PDF: ARCADIA
(2024)Objective
Evaluate whether apixaban is superior to aspirin for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy, but without atrial fibrillation.
Study Summary
Intervention
Apixaban 5 mg twice daily (or 2.5 mg BID if age ≥80 or renal dysfunction) vs. aspirin 81 mg daily. Randomized, double-blind, placebo-controlled phase 3 trial. N=1,015; mean follow-up 1.8 years.
Study Design
Arms: Apixaban 5 mg BID (n=737) vs Aspirin 81 mg daily (n=742)
Outcome
• Recurrent ischemic stroke or systemic embolism: HR 0.92 (95% CI 0.59–1.44)
• Recurrent stroke or death: HR 1.08 (95% CI 0.76–1.52)
• Symptomatic intracranial hemorrhage: 0 (apixaban) vs. 7 (aspirin)
• Major bleeding (non-intracranial): 0.7% vs. 0.8%; HR 1.02 (95% CI 0.29–3.52)
• All-cause mortality: HR 1.53 (95% CI 0.63–3.75)
Bottom Line
Apixaban did not significantly reduce the risk of recurrent stroke compared with aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation. Apixaban also did not significantly increase the risk of major bleeding.
Major Points
- The trial enrolled 1015 participants and was stopped early for futility after a planned interim analysis, with a mean follow-up of 1.8 years.
- Recurrent stroke occurred in 40 patients (annualized rate 4.4%) in both the apixaban and aspirin groups (HR 1.00; 95% CI 0.64–1.55; P=0.99).
- Symptomatic intracranial hemorrhage occurred in 0 patients receiving apixaban and 7 receiving aspirin (annualized rate 1.1%).
- Other major hemorrhages occurred in 5 patients in each group (apixaban: 0.7%; aspirin: 0.8%; HR 1.02; 95% CI 0.29–3.52).
- Atrial fibrillation was diagnosed in 14.7% of participants during follow-up, with a median detection time of 30 weeks.
- No heterogeneity of treatment effect was observed across seven prespecified subgroups.
Study Design
- Study Type
- Multicenter, double-blind, phase 3 randomized clinical trial
- Randomization
- Yes
- Blinding
- Double-blind (participants and outcome adjudicators were blinded; major hemorrhage assessed by sites).
- Sample Size
- 1015
- Follow-up
- Mean 1.8 years
- Centers
- 185
- Countries
- United States, Canada
Primary Outcome
Definition: Recurrent stroke of any type (ischemic, hemorrhagic, or undetermined type) in a time-to-event analysis
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 40 patients (annualized rate, 4.4%) | 40 patients (annualized rate, 4.4%) | 1 (0.64–1.55) | 0.99 |
Limitations & Criticisms
- Trial was stopped early for futility, limiting power to detect smaller treatment effects.
- Rigorous cryptogenic stroke definition may limit generalizability to broader clinical populations.
- Biomarker thresholds and selection criteria may not fully capture atrial cardiopathy spectrum.
- Subgroup with left atrial diameter index ≥3 cm²/m² was too small to allow treatment effect analysis.
- High rates of AF diagnosis during follow-up may reflect underlying pathophysiology, but benefit of preemptive anticoagulation remains unproven.
Citation
JAMA. 2024;331(7):573-581. doi:10.1001/jama.2023.27188