Stroke
Conditions
Keywords
Atrial Cardiopathy, Cryptogenic stroke, Ischemic stroke, Apixaban, Aspirin
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.
Interventions
DRUGApixaban
5 mg by mouth twice daily (2.5 mg for subjects meeting standard criteria for an adjusted dose).
DRUGAspirin
Aspirin 81 mg by mouth once daily.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Cincinnati
Medical University of South Carolina
Bristol-Myers Squibb
Pfizer
Roche Pharma AG
Weill Medical College of Cornell University
University of Washington
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Eligible patients will be allocated in a 1:1 ratio to apixaban or aspirin using the minimal sufficient balance randomization method to prevent serious treatment imbalances by study site.
Intervention model description
Active treatment will be either apixaban 5 mg or aspirin 81 mg. An adjusted dose of apixaban 2.5 mg will be used for subjects with at least two of the following: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or known serum creatinine greater than or equal to 1.5 mg/dL. There will be six possible study tablets: apixaban 5 mg (regular dose), apixaban 2.5 mg (adjusted dose), apixaban 5 mg placebo, apixaban 2.5 mg placebo, aspirin 81 mg, and aspirin placebo. All subjects will be randomized to receive active treatment with either active apixaban or active aspirin. Study treatments will be supplied in a double-dummy fashion as apixaban 5 mg (2.5 mg for the adjusted dose) or matching placebo, and aspirin 81 mg or matching placebo.
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
Countries
Canada, United States
Participant flow
Recruitment details
There were 37,443 potential participants screened, 2,730 were consented by 174 sites into the trial to undergo further criteria review and determine eligibility for randomization by criterion. Once a subject reached eligibility criteria for at least one of the three trial markers, they were approached for randomization. In the end, the study randomized 1,015 subjects at 141 sites (507 in apixaban arm & 508 in aspirin arm).
Pre-assignment details
2,730 subjects were consented, then 3 biomarkers were obtained and reviewed for randomization eligibility. 1,015 out of 2,730 were eligible and randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| Active Agent: Apixaban Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Apixaban
Apixaban: 5 mg by mouth twice daily (2.5 mg for subjects meeting standard criteria for an adjusted dose) and an aspirin placebo once daily. | 507 |
| Active Control: Aspirin Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Aspirin
Aspirin: Aspirin 81 mg by mouth once daily and an apixaban placebo twice daily. | 508 |
| Total | 1,015 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 28 | 23 |
| Overall Study | Lost to Follow-up | 10 | 15 |
| Overall Study | Other as reported in analysis | 4 | 1 |
| Overall Study | Withdrawal by Subject | 49 | 48 |
Baseline characteristics
| Characteristic | Active Agent: Apixaban | Total | Active Control: Aspirin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 305 Participants | 634 Participants | 329 Participants |
| Age, Categorical Between 18 and 65 years | 202 Participants | 381 Participants | 179 Participants |
| Age, Continuous | 67.8 years STANDARD_DEVIATION 10.8 | 68.0 years STANDARD_DEVIATION 10.9 | 68.2 years STANDARD_DEVIATION 11 |
| Atrial Cardiopathy Biomarker - Left atrial diameter index (cm/m2; site reported) | 1.9 cm/m2 STANDARD_DEVIATION 0.5 | 1.9 cm/m2 STANDARD_DEVIATION 0.5 | 1.9 cm/m2 STANDARD_DEVIATION 0.5 |
| Atrial Cardiopathy Biomarker - NTproBNP (pg/mL) | 288 pg/mL | 303 pg/mL | 318 pg/mL |
| Atrial Cardiopathy Biomarker - P-wave terminal force in lead V1 (µV*ms) | 4,716 µV*ms | 4,741 µV*ms | 4,766 µV*ms |
| CHA2DS2-VASc Score | 4.7 points in a score system STANDARD_DEVIATION 1.3 | 4.7 points in a score system STANDARD_DEVIATION 1.3 | 4.7 points in a score system STANDARD_DEVIATION 1.3 |
| Days from index stroke to randomization | 48 days | 50 days | 53 days |
| Ethnicity (NIH/OMB) Hispanic or Latino | 43 Participants | 82 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 462 Participants | 928 Participants | 466 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Medical Comorbidities - Diabetes mellitus | 156 Participants | 315 Participants | 159 Participants |
| Medical Comorbidities - Heart Failure | 36 Participants | 71 Participants | 35 Participants |
| Medical Comorbidities - Hypertension | 396 Participants | 784 Participants | 388 Participants |
| Medical Comorbidities - Ischemic Heart Disease | 58 Participants | 104 Participants | 46 Participants |
| Medical Comorbidities - Peripheral Arterial Disease | 12 Participants | 19 Participants | 7 Participants |
| Medical Comorbidities - Prior or Current Tobacco Use | 230 Participants | 430 Participants | 200 Participants |
| Medical Comorbidities - Prior stroke or TIA | 97 Participants | 197 Participants | 100 Participants |
| NIH Stroke Scale | 1 score on a scale | 1 score on a scale | 1 score on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 17 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 107 Participants | 214 Participants | 107 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 14 Participants | 8 Participants |
| Race (NIH/OMB) White | 381 Participants | 760 Participants | 379 Participants |
| Region of Enrollment Canada | 16 participants | 32 participants | 16 participants |
| Region of Enrollment United States | 491 participants | 983 participants | 492 participants |
| Sex: Female, Male Female | 272 Participants | 551 Participants | 279 Participants |
| Sex: Female, Male Male | 235 Participants | 464 Participants | 229 Participants |
| Weight (kg) | 85.1 kg STANDARD_DEVIATION 20.1 | 84.8 kg STANDARD_DEVIATION 20.2 | 84.5 kg STANDARD_DEVIATION 20.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 32 / 507 | 24 / 508 |
| other Total, other adverse events | 99 / 507 | 91 / 508 |
| serious Total, serious adverse events | 355 / 507 | 388 / 508 |
Outcome results
Primary
Number of Participants With Recurrent Stroke of Any Type
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).
