Week 23 – ARISTOTLE

“Apixaban versus Warfarin in Patients with Atrial Fibrillation”

N Engl J Med. 2011 Sep 15;365(11):981-92 [free full text]

Prior to the development of the DOACs, warfarin was the standard of care for the reduction of risk of stroke in atrial fibrillation. Drawbacks of warfarin include a narrow therapeutic range, numerous drug and dietary interactions, the need for frequent monitoring, and elevated bleeding risk. Around 2010, the definitive RCTs for the oral direct thrombin inhibitor dabigatran (RE-LY) and the oral factor Xa inhibitor rivaroxaban (ROCKET AF) showed equivalence or superiority to warfarin. Shortly afterward, the ARISTOTLE trial demonstrated the superiority of the oral factor Xa inhibitor apixaban (Eliquis).

Population:

patients with atrial fibrillation or flutter (2+ episodes at least 2 weeks apart), with at least one additional risk factor for stroke (age 75+, prior CVA/TIA, symptomatic CHF, or reduced LVEF)

pertinent exclusions: atrial fibrillation due to a reversible cause, moderate to severe mitral stenosis, Cr > 2.5

Intervention:    apixaban twice daily + placebo warfarin daily

(reduced 2.5mg apixaban dose given in pts with 2 or more of the following: age 80+, weight < 60, Cr > 1.5)

Comparison:   placebo apixaban twice daily + warfarin daily

Outcome:

  • 1º efficacy – stroke
    • (The pre-specified non-inferiority threshold was the preservation of 50% stroke risk reduction relative to warfarin.)
  • 1º safety – “major bleeding” (clinically overt and accompanied by Hgb drop of ≥ 2, “occurring at a critical site,” or resulting in death)
  • 2º efficacy – all-cause mortality
  • 2º safety – a composite of major bleeding and “clinically-relevant non-major bleeding”

Results:
9120 patients were assigned to the apixaban group, and 9081 were assigned to the warfarin group. None of the baseline characteristics differed among the treatment groups. Mean CHADS2 score was 2.1. Fewer patients in the apixaban group discontinued their assigned study drug. Median duration of follow-up was 1.8 years.

The incidence of stroke was 1.27% per year in the apixaban group vs. 1.60% per year in the warfarin group (HR 0.79, 95% CI 0.66-0.95, p<0.001). This reduction was consistent across all major subgroups (see Figure 2). Notably, the rate of hemorrhagic stroke was 49% lower in the apixaban group, and the rate of ischemic stroke was 8% lower in the apixaban group.

All-cause mortality was 3.52% per year in the apixaban group vs. 3.94% per year in the warfarin group (HR 0.89, 95% CI 0.80-0.999, p=0.047).

The incidence of major bleeding was 2.13% per year in the apixaban group vs. 3.09% per year in the warfarin group (HR 0.69, 95% CI 0.60-0.80, p<0.001). The rate of intracranial hemorrhage was 0.33% per year in the apixaban group vs. 0.80% per year in the warfarin group (HR 0.42, 95% CI 0.30-0.58, p<0.001). The rate of any bleeding was 18.1% per year in the apixaban group vs. 25.8% in the warfarin group (p<0.001).

Implication/Discussion:
In patients with non-valvular atrial fibrillation and at least one other risk factor for stroke, anticoagulation with apixaban significantly reduced the risk of stroke, major bleeding, and all-cause mortality relative to anticoagulation with warfarin.

This was a large RCT that was designed and powered to demonstrate non-inferiority but in fact was able to demonstrate the superiority of apixaban. Along with ROCKET AF and RE-LY, the ARISTOTLE trial ushered in the modern era of DOACs in atrial fibrillation. Apixaban was approved by the FDA for the treatment of non-valvular atrial fibrillation in 2012. Patient prescription cost is no longer a major barrier to prescription. These three major DOACs are all first-line therapies in the DC Medicaid formulary for the treatment of non-valvular AF. To date, no trial has compared the various DOACs directly.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. “Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost-effectiveness analysis,” BMJ 2017

Summary by Duncan F. Moore, MD

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