Carotid Revascularization and Medical Management for Asymptomatic CarotidStenosis Trial - Hemodynamics (CREST-H)

CREST-H Project Summary Cerebral hemodynamic failure in patients with high-grade carotid artery stenosis can impair cognition even if no overt clinical stroke has occurred, contributing independently to cognitive decline either directly or because of a higher occurrence of silent infarction. CREST-H addresses the compelling question of whether carotid revascularization can stabilize or reverse cognitive decline in a subset of patients with asymptomatic, high-grade carotid stenosis who have cerebral hemodynamic failure related to the carotid stenosis. Although there is mounting evidence from preclinical and clinical 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-H has just passed 65% of target enrollment, a process slowed by the pandemic. This grant renewal will allow us to complete the (revised) target enrollment for CREST-H. Randomization in CREST-H is done within the parent trial, CREST-2, which comprises a pair of outcome- blinded, Phase 3 clinical trials in patients with asymptomatic high-grade carotid artery stenosis, comparing stroke prevention and death for either carotid endarterectomy (CEA) or carotid artery stenting (CAS) plus intensive medical management (IMM) versus IMM alone. CREST-2 has just received notice of funding for an additional 5 years. Hemodynamic impairment is measured by an inter-hemispheral MRI or CT perfusion “time to peak” (TTP) delay on the side of stenosis. Patients with baseline hemodynamic impairment return for follow up brain imaging at 1 year. For those who are found to have baseline hemodynamic failure and cognitive impairment, the cognitive batteries at baseline and at 1 year will determine if those who are assigned to a revascularization arm in CREST-2 will have better cognitive outcomes than those in the medical-only arm. That treatment difference will be compared with the treatment difference among those who have no flow failure, that is, there will be a significant flow-failure-by-treatment interaction. We postulate that hemodynamically significant “asymptomatic” carotid disease may represent one of the few examples of a treatable cause of cognitive impairment. If cognitive decline can be arrested in these patients, then we will have established a new indication for carotid revascularization independent of the risk of recurrent stroke.