More Data Affirm No Cognitive Benefits of Carotid Revascularization: CREST-2

In patients with asymptomatic carotid artery stenosis, revascularization with stenting or carotid endarterectomy (CEA) does not significantly improve brain function scores, even in those with impaired hemodynamics at baseline, two CREST-2 analyses suggest.

A cognitive function analysis presented earlier this year and published recently in JAMA found no significant differences in learning, attention, memory, and executive function, or a composite of those, between patients randomized to revascularization plus medical management or medical management alone, with consistent results across age, sex, and degree of stenosis. Additionally, a hemodynamic subanalysis published alongside the cognitive function paper, which involved advanced imaging, showed no cognitive benefits regardless of cerebral hemodynamic flow status at baseline.

“The overall message of both papers is that once you have cognitive decline from carotid artery disease, revascularization is not going to have a clinical benefit on the ability to think or remember,” Ronald M. Lazar, PhD (University of Alabama at Birmingham), told TCTMD. “It constitutes some kind of injury that is not improved by restoring flow.” Lazar is lead author of the cognitive function analysis and coauthor of the hemodynamic substudy, for which Randolph Marshall, MD (Columbia University Irving Medical Center, New York, NY) was lead author.

CREST-2 consisted of two parallel trials that began more than a decade ago and pitted carotid stenting and endarterectomy against intensive medical therapy in patients with asymptomatic, high-grade carotid disease. In the main trial, stenting plus medical therapy was better than drug treatment alone in reducing the composite of any stroke or death within the first 44 days or ipsilateral ischemic stroke within up to 4 years of follow-up.

Lazar said the CREST-2 investigators had good reason to believe that by restoring flow, carotid stenting or surgery might improve or prevent cognitive decline. Flow change in stroke patients, for example, has been shown to be associated with reversal of cognitive impairment in some acute and subacute patients. However, data to support the theory in asymptomatic carotid stenosis patients were limited to small, nonrandomized studies. 

“What we found, unfortunately, in the people who had cognition issues at baseline, was they didn’t get better, they didn’t get worse. They just stayed the same,” Lazar added.

No Short- or Long-term Cognition Benefit

The hemodynamic substudy, known as CREST-H, was nested in the CREST-2 trial and included 291 patients (mean age 70 years). In those randomized to revascularization plus medical therapy, 32.3% were women and in those randomized to medical therapy alone, 42% were women. All had greater than 70% stenosis and underwent MRI or CT perfusion imaging for baseline hemodynamic impairment status.

At baseline, 17.5% of patients met criteria for reduced cognition, which was defined as a baseline composite cognitive z score ≤ -1.0 standard deviation. At 1 year, differences from baseline in time-to-peak contrast delay between the ipsilateral and contralateral cerebral cortex were not associated with changes in cognition, and no significant interactions were seen by treatment group or hemodynamic status.

The CREST-2 patients were followed for 4 years, which Lazar feels is a sufficient timeframe to be able to tell if revascularization makes a difference in cognition. Additionally, he said, if there exists an earlier window in which revascularization could make a difference in cognition, it’s unlikely that further clinical trials will be able to pinpoint it in a stable, asymptomatic population.

The overall message of both papers is that once you have cognitive decline from carotid artery disease, revascularization is not going to have a clinical benefit on the ability to think or remember. Ronald M. Lazar

In an accompanying editorial, Eric E. Smith, MD, MPH, and Aravind Ganesh, MD, DPhil (both University of Calgary, Canada), say the CREST-2 cognition studies appear to rule out the prevailing theory that hypoperfusion contributes to cognitive dysfunction in this population. They suggest that while cognitive benefits of revascularization can’t be entirely ruled out for a patient with carotid stenosis who has severe hemodynamic compromise, that situation is likely rare.

“More plausibly, these results suggest that cerebral autoregulatory and collateral mechanisms are sufficiently robust that cortical perfusion is preserved despite severe internal carotid artery stenosis, including through collateral flow from the posterior or external carotid circulations,” they write. 

Lazar and colleagues also suggest the possibility that cognitive changes after revascularization might be different in those with symptomatic carotid stenosis “whose ischemic event may provide timed evidence of when their hemodynamic status may have changed.” Still, they say, data on postrevascularization changes in cognition are variable and contradictory and until now have mostly been reported outside of clinical trials.

“I think we often make assumptions on what’s happening . . . and this was an opportunity to look at this in a well-done trial setting,” Lazar told TCTMD. He added that the CREST-2 investigators feel the cognitive data now “put the question to rest.”

According to Smith and Ganesh, the data also mean that physicians “should not counsel patients that cognition will improve after revascularization of asymptomatic carotid stenosis.” Instead, they add, discussion about benefits of carotid revascularization should continue to emphasize stroke prevention.