New Oral Anticoagulants: A
Review
Babak Moini, MD
Veterans Affairs Hospital
Noon Lecture Series
Acknowledgment:
 Some of the slides were borrowed from Amanda Miller
Phar.D.
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?
Oral Anticoagulants Available in
US
Coumadin
warfarin
Pradaxa®
dabigatran
Xarelto®
rivaroxaban
Eliquis®
apixaban
1954
2010
2011
2012
Mechanism
of Action
Mechanism
of Action
Medication
Coumadin (warfarin)
Vitamin K Antagonist
Pradaxa (dabigatran) Direct Thrombin Inhibitor
Xarelto (rivaroxaban) Factor Xa Inhibitor
Eliquis (apixaban)
Factor Xa Inhibitor
rivaroxaban
apixaban
dabigatran
http://www.healio.com/~/media/Images/News/Online/Orthopedics/2009/12_December/01/79_fig_400_307_
57368.gif
Pharmacology:
Coumadin
Dabigatran
Rivaroxaban
Apixaban
Bioavailability
100%
60-100%
50%
Protein bound
99%
90-95%
80-85%
Metabolism
CYP
Conjugation
CYP
CYP
Half Life
40hrs
12-17hrs
5-9hrs
12hrs
Onset of
action
72hrs
1-2hrs
2-4hrs
2-4hrs
Elimination
Liver
Renal
Renal
Renal
Indications:
Coumadin
Dabigatrn
Afib
(RELY)
DVT/PE
Not yet.
(RECOVER)
Post TKA/THA
DVT
prophylaxis
+
Rivaroxaban
(ROCKETAF)
Apixaban
(Aristotle)
+
(AVERROES)
(EINSTEIN)
(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.
Usual Dosing (A fib)
Warfarin
• Once daily, titrate to INR 2-3
Dabigatran
• 150 mg BID
• 75 mg BID (CrCl 15-30 ml/min)
Rivaroxaban
• 20 mg daily
• 15 mg daily (CrCl 15-50 ml/min)
Apixaban
• 5 mg BID
• 2.5 mg BID if any 2 of the following: age
> 80, wt < 60kg, SCr > 1.5
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
 No renal dose (CrCl < 30 ml/min  avoid)
Perioperative Recommendations
Dabigatran
• Hold 1-2 days before procedure
• CrCl < 50  hold 3-5 days
• Low bleed risk  hold 1 day
Rivaroxaban
• 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;119:3016-23
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.
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
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.
Switching To/From Warfarin
Medication
Recommendations for Conversion
Stop warfarin, initiate dabigatran when INR < 2
Dabigatran
Initiate warfarin 3 days before D/C dabigatran
Stop warfarin, initiate rivaroxaban when INR < 2-3
Rivaroxaban
Initiate warfarin with bridging 24 hours after D/C
rivaroxaban
Stop warfarin, initiate apixaban when INR < 2
Apixaban
Initiate warfarin with bridging when next apixaban
dose is due.
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
Gonsalves Et al. Mayo Clinic Proc. 5-2013
Trials vs Warfarin for A Fib
RE-LY
DAB vs WAR
ROCKET-AF
RIV vs WAR
ARISTOTLE
APIX vs WAR
Dabigatran
Rivaroxaban
Apixaban
Open-label,
blind outcomes,
noninferiority
Double-blind,
noninferiority
Double-blind,
noninferiority
n = 18,113
n = 14,264
n = 18,201
Randomization
D 150mg BID
D 110mg BID
W (INR 2-3)
R 20mg daily*
W (INR 2-3)
A 5mg BID*
W (INR 2-3)
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 < 30
CrCl < 25
Comparator
Design
Sample size
* Dose reductions for renal impairment
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
2.1
0-1
32%
0%
34%
2
36%
13%
36%
3-6
32%
87%
30%
Prior TIA/stroke
20%
55%
19%
TTR (INR @ goal)
64%
55%
62%
Median follow-up
2 yrs
1.9 yrs
1.8 yrs
Primary endpoint
Stroke (ischemic, hemorrhagic) + systemic embolism
Major Findings:
 RELY
 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% )
Key Safety Endpoints (% per
year)
RE-LY
ROCKET AF
ARISTOTLE
D110
D150
WAR
RIV
WAR
APIX
WAR
1o bleeding
endpoint*
2.71
3.11
3.36
14.9
14.5
2.13
3.09
Major bleed
2.71
3.11
3.36
5.55
5.42
2.13
3.09
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:
o RE-LY  major hemorrhage
o ROCKET-AF  major + non-major clinically relevant bleeding
o ARISTOTLE  ISTH (Int Soc Thromosis & Hemostasis) major
bleeding
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.
http://dx.doi.org/10.1016/j.amjcard.2012.03.049
Quick Review of EvidenceBased Medicine:
 I
 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
 IV
 Expert opinion
Anticoagulation Recommendations (AF)
Risk/CHADS2
CHEST 2012
AHA/ASA
No therapy > antithrombotic therapy (2B)
Low Risk
CHADS2 = 0
Intermediate
CHADS2 = 1
Aspirin (1A)
Aspirin (75-325mg) > OAC (2B) or aspirin + clopidogrel
(2B)
OAC > no therapy (1B)
Warfarin (1A)
OAC > aspirin (2B) or aspirin + clopidogrel (2B)
Aspirin, if patient
preference (1A)
OAC unsuitable or pt refuses: aspirin + clopidogrel over
aspirin monotherapy (2B)
OAC > no therapy (1A)
Warfarin (1A)
Dabigatran (1B)
Rivaroxaban (2A)
Apixaban (1B)
OAC > aspirin (1B) or aspirin + clopidogrel (1B)
High Risk
CHADS2 > 2
OAC unsuitable or pt refuses: aspirin + clopidogrel over
aspirin monotherapy (1B)
Dabigatran 150mg BID > warfarin (2B)
OAC = oral anticoagulation
Chest 2012; 141:e531Se575S
Stroke 2012;43: 3442-3453
New OAC:
 Pros:
 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
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!
The End!