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The novel oral anticoagulant apixaban has similar effects on stroke, systemic embolism and major bleeding in patients with atrial fibrillation (A-fib) whether they have been on previous warfarin therapy or not, according to a subanalysis of the ARISTOTLE trial published online July 26, 2013, ahead of print in the American Heart Journal.
ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation) randomized 18,201 patients with A-fib and at least 1 stroke risk factor to dose-adjusted warfarin plus placebo or the oral factor Xa inhibitor apixaban (5 mg [2.5 mg for those at high bleeding risk] twice daily) plus placebo. Apixaban proved superior to warfarin for preventing stroke or systemic embolism, the primary endpoint.
For the subanalysis, David Garcia, MD, of the University of Washington (Seattle, WA), and colleagues assessed the ARISTOTLE results according to whether patients were warfarin naive or not prior to study enrollment. This was done due to the observation from retrospective studies that patients with little or no exposure to anticoagulation may be at higher risk of adverse outcomes than patients who have been on such therapy previously.
In ARISTOTLE, less than half (42.9%) of patients were warfarin naive prior to study enrollment. Compared with patients randomized to warfarin, those receiving apixaban had numerically lower rates of stroke/systemic embolism and other endpoints regardless of prior warfarin use (table 1).
Table 1. Outcomes by Prior Warfarin Use (Per 100 Patient Years)
HR 95% CI
Stroke/Systemic EmbolismWarfarin NaiveWarfarin Experienced
Major BleedingWarfarin NaiveWarfarin Experienced
Intracranial BleedingWarfarin NaiveWarfarin Experienced
MortalityWarfarin NaiveWarfarin Experienced
DiscontinuationWarfarin NaiveWarfarin Experienced
Among all warfarin treated patients, the median percent time in therapeutic range (TTR) in ARISTOTLE was 66%—61.4% in those who were warfarin naive and 69.1% in those who had previously received warfarin (P < 0.001). During the first 90 days, the corresponding median TTRs were 43.7% and 54.9%, respectively (P < 0.001). The difference in TTR between warfarin-naive and warfarin-experienced patients was most noticeable in the subtherapeutic range (INR < 2.0).
“In the present prospective comparison, prior [warfarin] exposure did not modify the effect of apixaban relative to warfarin for most key efficacy and safety outcomes,” the authors conclude, adding that the results were similar to a subanalysis of the RE-LY trial, which found no interaction between lack of previous warfarin therapy and the effects of dabigatran vs. warfarin.
Similar to that trial, the current one suggests “that [warfarin] naivety should not impact decisions about whether to use apixaban or warfarin in clinical practice,” Dr. Garcia and colleagues note, adding that “treatment with apixaban as compared with warfarin will, in patients with [A-fib] and a raised risk for stroke, be associated with lower rates of stroke/systemic embolism and major bleeding both in patients switching from [warfarin] as well as in patients starting oral anticoagulation.”