Time frame: Up to 5 years of study participation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Agent: Apixaban | Number of Participants With Recurrent Stroke of Any Type | 40 Participants |
| Active Control: Aspirin | Number of Participants With Recurrent Stroke of Any Type | 40 Participants |
p-value: 0.9995% CI: [0.64, 1.55]Log Rank
Secondary
Number of Participant Deaths From Any Cause Number of Participants With All-cause Mortality.
Secondary safety outcome. This is the number of participants who had all-cause mortality during time of observation.
Time frame: Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.
Population: The safety sample includes all participants who are randomized and receive at least one dose of study medication. The safety sample will include all safety outcomes from randomization until 30 days after permanent discontinuation of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Agent: Apixaban | Number of Participant Deaths From Any Cause Number of Participants With All-cause Mortality. | 12 Participants |
| Active Control: Aspirin | Number of Participant Deaths From Any Cause Number of Participants With All-cause Mortality. | 8 Participants |
p-value: 0.3595% CI: [0.63, 3.75]Log Rank
Secondary
Number of Participants With Major Hemorrhage Other Than Intracranial Hemorrhage.
This is the number of participants who had major hemorrhage other than intracranial hemorrhage.
Time frame: Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.
Population: The safety sample includes all participants who are randomized and receive at least one dose of study medication.~The safety sample will include all safety outcomes from randomization until 30 days after permanent discontinuation of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Agent: Apixaban | Number of Participants With Major Hemorrhage Other Than Intracranial Hemorrhage. | 5 Participants |
| Active Control: Aspirin | Number of Participants With Major Hemorrhage Other Than Intracranial Hemorrhage. | 5 Participants |
p-value: 0.9895% CI: [0.29, 3.52]Log Rank
Secondary
Number of Participants With Recurrent Ischemic Stroke or Systemic Embolism
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.
Time frame: Up to 5 years of study participation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Agent: Apixaban | Number of Participants With Recurrent Ischemic Stroke or Systemic Embolism | 37 Participants |
| Active Control: Aspirin | Number of Participants With Recurrent Ischemic Stroke or Systemic Embolism | 40 Participants |
p-value: 0.7295% CI: [0.59, 1.44]Log Rank
Secondary
Number of Participants With Recurrent Stroke of Any Type or Death From Any Cause
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.
Time frame: Up to 5 years of study participation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Agent: Apixaban | Number of Participants With Recurrent Stroke of Any Type or Death From Any Cause | 67 Participants |
| Active Control: Aspirin | Number of Participants With Recurrent Stroke of Any Type or Death From Any Cause | 62 Participants |
p-value: 0.6795% CI: [0.76, 1.52]Log Rank
Secondary
Number of Participants With Symptomatic Intracranial Hemorrhage (Including Symptomatic Hemorrhagic Transformation of an Ischemic Stroke)
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.
Time frame: Through 30 days after permanent discontinuation of the study drug, a duration of up to 5 years for each participant.
Population: The safety sample includes all participants who are randomized and receive at least one dose of study medication.~The safety sample will include all safety outcomes from randomization until 30 days after permanent discontinuation of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Agent: Apixaban | Number of Participants With Symptomatic Intracranial Hemorrhage (Including Symptomatic Hemorrhagic Transformation of an Ischemic Stroke) | 0 Participants |
| Active Control: Aspirin | Number of Participants With Symptomatic Intracranial Hemorrhage (Including Symptomatic Hemorrhagic Transformation of an Ischemic Stroke) | 7 Participants |
p-value: 0.0295% CI: [-0.018, -0.003]Exact Binomial Test