A New Asymptomatic Carotid Stenosis Paradigm? CREST-2 Trial Unified Results

Severe asymptomatic carotid stenosis continues to be controversial seeing the optimization of intensive medical therapy (IMT) and the availability lower periprocedural risk revascularization techniques. In this context, the CREST-2 trial was designed to determine whether revascularization — either by carotid artery stenting (CAS) or carotid endarterectomy (CEA) — brings an additional benefit to stroke risk reduction vs OMT alone.

To this end, two parallel, multicenter randomized trials were conducted, comparing IMT vs. CAS on one hand, and IMT vs. CEA on the other. They included a total of 2,485 patients with asymptomatic carotid stenosis ≥70%, confirmed by noninvasive imaging or digital angiography. 36% to 39% were women, mean age 70. Mean follow-up was 3.6 years for CAS and 4.0 years for CEA.

The combined primary endpoint was any stroke or death within the first 44 days after randomization, as well as ipsilateral ischemic stroke between day 44 and year 4. Secondary endpoints included other imaging-based criteria for stroke, contralateral events, periprocedural adverse events, and analyses of prespecified subgroups.

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CAS was a transfemoral procedure under local anesthesia with or without conscious sedation and required mandatory use of embolic protection systems. There are no details on use of predilation, direct stenting, postdilation, or protection type (distal or proximal); these decisions were left to the operators. Patients received aspirin and clopidogrel starting 48 hours before procedure and continued with dual antiplatelet therapy for 30 days, followed by lifelong aspirin. CEA was also performed under standardized protocols, with specific certification, to keep periprocedural complication rates below 3%.

The unified outcomes have shown relevant differences between these two revascularization strategies. In IMT vs. CAS, four-year primary endpoint cumulative incidence resulted 6.0% for IMT vs 2.8% for CAS, with an absolute difference of 3.2 percentage points (p = 0.02) and a relative risk (RR) of 2.13 (95% CI 1.15–4.39) in favor of endovascular revascularization. During the first 44 days, there were no events in the IMT group, whereas 8 events (1.3%) were observed in the CAS group. After day 44, ipsilateral ischemic stroke occurred in 28 patients among IMT patients vs 7 in the CAS group, with annual rates of 1.7% and 0.4%, respectively (RR 4.07; 95% CI 1.78–9.31).

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In contrast, when comparing IMT vs. CEA, the 4-year incidence of primary endpoint was 5.3% for IMT and 3.7% for CEA, with no statistical significance (p = 0.24). Periprocedural events occurred in 0.5% among IMT patients and 1.5% of surgical patients, while the annual incidence of ipsilateral ischemic stroke after day 44 was 1.3% for IMT and 0.5% for CEA (RR 2.38; 95% CI 1.13–5.00). In both trials, IMT effectively controlled risk factors, achieving systolic blood pressure <130 mmHg and LDL <70 mg/dL in more than 70 – 80% of patients.

Conclusion

In patients with severe asymptomatic carotid stenosis, CREST-2 has shown carotid angioplasty combined with optimal intensive medical therapy significantly reduces the risk of stroke at 4 years compared against medical therapy alone. In contrast, endarterectomy did not show a significant additional benefit compared against contemporary medical management.

Original Title: Medical Management and Revascularization for Asymptomatic Carotid Stenosis.

Reference: Thomas G. Brott, et al., CREST-2 Investigators. New England Journal of Medicine, 2025.