ARCADIA
Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial
Year of Publication: 2024
Authors: Hooman Kamel, MD; W. T. Longstreth Jr, MD; David L. Tirschwell, ..., MD; for the ARCADIA Investigators
Journal: JAMA
Citation: JAMA. 2024;331(7):573-581. doi:10.1001/jama.2023.27188
Link: https://jamanetwork.com/journals/jama/fullarticle/2814890
PDF: Clinical Question
Is anticoagulation with apixaban superior to antiplatelet therapy with aspirin for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy but no atrial fibrillation?
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.
Design
Study Type: Multicenter, double-blind, phase 3 randomized clinical trial
Randomization: 1
Blinding: Double-blind (participants and outcome adjudicators were blinded; major hemorrhage assessed by sites).
Enrollment Period: February 1, 2018, through February 28, 2023
Follow-up Duration: Mean 1.8 years
Centers: 185
Countries: United States, Canada
Sample Size: 1015
Analysis: Intention-to-treat for efficacy using log-rank test and unadjusted HRs; prespecified sensitivity analyses included competing risk regression and censoring at AF diagnosis. On-treatment population used for safety. Software: Stata/MP v18.
Inclusion Criteria
- Age ≥45 years
- Cryptogenic ischemic stroke (per ESUS criteria)
- Brain imaging ruling out hemorrhage
- mRS score ≤4
- Randomization ≤180 days from stroke onset
- Evidence of atrial cardiopathy: ≥1 of (PTFV1 >5000 µV×ms; NT-proBNP >250 pg/mL; LA diameter index ≥3 cm/m²)
Exclusion Criteria
- Any history of atrial fibrillation or LVEF <30%
- Indication or contraindication to aspirin or apixaban
- History of spontaneous intracranial hemorrhage
- Creatinine ≥2.5 mg/dL
- Clinically significant bleeding diathesis
- Multiple potential stroke etiologies or incomplete diagnostic evaluation
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age, mean (SD), y | 68.2 (11.0) | 67.8 (10.8) |
| Female, n (%) | 279 (54.9) | 272 (53.7) |
| Race - Asian, n (%) | 10 (2.0) | 7 (1.4) |
| Race - Black or African American, n (%) | 107 (21.4) | 107 (21.4) |
| Race - White, n (%) | 379 (75.8) | 381 (76.0) |
| Race - Other, n (%) | 4 (0.8) | 6 (1.2) |
| Ethnicity - Hispanic or Latino, n (%) | 39 (7.7) | 43 (8.5) |
| Ethnicity - Not Hispanic or Latino, n (%) | 466 (92.3) | 462 (91.5) |
| Weight, mean (SD), kg | 84.5 (20.2) | 85.1 (20.1) |
| Hypertension, n (%) | 388 (76.4) | 396 (78.1) |
| Prior or current tobacco use, n (%) | 200 (39.4) | 230 (45.4) |
| Diabetes, n (%) | 159 (31.3) | 156 (30.8) |
| Prior stroke or TIA, n (%) | 100 (19.7) | 97 (19.1) |
| Ischemic heart disease, n (%) | 46 (9.1) | 58 (11.4) |
| Heart failure, n (%) | 35 (6.9) | 36 (7.1) |
| Peripheral arterial disease, n (%) | 7 (1.4) | 12 (2.4) |
| CHA2DS2-VASc score, mean (SD) | 4.7 (1.3) | 4.7 (1.3) |
| NIH Stroke Scale score, median (IQR) | 1 (0–3) | 1 (0–3) |
| NT-proBNP median (IQR), pg/mL | 318 (130–551) | 288 (87–535) |
| PTFV1, mean (SD), µV×ms | 4766 (2920) | 4716 (2515) |
| LA diameter index, mean (SD), cm/m² | 1.9 (0.5) | 1.9 (0.5) |
| Days from index stroke to randomization, median (IQR) | 53 (23–100) | 48 (21–96) |
Arms
| Field | Apixaban Group | Control |
|---|---|---|
| Intervention | Apixaban 5 mg twice daily (or 2.5 mg twice daily if dose reduction criteria met) plus aspirin placebo once daily | Aspirin 81 mg once daily plus apixaban placebo twice daily |
| Duration | Mean 1.8 years | Mean 1.8 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Recurrent stroke of any type (ischemic, hemorrhagic, or undetermined type) in a time-to-event analysis | Primary | 40 patients (annualized rate, 4.4%) | 40 patients (annualized rate, 4.4%) | 1 | 0.99 |
| Composite of recurrent ischemic stroke or systemic embolism | Secondary | 40 events (annualized rate, 4.4%) | 37 events (annualized rate, 4.1%) | 0.92 | 0.72 |
| Composite of recurrent stroke of any type or death from any cause | Secondary | 62 events (annualized rate, 6.8%) | 67 events (annualized rate, 7.3%) | 1.08 | 0.66 |
| Symptomatic intracranial hemorrhage (on-treatment population) | Adverse | 7 patients (annualized rate, 1.1%) | 0 patients (annualized rate, 0%) | 0.01 | |
| Major hemorrhage (other than intracranial hemorrhage) (on-treatment population) | Adverse | 5 patients (annualized rate, 0.8%) | 5 patients (annualized rate, 0.7%) | 1.02 | 0.97 |
| All-cause mortality (on-treatment population) | Adverse | 8 patients (annualized rate, 1.2%) | 12 patients (annualized rate, 1.8%) | 1.53 | 0.35 |
Subgroup Analysis
No significant heterogeneity of treatment effect was observed across seven prespecified subgroups, including age, sex, race/ethnicity, weight, NT-proBNP level, PTFV1, and LA diameter index.
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.
Funding
National Institutes of Health (NIH); BMS-Pfizer provided in-kind apixaban and placebo; Roche Diagnostics provided laboratory funding for NT-proBNP assays.
Based on: ARCADIA (JAMA, 2024)
Authors: Hooman Kamel, MD; W. T. Longstreth Jr, MD; David L. Tirschwell, ..., MD; for the ARCADIA Investigators
Citation: JAMA. 2024;331(7):573-581. doi:10.1001/jama.2023.27188
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