Pharmacologic Profiles of Approved and
Investigational Oral Anticoagulants
Warfarin
Dabigatran Rivaroxaban
Apixaban
Edoxaban
Target
Vitamin K
epaxide
Thrombin
Xa
Xa
Xa
Administration
Once daily
Twice daily
Once daily
Twice daily
Once daily
Prodrug
No
Yes
No
No
No
Half-life
40 hrs
12-14 hours
9-13 hours
8-15 hours
6-11 hours
Bioavailability
>95%
6.5%
80%
~66%
50%
80%
30-60%
25%
35-39%
2 hours
2.5-4 hours
3 hours
1-2 hours
No
Yes
Yes
Yes
Renal
Minor
excretion
Time to Peak
72-96 hours
Plasma
Metabolized by
Yes
CYP3A4
Uchiyama S, et al. J Stroke Cerebrovasc Dis. 2012;21:165-173; Eriksson BI,
et al. Annu Rev Med. 2011;62:41-57
Dosing Recommendations of FDA Approved New
Oral Anticoagulants by Degree of Renal Function
CrCl
Dosing Recommendations
> 30 mL/min
150 mg BID
15-30 mL/min
75 mg BID
> 50 mL/min
20 mg/day*
15-50 mL/min
15 mg/day*
Dabigatran
Rivaroxaban
*With evening meal
Abbreviations: BID, twice daily; CrCl, creatinine clearance
Pradaxa® (dabigatran etexilate mesylate) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.;
2012.
Xarelto® (rivaroxaban) [package insert]. Raritan, NJ: Janssen Pharmaceuticals, Inc.; 2012.
RE-LY
Randomized Evaluation of Long-Term Anticoagulation Therapy
• Study Design: PROBE (N = 18,113)
• Primary Efficacy:
All stroke or systemic embolism
• Primary Safety:
Major bleeding
• Mean Follow-up: 2 years
• Inclusion:
NVAF and ≥ 1 risk factor*
• Exclusion for Renal Impairment:
CrCl < 30 mL/min
• Mean CHADS2 Score: 2.1
– CHADS2 score of ≥3: 33%
• Mean TTR: 64%
Warfarin
Dabigatran 150 mg BID
Event Rate Event Rate
(%/y)
(%/y)
RR (95% CI)†
P
Value
Efficacy
Stroke or
Systemic
Embolism
1.7%
1.1%
0.66 (0.53–0.82) <.001‡
Hemorrhagic
Stroke
0.38%
0.10%
0.26 (0.14–0.49)
<.001
3.4%
3.1%
0.93 (0.81–1.07)
.31
0.74%
0.30%
0.40 (0.27–0.60)
<.001
Safety
Major
Bleeding
Intracranial
Bleeding
*Risk factors: prior stroke/TIA; LVEF < 40%; NYHA Class ≥ II; aged ≥ 75 years, or aged 65-74 years with
DM, HTN, or CAD
†vs dose-adjusted warfarin; ‡for both inferiority and superiority
Abbreviations: BID, twice daily; CI, confidence interval; CAD, coronary artery disease; CHADS 2, congestive heart failure,
hypertension, age, diabetes, prior stroke; DM, diabetes mellitus; CrCl, creatinine clearance; DM, diabetes mellitus; HTN,
hypertension; LVEF, left ventricular ejection fraction; NVAF, nonvalvular atrial fibrillation; NYHA = New York Heart
Association; PROBE, prospective, randomized, open-blinded, end-point evaluation; RR, relative risk; TIA, transient
ischemic attack; TTR, time in therapeutic range
Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151
ROCKET-AF
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin
K Antagonism for Prevention of Stroke and Embolism in Atrial Fibrillation
• Study Design:
Randomized, double-blind,
double-dummy (N = 14,264)
• Primary Efficacy:
Composite of all stroke and
systemic embolism
• Primary Safety:
Composite of major and nonmajor clinically-relevant bleeding
events
• Mean Follow-up: 1.9 years
• Inclusion:
NVAF and prior stroke/TIA or ≥ 2
risk factors*
• Exclusion for Renal Impairment:
CrCl < 30 mL/min
• Mean CHADS2 Score: 3.5
– CHADS2 score of ≥3: 87%
• Mean TTR: 55%
Warfarin
Rivaroxaban 20 mg/day
Event
Event Rate
Rate (%/y)
(%/y)
HR (95% CI)†
P
Value
Efficacy: Stroke & Systemic Embolism
Per Protocol
Analysis
2.2%
1.7%
0.79 (0.66–0.96)
<.001‡
By ITT
2.4%
2.1%
0.88 (0.74–1.03)
<.001‡
.12§
Major &
Non-major
Bleeding
14.5%
14.9%
1.03 (0.96–1.11)
.44
Intracranial
Bleeding
0.7%
0.5%
0.67 (0.47–0.93)
.02
Safety
*Risk factors: HF or LVEF ≤ 35%, HTN, aged ≥ 75 years, or DM (i.e., a CHADS2 score ≥ 2, on a scale ranging
from 1 to 6, with higher scores indicating a greater risk of stroke).
†vs dose-adjusted warfarin; ‡for noninferiority; §for superiority
Abbreviations: CI, confidence interval; CHADS2, congestive heart failure, hypertension, age, diabetes, prior stroke; CrCl,
creatinine clearance; DM, diabetes mellitus; HR, hazard ratio; HTN, hypertension; ITT, intent-to-treat; LVEF, left ventricular
ejection fraction; NVAF, nonvalvular atrial fibrillation; TIA, transient ischemic attack; TTR, time in therapeutic range
Patel MR, et al. N Engl J Med. 2011;365:883-891.
ARISTOTLE
Apixaban for Reduction in Stroke and Other Thromboembolic
Events in AF
• Study Design:
Randomized, double-blind,
double-dummy (N = 18,201)
• Primary Efficacy:
All stroke or systemic embolism
• Primary Safety:
Major bleeding (ISTH criteria)
• Mean Follow-up: 1.8 years
• Inclusion:
NVAF and ≥ 1 risk factor*
• Exclusion for Renal
Impairment:
CrCl < 25 mL/min
• Mean CHADS2 Score: 2.1
– CHADS2 score of ≥3: 30%
• Mean TTR: 62%
Warfarin
Apixaban 5 mg BID
Event
Event Rate
Rate (%/y)
(%/y)
HR (95% CI)†
P
Value
Efficacy
Stroke or
Systemic
Embolism
1.6%
1.3%
0.79 (0.66–0.95)
<.001‡
.01§
Hemorrhagic
Stroke
0.47%
0.24%
0.51 (0.35–0.75)
<.001
3.1%
2.1%
0.69 (0.60–0.80)
<.001
0.8%
0.3%
0.42 (0.30–0.58)
<.001
Safety
Major
Bleeding
Intracranial
Bleeding
*Risk factors: aged ≥ 75 years; prior stroke/TIA; symptomatic HF or LVEF ≤ 40%; DM; HTN (ontreatment); †vs dose-adjusted warfarin; ‡for noninferiority; §for superiority
Abbreviations: BID, twice daily; CI, confidence interval; CHADS2, congestive heart failure, hypertension, age, diabetes,
prior stroke; CrCl, creatinine clearance; DM, diabetes mellitus; HR, hazard ratio; HTN, hypertension; ISTH, International
Society of Thrombosis and Haematosis; LVEF, left ventricular ejection fraction; NVAF, nonvalvular atrial fibrillation; TIA,
transient ischemic attack; TTR, time in therapeutic range
Granger CB, et al. N Engl J Med. 2011;365:981-992.