For patients with severe asymptomatic carotid artery stenosis, adding revascularization with either carotid artery stenting (CAS) or carotid endarterectomy (CEA) to intensive medical management (IMM) did not improve cognition compared with IMM alone, according to results from the CREST-2 randomized trials, in an analysis of secondary outcomes published in JAMA. A related CREST-H substudy of CREST-2 also found no cognitive benefit from revascularization over one year, regardless of cerebral hemodynamic status, suggesting that restoring cerebral blood flow may not improve cognition in chronic asymptomatic carotid stenosis.

For the prespecified cognitive secondary outcomes in the CREST-2 trials, participants completed five cognitive tests assessing learning, memory, executive function, attention and processing speed before treatment and annually for up to four years. Cognitive performance was assessed centrally by telephone across 146 clinical sites, with evaluators blinded to treatment assignment.

The patients were ≥35 years old with ≥70% asymptomatic carotid artery stenosis and they were enrolled from December 2014 through July 2024. Follow-up ended in July 2025.

Overall, 91% of participants completed cognitive assessments: 1,078 in the CAS trial (529 assigned to CAS + IMM; 549 to IMM alone) and 1,087 in the CEA trial (543 assigned to CEA + IMM; 544 to IMM alone). Mean age was 70 years and 38% were female. After a mean follow-up of 2.2 years, cognitive outcomes were similar between the revascularization plus IMM groups and IMM-alone groups, with no significant differences in overall cognition or individual cognitive test scores.

"Based on results of the current trial, the assumption that revascularization would ameliorate these deficits is not validated," write Ronald M. Lazar, PhD, et al. "Whether there would be selective benefit of improved hemodynamics among those with diminished baseline cognition was not prespecified in CREST-2 but was addressed in CREST-H."

CREST-H, a multicenter phase 3 substudy of CREST-2, enrolled adults aged 35 to 86 years without dementia who had at least an eighth-grade education and unilateral asymptomatic internal carotid artery stenosis of ≥70%. Participants were enrolled at 61 centers in North America from January 2018 to July 2024. Baseline hemodynamic impairment was assessed with magnetic resonance or computed tomographic perfusion imaging, and follow-up ended in July 2025.

The primary outcome was the between-group difference in composite cognitive z score over one year, based on the same five cognitive tests.

Among 392 enrolled participants (mean age, 71 years; 32% female), 291 were eligible for analysis and 51 had reduced cognition at baseline, including 25 in the revascularization plus IMM group and 26 in the IMM-alone group. In participants with baseline cognitive impairment, scores improved slightly over one year in both treatment groups, but the difference between revascularization plus IMM and IMM alone was not significant, regardless of cerebral hemodynamic status.

"These findings complement the results of cognitive outcomes from the parent trial," write Randolph S. Marshall, MD, MS, et al. "The rejection of the hemodynamic treatment hypothesis may be interpreted as evidence that cognitive dysfunction may not be reversible by revascularization of a hypoperfused hemisphere in chronic, asymptomatic carotid disease."