Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke - ARCADIA

Contribution To Literature:

The ARCADIA trial showed that in patients with cryptogenic stroke and atrial cardiopathy, apixaban did not reduce the risk of recurrent stroke compared with low dose aspirin.


The goal of the trial was to determine whether apixaban reduces the risk of recurrent stroke compared with low dose aspirin in patients with cryptogenic ischemic stroke and evidence of atrial cardiopathy but without atrial fibrillation (AF).

Study Design

  • Multicenter
  • Randomized
  • Double-blind, double-dummy

Patients with cryptogenic stroke and evidence of atrial cardiopathy without AF were randomized within 180 days of stroke to receive twice daily apixaban 5 mg or 2.5 mg (if dose reduction indicated) and aspirin placebo daily (n = 507) or aspirin 81 mg daily and apixaban placebo twice daily (n = 508). Patients diagnosed with AF following randomization were crossed over to open-label anticoagulation but included in their original treatment arm for analysis.

  • Total number of enrollees: 1,015
  • Mean duration of follow-up: 1.8 years
  • Mean patient age: 68 years
  • Percentage female: 54%

Inclusion criteria:

  • Age ≥45 years
  • Cryptogenic ischemic stroke, defined as absence of: (1) lacunar infarct, (2) obstructive intracranial or cervical atherosclerotic disease, (3) cardiac thrombus or high-risk features on echocardiography, AND (4) prothrombotic arrhythmias on both electrocardiography (ECG) and ≥24-hour rhythm monitoring
  • Modified Rankin Scale score ≤4
  • Atrial cardiopathy, defined as ≥1 of: V1 P-wave terminal force >5000 µV·ms, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) >250 pg/mL, or indexed left atrial diameter ≥3 cm/m2 on transthoracic echocardiography (TTE)

Exclusion criteria:

  • AF diagnosed prior to randomization
  • Left ventricular ejection fraction <30%
  • Other indication or contraindication for anticoagulation or antiplatelet therapy
  • Prior spontaneous intracranial hemorrhage
  • Serum creatinine ≥2.5 mg/dL

Other salient features/characteristics:

  • Median time post-stroke to randomization: 50 days
  • Median National Institutes of Health Stroke Scale score at randomization: 1
  • Mean CHA2DS2-VASc score: 4.7
  • Atrial cardiopathy criteria met: ECG, 53%; NT-proBNP, 61%; TTE, 1%
  • AF was diagnosed in 15% of participants at a median of 30 weeks post-randomization

Principal Findings:

The primary outcome, annualized rate of recurrent ischemic or hemorrhagic stroke, for apixaban vs. aspirin, was: 4.4% vs. 4.4%, hazard ratio [HR] 1.00 (95% confidence interval [CI] 0.64-1.55, p = 0.99).

  • Prespecified analysis censoring patient data following AF diagnosis: HR 1.05 (95% CI 0.66-1.65)

Secondary efficacy outcomes for apixaban vs. aspirin:

  • Composite annualized rate of recurrent ischemic stroke and systemic embolism: 4.1% vs. 4.4%, HR 0.92 (95% CI 0.59-1.44)
  • Composite annualized rate of recurrent stroke and all-cause death: 7.3% vs. 6.8%, HR 1.08 (95% CI 0.76-1.52)

Primary safety outcomes for apixaban vs. aspirin:

  • Annualized rate of symptomatic intracranial hemorrhage: 0% vs. 1.1%
  • Annualized rate of other major extracranial hemorrhage: 0.7% vs. 0.8%, HR 1.02 (95% CI 0.29-3.52)

Secondary safety outcome, all-cause death, for apixaban vs. aspirin: 1.8% vs. 1.2%, HR 1.53 (95% CI 0.63-3.75)


The ARCADIA trial failed to demonstrate reduction in recurrent stroke risk using apixaban therapy versus low dose aspirin therapy in patients with cryptogenic stroke and atrial cardiopathy. This was despite observational data suggesting an association between atrial cardiopathy and stroke risk independent of AF. The authors hypothesize that this may reflect either underdetection of subclinical AF in prior studies or confounding by comorbid pathologies such as increased intracranial or cervical atherosclerotic disease. The latter possibility may increase risk of non-thromboembolic stroke, which may not have been affected by anticoagulation despite the relatively high mean baseline CHA2DS2-VASc score in the study cohort.

The prespecified sensitivity analysis censoring data following crossover for post-randomization AF did not affect the primary endpoint. Post-randomization AF was, however, seen in 15% of patients, supporting the association between markers of atrial cardiopathy and risk of incident AF. Therefore, although the current data do not support routine anticoagulation following stroke in atrial cardiopathy, such patients may benefit from additional monitoring for atrial arrhythmias that may increase their risk of subsequent cardioembolic stroke.


Kamel H, Longstreth WT Jr, Tirschwell DL, et al. Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial. JAMA 2024;Feb 7:[Epub ahead of print].

Editorial Comment: Marcus GM, Ovbiagele B. Anticoagulation for Atrial Cardiopathy in Cryptogenic Stroke. JAMA 2024;Feb 7:[Epub ahead of print].

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention

Keywords: Anticoagulants, Stroke

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