CREST-H

Principal Investigator: Jennifer Majersik
Keywords: carotid revascularization , medical management , asymptomatic carotid stenosis , hemodynamics Department: Neurology
IRB Number: 00107226 Co Investigator: Adam  DeHavenon
Specialty: Neurology, Neurology
Sub Specialties: Neuroimaging, Stroke
Recruitment Status: Not yet recruiting

Contact Information

Kinga Aitken
kinga.aitken@hsc.utah.edu
801-581-5523

Brief Summary

A. Specific Aims
Vascular cognitive impairment is widely described as a step-wise or progressive disease resulting from accumulated ischemic injury.23-26 Cerebral hemodynamic failure in patients with high-grade carotid artery stenosis can also impair cognition even if no overt clinical stroke has occurred27-28, contributing independently to cognitive decline either directly29, or as a consequence of a higher occurrence of silent infarction by thrombosis or embolism. Although there is compelling preliminary evidence from case series and physiological studies that hemodynamic impairment affects cognition in patients with carotid occlusive disease, treatment of this condition has never been tested in a randomized clinical trial. CREST-2 is a pair of outcome-blinded, Phase 3 clinical trials in patients with asymptomatic high-grade carotid artery stenosis, which compares stroke prevention and death for carotid endarterectomy (CEA) plus intensive medical mangement (IMM) versus IMM alone, and carotid artery stenting (CAS) plus IMM versus IMM alone. Our proposal addresses the intriguing question regarding the potential reversibility of cognitive decline when it arises from abnormal cerebral hemodynamics. Five hundred CREST-2 patients will undergo perfusion-weighted MRI (PWI) to identify patients with hemodynamic impairment. If cognitive impairment is identified, and reversed or stabilized in these patients, then we will have established a new indication for carotid revascularization, independent of the risk of stroke and importantly, reducing the public health burden of vascular cognitive impairment.
Specific Aim. To determine whether cognition can be improved by revascularization among a subset of CREST-2 patients with hemodynamic impairment at baseline.
Hypothesis 1. Among patients randomized in CREST-2 who have impaired cognition at baseline (as measured by CREST-2 cognitive battery baseline Z-score ≤ -1.0), those assigned to revascularization by CEA or CAS plus IMM will have greater improvement in cognition at 1 year compared to those assigned to IMM alone if they had flow failure at baseline (as measured by PWI time to peak (TTP) > 2 sec), and compared to an identical group of patients without flow failure, adjusting for age, baseline cognitive performance, depression, prior cerebral infarcts, subsequent silent infarction, WMH volume, and microbleeds.
Hypothesis 2. Among those with baseline cognitive and hemodynamic impairment assigned to revascularization by CEA or CAS, degree of improvement in cognition will correlate with degree of improvement in TTP.
Hypothesis 3. Among CREST-2 patients with hemodynamic and cognitive impairment at baseline, the difference in cognitive performance between the revascularization versus medical-only groups will be maintained during yearly CREST-2 follow exams up to 4 years.
Secondary aims:
Secondary Aim 1: To determine if the number of silent infarcts at 1 year is different between the revascularization and the medical-only arms.

Hypothesis S2: Among CREST-2 patients with hemodynamic impairment at baseline, there will be fewer new silent infarcts (e.g. due to embolization) at 1 year among those assigned to revascularization compared with patients in the medical-only arm
Secondary Aim 2: To determine if the WMH volume is different at 1 year between the revascularization and the medical-only arms.
Hypothesis S3: Among CREST-2 patients with hemodynamic impairment at baseline, change in WMH volumes at 1 year will be less among those assigned to revascularization compared with patients in the medical-only arm.
Exploratory Aim: We will assess additional imaging markers including TTP delay >4 sec, circle of Willis collateral pattern, mean transit time (MTT), Tmax, CBF, and cerebral blood volume (CBV) to determine with greater specificity possible physiological mechanisms.

Inclusion Criteria

Inclusion criteria include randomization in CREST-2 . Specifically:

Age 35-86 years
provision of appropriate consent
willingness and ability to participate in study procedures
≥70% ICA stenosis
No ipsilateral stroke or TIA within 180 days of randomization
No chronic or paroxysmal atrial fibrillation requiring anticoagulation
Anatomy amenable to stenting (CAS trial); No surgical contraindication (for CEA trial)

Exclusion Criteria

All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation.
unable to undergo MRI (e.g. metal in body, pacemaker)
allergy to gadolinium contrast dye
Either creatinine ≥ 2.5 mg/dl or GFR < 30cc/min
pre-existing diagnosis of dementia
contralateral ICA stenosis >70% by MRA, CTA or Doppler unltrasound
history of severe head trauma defined by loss of consciousness >30 minutes, or seizure
use of illicit drugs within the last 6 months
major depression
education less than 8 years