- 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 no later than 120 days after stroke onset.
- ESUS, defined as all of the following:
- Stroke 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, ≤2.0 cm on MRI diffusion images, or ≤1.5 cm on MRI T2-weighted 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% 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 AF, 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%, 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 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.
- 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.
- Left ventricular ejection fraction <30%.
- Definite indication for antiplatelet agent (e.g., aspirin or clopidogrel after implantation of a coronary artery stent).
- 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 (see MOP for definition).
- Clinically significant bleeding diathesis.
- Anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 109/L) that is chronic in the judgment of the investigator.
- GI bleeding within the past year considered clinically significant by the investigator.
- Pregnancy risk: − Female patient who is known to be pregnant.
- Female patient who is sexually active and premenopausal without a negative pregnancy test performed after stroke onset.
- Female patient who is sexually active and premenopausal, and who does not commit to adequate birth control.
- Male patient who is sexually active with a premenopausal female partner, and who does not commit to adequate birth control.
- 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 to obtain written, informed consent from patient or surrogate for trial participation.
Testing smartphone connected home BP monitoring vs. usual care for outpatient BP control.
- Adult, age ≥ 18 years
- History of ischemic stroke or high risk TIA (defined by ABCD2 ≥ 4) within 5 years prior to enrollment
- Hypertensive at time of enrollment, defined by SBP>140 mm Hg or DBP >90 mm Hg at the time of study screening
- Must own a smart phone capable of interacting with the connected blood pressure cuff (Apple iPhone 3GS or higher; Android 4.0 or higher with Bluetooth connectivity)
- Willingness and ability to sign informed consent by patient
- Moderate or severe disability, defined by modified Rankin Scale ≥ 3.
- Expected residence in a rehabilitation hospital, nursing facility or assisted living community during the study period.
- Upper arm circumference <9 inches or >17 inches
- Inability to monitor BP in both of the upper arms (i.e. history of bilateral radical mastectomy, bilateral severe subclavian stenosis, or bilateral arterial venous fistulas for dialysis).
- Blood pressure discrepancy between arms of >10 mm Hg.
- Inability to follow-up at 90 days and return BP monitor
- Active participation in another clinical trial
- Pregnant women
The goal of this study is to improve walking ability after stroke. Trial arms, 1) fast walking training with a step activity monitoring program (FAST+SAM) , 2) fast walking training alone (FAST) 3) a step activity monitoring and feedback program alone (SAM).
– age 21-85
– >6 months post stroke
– able to walk without assistance from another person (assistive devices are allowed)
– self-selected walking speed > 0.3 m/s and < 1.0 m/s
– resting heart rate between 40 and 100 beats per minute
– resting blood pressure between 90/60 and 170/90
– evidence of cerebellar stroke
– other potentially disabling neurologic conditions in addition to stroke
– lower limb botulinum toxin injection < 4 months prior
– current participation in physical therapy
– inability to walk outside of home prior to stroke
– coronary artery bypass graft, stent placement, or myocardial infarction within past 3 months
– musculoskeletal pain that limits activity
– inability to communicate with investigators
– score >1 on question 1b and >0 on question 1c on NIH Stroke Scale
General Inclusion Criteria
- Patients ≥35 years old.
- Carotid stenosis defined as:
- Stenosis ≥70% by catheter angiography (NASCET Criteria);
- by DUS with ≥70% stenosis defined by a peak systolic velocity of at least 230 cm/s plus at least one of the following:
- a) an end diastolic velocity ≥100 cm/s, or
- b) internal carotid/common carotid artery peak systolic velocity ratio ≥4.0, or
- c) CTA with ≥ 70% stenosis, or
- d) MRA with ≥ 70% stenosis.
- No medical history of stroke or TIA ipsilateral to the stenosis within 180 days of randomization. Life-long asymptomatic patients will be defined as having no medical history of stroke or transient ischemic attack and negative responses to all of the symptom items on the Questionnaire for Verifying Stroke-free Status (QVSS).18
- Patients must have a modified Rankin Scale score of 0 or 1 at the time of informed consent.
- Women must not be of childbearing potential or, if of childbearing potential, have a negative pregnancy test prior to randomization.
- Patients must agree to comply with all protocol-specified follow-up appointments.
- Patients must sign a consent form that has been approved by the local governing Institutional Review Board (IRB)/Medical Ethics Committee (MEC) of the respective clinical site.
- Randomization to treatment group will apply to only one carotid artery for patients with bilateral carotid stenosis. Management of the non-randomized stenosis may be done in accordance with local PI recommendation. Treatment of the non-study internal carotid artery must take place at least 30 days prior to randomization, or greater than 44 days after randomization and 30 days after the study procedure is completed (whichever is longer).
