CREST-2 Trials: Stenting and Endarterectomy vs Intensive Medical Management for Asymptomatic Carotid Stenosis
In adults with asymptomatic ≥70% carotid stenosis, does revascularization (stenting OR endarterectomy, two parallel trials) added to modern intensive medical management reduce the 4-year composite of periprocedural stroke, MI, or death plus ipsilateral stroke compared with intensive medical management alone?
Brott TG, et al. for the CREST-2 Investigators (NEJM 2026;394:219-231) · doi:10.1056/NEJMoa2508800 · 2,485 patients
Population
Included
- Age 35 years or older
- ≥70% stenosis of the index extracranial carotid artery by Doppler ultrasonography (peak systolic velocity ≥230 cm/s plus a confirmatory criterion), CTA, MRA, or catheter angiography
- No stroke, TIA, or amaurosis fugax in the carotid territory within 180 days before randomization
- Eligible for both intensive medical management and the assigned revascularization (stenting trial OR endarterectomy trial. Site-determined)
- Anatomy suitable for the assigned revascularization procedure
- Patients 35 years of age or older
- No history of stroke, transient ischemic attack (TIA), or amaurosis fugax in the carotid-artery territory within 180 days before randomization
- Stenosis of at least 70% as assessed by Doppler ultrasonography showing a peak systolic velocity of at least 230 cm per second and any of the following findings: an end diastolic velocity of at least 100 cm per second, a peak systolic velocity ratio of the internal carotid artery to common carotid artery of at least 4.0, or at least 70% stenosis on computed tomographic angiography (CTA) or magnetic resonance angiography (MRA)
- Or at least 70% stenosis on CTA or MRA
- Or at least 70% stenosis on catheter angiography alone
Excluded
- Previous disabling stroke
- Unstable angina
- Atrial fibrillation prompting anticoagulation
- Recent (within 180 days) symptoms attributable to the index carotid artery
- A previous disabling stroke
- Unstable angina
- Atrial fibrillation prompting anticoagulation
Source: Brott TG et al. for the CREST-2 Investigators, New England Journal of Medicine 2026;394:219-231· Retrieved 2026-06-09
Primary Outcome — Stenting Trial
4-year periprocedural stroke/death + ipsilateral stroke (CAS vs medical alone)
Negligible absolute difference
4-yr primary composite
Endarterectomy trial (parallel arm): CEA 3.7% vs medical 5.3% (ARD −1.6 pp, P=0.24). The endarterectomy primary was not met. The two trials must be interpreted separately; the modality split is clinically important.
Study Arms
- Agent
- Carotid-artery stenting performed with embolic protection, in accordance with guidelines and operators standard procedures
- Route
- Endovascular (transfemoral or alternative access)
- Frequency
- Single revascularization procedure
- Co-interventions
- Starting 48 hours before the procedure, patients received aspirin 325 mg daily and clopidogrel 75 mg twice daily. After stenting, clopidogrel 75 mg daily and aspirin 75 to 325 mg daily for 30 days, followed by aspirin 70 to 325 mg daily thereafter. Plus intensive medical management identical to the control arm
CREST-2 comprised two parallel observer-blinded trials. In the stenting trial, carotid-artery stenting plus intensive medical management was compared with intensive medical management alone. Antiplatelet and procedure detail from Brott NEJM 2026 p.220-221 (Stenting and Endarterectomy). Stenting-trial primary outcome met: 4-year primary-outcome incidence 2.8% (stenting) vs 6.0% (medical), P=0.02 for the absolute difference.
- Agent
- Carotid endarterectomy performed in accordance with guidelines and operators standard procedures
- Route
- Open surgical
- Frequency
- Single revascularization procedure
- Co-interventions
- Aspirin 325 mg daily for at least 48 hours before the procedure and 70 to 325 mg daily thereafter; periprocedural anticoagulation with either heparin or bivalirudin was required. Plus intensive medical management identical to the control arm
In the endarterectomy trial, carotid endarterectomy plus intensive medical management was compared with intensive medical management alone. Detail from Brott NEJM 2026 p.220-221. Endarterectomy-trial primary outcome not met: 4-year primary-outcome incidence 3.7% (endarterectomy) vs 5.3% (medical), P=0.24 for the absolute difference.
- Agent
- Protocol-driven intensive medical management of cardiovascular risk factors
- Route
- Medical
- Co-interventions
- Primary targets were a systolic blood pressure of less than 130 mm Hg (the initial target of less than 140 mm Hg was reduced in 2018 after guideline changes) and a low-density lipoprotein cholesterol level of less than 70 mg per deciliter. Elevated glucose, glycated hemoglobin, and lifestyle factors (smoking, excess body weight, physical inactivity) were managed; health coaching was provided by telephone. Alirocumab was donated by the manufacturer after 2018
Control arm in both parallel trials = intensive medical management alone, the same protocol applied across both trials except for the period of antiplatelet use before and after revascularization. Source: Brott NEJM 2026 p.220 (Intensive Medical Management).
Safety
All-cause death by 4 years (stenting trial)
7.8%
11%
Stenting trial: 48 of 616 (7.8%) deaths in stenting group vs 69 of 629 (11.0%) in medical-therapy group across 4 years of follow-up. Endarterectomy trial: 54 of 617 (8.8%) CEA vs 60 of 623 (9.6%) medical-therapy. Trial not powered to detect mortality differences. Source: Brott TG et al., NEJM 2026, Discussion p.225.
Periprocedural stroke/death (days 0–44, stenting trial)
1.3%
0%
Stenting trial periprocedural events: 8 of 616 stenting (1.3%, 95% CI 0.6–2.5; 7 strokes, 1 death) vs 0 of 629 medical-therapy (0.0%, 95% CI 0.0–0.6). Endarterectomy trial periprocedural events: 9 of 617 CEA (1.5%, 95% CI 0.7–2.8) vs 3 of 623 medical-therapy (0.5%, 95% CI 0.1–1.4). Source: Brott TG et al., NEJM 2026, Table 2 p.228.
Trial Design
Type
- Two parallel, multicenter, observer-blinded randomized controlled trials
- 1:1 allocation in each trial
- Intention-to-treat analysis; pre-specified interim analysis with alpha adjustment to 0.047
- 155 sites across Australia, Canada, Israel, Spain, and the United States
Timeline
Enrolled December 2014 to early 2024; follow-up through July 2025
N
2,485
Enrollment
2,485 patients across two parallel randomized trials (1,245 stenting trial / 1,240 endarterectomy trial) at 155 sites in Australia, Canada, Israel, Spain, US. Each trial: 1:1 randomization to revascularization plus intensive medical management vs intensive medical management alone. Observer-blinded outcome adjudication. Pre-specified interim analysis with alpha adjustment to 0.047. Enrolled December 2014 to early 2024; follow-up through July 2025. Published NEJM 2026.
ClinicalTrials.gov
NCT02089217Bedside Pearl
CREST-2 is two parallel trials in asymptomatic ≥70% carotid stenosis. Stenting beat modern intensive medical management at 4 years (2.8% vs 6.0%, NNT 31). Endarterectomy did not reach significance (3.7% vs 5.3%, P=0.24). Intensive medical management is the modern default; revascularization is now a shared-decision conversation.