-
3
Class I
recommendation. If
end-stage CKD, choose
warfarin

10. New Oral Anticoagulants
(NOACs)
• Direct thrombin (Factor IIa) inhibitor
o Dabigatran (Pradaxa)  RE-LY trial
• Direct Factor Xa inhibitors
o Rivaroxaban (Xarelto)  ROCKET-AF trial
o Apixaban (Eliquis)  ARISTOTLE trial
o Edoxaban (Savaysa) ENGAGE-AF trial

12. Characteristics of NOACs1,5,6-9
Dabigatran Apixaban Rivaroxaban Edoxaban
Direct factor inhibition IIa Xa Xa Xa
Bioavailability (Frel) 6 % 80 % 80 % 62 %
Peak action (tmax) 1–3 h 1–3 h 1–3 h 1-2 h
Protein binding 35% 84% 92–95% 55%
Renal clearance 80% 25% 33% 50%
Half life 13.8 h 15.1 h 9-12 h 10-14 h
Dosing 75-150 mg BID 2.5-5 mg BID 20 mg daily 30-60 mg daily
Reversal agent
Idarucizumab
(Praxbind)
Andaxanet
(ANNEXA-R)
in phase III
trials
Andaxanet
(ANNEXA-R)
in phase III
trials
Andaxanet
(ANNEXA-R)
in phase III
trials

13. Atrial Fibrillation Studies10-14
Trial RE-LY ARISTOTLE ROCKET-AF ENGAGE-AF
Design Randomized,
open Label
N=18,113
Randomized,
double blind
N=18,209
Randomized,
double blind &
dummy
N=14,000
Randomized, double
blind & dummy
N = 21,105 patients
Median Age 71 70 73 72
Female 36 % 36 % 43 % 38 %
Treatment Dabigatran
150 mg BID
Apixaban
5 mg BID
Rivaroxaban
20 mg daily
Edoxaban
60 mg daily
Comparator Warfarin 2-3
(67 % TTR)
Warfarin 2-3
(66 % TTR)
Warfarin 2-3
(57.8 % TTR)
Warfarin 2-3
(68 % TTR)
CHADS2
Scores
Average = 2.1 Average = 2.1 Average = 3.5 Average = 2.8
0-1 32 % 34 % 0 % 0 %
2 35 % 36 % 13 % 46 %
3-6 33 % 30 % 87 % 54 %
Time in Therapeutic Range = TTR

14. Primary Endpoint – Stroke15

15. Primary Endpoint – Stroke10-15
Study NOAC VKA Outcome
RE-LY Dabigatran
1.1 %
Warfarin
1.7 %
RR 0.66 95% CI 0.53-0.82
P < 0.001 Superiority
ARISTOTLE Apixaban
1.3 %
Warfarin
1.6 %
HR 0.79 95% CI 0.66-0.95
P < 0.001 Non-inferiority
P = 0.01 Superiority
ROCKET-AF Rivaroxaban
1.7 %
Warfarin
2.2 %
HR 0.79 95% CI 0.66-0.96
P < 0.001 Non-inferiority
ENGAGE-AF Edoxaban
1.18 %
Warfarin
1.5 %
HR 0.79 95% CI 0.63-0.99
P < 0.001 Non-inferiority

16. Major Bleeding15

17. Major Bleeding10-15
Study NOAC VKA Outcome
RE-LY Dabigatran
3.3 %
Warfarin
3.6 %
RR 0.93
95% CI 0.81-1.07
P = 0.31
ARISTOTLE Apixaban
2.1 %
Warfarin
3.1 %
HR 0.69
95% CI 0.60-0.8
P < 0.001
ROCKET-AF Rivaroxaban
3.6 %
Warfarin
3.4 %
HR 1.04
95% CI 0.90-1.20
P = 0.58
ENGAGE-AF Edoxaban
2.75 %
Warfarin
3.34 %
HR 0.80
95% CI 0.71-0.91
P < 0.001

18. Efficacy and Safety15

19. Intracranial Hemorrhage10-15
Study NOAC VKA Outcome
RE-LY Dabigatran
0.3 %
Warfarin
0.7 %
RR 0.40
95% CI 0.27-0.60
P < 0.001
ARISTOTLE Apixaban
0.3 %
Warfarin
0.8 %
HR 0.42
95% CI 0.30-0.58
P < 0.001
ROCKET-AF Rivaroxaban
0.5 %
Warfarin
0.7 %
HR 0.67
95% CI 0.47-0.93
P = 0.02
ENGAGE-AF Edoxaban
0.26 %
Warfarin
0.47%
HR 0.54
95% CI 0.38-0.77
P < 0.001

