CREST-2 Trial Shows Carotid Revascularization Fails to Improve Cognitive Function in Asymptomatic Patients
Key Insights
The CREST-2 trial, involving 2,165 patients across 155 sites, found no significant cognitive improvement following carotid revascularization procedures compared to intensive medical therapy alone.
Both carotid endarterectomy and stenting failed to enhance cognitive performance across five neuropsychological assessments measuring learning, attention, memory, and executive function over an average 2.8-year follow-up period.
The findings challenge previous expectations that improving blood flow to the brain through carotid procedures would boost cognitive abilities, even in patients with the poorest baseline cognitive function.
A major clinical trial has definitively shown that procedures to restore blood flow in narrowed carotid arteries do not improve cognitive function in patients with asymptomatic carotid stenosis, challenging long-held assumptions about the cognitive benefits of revascularization.
The CREST-2 trial cognitive analysis, presented at the American Stroke Association (search)'s International Stroke (search) Conference 2026, examined 2,165 patients across 155 sites and found no meaningful differences in thinking or memory between those who underwent revascularization procedures and those receiving intensive medical therapy alone.
Major Trial Findings Challenge Treatment Expectations
"Whether patients undergo a procedure to remove plaque in the carotid artery (search), known as a carotid endarterectomy, stenting to insert a flexible tube to hold open the narrowed part of the artery, or a combination of medications and lifestyle guidance without a procedure, there should be no expectation that cognition will improve after the treatment," said study lead author Ronald M. Lazar, Ph.D., a professor of neurology at the University of Alabama at Birmingham and director of the UAB Evelyn F. McKnight Brain Institute.
The comprehensive study tracked patients for an average of 2.8 years, administering cognitive tests annually to assess five key neuropsychological domains: word list learning, digit span attention, word list delayed recall, animal naming, and controlled oral word association. Linear mixed models confirmed that neither carotid endarterectomy nor stenting significantly influenced cognitive trajectories compared to medical management.
Robust Study Design Validates Negative Results
The CREST-2 trial represents the largest randomized study ever conducted examining cognitive outcomes in patients with asymptomatic carotid disease. The cognitive test battery, administered by telephone at baseline and annually for up to four years, generated 7,060 individual test results during the trial period.
To ensure the sensitivity of their cognitive assessments, researchers performed an additional analysis showing that patients who suffered strokes during follow-up demonstrated significant and measurable declines in cognitive function. "This confirms to us the sensitivity of our cognitive battery," Lazar noted.
The findings remained consistent even among participants with the poorest cognitive function at baseline, who were expected to gain the most from revascularization treatments.
Clinical Context and Previous Research
Prior research had established that patients with carotid stenosis typically perform worse on cognitive tests before treatment. In 2021, Lazar and colleagues published results showing that 786 CREST-2 patients with severe but symptom-free carotid stenosis scored lower on cognitive tests, particularly memory assessments, compared to matched control groups.
"The 2021 analysis indicated that revascularization might improve cognitive function," Lazar explained. However, the current long-term follow-up data contradicts these earlier expectations.
Carotid artery stenosis (search) occurs when major blood vessels in the neck become narrowed due to plaque buildup. Standard treatment includes intensive medical therapy with aspirin, blood pressure and cholesterol medications, and lifestyle modifications. When arteries become more than 70% blocked, doctors may recommend surgical procedures to reopen them.
Implications for Clinical Practice
The results may significantly influence how clinicians counsel patients about potential benefits of carotid procedures. "Health care professionals can no longer assert that treatment of carotid stenosis will improve cognition," Lazar stated. "However, worsening cognition over time may be a signal that treatment may need to be reevaluated and possibly adjusted."
Seemant Chaturvedi, MD, from the University of Maryland School of Medicine and a CREST-2 executive committee member, noted that the lack of cognitive improvement is "maybe not that surprising" given the complexity of factors affecting cognitive ability, including small-vessel disease burden, Alzheimer's-related changes, APOE status, and sleep apnea.
Study Limitations and Future Research
The study acknowledged several limitations. All cognitive testing was conducted by telephone, preventing assessment of visuo-spatial skills and the full range of executive functions like complex decision-making. Additionally, only English-speaking participants were included, potentially limiting generalizability to other language or cultural backgrounds.
The research could not determine whether reduced blood flow alone explains cognitive decline (search) in carotid artery (search) disease patients. "Some characteristics of a blockage can cause small particles to travel to the brain. These particles may, over time, affect how the brain functions. This is an area we plan to explore in our future research," Lazar said.
The findings suggest that patients with greater than 70% stenosis and diminished cognition may already have irreversible neurologic injury that cannot be restored through revascularization procedures, fundamentally changing expectations about the cognitive benefits of carotid interventions.