Efficacy and Safety of Apixaban Compared

with Warfarin According to Patient Risk of

Stroke and Bleeding in Atrial Fibrillation
Presented by Renato D. Lopes, MD, PhD,
Duke Clinical Research Institute, Duke University, USA
for the ARISTOTLE investigators.

Disclosures for Renato D. Lopes

Institutional research grants from:
Bristol-Myers Squibb

Advisory board or consultancy for:

Boehringer Ingelheim and Bristol-Myers Squibb

Background
Warfarin is very effective at preventing stroke in patients with atrial
fibrillation (AF), but it has several limitations.

The need to assure optimal benefit given the known bleeding risks of
warfarin has led to the development of risk scores for
thromboembolism and bleeding in patients with AF.

Scores are important tools to predict the risk of stroke and bleeding in
patients with AF and to inform decisions regarding the use of
antithrombotic therapy.

The value of these scores in guiding decision making in patients with

AF receiving apixaban, a novel oral factor Xa inhibitor, is uncertain.

Atrial Fibrillation with at Least One

Additional Risk Factor for Stroke
Inclusion
Inclusion risk
risk factors
factors
Age
Age 75
75 years
years
Prior
Prior stroke,
stroke, TIA
TIA or
or SE
SE
HF
HF or
or LVEF
LVEF 40%
40%
Diabetes
Diabetes mellitus
mellitus
Hypertension
Hypertension

Randomize
double blind,
double dummy
(n = 18,201)

Apixaban 5 mg oral twice daily

(2.5 mg BID in selected patients)

Exclusion
Exclusion
Mechanical
Mechanical prosthetic
prosthetic valve
valve
Severe
Severe renal
renal insufficiency
insufficiency
Need
Need for
for aspirin
aspirin plus
plus
thienopyridine
thienopyridine

Warfarin
(target INR 2-3)

Warfarin/warfarin placebo adjusted by INR/sham INR

based on encrypted point-of-care testing device
Primary outcome: stroke or systemic embolism

Main Trial Results

Stroke or systemic embolism

ISTH major bleeding

21% RRR

Apixaban 212 patients, 1.27% per year

Warfarin 265 patients, 1.60% per year
HR 0.79 (95% CI, 0.660.95); P=0.011

31% RRR

Apixaban 327 patients, 2.13% per year

Warfarin 462 patients, 3.09% per year
HR 0.69 (95% CI, 0.600.80); P<0.001

Median TTR 66%

Objectives
We conducted this analysis of the ARISTOTLE population to assess
the efficacy and safety of apixaban compared with warfarin according
to CHADS2 and HAS-BLED scores in patients with AF.

Pre-specified outcomes:
Stroke or systemic embolism (primary efficacy outcome).
ISTH Major bleeding (primary safety outcome).
Mortality.

Post-hoc explored outcomes:

Intracranial bleeding.
Net clinical benefit (the composite of stroke, systemic embolism, major
bleeding, and all-cause mortality).

Methods
The efficacy, safety, and balance of efficacy and safety of apixaban and warfarin
were compared across patient risk categories classified by:

1.CHADS2 (low risk: 0-1, medium risk: 2, high risk: 3) and

2.HAS-BLED (low risk: 0-1, medium risk: 2, high risk: 3) scores.

Statistical Analysis
Efficacy analyses included all randomized patients (18201 subjects).
The analyses of bleeding events included all patients who received at
least one dose of study drug (18140 subjects).

Analyses based on interactions between treatment and categories of

CHADS2 and HAS-BLED were performed using a Cox proportional
hazards model.

Baseline Characteristics

Correlation between CHADS2 and

HAS-BLED scores

Data presented at number (%).

Stroke/Systemic Embolism

ISTH Major Bleeding

Intracranial Bleeding

All-cause Mortality

Net Clinical Benefit:

Stroke, Systemic Embolism, Major Bleeding,
or All-cause Mortality

Limitations

The absence of patients with CHADS2 score of 0 does not

permit an assessment of the benefit / risk profile of
apixaban in this low-risk group of patients with AF.

We calculated labile INR based on one single INR value

among warfarin-experienced patients at baseline and this
is different from how labile INR was initially described (TTR
less than 60%).

Our results were derived from a large clinical trial

population that differs from an unselected clinical patient
population.

Conclusion

The benefits of apixaban compared with warfarin in

reducing stroke or systemic embolism, all-cause mortality,
and causing less bleeding are consistent across AF
patients with a wide range of stroke and bleeding risks as
assessed by the CHADS2 and HAS-BLED scores.

Patients with AF and at the highest risk of bleeding may

have the greatest reduction (both relative and absolute) in
intracranial bleeding with apixaban as compared with
warfarin.

Thank you