CREST-2 Substudy Shows No Cognitive Benefit of Carotid Revascularization in Asymptomatic Carotid Stenosis

New late-breaking data, presented at the 2026 International Stroke Conference (ISC), held February 4-6, in New Orleans, Louisiana, from a substudy of the CREST-2 trial (NCT02089217) indicated that revascularization to improve cerebral blood flow in patients with asymptomatic carotid stenosis was not associated with improvements in cognitive outcomes.¹ These results may help guide clinicians in counseling patients regarding the anticipated benefits of carotid revascularization procedures.²

Baseline data of CREST-2 indicated that 786 patients with severe asymptomatic carotid stenosis had lower cognition scores, particularly in memory, prior to treatment, compared with a demographical and cardiovascular risk–matched population from a separate study.³ Following treatment initiation, 5818 cognitive test batteries were administered over a mean follow-up of 2.76 years. In the substudy, findings revealed no differences in cognition observed between participants who underwent carotid revascularization and those treated with intensive medical management alone.

“The data show pretty clearly that prior to revascularization there is cognitive decline beforehand, presumably as a result of flow failure across the stenosis,” lead author Ronald M. Lazar, PhD, FAHA, a professor of neurology and neurobiology at the University of Alabama at Birmingham (UAB) and director of the UAB McKnight Brain Institute, told NeurologyLive^® in a recent interview. “The notion is that, based on the work in stroke, where reperfusion therapy results in significant improvement in neurologic function, revascularization might not only reduce the risk of stroke in these individuals but, in fact, improve cognition as well.”

The CREST-2 study comprises of 2 randomized controlled trials comparing carotid revascularization plus intensive medical management with intensive medical management alone in patients with asymptomatic high-grade carotid stenosis. Cognition was a prespecified secondary outcome and was assessed at baseline and annually for up to 4 years. Treatment-related differences in cognitive performance were evaluated by comparing trajectories of a composite cognitive summary score and individual component scores from 5 cognitive tests administered by telephone to participants randomized in the United States.

READ MORE: Integrating GFAP Improves Accuracy of Large Vessel Occlusion Detection in Acute Stroke Settings

“This was the largest randomized clinical trial in which cognition was a prespecified outcome. We had more than 2,000 patients, and we administered more than 7,000 test batteries to these individuals. We found there was no impact of revascularization compared with medical therapy on cognitive status during the course of the follow-up; even those with worse cognitive function at baseline didn’t get significant benefit,” Lazar told NeurologyLive. “The fact that stroke produced a radical change in cognition assured us that the metric we were using for cognitive outcomes was sensitive to neurologic status. In the end, we conclude that a chronic lesion preventing flow in the carotid might produce irreversible neurologic injury, which we never fully understood before.”

Authors noted that the study was unable to determine whether reduced cerebral blood flow is the primary contributor to cognitive decline in patients with carotid artery disease. Additional limitations of the analysis include the use of telephone-based cognitive assessments, which precluded evaluation of visuospatial skills and the full range of executive functions, such as decision-making. Furthermore, researchers reported that the substudy included only English-speaking participants, which may limit the generalizability of the findings to other patient populations.

“These results from CREST-2 do not provide evidence of benefit of carotid revascularization on cognitive function among patients with significant carotid stenosis, although there is a benefit for stroke reduction,” Mitchell Elkind, MD, MS, FAHA, FAAN, chief science officer for Brain Health and Stroke at the American Heart Association, said in a statement.² “Cognitive decline associated with aging is a complex problem; however, restoration of blood flow through the large vessels alone may not be sufficient to address the many other pathways to decline, such as inflammation, neurodegeneration and small vessel disease. More research on how to mitigate cognitive decline and reduce dementia risk is needed, which is why the American Heart Association has supported study of these important areas and others.”

Click here for more coverage of ISC 2026.

REFERENCES
1. Lazar RM, Meschia JF, Edwards LJ, et al. The Effect of Treatment on Cognitive Function in Patients with Asymptomatic Carotid Artery Stenosis: The CREST-2 Trial. Presented at: International Stroke Conference; February 4-6, 2026; New Orleans, Louisiana. LB003.
2. Improving blood flow to the brain in arteries with plaque did not improve cognitive skills. News release. American Stroke Association. February 4, 2026. Accessed February 4, 2026. https://newsroom.heart.org/news/improving-blood-flow-to-the-brain-in-arteries-with-plaque-did-not-improve-cognitive-skills
3. Lazar RM, Wadley VG, Myers T, et al. Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial. Stroke. 2021;52(12):3855-3863. doi:10.1161/STROKEAHA.120.032972