Article Citation: Brott TG, Howard G, Lal BK, et al; CREST-2 Investigators. Medical Management and Revascularization for Asymptomatic Carotid Stenosis. N Engl J Med. 2025 Nov 21. doi:10.1056/NEJMoa2508800

Background: Carotid artery disease is a recognized risk factor for acute ischemic stroke. Randomized controlled studies have demonstrated a benefit of carotid revascularization in patients with carotid stenosis and recent ipsilateral ischemic symptoms (e.g. stroke or transient ischemic attack). However, the role of carotid revascularization with either carotid artery stenting (CAS) or carotid endarterectomy (CEA) in asymptomatic patients with high-grade carotid stenosis remains controversial.

Multiple randomized controlled studies from the 1990s and early 2000s demonstrated that CEA in asymptomatic patients with high-grade carotid stenosis decreased the risk of subsequent strokes. However, how to extrapolate these earlier trials to the modern era—given advances in medical management, CEA, and CAS—remains uncertain. CREST-2 aimed to determine whether intensive medical management in conjunction with either CAS or CEA (in two parallel trials) or intensive medical management alone would be superior in asymptomatic patients with high-grade carotid stenosis.

Methods: CREST-2 was a multinational study that consisted of two parallel, observer-blinded, randomized controlled studies: a stenting trial that compared intensive medical management (medical-therapy group) to intensive medical management plus CAS (stenting group) and a CEA trial that compared intensive medical management (medical-therapy group) to intensive medical management plus CEA (endarterectomy group).

Inclusion criteria included: patients over the age of 35 who had no history of stroke, TIA, or amaurosis fugax in the ipsilateral carotid territory within 180 days with either angiographic imaging alone or sonographic imaging in conjunction with non-invasive CTA or MRA imaging demonstrating at least 70% stenosis of the carotid artery. Stenosis could be established by duplex ultrasonography meeting prespecified velocity criteria and/or CTA/MRA/catheter angiography. Exclusion criteria included: history of prior disabling stroke, unstable angina, or atrial fibrillation necessitating systemic anticoagulation.

Medical management in all groups was the same, apart from pre and post procedural antiplatelet use in the CEA and CAS groups. Intensive medical management included targeting a systolic blood pressure of <130 mm Hg (the initial target of <140 mm Hg was reduced in 2018 after guideline changes) and LDL of <70 mg/dL, glycemic control, and modification of lifestyle factors such as cigarette use, weight management, and physical activity.

Those who underwent CAS received aspirin 325mg daily and clopidogrel 75mg twice daily starting 48 hours prior to the procedure; after stenting, patients received clopidogrel 75mg daily and aspirin 75-325 mg daily for 30 days, followed by aspirin 70-325 mg daily thereafter. Those who underwent CEA received aspirin 325mg daily for at least 48 hours prior to surgery and 70-325mg daily thereafter. Periprocedural anticoagulation with either heparin or bivalirudin was required for CEA.

Patient follow-up was conducted at 12-36 hours post procedure, 44 days post procedure (periprocedural period), 4, 8, and 12 months, and every 6 months for 4 years. Neuroimaging was pursued when clinically indicated; MRI or CT was recommended for an NIHSS increase ≥2 points from baseline, and additional evaluation was performed when stroke/TIA was suspected.

The primary endpoint, which was analyzed according to the intention-to-treat principle, was a 4-year composite of any stroke or death from randomization to 44 days or ipsilateral ischemic stroke in the remaining follow-up period for up to 4 years. Secondary endpoints included: primary outcome plus contralateral stroke, tissue-based stroke composites, and related prespecified stroke outcomes.

Results: In total, 1245 patients were randomized in the CAS trial and 1240 patients were randomized in the CEA trial. The patients in all arms of the trial were well-matched with respect to demographics and cardiovascular comorbidities. There was a crossover rate of 17% in the CAS trial from medical management to revascularization (both CEA and CAS) and 7% of patients randomized to CAS did not undergo any procedure. In the endarterectomy trial, 18% crossed over from medical therapy to revascularization (CEA or CAS), and 4% assigned to endarterectomy did not undergo any procedure. The percentage of patients with risk factor control in-range in all arms increased in the first few months of the trial and remained sustained.

In the CAS trial, the primary outcome occurred in 6% of patients in the medical arm and 2.8% in the CAS arm, noting an absolute risk reduction of 3.2% (95% CI, 0.6-5.9, p = 0.02) and a relative risk in the medical arm compared to the CAS arm of 2.13 (95% CI, 1.15-4.39). In the periprocedural period (day 0-44), there were 0 strokes or deaths in the medical arm and 7 strokes and 1 death in the CAS arm (1.3%) After 44 days, there was a 1.7% annual rate of ipsilateral ischemic stroke in the medical arm and 0.4% annual rate of ipsilateral ischemic stroke in the CAS arm, noting a relative risk in the medical arm compared to the CAS arm of 4.07 (95% CI, 1.78 to 9.31).

In the CEA trial, the primary outcome occurred in 5.3% of patients in the medical arm and 3.7% in the CEA arm, noting an absolute risk reduction of 1.6% (95% CI, -1.1 to 4.3, p = 0.24) and a relative risk in the medical arm compared to the CEA arm of 1.43 (95% CI, 0.78-2.72). In the periprocedural period (day 0-44), there were 3 strokes in the medical arm (0.5%) and 9 in the CEA arm (1.5%). After 44 days, there was a 1.3% annual rate of ipsilateral ischemic stroke in the medical arm and 0.5% annual rate of ipsilateral ischemic stroke in the CEA arm, noting a relative risk in the medical arm compared to the CEA arm of 2.38 (95% CI, 1.13 to 5.00).

The peri and post procedural period annual event rate of the primary outcome in the medical arms of both the CAS and CEA trials were similar (1.6% and 1.4%, respectively). And secondary outcome results were similar to those seen in the primary outcome analyses.

Commentary: CREST-2 results show that in asymptomatic patients with high-grade carotid artery stenosis, carotid artery stenting in addition to intensive medical management decreased the risk of periprocedural stroke or death or post procedural ipsilateral stroke within 4 years compared to intensive medical management alone, with a number needed to treat of 31 to prevent one primary outcome event. The primary endpoint was not statistically different among patients who underwent CEA in addition to intensive medical management and those who were managed with intensive medical management alone.

Other studies have preceded CREST-2 in attempting to address this question, such as SPACE-2 and ECST-2. However these were limited by low patient enrollment, less stringent criteria for adjudication of carotid artery stenosis, and a partially mixed population of both symptomatic and asymptomatic carotid artery disease.

Limitations of CREST-2 included unblinded patients and treating physicians, developments of novel and more potent medical management strategies including PCSK9 inhibitors and GLP-1 receptor agonists that occurred during the trial period whose effects may not have been fully captured in these results, the lack of inclusion of TCAR, and the inclusion of only high-volume and well-trained CAS and CEA operators that may reduce the generalizability of these results.

Nonetheless, the results of CREST-2 provide the most rigorous data for the management of asymptomatic carotid disease to date by comparing modern era revascularization strategies to medical management alone.

Editor’s Note: For additional interpretation and clinical context, read the accompanying Currents NEWS Editor Commentary on CREST-2.

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