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ARCADIA

Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial

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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

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?

Study Overview

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

In patients with recent cryptogenic stroke and atrial cardiopathy (elevated NT-proBNP, abnormal P-wave terminal force, or enlarged left atrium), apixaban did not reduce the risk of recurrent stroke compared with aspirin. The trial was stopped early for futility.

Intervention

Apixaban 5 mg or 2.5 mg twice daily (dose reduction to 2.5 mg BID when standard criteria were met) vs. aspirin 81 mg daily. Randomized, double-blind, phase 3 trial. N=1,015; mean follow-up 1.8 years.

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: Enrollment/screening ran February 1, 2018 through December 14, 2022; final outcome data collected 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

Arms

Field	Apixaban Group	Control
Intervention	Apixaban 5 mg twice daily (or 2.5 mg twice daily if standard 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 events / 910 person-years (annualized rate, 4.4%)	40 events / 913 person-years (annualized rate, 4.4%)	1	0.99
Composite of recurrent ischemic stroke or systemic embolism	Secondary	40 events / 909 person-years (annualized rate, 4.4%)	37 events / 913 person-years (annualized rate, 4.1%)	0.92
Composite of recurrent stroke of any type or death from any cause	Secondary	62 events / 910 person-years (annualized rate, 6.8%)	67 events / 913 person-years (annualized rate, 7.3%)	1.08
Symptomatic intracranial hemorrhage (on-treatment population)	Adverse	7 events / 660 person-years (annualized rate, 1.1%)	0 events / 668 person-years (annualized rate, 0%)
Major hemorrhage (other than intracranial hemorrhage) (on-treatment population)	Adverse	5 events / 664 person-years (annualized rate, 0.8%)	5 events / 668 person-years (annualized rate, 0.7%)	1.02
All-cause mortality (on-treatment population)	Adverse	8 events / 666 person-years (annualized rate, 1.2%)	12 events / 668 person-years (annualized rate, 1.8%)	1.53

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 cm/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)