1. New Oral Anticoagulants: A Review
Babak Moini, MD
Veterans Affairs Hospital
Noon Lecture Series

2. Acknowledgment:
Some of the slides were borrowed from Amanda Miller Phar.D.

3. Case1
68 male with hx of DM, CHF and prior ischemic CVA admitted for new afib. He has a hx of non-compliance.
CHADs2: 4.
Which anticoagulant to send him home with?

4. Oral Anticoagulants Available in US
Coumadin
warfarin
1954
Pradaxa®
dabigatran
2010
Xarelto®
rivaroxaban
2011
Eliquis®
apixaban
2012

5. Mechanism of Action Medication Mechanism of Action Coumadin (warfarin)
Vitamin K Antagonist
Pradaxa (dabigatran)
Direct Thrombin Inhibitor
Xarelto (rivaroxaban)
Factor Xa Inhibitor
Eliquis (apixaban)

6. rivaroxaban apixaban dabigatran

7. Pharmacology: Coumadin Dabigatran Rivaroxaban Apixaban Bioavailability
100%
3-7%
60-100%
50%
Protein bound
99%
30%
90-95%
80-85%
Metabolism
CYP
Conjugation
Half Life
40hrs
12-17hrs
5-9hrs
12hrs
Onset of action
72hrs
1-2hrs
2-4hrs
Elimination
Liver
Renal

8. Indications: US + + (RELY) + (ROCKET-AF) + (Aristotle) + (EINSTEIN)
Coumadin
Dabigatrn
Rivaroxaban
Apixaban
Afib +
+ (RELY)
+ (ROCKET-AF)
+ (Aristotle)
+ (AVERROES)
DVT/PE
Not yet. (RECOVER)
+ (EINSTEIN)
Post TKA/THA
DVT prophylaxis
+ (RECORD 1-3)
+ (ADVANCE)
Not yet approved: Rivaroxaban for prophylaxis of DVT in medically ill patients
(MAGELLAN). Rivaroxaban vs Enoxaparin. NI < 30 days, superior at 35 days.

9. Usual Dosing (A fib) 5 mg BID
Warfarin
Once daily, titrate to INR 2-3
Dabigatran
150 mg BID
75 mg BID (CrCl ml/min)
Rivaroxaban
20 mg daily
15 mg daily (CrCl ml/min)
Apixaban
5 mg BID
2.5 mg BID if any 2 of the following: age > 80, wt < 60kg, SCr > 1.5
Lack of and/or limited clinical evidence for reduced doses

10. Usual Dosing (VTE) Only FDA-approved agent = rivaroxaban
VTE Prophylaxis (knee/hip surgery)
10mg once daily (up to 35 days)
No renal dose (CrCl < 30 ml/min  avoid)
VTE Treatment:
15 mg BID x 3 weeks then 20mg daily

11. Perioperative Recommendations
Dabigatran
Hold 1-2 days before procedure
CrCl < 50  hold 3-5 days
Rivaroxaban
Low bleed risk  hold 1 day
CrCl < 30/ low risk  hold 2 days
High bleed risk  hold 2 days
CrCl < 30/ high risk  hold 4 days
Apixaban
Low bleed risk  hold x 1 day
High bleed risk  hold x 2 days
Dabigatran PI, Blood 2012;119:

12. Major Side Effects: Bleeding: varied definition in each study.GI
ICH
Major (drop in Hgb by 2, life threatening).
Dabigatran:
Pills are made in acidic content, hence has 20% rate of GI side effects.
? Observed increase risk of GI bleeding.

13. Monitoring Levels: Coumadin: INR
New Oral anticoagulants: no standardized studies. No accurate quantitative measures.
Dabigatran: ECT, Thrombin clotting time
Rivaroxaban: special anti-Xa activity
Abixaban special anti-Xa activity
ECT: ecarin clotting time, a thrombin clotting time assay.

14. Drug-Drug Interactions:
No where as severe as with Warfarin.
Dabigatran: P-glycoprotein, pro-drug.
Needs acidic environment, avoid co-administration with PPI.
Rivaroxaban: CYP-450 and P-glycoprotein.
Caution with dual inhibitors (Ketoconazole, Itroconazole, Clarithromycin).
No dose adjustments needed.
Abixaban: CYP3A4 and P-glycoprotein.
Decrease dose to 2.5mg bid in dual inhibitors.

15. Switching To/From Warfarin
Medication
Recommendations for Conversion
Dabigatran
Stop warfarin, initiate dabigatran when INR < 2
Initiate warfarin 3 days before D/C dabigatran
Rivaroxaban
Stop warfarin, initiate rivaroxaban when INR < 2-3
Initiate warfarin with bridging 24 hours after D/C rivaroxaban
Apixaban
Stop warfarin, initiate apixaban when INR < 2
Initiate warfarin with bridging when next apixaban dose is due.

