Study by: Granger et al.NEJM, September 2011,Vol. 365. No.

11Presented by: Amelia Crawford PA-S2

Apixaban versus Warfarin in Patients with Atrial Fibrillation

Background

Vitamin K Antagonists (Warfarin) are routinely used in stroke prevention in patients with A.fib

Downfalls of Warfarin:1. variable response2. requires regular monitoring (INR)3. bleeding risks4. 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 embolismsymptomatic 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 stenosisother conditions requiring anti-coagulation

(prosthetic heart valve)stroke within previous 7 daysneed for >165mg ASA daily or both ASA &

clopidiogrel renal insufficiency (SCr >2.5mg/dl or CrCl

<25ml/min)

InterventionsPatients 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:

> 80YOABody weight of 60kg or <Serum Creatinine of 1.5mg/dl or >

Patients received monthly study visits to monitor INRINR’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 AnalysisPrimary & Secondary analyses performed

using the Cox proportional hazards model

ResultsPrimary 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 (A)

Event Rate (A)

Patients w/Event

(W)

Event Rate

(W)

Hazard Ratio

P Value

Stroke or SE:IschemicHemorrhagicSystemic Embolism

2121624015

1.27 %/yr0.970.240.09

2651757817

1.60 %/yr1.050.470.10

0.79 (0.66–0.95)0.92 (0.74–1.13)0.51 (0.35–0.75)0.87 (0.44–1.75)

0.010.4<0.0010.047

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 = 0.023Warfarin = 265/9081 = 0.029

Relative Risk Reduction= 0.211- 0.79

Absolute Risk Reduction = 0.0060.029-0.023

NNT= 167 patients1/0.006

NNH (Major Bleeding) = 67NNH (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 subgroupsPredominant 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 Inhibitor2. Rivaroxaban- Factor Xa Inhibitor

All 3 have been shown to be non-inferior to Warfarin in stroke prevention