World Stroke Organization The Paper of The Month – December
19 Dec 2025CREST-2: Revascularization in Asymptomatic Carotid Stenosis in the Era of Intensive Medical Therapy
CREST-2: Revascularization in Asymptomatic Carotid Stenosis in the Era of Intensive Medical Therapy
Prof. Octavio Marques Pontes-Neto, MD, PhD – Editor-in-Chief, World Stroke Academy
This article is a commentary on the following: Medical Management and Revascularization for Asymptomatic Carotid Stenosis, The New England Journal of Medicine, https://www.nejm.org/doi/abs/10.1056/NEJMoa2508800
Commentary:
The CREST-2 program delivers the most definitive randomized evidence to date on the management of high-grade asymptomatic carotid stenosis in contemporary practice.1 Results were recently published in The New England Journal of Medicine. In two parallel, observer-blinded trials across 155 centers, patients with ≥70% stenosis were assigned either to intensive medical management (IMM) alone or to revascularization plus IMM: one trial testing transfemoral carotid-artery stenting (CAS) and the other carotid endarterectomy (CEA). The primary outcome combined any stroke or death within 44 days and ipsilateral ischemic stroke thereafter through four years. IMM targeted SBP <130 mmHg (tightened during the trial) and LDL-C <70 mg/dL, with centralized oversight, coaching, and access to lipid-lowering therapies, reflecting best-in-class prevention.
The stenting trial showed a significant advantage for CAS+IMM over IMM alone: four-year primary events were 2.8% vs. 6.0% (absolute difference 3.2 points; P=0.02). While the periprocedural window (0–44 days) favored IMM (0 vs. 1.3% stroke/death with stenting), the post-44-day ipsilateral stroke rate strongly favored CAS (annual 0.4% vs. 1.7%; relative risk ≈4 for IMM vs. CAS), yielding a clinically relevant net benefit for stenting when delivered in certified, high-volume centers. The Kaplan–Meier curves in Figure 2A visually separate in favor of CAS after the early hazard period, underscoring the trade-off of a small procedural risk for a sustained reduction in ipsilateral events over time.
In contrast, the endarterectomy trial did not meet significance: four-year primary events were 3.7% with CEA+IMM vs. 5.3% with IMM (absolute difference 1.6 points; P=0.24). As with CAS, there was an early periprocedural signal against CEA (1.5% vs. 0.5% stroke within 44 days), offset by lower post-procedural ipsilateral stroke rates thereafter (annual 0.5% vs. 1.3%), but the aggregate effect did not cross the statistical threshold. Taken together, CREST-2 suggests that stenting, under strict quality control, can add incremental protection against ipsilateral stroke beyond modern prevention, whereas endarterectomy did not demonstrate superiority over IMM alone in this cohort and timeframe.
A notable strength is how thoroughly risk-factor control was achieved across all arms (see Figure 1 for sustained attainment of SBP and LDL-C targets), likely compressing absolute event rates and raising the bar for any procedural strategy to show benefit. Trial design safeguards included independent stroke adjudication and MRI-first imaging for event confirmation, while operator credentialing (with documented low periprocedural complications) ensured contemporary, high-quality procedures. Still, limitations matter: patients and treating clinicians were unblinded; evolving standards (e.g., lower BP targets, availability of PCSK9 inhibitors, modern diabetes/obesity therapies) may have further lowered background risk; and results reflect expert centers with vetted operators, which has implications for generalizability.
Clinically, CREST-2 reframes decision-making for asymptomatic ≥70% stenosis. First, IMM is foundational: disciplined control of BP and LDL-C and lifestyle optimization substantially reduce stroke risk and should be universal. Second, CAS can be considered for selected patients at expert centers with low periprocedural risk, particularly when long-term ipsilateral protection is prioritized and patient values favor a procedural approach; meticulous peri- and post-procedural antiplatelet management is essential. Third, while CEA remains durable in experienced hands and may be warranted for specific anatomic or clinical scenarios, these trial data do not demonstrate a significant aggregate advantage over IMM alone at four years. Shared decision-making should incorporate local operator outcomes, anatomy, comorbidity, life expectancy, and patient preferences.
For research and policy, CREST-2 points to opportunities: identifying plaque features or imaging biomarkers that enrich for procedural benefit; defining which asymptomatic patients profit most from revascularization, by stenosis biology, progression, microembolization, or contralateral disease, and evaluating transcarotid approaches not tested here. As event rates decline with ever-better prevention, trials must be large, selective, and longer-term. For now, the message is clear: in high-grade asymptomatic carotid stenosis, best medical therapy is non-negotiable; CAS adds benefit in expert hands; and CEA, in this program, did not surpass medical therapy within four years. CREST-2 resets the balance toward precision selection for revascularization, anchored to rigorous prevention for all.
References:
1 – Brott TG, Howard G, Lal BK, Voeks JH, Turan TN, Roubin GS, Lazar RM, Brown RD Jr, Huston J 3rd, Edwards LJ, Jones M, Clark WM, Chamorro Á, Llull L, Mena-Hurtado C, Heck D, Marshall RS, Howard VJ, Moore WS, Barrett KM, Demaerschalk BM, Sangha N, Aronow H, Foster M, Sternbergh WC 3rd, Shawl F, Lanzino G, Rapp J, Tran HS, Ecker R, Mackey A, Ali V, Given C 2nd, Teal P, Kashyap VS, Mukherjee D, Harrigan M, Silverman S, Koopmann M, Wadley VG, Zhang Y, Rhodes JD, Chaturvedi S, Meschia JF; CREST-2 Investigators. Medical Management and Revascularization for Asymptomatic Carotid Stenosis. N Engl J Med. 2025 Nov 21. doi: 10.1056/NEJMoa2508800. Epub ahead of print. PMID: 41269206.
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