16. Treatment of Bleeding:
No evidence based guidelines.
Remember that unlike Coumadin, the new OAC will continuously bind to factor Xa or thrombin, hence making FFP less useful.
Current available Rx for life threatening active bleeding: based on case reports.
Factor VII
PCC: 3 and 4 factor concentrates.
HD: only for Dabigatran. Large volume of distribution.
Charcoal
PCC: prothrombin compex concentrates.
Gonsalves Et al. Mayo Clinic Proc

17. Trials vs Warfarin for A Fib
RE-LY
DAB vs WAR
ROCKET-AF
RIV vs WAR
ARISTOTLE
APIX vs WAR
Comparator
Dabigatran
Rivaroxaban
Apixaban
Design
Open-label,
blind outcomes, noninferiority
Double-blind, noninferiority
Sample size
n = 18,113
n = 14,264
n = 18,201
Randomization
D 150mg BID
D 110mg BID
W (INR 2-3)
R 20mg daily*
A 5mg BID*
Inclusion
Criteria
Nonvalvular AF with increased stroke risk
Nonvalvular AF with prior stroke or >2 risk factors
Nonvalvular AF with >1 risk factor for stroke
Exclusion
CrCl < 30
CrCl < 25
* Dose reductions for renal impairment

18. Trials vs Warfarin for A fib
RE-LY
DAB vs WAR
ROCKET-AF
RIV vs WAR
ARISTOTLE
APIX vs WAR
Average age (yrs) 71 73 70
Mean CHADS2
2.1
3.5
0-1
32% 0%
34% 2
36%
13%
3-6
87%
30%
Prior TIA/stroke
20%
55%
19%
TTR goal)
64%
62%
Median follow-up
2 yrs
1.9 yrs
1.8 yrs
Primary endpoint
Stroke (ischemic, hemorrhagic) + systemic embolism

19. Major Findings: RELY ROCKET-AF ARISTOTLE:
Dabigatran 110mg NI to Warfarin (1.53% vs 1.69%).
Dabigatran 150mg superior to Warfarin ONLY if compared with sub-optimal INR subgroup (1.11 % vs 1.69%).
Major bleeding less with 110mg (2.71 vs 3.11%).
ROCKET-AF
Rivaroxaban NI to Warfarin (2.1% vs 2.4%)
Less ICH or fatal bleeding (0.4% vs 0.8% )
ARISTOTLE:
Abixaban Superior to Warfarin (1.27% vs 1.6% )
Less Major bleeding (1.4% vs 2.1% )

20. Key Safety Endpoints (% per year)
RE-LY
ROCKET AF
ARISTOTLE
D110
D150
WAR
RIV
APIX
1o bleeding endpoint*
2.71
3.11
3.36
14.9
14.5
2.13
3.09
Major bleed
5.55
5.42
GI bleeding
1.12
1.51
1.02
3.2
2.2
0.76
0.86
Intracranial hemorrhage
0.23
0.3
0.74
0.5
0.7
0.33
0.8
*: Primary safety endpoint:
RE-LY  major hemorrhage
ROCKET-AF  major + non-major clinically relevant bleeding
ARISTOTLE  ISTH (Int Soc Thromosis & Hemostasis) major bleeding

21. Figure 3 Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF.

22. Quick Review of Evidence- Based Medicine:
A: Systemic review of multiple RCTs / multiple RTCs
B: High quality single RTC
II:
A: Systemic review of cohort studies
B: High quality cohort studie(s)
III:
Systemic review of Case/Control studies / Case Control studies IV
Case reports
Expert opinion

23. Anticoagulation Recommendations (AF)
Risk/CHADS2
CHEST 2012
AHA/ASA
Low Risk
CHADS2 = 0
No therapy > antithrombotic therapy (2B)
Aspirin (75-325mg) > OAC (2B) or aspirin + clopidogrel (2B)
Aspirin (1A)
Intermediate
CHADS2 = 1
OAC > no therapy (1B)
OAC > aspirin (2B) or aspirin + clopidogrel (2B)
OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (2B)
Warfarin (1A)
Aspirin, if patient preference (1A)
High Risk
CHADS2 > 2
OAC > no therapy (1A)
OAC > aspirin (1B) or aspirin + clopidogrel (1B)
OAC unsuitable or pt refuses: aspirin + clopidogrel over aspirin monotherapy (1B)
Dabigatran 150mg BID > warfarin (2B)
Dabigatran (1B)
Rivaroxaban (2A)
Apixaban (1B)
Chest 2012; 141:e531S-e575S
Stroke 2012;43:
OAC = oral anticoagulation

24. New OAC: Pros: Cons: Easy administration Immediate effect
Much less food and drug interactions
One dose fits all
The names sound so much cooler than WARFARIN.
Cons:
Expensive
Inability to monitor compliance
Short duration: loss of effect with a single missed dose
No safe/reliable antidotes
? Bleeding. Observational bias vs real difference.
Renal dosing

25. Take home message:
Coumadin still remains the drug of choice for many patients due to cost, past experience and known side effects.
Many new OAC are in the pipeline, expect a barrage of pharma bombardments, must remain objective as many of the studies have different inclusion/exclusion criteria, definition of end points and side effects.
Each patient may benefit from a different type of OAC based on comorbidities and drug side effect profile.
Watch out for recall bias with the new OAC among your own colleagues.
Patient compliance is a major factor: remember with the new OAC one missed dose means a lot!

26. The End!