Background
Phase 3 double-blind RCT (AVERROES). 5,599 patients with non-valvular AF deemed unsuitable for vitamin K antagonist therapy (refused warfarin or INR management deemed too difficult), with CHADS score ≥1. Designed to compare apixaban to aspirin — which was the de facto anticoagulation alternative for AF patients not on warfarin at time of trial. Trial stopped early at median 1.1 years for efficacy. Three-country (North America, Europe, India). Median CHADS2 score 2.0.
Interventions and follow up
Arm A: Apixaban 5 mg orally twice daily (2.5 mg BID if ≥2 dose-reduction criteria: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL)
Arm B: Aspirin 81–324 mg orally once daily
Primary endpoint: Stroke (ischemic or hemorrhagic) or systemic embolism
mFollow up: 1.1 years (median; stopped early)
Arm B: Aspirin 81–324 mg orally once daily
Primary endpoint: Stroke (ischemic or hemorrhagic) or systemic embolism
mFollow up: 1.1 years (median; stopped early)
Results
Stroke/systemic embolism: 1.6%/yr (apixaban) vs 3.7%/yr (aspirin), HR 0.45 (95% CI 0.32–0.62), P<.001
Major bleeding: 1.4%/yr vs 1.2%/yr (HR 1.13, P=.57) — not significantly different
ICH: 0.4% vs 0.4% — similar
All-cause mortality: 3.5%/yr vs 4.4%/yr (HR 0.79, P=.07)
Major bleeding: 1.4%/yr vs 1.2%/yr (HR 1.13, P=.57) — not significantly different
ICH: 0.4% vs 0.4% — similar
All-cause mortality: 3.5%/yr vs 4.4%/yr (HR 0.79, P=.07)
Adverse events
Main adverse events: Major bleeding not significantly increased vs aspirin. GI bleeding comparable. ICH similar between arms. Discontinuation 17.9% (apixaban) vs 20.5% (aspirin) — similar. Drug interactions minimal. No hepatotoxicity. Safety profile favorable for apixaban in this unsuitable-for-warfarin population.
Conclusions
Apixaban reduced stroke risk by 55% compared to aspirin in AF patients not on warfarin, without significant increase in major bleeding, definitively establishing that aspirin alone is inadequate for AF stroke prevention and that apixaban should be used instead when VKA is not feasible.
Key Limitations
Key Limitations: Stopped early for efficacy (median 1.1 years) — limited long-term safety data. Patients selected as 'unsuitable for warfarin' by physician judgment — heterogeneous risk profile. Aspirin doses varied (81–324 mg). Many patients might have been manageable on DOACs with appropriate dose reduction — the 'unsuitable for warfarin' label in 2011 may no longer apply to DOACs given their simpler management. Cannot directly compare to warfarin or other DOACs.
Clinical Context
AVERROES was practice-changing: it definitively ended the use of aspirin as an alternative to anticoagulation in AF. ACC/AHA/ESC guidelines recommend against aspirin for AF stroke prevention (Class III harm) based largely on AVERROES and CHA2DS2-VASc evidence. Apixaban is guideline-preferred DOAC for most AF patients including those with prior GI bleeding, elderly, and those with renal impairment (with dose reduction). Aspirin for AF is now considered substandard care except in very specific circumstances.
References