AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke

Phase 3

Terminated

Conditions: Stroke

Interventions: Drug: Apixaban
Drug: Aspirin

Registration Number: NCT03192215

Lead Sponsor: Columbia University

Brief Summary: Objectives

* Primary: To test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in patients with cryptogenic ischemic stroke and atrial cardiopathy.

* Secondary: To test the hypothesis that the relative efficacy of apixaban over aspirin increases with the severity of atrial cardiopathy.

Detailed Description: 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 up to 200 sites in and out of the NINDS StrokeNet consortium. Subjects will be followed for a minimum of 1.5 years and a maximum of 7 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1015

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 180 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, moderate or severe 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 atrial fibrillation (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.For Canadian sites only, estimated creatinine clearance (eCrCl) <15 mL/min is also an exclusion criterion.
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.

To be eligible for randomization, consented participants must meet criteria for atrial cardiopathy in addition to the inclusion/exclusion criteria above.

Atrial cardiopathy is defined as ≥1 of the following:

PTFV1 >5,000 μV*ms on 12-lead ECG (ECG criterion).
Serum NT-proBNP >250 pg/mL (NT-proBNP criterion).
Left atrial diameter index ≥3 cm/m2 on echocardiogram (i.e., severe left atrial enlargement) (ECHO criterion)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active agent: Apixaban	Apixaban	Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Apixaban
Active control: Aspirin	Aspirin	Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Aspirin

Primary Outcome Measures

Name	Time	Method
Number of Participants With Recurrent Stroke of Any Type	Up to 5 years of study participation.	Participants were monitored for up to 5 years of study participation. This is the number of participants who had recurrent stroke of any type (ischemic, hemorrhagic, or of unclear type).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Recurrent Ischemic Stroke or Systemic Embolism	Up to 5 years of study participation.	Secondary efficacy outcome A. Participants were monitored for up to 5 years. This is the number of participants who had recurrent ischemic stroke or systemic embolism during the time of observation.
Number of Participants With Recurrent Stroke of Any Type or Death From Any Cause	Up to 5 years of study participation.	Secondary efficacy outcome B. Participants were monitored for up to 5 years. This is the number of participants who had recurrent stroke of any type or death from any cause during the observation time.
Number of Participants With Major Hemorrhage Other Than Intracranial Hemorrhage.	Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.	This is the number of participants who had major hemorrhage other than intracranial hemorrhage.
Number of Participant Deaths From Any Cause Number of Participants With All-cause Mortality.	Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.	Secondary safety outcome. This is the number of participants who had all-cause mortality during time of observation.
Number of Participants With Symptomatic Intracranial Hemorrhage (Including Symptomatic Hemorrhagic Transformation of an Ischemic Stroke)	Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.	Primary safety outcome A. This is the number of participants who had symptomatic intracranial hemorrhage from any cause during the time of observation. Symptomatic intracranial hemorrhage includes symptomatic hemorrhagic transformation of ischemic stroke, which required new symptoms or signs adjudicated as being due to the hemorrhagic transformation or a patient whose initial imaging was judged to include hemorrhagic transformation of an ischemic stroke.

Trial Locations

Locations (176): University of Alabama
🇺🇸
Birmingham, Alabama, United States
University of South Alabama University Hospital
🇺🇸
Mobile, Alabama, United States
Chandler Regional Medical Center Chandler, AZ
🇺🇸
Chandler, Arizona, United States
St. Joseph's Hospital and Medical Center
🇺🇸
Phoenix, Arizona, United States
Banner University Medical Center - Tucson
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Tucson, Arizona, United States
Mercy San Juan Medical Center (Dignity Health)
🇺🇸
Carmichael, California, United States
Eden Medical Center
🇺🇸
Castro Valley, California, United States
Rancho Los Amigos National Rehabilitation Center
🇺🇸
Downey, California, United States
Fountain Valley Regional Hospital and Medical Center
🇺🇸
Fountain Valley, California, United States
Community Regional Medical Center
🇺🇸
Fresno, California, United States
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University of Alabama
🇺🇸Birmingham, Alabama, United States