PDF: ARISTOTLE
(2011)Objective
To compare the efficacy and safety of apixaban versus warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation.
Study Summary
• The ARISTOTLE trial showed that apixaban was superior to warfarin in reducing stroke or systemic embolism, caused less major bleeding, and reduced all-cause mortality in patients with atrial fibrillation and at least one stroke risk factor..
Intervention
Apixaban 5 mg BID (2.5 mg in select patients) vs. warfarin (INR 2.0–3.0), double-blind, randomized trial. Median follow-up: 1.8 years.
Inclusion Criteria
Patients with atrial fibrillation or flutter and at least one risk factor for stroke (age ≥75, prior stroke/TIA, symptomatic heart failure, LV EF ≤40%, hypertension, or diabetes).
Study Design
Arms: Apixaban vs. Warfarin
Patients per Arm: Apixaban: 9120, Warfarin: 9081
Outcome
• Primary outcome (stroke or systemic embolism): 1.27%/yr with apixaban vs 1.60%/yr with warfarin (HR 0.79, P=0.01). <br>• Hemorrhagic stroke: 0.24%/yr vs 0.47%/yr (HR 0.51, P<0.001). <br>• Major bleeding: 2.13%/yr vs 3.09%/yr (HR 0.69, P<0.001). <br>• All-cause mortality: 3.52% vs 3.94% (HR 0.89, P=0.047). <br>• Apixaban also reduced the composite outcome of stroke, MI, embolism, and death (HR 0.88, P=0.01)..
Bottom Line
Apixaban was superior to warfarin in preventing stroke/systemic embolism, caused less bleeding, and reduced mortality.
Major Points
- Largest DOAC vs warfarin trial: 18,201 patients with AF and ≥1 CHADS2 risk factor randomized across 1,034 centers in 39 countries.
- Triple benefit: apixaban was superior for efficacy (stroke/SE: 1.27% vs 1.60%/yr, HR 0.79, P=0.01), superior for safety (major bleeding: 2.13% vs 3.09%/yr, HR 0.69, P<0.001), and reduced all-cause mortality (3.52% vs 3.94%/yr, HR 0.89, P=0.047).
- Hemorrhagic stroke reduced by 49% (0.24% vs 0.47%/yr, HR 0.51, P<0.001). Ischemic stroke rates were similar (0.97% vs 1.05%/yr, HR 0.92, P=0.42).
- Dose reduction criteria: apixaban 2.5 mg BID if ≥2 of: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL (~5% of patients received reduced dose).
- Double-dummy design: patients received either apixaban + warfarin-placebo or warfarin + apixaban-placebo, with sham INR monitoring to maintain blinding.
- Mean CHADS2 score was 2.1; 34% had prior stroke/TIA/SE (highest risk subgroup). Median TTR for warfarin arm was 62%.
- ARISTOTLE established apixaban as the preferred DOAC for AF-related stroke prevention per 2019 AHA/ACC guidelines.
Study Design
- Study Type
- Randomized, double-blind, double-dummy, controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 18201
- Follow-up
- Median 1.8 years
- Centers
- 1034
- Countries
- North America, South America, Europe, Asia Pacific
Primary Outcome
Definition: Stroke or systemic embolism
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1.60%/year | 1.27%/year | 0.79 (0.66–0.95) | 0.01 |
Limitations & Criticisms
- Median follow-up 1.8 years — limited data on very long-term safety and efficacy.
- Excluded recent stroke (within 7 days) — acute-phase efficacy not directly tested.
- Excluded severe renal impairment (CrCl <25 mL/min) — safety in dialysis patients unknown.
- Warfarin arm TTR was 62% — reasonable but not optimal. Sites with excellent TTR may see smaller advantage for apixaban.
- No reversal agent was available during the trial (andexanet alfa approved later in 2018).
- 31% of patients used concomitant aspirin — may confound bleeding comparisons.
- Industry-funded (Bristol-Myers Squibb and Pfizer) — sponsors of apixaban.
- Ischemic stroke rates were similar between groups (HR 0.92, P=0.42) — superiority was primarily driven by hemorrhagic stroke reduction.
- Limited data on very low CHA2DS2-VASc scores (0–1) where treatment benefit may not outweigh bleeding risk.
Citation
Granger CB, et al. N Engl J Med. 2011;365(11):981–992.