AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke

ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3
clinical trial of apixaban versus aspirin in patients who have evidence of atrial cardiopathy
and a recent stroke of unknown cause. Eleven hundred subjects will be recruited over 2.5
years at 120 sites in the NINDS StrokeNet consortium. Subjects will be followed for a minimum
of 1.5 years and a maximum of 4 years for the primary efficacy outcome of recurrent stroke
and the primary safety outcomes of symptomatic intracranial hemorrhage and major hemorrhage
other than intracranial hemorrhage.

Inclusion Criteria:

- Age ≥ 45 years.

- Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.

- Modified Rankin Scale (MRS) score ≤ 4.

- Ability to be randomized within 3 to 120 days after stroke onset.

- ESUS, defined as all of the following:

- Stroke detected by CT or MRI that is not lacunar. Lacunar is defined as a
subcortical (this includes pons and midbrain) infarct in the distribution of the
small, penetrating cerebral arteries whose largest dimension is ≤1.5 cm on CT or
≤2.0 cm on MRI diffusion images/<1.5 cm on T2 weighted MR images. The following
are not considered lacunes: multiple simultaneous small deep infarcts, lateral
medullary infarcts, and cerebellar infarcts. Patients with a clinical lacunar
stroke syndrome and no infarct on imaging are excluded.

- Absence of extracranial or intracranial atherosclerosis causing ≥50 percent
luminal stenosis of the artery supplying the area of ischemia. Patients must
undergo vascular imaging of the extracranial and intracranial vessels using
either catheter angiography, CT angiogram (CTA), MR angiogram (MRA), or
ultrasound, as considered appropriate by the treating physician and local
principal investigator.

- No major-risk cardioembolic source of embolism, including intracardiac thrombus,
mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors,
mitral stenosis, myocardial infarction within the last 4 weeks, left ventricular
ejection fraction <30 percent, valvular vegetations, or infective endocarditis).
Patent foramen ovale is not an exclusion. All patients must undergo
electrocardiogram, transthoracic or transesophageal echocardiography (TTE or TEE)
and at least 24 hours of cardiac rhythm monitoring (Holter monitor or telemetry
or equivalent). Additional cardiac imaging, such as cardiac MRI, or cardiac CT
will be performed at the discretion of the local treating physician and principal
investigator. Additional cardiac rhythm monitoring, such as monitored cardiac
outpatient telemetry (MCOT) or an implanted cardiac monitor, will be at the
discretion of the treating physician and local principal investigator.

- No other specific cause of stroke identified, such as arteritis, dissection,
migraine, vasospasm, drug abuse, or hypercoagulability. Special testing, such as
toxicological screens, serological testing for syphilis, and tests for
hypercoagulability, will be performed at the discretion of the treating physician
and local principal investigator.

Exclusion Criteria:

- History of AF, AF on 12-lead ECG, or any AF of any duration during heart-rhythm
monitoring prior to randomization.

- Clear indication for treatment-dose anticoagulant therapy, such as venous
thromboembolism or a mechanical heart valve.

- Need for antiplatelet agent, such as aspirin or clopidogrel

- History of spontaneous intracranial hemorrhage.

- Chronic kidney disease with serum creatinine ≥2.5 mg/dL.

- Active hepatitis or hepatic insufficiency with Child-Pugh score B or C.

- Clinically significant bleeding diathesis.

- Unresolved anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 10E9/L).

- Clinically significant gastrointestinal bleeding within the past year (e.g., not due
to external hemorrhoids).

- At risk for pregnancy: premenopausal or postmenopausal woman within 12 months of last
menses without a negative pregnancy test or not committing to adequate birth control,
which includes an oral contraceptive, two methods of barrier birth control such as
condom with or without spermicidal lubricant + diaphragm, or abstinence.

- Known allergy or intolerance to aspirin or apixaban.

- Concomitant participation in another clinical trial involving a drug or acute stroke
intervention.

- Considered by the investigator to have a condition that precludes follow-up or safe
participation in the trial.

- Inability of either participant or surrogate to provide written, informed consent for
trial participation.