20. Dosing Schedules for AFib1,6-9
Agent Dosing Recommendations
Dabigatran
75mg, 150mg
CrCl > 30 mL/min: 150 mg BID
CrCl 15 to 30 mL/min: 75 mg BID*
Avoid < 15 mL/min
Apixaban
2.5mg, 5mg
CrCl > 15 mL/min: 5 mg BID
Any 2 ( > 80 yrs, < 60 kg, SCr > 1.5 mg/dL: 2.5 mg
BID)
Avoid < 15 mL/min
Rivaroxaban
10mg, 15mg,
20mg
CrCl > 50 mL/min: 20 mg daily
CrCl 15-50 mL/min: 15 mg daily
Avoid CrCl < 15 mL/min
Edoxaban
15mg, 30mg,
60mg
CrCl > 95 mL/min: use not recommended**
CrCl 51-95 mL/min: 60 mg daily
CrCl 15-50 mL/min: 30 mg daily
Avoid CrCl < 15 mL/min

21. Which patients are good candidates
for NOACs?
Patients who:
• Find INR testing/monitoring burdensome
• Limited access to healthcare, unable to drive, etc.
• Despite adherence to provider recommendations,
have low “time in therapeutic range”
• Can afford (or arrange to get) the new drugs
• Have moderate-normal renal function
If a patient has maintained a stable INR, the conservative
approach is to continue current warfarin therapy.

22. Cost Analysis16
 Incremental medical costs to a US health payer of an AFib
patient experiencing a clinical event during 1 year following
the event were obtained from published literature and
adjusted for inflation. Medical costs, excluding drug
costs, were evaluated and compared for each NOAC vs
Warfarin.
 In a patient year, the medical cost reduction associated
with NOAC usage instead of Warfarin was estimated to be
 $179 for Dabigatran
 $89 for Rivaroxaban
 $485 for Apixaban

23. Differences in Yearly Medical Costs of AFib
Patients Treated with NOAC vs Warfarin17

24. PBM Management
• Allow a fixed number of preauthorized PAs
o Prior authorizations cost the health care system about $50 each
• Quantity limit of 60 tablets per month
• Sample Prior Authorization Criteria for Eliquis for Afib
o Does the patient have a mechanical heart valve?
o Does the patient live > 70 miles from A healthcare facility?
o Does the patient have a CrCl > 15 mL/min?
o Has the patient failed warfarin due to intolerance or contraindication?
• Is there documented evidence that the patient’s TTR has been <
50%

25. Conclusion
• Patient selection for use is critical
o All NOACs show better results in bleeding and stroke risk in
patients with non-valvular atrial fibrillation than warfarin
• excluding GI bleeding
o NOACs provide a safe and efficacious alternative to warfarin
• Well managed warfarin will remain an option
o There are many challenges to anticoagulation therapy with
warfarin
• Pharmacists and physicians must work together to
individualize anticoagulant therapy for each patient.

26. References
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text
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Guidelines Committee. Canadian Cardiovascular Society atrial fibrillation guidelines
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(CPG). 2012 focused update of the ESC Guidelines for the management of atrial
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27. References cont.
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Aug 1;110(3):453-60. Pub Med PMID: 22537354.6. Dabigatran Etexilate Mesylate
Drug Facts and Comparisons. Facts and Comparisons [database online]. Clinical
Drug Information, LLC.; From http://online.factsandcomparisons.com
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http://online.factsandcomparisons.com
8. Apixaban Drug Facts and Comparisons. Facts and Comparisons [database
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http://online.factsandcomparisons.com
9. Edoxaban Drug Facts and Comparisons. Facts and Comparisons [database
online]. Clinical Drug Information, LLC.; From
http://online.factsandcomparisons.com

28. References cont.
10. Warfarin Sodium Drug Facts and Comparisons. Facts and Comparisons
[database online]. Clinical Drug Information, LLC.; From
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Al-Khalidi HR, et al.; ARISTOTLE Committees and Investigators. Apixaban
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References cont.

30. Thank You
BlueCross & Blue
Shield of Nebraska!
Questions???