- Carotid stenosis must be treatable with CEA, CAS, or either procedure.
General Exclusion Criteria
- Intolerance or allergic reaction to a study medication without a suitable management alternative.
- GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy.
- Prior major ipsilateral stroke in the past with substantial residual disability (mRS ≥ 2) that is likely to confound study outcomes.
- Severe dementia.
- Intracranial hemorrhage within the past 12 months.
- Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke.
- Patient objects to future blood transfusions.
- Platelet count <100,000/μl or history of heparin-induced thrombocytopenia.
- Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents.
- Chronic atrial fibrillation.
- Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation.
- Other high-risk cardiac sources of emboli, including left ventricular aneurysm, severe cardiomyopathy, aortic or mitral mechanical heart valve, severe calcific aortic stenosis (valve area < 1.0 cm2), endocarditis, moderate to severe mitral stenosis, left atrial thrombus, or any intracardiac mass, or known unrepaired PFO with prior paradoxical embolism.
- Unstable angina defined as rest angina with ECG changes that is not amenable to revascularization (patients should undergo planned coronary revascularization at least 30 days before randomization).
- Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months.
- Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value.
- Known malignancy other than basal cell non-melanoma skin cancer. There are two exceptions to this rule: patients with prior cancer treatment and no recurrence for >5 years are eligible for enrollment and cancer patients with life expectancy of greater than 5 years are eligible for enrollment.
- Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month.
- Serum creatinine ≥2.5 mg/dl or estimated GFR ≤40 cc/min (at screening).
- Major (non-carotid) surgery/procedures planned within 3 months after enrollment.
- Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney).
- Actively participating in another drug or aortic arch or cerebrovascular device trial for which participation in CREST-2 would be compromised with regard to follow-up assessment of outcomes or continuation in CREST-2.
- Inability to understand and cooperate with study procedures or provide informed consent.
- Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy).
- Previous ipsilateral CEA or CAS.
- Ipsilateral internal or common carotid artery occlusion.
- Intra-carotid floating thrombus.
- Ipsilateral intracranial aneurysm > 5 mm.
- WHO Class III obesity (BMI >40 kg/m2).
- Contra-lateral common or internal carotid artery occlusion.
- Coronary artery disease with two or more proximal or major diseased coronary arteries with ≥ 70% stenosis that have not, or cannot, be revascularized.
- Any of the following anatomical: radical neck dissection; surgically inaccessible lesions (e.g. above cervical spine level 2 (C2)); adverse neck anatomy that limits surgical exposure (e.g. spinal immobility – inability to flex neck beyond neutral or kyphotic deformity, or short obese neck); presence of tracheostomy stoma; laryngeal nerve palsy contralateral to target vessel; or previous extracranial-intracranial or subclavian bypass procedure ipsilateral to the target vessel.
- Occlusive or critical ilio-femoral disease including severe tortuosity or stenosis that necessitates additional endovascular procedures to facilitate access to the aortic arch or that prevents safe and expeditious femoral access to the aortic arch. “String sign” of the ipsilateral common or internal carotid artery.
- Angiographic, CT, MR or ultrasound evidence of severe atherosclerosis of the aortic arch or origin of the innominate or common carotid arteries.
Specific carotid endarterectomy exclusion criteria
Patients who are being considered for revascularization by CEA must not have any of the following criteria:
- Serious adverse reaction to anesthesia not able to be overcome by pre-medication.
- Distal/intracranial stenosis greater than index lesion.
Specific Carotid Artery Stenting Exclusion Criteria
Patients who are being considered for revascularization by CAS must not have any of the following criteria:
- Allergy to intravascular contrast dye not amenable to pre-medication.
- Type III, aortic arch anatomy.
- Angulation or tortuosity (≥ 90 degree) of the innominate and common carotid artery that precludes safe, expeditious sheath placement or that will transmit a severe loop to the internal carotid after sheath placement.
- Severe angulation or tortuosity of the internal carotid artery (including calyceal origin from the carotid bifurcation) that precludes safe deployment of embolic protection device or stent. Severe tortuosity is defined as 2 or more ≥ 90 degree angles within 4 cm of the target stenosis.
- Proximal/ostial CCA, innominate stenosis or distal/intracranial stenosis greater than index lesion.
Excessive circumferential calcification of the stenotic lesion defined as >3mm thickness of calcification seen in orthogonal views on fluoroscopy.(Note: Anatomic considerations such as tortuosity, arch anatomy, and calcification must be evaluated even more carefully in elderly subjects (≥ 70 years).)
- Target ICA vessel reference diameter <4.0 mm or >9.0 mm. Target ICA measurements may be made from angiography of the contralateral artery. The reference diameter must be appropriate for the devices to be used.
- Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD).
- Non-contiguous lesions and long lesions (>3 cm).
- Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement.