Apixaban versus Warfarin in Patients
with Atrial Fibrillation
Study by: Granger et al.
NEJM, September 2011,Vol. 365. No. 11
Presented by: Amelia Crawford PA-S2
Background
 Vitamin K Antagonists (Warfarin) are routinely used in stroke
prevention in patients with A.fib
 Downfalls of Warfarin:
 1. variable response
 2. requires regular monitoring (INR)
 3. bleeding risks
 4. food & drug interactions
 Apixaban is a direct factor Xa inhibitor that has demonstrated stroke
risk reduction in patients compared with Aspirin and does not require
INR monitoring
Objectives
 Primary: To determine whether Apixaban was non-inferior to
Warfarin in decreasing the rate of stroke/systemic embolism in
patients with A.fib and at least one additional risk factor for
stroke.
 Non-Inferiority Hypothesis: Apixaban preserves at least 50%
of relative risk reduction in the risk of stroke or systemic embolism
associated with Warfarin
 Secondary: Determine if Apixaban was superior to Warfarin
with respect to primary outcome and rates of major bleeding and
death.
Design
 Randomized, Double Blind Trial
 ARISTOTLE Trial- December 2006 to April 2010 funded by
Bristol-Myers, Squibb and Pfizer
Study Population
18,201 patients from 1034 clinical sites in 39 countries w/ 2 year
follow up
Patients with a.fib or flutter + one additional risk factor for stroke:
 75 YOA or older,
 prior history of stroke, TIA, or systemic embolism
 symptomatic HF within 3 months or LVEJ<40%
 DM
 HTN requiring pharmacologic therapy
9120 patients assigned to Apixaban and 9081 assigned to Warfarin
Patients were similar in baseline characteristics: age, CHAD score,
previous anticoagulation treatment, hx of stroke, etc)
Exclusion Criteria
 reversible a.fib
 severe mitral stenosis
 other conditions requiring anti-coagulation (prosthetic heart valve)
 stroke within previous 7 days
 need for >165mg ASA daily or both ASA & clopidiogrel
 renal insufficiency (SCr >2.5mg/dl or CrCl <25ml/min)
Interventions
 Patients were randomized to receive either:
 2mg doses of Warfarin in order to achieve INR between 2-3.
 Apixaban 5mg BID
 Apixaban 2.5mg BID if patient had 2 of the following:
> 80YOA
 Body weight of 60kg or <
 Serum Creatinine of 1.5mg/dl or >

 Patients received monthly study visits to monitor INR
 INR’s were monitored using blinded, encrypted point of care
INR device, and an algorithm was used to guide warfarin dose
 Patients were visited every 3 months to assess clinical outcomes
& adverse events.
Outcomes
 Primary Efficacy Outcome= Stroke or Systemic Embolism
 Secondary Efficacy Outcome= Death from any cause
 Primary Safety Outcome= Major bleeding (required transfusion or
resulted in death)
 Secondary Safety Outcome= Non-major bleeding that required
medical care
Statistical Analysis
 Primary & Secondary analyses performed using the Cox
proportional hazards model
Results
 Primary Efficacy Outcomes:
 Primary outcome of stroke or systemic embolism was lower for
Apixaban group than Warfarin group:
 212 pts in apixaban, 265 pts in warfarin,
 HR = 0.79; CI 0.66-0.95; P<0.001 for noninferiority & P = 0.01 for
superiority
 Reduction in primary outcome with Apixaban was consistent
across all major subgroups (age, sex, weight, type of a.fib, dm,
hf, prior stroke/tia, renal impairment)
Results
 Secondary Efficacy Outcomes:
 Death rate lower in Apixaban group than in Warfarin group:
 3.52% vs 3.94% per year: HR 0.89; 95% CI, 0.80-0.99; P= 0.047
Results
 Primary Safety Outcomes:
 Major Bleeding was lower in Apixaban group (2.13%) compared
with Warfarin group (3.09%)
 HR= 0.69; 95% CI, 0.60-0.80; P<0.001
 Rate of any bleeding was 18.1% with Apixaban and 25.8% with
Warfarin, with an absolute risk reduction of 7.7 percentage points
(P<0.001)
Outcome
Patients
w/ Event
Event
Rate
Patients
w/Event
Event Rate
Hazard Ratio
P
Value
(A)
(A)
(W)
(W)
Stroke or SE:
Ischemic
Hemorrhagic
Systemic
Embolism
212
162
40
15
1.27 %/yr
0.97
0.24
0.09
265
175
78
17
1.60 %/yr
1.05
0.47
0.10
0.79 (0.66–0.95)
0.92 (0.74–1.13)
0.51 (0.35–0.75)
0.87 (0.44–1.75)
0.01
0.4
<0.001
0.047
Death from
any Cause
603
3.52 %/yr
699
3.94%/yr
0.89 (0.80–0.998)
0.047
Calculations for Primary Outcome
Relative Risk = 0.79
Apixaban= 212/9120 = 0.023
Warfarin = 265/9081 = 0.029
Relative Risk Reduction= 0.21
1- 0.79
Absolute Risk Reduction = 0.006
0.029-0.023
NNT= 167 patients
1/0.006
NNH (Major Bleeding) = 67
NNH (Death) = 125
Summary of Results
 In patients with A.fib + one or more risk factors for stroke, the
use of Apixaban compared with Warfarin, significantly reduced the
risk of:
 1. Stroke/Systemic Embolism (21% decrease)
 2. Major Bleeding (31% decrease)
 3. Death (11% decrease)
Results were consistent across subgroups
Predominant effect is hemorrhagic stroke prevention (49% lower rate
than warfarin)
Conclusions
 In patients with A.fib, Apixaban is as effective as Warfarin at
preventing stroke & systemic embolism, causes less bleeding, and
results in lower mortality.
 Advantages of Apixaban: rapid absorption, 12hr half-life,
25% renal excretion, no need for INR monitoring
 Other options on the horizon:
 1. Dabigatran- Direct Thrombin Inhibitor
 2. Rivaroxaban- Factor Xa Inhibitor
All 3 have been shown to be non-inferior to Warfarin in stroke
prevention