ARCADIA-MRI
(2025)Objective
Evaluate whether apixaban reduces incident nonlacunar covert infarcts compared to aspirin in patients with cryptogenic stroke and atrial cardiopathy.
Study Summary
Intervention
Ancillary MRI substudy to the ARCADIA trial. N=174 participants with cryptogenic stroke and atrial cardiopathy, randomized to: • Apixaban 5 mg BID • Aspirin 81 mg daily MRI obtained at baseline (index stroke) and at study completion. Primary outcome: incident nonlacunar covert infarct identified by blinded readers.
Study Design
Arms: Array
Outcome
• Weighted relative risk: 0.29; 95% CI 0.10–0.83
• Median follow-up: 811 days
• Age: mean 66 years; mRS median 1; 52.3% male
• Baseline characteristics were balanced between arms
• Suggests apixaban may reduce subclinical brain injury even in absence of clinical stroke reduction
Bottom Line
Among patients with recent cryptogenic stroke and atrial cardiopathy enrolled in ARCADIA, apixaban compared with aspirin was associated with markedly fewer incident nonlacunar covert infarcts on MRI (5.1% vs 17.9%; weighted RR 0.29, 95% CI 0.10–0.83; P=0.02). The result contrasts with the neutral primary outcome of the parent ARCADIA trial and should be viewed as hypothesis-generating — the substudy enrolled a small, more drug-adherent subset and the CI is wide.
Major Points
- ARCADIA-MRI was an ancillary MRI substudy of the ARCADIA trial (apixaban vs aspirin in cryptogenic stroke with atrial cardiopathy).
- 310 of 1015 ARCADIA participants (31%) enrolled; 174 (56% of enrolled) had adequate baseline and follow-up MRIs and were included in the primary analysis (apixaban n=79, aspirin n=95).
- Primary endpoint — incident nonlacunar covert infarct on follow-up MRI — occurred in 5.1% with apixaban vs 17.9% with aspirin (weighted RR 0.29, 95% CI 0.10–0.83; P=0.02).
- Composite of nonlacunar covert infarct or nonlacunar symptomatic stroke: 9% vs 26%, RR 0.36 (0.17–0.79), P=0.01.
- No benefit on covert lacunar infarcts (10% vs 13%, RR 0.80, 0.34–1.86) — consistent with cardioembolic mechanism for nonlacunar infarcts.
- Annualized nonlacunar covert infarct rate: 2.0% (apixaban) vs 7.4% (aspirin) — lower than the prespecified 13.5% projection.
- Result is discordant with the neutral parent ARCADIA trial (HR 1.00 for recurrent stroke); authors attribute discordance to higher drug adherence in the MRI substudy (15.5% premature discontinuation vs 50.8% in ARCADIA-MRI screen failures) and selection of a more compliant cohort.
- Median follow-up 27 months; MRI scans interpreted by 2 raters blinded to treatment (interrater κ 0.81 for nonlacunar infarct).
- No differential treatment effect across prespecified subgroups (NT-proBNP, ECG, age, race, diabetes, sex, baseline mRS).
- Limitations: small sample (174 of 1015 ARCADIA participants), wide CI, baseline imbalances (more prior stroke/TIA and higher NT-proBNP in aspirin arm), high COVID-era attrition.
- Authors conclude results are hypothesis-generating and may justify on-treatment analysis of the parent ARCADIA trial.
Study Design
- Study Type
- Prospective, multicenter, double-blind, parallel-arm RCT — ancillary MRI substudy of ARCADIA
- Randomization
- Yes
- Blinding
- Double-blind; MRI raters masked to treatment assignment
- Sample Size
- 174
- Follow-up
- Median 27 months (median 811 days between baseline and follow-up MRI; IQR 487–1288)
- Centers
- 75
- Countries
- USA
Primary Outcome
Definition: Incident nonlacunar covert infarct on follow-up MRI (new ischemic lesion not present on baseline MRI, not lacunar, not from growth of index infarct, identified by 2 masked raters)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 17.9% (17/95) | 5.1% (4/79) | - (0.10–0.83) | P=0.02 |
Limitations & Criticisms
- Small sample size (174 of 1015 ARCADIA participants, 17%) — relatively few events with wide confidence intervals (RR 0.29, 95% CI 0.10–0.83).
- Discordant with the neutral primary outcome of the parent ARCADIA trial (HR 1.00 for recurrent stroke). Authors attribute discordance to higher drug adherence in the MRI substudy population (15.5% premature discontinuation vs 50.8% in screen failures).
- Highly selected population: required no permanent discontinuation of study drug at consent + ability/willingness to undergo MRI; results may not generalize to less adherent patients.
- Baseline imbalances: aspirin arm had numerically more prior stroke/TIA (25.5% vs 15.2%) and higher NT-proBNP (271 vs 199 pg/mL), which could have inflated the apparent treatment effect.
- COVID-19 pandemic affected MRI completion rates — 56% adequate MRIs is lower than typical for an MRI substudy.
- Aspirin-arm nonlacunar covert infarct rate (7.4%/yr) was substantially lower than the prespecified 13.5% projection, raising questions about external validity.
- Hypothesis-generating only — authors explicitly note results should not change practice without a definitive on-treatment analysis or replication.
Citation
JAMA Neurol. 2025;82(3):220-227. doi:10.1001/jamaneurol.2024.4838