CREST-2
Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trials
Clinical Question
Among patients with asymptomatic high-grade carotid stenosis, does adding carotid revascularization (stenting or endarterectomy) to intensive medical management provide greater benefit than intensive medical management alone in preventing stroke?
Bottom Line
In patients with asymptomatic high-grade carotid stenosis, carotid-artery stenting plus intensive medical management significantly reduced the 4-year composite of periprocedural (≤44 days) stroke or death or ipsilateral ischemic stroke (through 4 years) compared with 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 vs 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 or 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
Design
Study Type: Two parallel, observer-blinded, randomized controlled trials
Randomization: 1
Blinding: Observer-blinded (stroke adjudicators unaware of treatment assignment). Patients and treating physicians were not blinded
Enrollment Period: First patient randomized December 10, 2014 (stenting trial) and December 9, 2014 (endarterectomy trial); last follow-up visits completed July 31, 2025 (stenting) and September 30, 2024 (endarterectomy). The paper does not report the exact date enrollment closed.
Follow-up Duration: 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
Sample Size: 2485
Analysis: Intention-to-treat analysis. Kaplan-Meier curves for event rates with cumulative-incidence function accounting for competing risk of death. Assumption-free re-randomization test with 10,000 replications for significance testing. Bootstrap methods with 100,000 replications for 95% confidence intervals. Poisson regression for annual event rates. O'Brien-Fleming boundaries for interim analysis with final alpha=0.047
Inclusion Criteria
- Age ≥35 years
- No history of stroke, transient ischemic attack, or amaurosis fugax in carotid territory within 180 days before randomization
- Stenosis ≥70% assessed by duplex ultrasound with peak systolic velocity ≥230 cm/sec AND one of: end diastolic velocity ≥100 cm/sec, peak systolic velocity ratio (ICA/CCA) ≥4.0, or ≥70% stenosis on CTA or MRA
- OR stenosis ≥70% on catheter angiography alone
Exclusion Criteria
- Previous disabling stroke
- Unstable angina
- Atrial fibrillation prompting anticoagulation
Arms
| Field | Control | Stenting Trial - Carotid-Artery Stenting | Control | Endarterectomy Trial - Carotid Endarterectomy |
|---|---|---|---|---|
| Intervention | Intensive medical management with protocol-driven oversight. Primary targets: systolic BP <130 mmHg (changed from <140 mmHg in 2018), LDL cholesterol <70 mg/dL. Management of glucose, glycated hemoglobin, lifestyle factors (smoking cessation, weight management, physical activity). Telephone health coaching. Antiplatelet therapy per standard care. Free medications available including alirocumab after 2018 | Transfemoral carotid-artery stenting with embolic protection (required) plus intensive medical management. Local anesthesia for femoral access with or without conscious sedation. Antiplatelet regimen: aspirin 325 mg daily plus clopidogrel 75 mg twice daily starting 48 hours before procedure, then clopidogrel 75 mg daily plus aspirin 75-325 mg daily for 30 days, followed by aspirin 70-325 mg daily thereafter. Alternative antiplatelet regimens if clopidogrel/aspirin contraindicated | Intensive medical management with protocol-driven oversight. Primary targets: systolic BP <130 mmHg (changed from <140 mmHg in 2018), LDL cholesterol <70 mg/dL. Management of glucose, glycated hemoglobin, lifestyle factors (smoking cessation, weight management, physical activity). Telephone health coaching. Antiplatelet therapy per standard care. Free medications available including alirocumab after 2018 | Carotid endarterectomy plus intensive medical management. General anesthesia in 89% of cases. Antiplatelet regimen: aspirin 325 mg daily for at least 48 hours before procedure, then aspirin 70-325 mg daily thereafter. Periprocedural anticoagulation with heparin or bivalirudin required |
| Duration | 4 years | 4 years | 4 years | 4 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| 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 the remaining follow-up period up to 4 years (postprocedural period) | Primary | Medical management alone: Stenting trial 6.0%, Endarterectomy trial 5.3% (4-year composite of periprocedural stroke or death, or ipsilateral ischemic stroke through 4 years) | Revascularization + medical: Stenting 2.8%, Endarterectomy 3.7% (4-year composite) | Stenting: RR 2.13, absolute difference 3.2%, NNT=31. Endarterectomy: RR 1.43, absolute difference 1.6% | Stenting: P=0.02 (significant). Endarterectomy: P=0.24 (not significant) |
| Periprocedural stroke or death (days 0-44) - Stenting trial | Medical Therapy: 0/629 (0.0%, 95% CI 0.0-0.6) | Secondary | 8/616 (1.3%, 95% CI 0.6-2.5) | Difference -1.3% (95% CI -2.2 to 0.4) | Not reported | |
| Periprocedural stroke or death (days 0-44) - Endarterectomy trial | Medical Therapy: 3/623 (0.5%, 95% CI 0.1-1.4) | Secondary | 9/617 (1.5%, 95% CI 0.7-2.8) | Difference -1.0% (95% CI -2.1 to 0.1) | Not reported | |
| Postprocedural ipsilateral ischemic stroke (annual rate) - Stenting trial | Medical Therapy: 1.7% per year (95% CI 1.1-2.4), 28 events/1686 person-years | Secondary | 0.4% per year (95% CI 0.2-0.9), 7 events/1714 person-years | RR 4.07 (95% CI 1.78-9.31) | Not reported | |
| Postprocedural ipsilateral ischemic stroke (annual rate) - Endarterectomy trial | Medical Therapy: 1.3% per year (95% CI 0.9-2.0), 23 events/1761 person-years | Secondary | 0.5% per year (95% CI 0.3-1.0), 10 events/1823 person-years | RR 2.38 (95% CI 1.13-5.00) | Not reported | |
| Tissue-based stroke definitions (4-year composite) | Medical Therapy: Results similar to primary outcome with WHO-defined stroke | Secondary | Results similar to primary outcome with WHO-defined stroke | Not reported | ||
| Nondisabling stroke outcomes | Medical Therapy: Concordant with primary outcome in both trials | Secondary | Concordant with primary outcome in both trials | Not reported | ||
| Disabling stroke | Medical Therapy: Low rates in all groups including medical therapy | Secondary | Low rates in all groups | Not reported | ||
| Death - Stenting trial | Adverse | 69 (11.0%) | 48 (7.8%) | Not reported | |
| Death - Endarterectomy trial | Adverse | 60 (9.6%) | 54 (8.8%) | Not reported | |
| Carotid revascularization - Stenting trial | Adverse | 118 (18.8%) | 29 (4.7%) | Not reported | |
| Carotid revascularization - Endarterectomy trial | Adverse | 131 (21.0%) | 44 (7.1%) | Not reported | |
| No revascularization received when assigned - Stenting trial | Adverse | 41 (7%) | Not applicable | ||
| No revascularization received when assigned - Endarterectomy trial | Adverse | 24 (4%), with 22 not receiving any procedure and 2 receiving carotid-artery stenting | Not applicable |
Subgroup Analysis
Eleven prespecified subgroups analyzed including age (<70, ≥70, <80, ≥80), sex, peak systolic velocity (<342, ