Atrial fibrillation (AF) is associated with increased risk of
stroke that can be attenuated with
vitamin K antagonists (VKAs).
Vitamin K antagonist use is limited, in part, by the high incidence of complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the
factor Xa inhibitor,
apixaban, is noninferior to
warfarin at reducing the combined endpoint of
stroke (ischemic or hemorrhagic) and systemic
embolism in patients with AF and at least 1 additional risk factor for
stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive
apixaban or
warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and
warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine
treatment duration. The key secondary objectives are to determine if
apixaban is superior to
warfarin for the combined endpoint of
stroke (ischemic or hemorrhagic) and systemic
embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38;
apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with
apixaban is >1.38 times higher than with
warfarin. ARISTOTLE will determine whether
apixaban is noninferior or superior to
warfarin in preventing
stroke and systemic
embolism; whether
apixaban has particular benefits in the
warfarin-naïve population; whether it reduces the combined rate of
stroke, systemic
embolism, and death; and whether it impacts
bleeding.