For decades, the management of asymptomatic carotid stenosis sat in a gray zone: older trials suggested a small benefit of carotid endarterectomy (CEA) over standard medical therapy, but improvements in intensive medical management called into question the value of routine revascularization for stroke prevention. And carotid artery stenting (CAS) has emerged as a less invasive alternative to CEA.

CREST-2 was designed to answer a simple but consequential question: in patients with high-grade asymptomatic carotid stenosis, does adding revascularization — either CEA or transfemoral CAS (TF-CAS) — to contemporary medical management improve outcomes vs intensive medical management alone?

CEA did not demonstrate a statistically significant incremental benefit over modern medical therapy, according to the results, published late last year in The New England Journal of Medicine.

The composite of any stroke or death in the first 44 days after the procedure or ipsilateral stroke during the remaining 4 years follow-up (primary endpoint) was lower with CEA but it did not reach statistical significance (3.7% vs 5.3% with medical therapy; P = .24). Nine strokes occurred in the CEA group and three in the medical therapy group.

End of the Road for CEA in Asymptomatic Disease?

CREST-2 “closes the chapter on routine CEA for all comers” with significant asymptomatic carotid stenosis. “That is not justified,” Prakash Krishnan, MD, director of endovascular services, Mount Sinai Fuster Heart Hospital, New York City, told Medscape Medical News.

He believes that future use should depend on patient selection and plaque characteristics.

“It’s very difficult to say that carotid endarterectomy has no role. It still remains reasonable in select asymptomatic patients where there’s a baseline stroke risk. One of the things that wasn’t taken into consideration [in CREST-2] was the high-risk features of a plaque,” Krishnan told Medscape Medical News.

James Grotta, MD, with Memorial Hermann Health System, Houston, is also not ready to totally abandon CEA in asymptomatic patients.

“While not studied in CREST-2, plaque morphology and novel biomarkers may prove to be important determinants of which asymptomatic patients are at highest risk, allowing us to target patients who would benefit most from intervention, including deciding between CAS and CEA,” he wrote in an editorial in Stroke Vascular Interventional Neurology.

Given a host of caveats and considerations, “pending further studies, I think there may still be a role for CEA in selected patients, especially a heavily calcified stenosis in an asymptomatic man,” Grotta wrote.

Stenting fared better in the trial. CREST-2 has provided the “strongest evidence that we have” that TF-CAS and maximum medical therapy “beat best medical management alone,” Krishnan told Medscape Medical News.

In CREST-2, the rate of the primary composite endpoint was lower with TF-CAS than with medical therapy alone (2.8% vs 6.0%; P = .02). But this benefit came with an early hazard. From day 0 to 44, seven strokes and one death occurred in the stenting group vs none in the medical therapy group.

Has CREST-2 Changed Clinical Practice?

Krishnan told Medscape Medical News that it’s tough to say whether CREST-2 has changed medical practice. “It’s evolving. It’s probably too early to call it settled,” he said. He noted that even before CREST-2, several factors were already “pushing practice” toward carotid stenting, including reimbursement “which drives practice.”

Krishnan also noted that “guidelines are always going to lag and the education on this particular trial will also take some time to disseminate. It will take a little bit of time for this to really affect practice,” he said.

Echoing Krishnan, the coauthors of an editorial on CREST-2 concluded, “that there is no longer a role for routine carotid endarterectomy in persons with asymptomatic stenosis.”

As for TF-CAS, Martin Brown, MD, with University College London, London, England, and Leo Bonati, MD, with Basel University, Basel, Switzerland, argue that “caution is required” because the rate of stroke with stenting likely reflects careful patient selection and skilled interventionalists, which are not available in all vascular centers.

The difference between stenting and medical management rests on a small number of events; “if only three more events had occurred in the stenting group, the difference would no longer be significant,” they pointed out.

An “equally important issue,” in their view, is whether the benefit seen over 4 years justifies the early increase in risk. As Brown and Bonati put it — for 100 patients treated with stenting, only about one per year will benefit by avoiding a stroke, at a price of about one patient having a stroke or dying from the stenting procedure. Over a 4-year period, 95 of 100 patients will have undergone an unnecessary procedure.

What’s Reasonable Post-CREST-2?

The editorialists said it’s “reasonable” to start intensive medical therapy immediately and delay revascularization until symptoms develop for most patients, with exceptions for patients who prefer to take the risk for revascularization or who can’t take medical therapy, in which case stenting would be the choice for suitable patients at expert centers.

Medscape commentator John Mandrola, MD, agreed. “This data closes the chapter on CEA for asymptomatic disease,” wrote Mandrola, clinical electrophysiologist, Baptist Medical Associates, Louisville, Kentucky.

His advice: “Start medical therapy and be aggressive. As for stenting, it’s the same. Start medical therapy, and symptoms are likely to occur in a small number of patients and for those you can proceed based on anatomy.” Intensive medical therapy in CREST-2 comprised cardiovascular risk factor management with drugs and lifestyle coaching including a systolic blood pressure target of ≤ 130 mm Hg and low-density lipoprotein cholesterol levels ≤ 70 mg/dL.

Mandrola expects that CREST-2 study will lead to a “sea change” in the treatment of asymptomatic carotid artery disease in the US. CREST-2 made his list of top cardiovascular trials of 2025 and the American Heart Association’s annual list of major research findings.

What About Transcarotid Artery Revascularization (TCAR)?

Medical therapy is not the only treatment to evolve. TCAR was not evaluated in CREST-2 because it was not widely used when the trial started. This stent technique uses flow reversal and was developed specifically to avoid high-risk maneuvers including manipulation of the aortic arch and unprotected crossing of the carotid lesion when deploying the embolic protection filter. 

It has accumulated “real-world and prospective study signals of lower risk of stroke or death vs TF-CAS,” Krishnan told Medscape Medical News.

For example, in a propensity score-matched analysis of data from 3286 matched pairs of patients who underwent TCAR or TF-CAS, the risk for in-hospital stroke or death was 1.6% with the transcarotid approach vs 3.1% with the transfemoral approach, a difference that was statistically significant.

Krishnan noted that there are no randomized controlled trials of these two approaches and probably never will be, “but the evidence is strong for TCAR with low periprocedural rates, especially in the ROADSTER studies.”

In a commentary on CREST-2 published in Endovascular Today, leadership of the Society for Vascular Surgery agreed with theCREST-2 findings that “medical management of all patients with carotid disease should be optimized and that TF-CAS procedures performed by highly trained, experienced interventionalists in carefully chosen patients may be appropriate treatment.”

“However, TCAR and CEA continue to play an important role in appropriately selected patients with asymptomatic carotid disease,” the authors wrote.