Background
Phase 3 double-blind, double-dummy RCT. 18,201 patients with non-valvular AF and ≥2 CHADS2 risk factors (mean CHADS2 2.1) in 39 countries. Apixaban (Eliquis) is a direct oral factor Xa inhibitor. ARISTOTLE was the pivotal trial for apixaban in AF, demonstrating superiority over warfarin for both stroke prevention AND major bleeding — the only AF DOAC trial to achieve superiority on both efficacy and safety primary outcomes with true double-blind design. Median follow-up 1.8 years.
Interventions and follow up
Arm A: Apixaban 5 mg orally twice daily (2.5 mg BID if ≥2 of: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL)
Arm B: Warfarin dose-adjusted to INR 2.0–3.0
Primary endpoint: Stroke (ischemic or hemorrhagic) or systemic embolism
mFollow up: 1.8 years (median)
Arm B: Warfarin dose-adjusted to INR 2.0–3.0
Primary endpoint: Stroke (ischemic or hemorrhagic) or systemic embolism
mFollow up: 1.8 years (median)
Results
Stroke/systemic embolism: 1.27%/yr (apixaban) vs 1.60%/yr (warfarin), HR 0.79 (95% CI 0.66–0.95), P=.01 for superiority
Major bleeding: 2.13%/yr vs 3.09%/yr, HR 0.69 (0.60–0.80), P<.001
Intracranial hemorrhage: 0.24%/yr vs 0.47%/yr, HR 0.51 (0.35–0.75), P<.001
All-cause mortality: 3.52%/yr vs 3.94%/yr, HR 0.89 (0.80–0.99), P=.047
Major bleeding: 2.13%/yr vs 3.09%/yr, HR 0.69 (0.60–0.80), P<.001
Intracranial hemorrhage: 0.24%/yr vs 0.47%/yr, HR 0.51 (0.35–0.75), P<.001
All-cause mortality: 3.52%/yr vs 3.94%/yr, HR 0.89 (0.80–0.99), P=.047
Adverse events
Main adverse events: Overall AE rate similar. GI bleeding comparable (0.76% vs 0.86%, not increased unlike dabigatran 150mg). Intracranial bleeding markedly reduced. Liver function: ALT elevation rate similar. No specific dietary restrictions. No routine INR monitoring required. Discontinuation rates similar (25% each arm). Minor bleeding less with apixaban.
Conclusions
Apixaban was superior to warfarin for stroke/embolism prevention, major bleeding reduction, ICH reduction, and all-cause mortality in non-valvular AF, establishing it as the preferred DOAC for AF in most risk groups.
Key Limitations
Key Limitations: Warfarin TTR was 62% (below that of specialized anticoagulation clinics), potentially inflating benefit. CHADS2 ≥2 enrichment limits generalizability to low-risk AF (where net benefit is smaller). Dose reduction criteria (2.5 mg BID) needed for specific elderly patients — real-world underdosing is frequent. No direct comparison to other DOACs within ARISTOTLE. Results may not apply to patients with severe renal impairment (CrCl <25 mL/min) or mechanical valves.
Clinical Context
FDA approved December 2012 (Eliquis, BMS/Pfizer) for non-valvular AF. Apixaban has become the most prescribed DOAC in the US, driven by ARISTOTLE's unique combination of superior efficacy AND safety vs warfarin, plus no GI bleeding excess. Specific reversal: andexanet alfa (Andexxa, 2018). ACC/AHA AF guidelines give apixaban a Class I recommendation. Preferred in patients with prior GI bleeding history over dabigatran 150mg or rivaroxaban.
References