CREST-2
(2025)Objective
To determine whether adding carotid revascularization (stenting or endarterectomy) to intensive medical management provides greater benefit than intensive medical management alone in preventing stroke among patients with asymptomatic high-grade carotid stenosis
Study Summary
• In the endarterectomy trial, adding carotid endarterectomy to intensive medical management did not show significant benefit compared to medical management alone (3.7% vs 5.3%, P=0.24)
• Both revascularization procedures had low rates of disabling stroke, with most events being minor or nondisabling
Intervention
Stenting trial: transfemoral carotid-artery stenting with embolic protection plus intensive medical management vs intensive medical management alone. Endarterectomy trial: carotid endarterectomy plus intensive medical management vs intensive medical management alone. Intensive medical management included BP target <130 mmHg, LDL <70 mg/dL, antiplatelet therapy, diabetes control, and lifestyle modifications
Inclusion Criteria
Age ≥35 years, asymptomatic carotid stenosis ≥70% (no stroke/TIA/amaurosis fugax in territory within 180 days), stenosis confirmed by duplex ultrasound with peak systolic velocity ≥230 cm/sec plus additional criteria (end diastolic velocity ≥100 cm/sec, PSV ratio ≥4.0, or ≥70% stenosis on CTA/MRA) or ≥70% on catheter angiography
Study Design
Arms: Stenting trial: Medical therapy alone (N=629) vs Stenting + medical therapy (N=616). Endarterectomy trial: Medical therapy alone (N=623) vs Endarterectomy + medical therapy (N=617)
Patients per Arm: Stenting trial: 629 medical therapy, 616 stenting. Endarterectomy trial: 623 medical therapy, 617 endarterectomy
Outcome
• Endarterectomy trial: 4-year primary outcome rate 5.3% (medical) vs 3.7% (endarterectomy), absolute difference 1.6%, relative risk 1.43
• Periprocedural strokes occurred in 0% medical vs 1.3% stenting, and 0.5% medical vs 1.5% endarterectomy
Bottom Line
In patients with asymptomatic high-grade carotid stenosis, carotid-artery stenting plus intensive medical management significantly reduced the 4-year risk of stroke or death compared to intensive medical management alone (2.8% vs 6.0%, P=0.02, NNT=31). Carotid endarterectomy plus intensive medical management did not show a significant benefit compared to medical management alone (3.7% vs 5.3%, P=0.24).
Major Points
- Two parallel randomized observer-blinded trials comparing revascularization plus intensive medical management versus intensive medical management alone
- Stenting trial showed significant benefit with 3.2 percentage point absolute risk reduction (P=0.02)
- Endarterectomy trial did not reach statistical significance with 1.6 percentage point absolute risk reduction (P=0.24)
- Intensive medical management achieved excellent risk factor control across all groups (BP <130 mmHg, LDL <70 mg/dL)
- Periprocedural stroke/death rates were low: 1.3% for stenting and 1.5% for endarterectomy
- Post-procedural ipsilateral stroke rates strongly favored revascularization in both trials
- All treatment groups, including medical therapy alone, had low rates of disabling stroke
- Crossover rates were 17-18% from medical therapy to revascularization
Study Design
- Study Type
- Two parallel, observer-blinded, randomized controlled trials
- Randomization
- Yes
- Blinding
- Observer-blinded (stroke adjudicators unaware of treatment assignment). Patients and treating physicians were not blinded
- Sample Size
- 2485
- Follow-up
- Median 3.6 years (IQR 1.6-4.0) for stenting trial, median 4.0 years (IQR 2.0-4.0) for endarterectomy trial, up to 4 years maximum
- Centers
- 155
- Countries
- United States, Canada, Australia, Israel, Spain
Primary Outcome
Definition: 4-year composite of any stroke (ischemic or hemorrhagic) or death assessed from randomization to 44 days (periprocedural period), or ipsilateral ischemic stroke assessed during remaining follow-up up to 4 years (postprocedural period)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - (Stenting trial: absolute difference 3.2% (95% CI 0.6-5.9), RR 2.13 (95% CI 1.15-4.39). Endarterectomy trial: absolute difference 1.6% (95% CI -1.1 to 4.3), RR 1.43 (95% CI 0.78-2.72)) | Stenting trial: P=0.02. Endarterectomy trial: P=0.24 |
Limitations & Criticisms
- Unblinded design - patients and treating physicians aware of treatment assignment, though stroke adjudicators were blinded
- Changes in medical therapy practices during trial period may have lowered stroke rates and affected relative benefit of revascularization
- Results may not generalize to broader practice as revascularization performed only by well-trained, certified, high-volume operators with validated credentialing
- Transcarotid-artery revascularization came into use after approximately half of patients enrolled and could not be incorporated
- Tipping-point analysis showed stenting trial significance could be affected by change in outcome of 3-4 patients (>10% relative change in events)
- Some postprocedural strokes may not have been causally related to carotid revascularization as it does not prevent all stroke mechanisms
- Crossover rates of 17-18% from medical therapy to revascularization may have diluted treatment effect
- Limited power in endarterectomy trial to detect difference - tipping point analysis suggested significance would require 6-7 additional events in medical therapy group
- Follow-up duration limited to median 3.6-4.0 years - longer-term outcomes unknown
- Relatively small absolute number of events despite large sample size
Citation
Brott TG, Howard G, Lal BK, et al. Medical Management and Revascularization for Asymptomatic Carotid Stenosis. N Engl J Med 2025. DOI: 10.1056/NEJMoa2508800