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Pfizer, Bristol-Myers Squibb, and Arrhythmia Watch Team

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Apixaban was shown to be superior to warfarin for the reduction of stroke or systemic embolism with significantly less major bleeding in patients with atrial fibrillation in the Phase 3 ARISTOTLE trial, according to results presented during a packed Hot Line session at the 2011 European Society of Cardiology Congress in Paris, and published simultaneously in The New England Journal of Medicine.1

ARISTOTLE, evaluated apixaban, a new oral direct Factor Xa inhibitor, compared to warfarin for the prevention of stroke or systemic embolism in 18,201 patients with atrial fibrillation (AF) and at least one risk factor for stroke. Apixaban as compared with warfarin significantly reduced the relative risk of stroke or systemic embolism by 21% (p=0.01), major bleeding by 31% (p<0.001), and all-cause mortality by 11% (p=0.047).<sup>1</sup>a

Conducted in 1,034 centres in 39 countries, the study was coordinated by the Duke Clinical Research Institute, Durham, N.C., and Uppsala Clinical Research Institute, Uppsala, Sweden.

“The risk for stroke in patients with AF is a major public health concern in an aging population,” said Dr. Christopher B. Granger, Professor of Medicine, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA, and lead investigator of the study. “We are therefore encouraged by the outcome of the ARISTOTLE trial, which showed that apixaban, as compared with warfarin, significantly reduced the risk of stroke or systemic embolism, major bleeding, and mortality.”


ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), a randomised, double-blind, multicentre, head-to-head trial, included 18,201 patients with AF and at least one additional risk factor for stroke. The mean CHADS2 risk score for the study population was 2.1. Patients were randomised to receive either apixaban (n=9,120) 5 mg orally twice daily (2.5 mg twice daily in selected patients) or warfarin (n=9,081) dosed to achieve a target INR (International Normalised Ratio) of 2.0-3.0.

The key study outcomes were pre-specified in a hierarchical manner that sequentially tested apixaban versus warfarin for non-inferiority on the composite endpoint of stroke or systemic embolism; superiority on the composite endpoint of stroke or systemic embolism; superiority on major bleeding; and superiority on all-cause death. The efficacy analyses included all randomised patients (“intention to treat”); bleeding analyses were “on treatment” and included all randomised patients who received at least one dose of study drug. Apixaban demonstrated non-inferiority (p<0.001) for the primary efficacy outcome, composite of stroke or systemic embolism, compared with warfarin. The relative risk reduction was 21% with annual event rates of 1.27% for apixaban and 1.60% for warfarin in an intention to treat analysis. Additionally, apixaban met the key secondary objective of superiority for the primary outcome of the composite of stroke or systemic embolism (p=0.01). The predominant effect on stroke prevention was on haemorrhagic stroke, which was 49% lower with apixaban than warfarin (p<0.001), along with an effect on ischaemic or uncertain stroke that was 8% lower with apixaban than with warfarin (p=0.42, NS).

Results from ARISTOTLE also demonstrated that apixaban was superior to warfarin for the primary safety outcome of ISTH major bleeding (p<0.001), yielding a significant relative risk reduction of 31%, with annual event rates of 2.13% for apixaban and 3.09% for warfarin. Additionally, apixaban significantly reduced the risk for ISTH major or clinically relevant non-major bleeding by 32% (p<0.001) compared to warfarin. Any bleeding was reduced 29 % per year compared with warfarin (p<0.001). With apixaban, the risk for intracranial haemorrhage was significantly reduced by 58% compared with warfarin (p<0.001).

ARISTOTLE demonstrated that apixaban is the first novel oral anticoagulant to significantly reduce all-cause death compared to warfarin. For the pre-specified key secondary efficacy outcome of all-cause death, apixaban was superior to warfarin (p=0.047). Specifically, there was a statistically significant 11% relative risk reduction with apixaban compared to warfarin, with annual event rates of 3.52% and 3.94%, respectively. (Table 1)

Table 1. Apixaban versus warfarin, significantly reduced relative risk of:

  • Stroke or systemic embolism by 21% (p=0.01)
  • Major bleeding by 31% (p<0.001)
  • All-cause mortality by 11% (p=0.047)

In ARISTOTLE, adverse events were similar in the apixaban (81.5%) and warfarin (83.1%) groups, as were serious adverse events (35.0% with apixaban and 36.5% with warfarin). Discontinuation of study drug was significantly less common with apixaban (25.3% of patients, 3.6% due to death) than with warfarin (27.5% of patients, 3.8% due to death; p=0.001). Data presented by the trial co-investigator, Professor Lars Wallentin, Uppsala Clinical Research Centre, Sweden, showed that , among patients on warfarin, time in therapeutic range (TTR) as assessed by INR (International Normalised Ratio) range of 2.0–3.0 was a median of 66.0% and mean of 62.2%, excluding INR values during the seven days following randomisation and during study drug interruptions.

Overall, safety and efficacy findings were consistent across subgroups, including geographical regions, warfarin experienced and naïve patients, age groups, sexes, differences in renal function, differences in risk for stroke, as well as in other predefined subgroups.


Apixaban (Eliquis) is not yet approved for the prevention of stroke or systemic embolism in patients with AF. Bristol-Myers Squibb and Pfizer recently announced the first regulatory approval for apixaban in the 27 countries of the European Union (EU) for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.

Apixaban is being investigated within the EXPANSE Clinical Trials Programme, which is projected to include nearly 60,000 patients worldwide across multiple indications and patient populations and includes a total of nine completed or ongoing, randomised, double-blind Phase 3 trials, including ARISTOTLE. The apixaban AF clinical trial programme, which includes ARISTOTLE and AVERROES, was designed to comprehensively evaluate apixaban in approximately 24,000 patients with AF, including patients who are expected or demonstrated to be unsuitable for vitamin K antagonist (VKA) therapy.


1 Granger CB et al.  Apixaban versus warfarin in patients with atrial fibrillation.  N Engl J Med 2011 Aug 28; doi 10.1056/NEJMoa1107039.

Published on: September 7, 2011

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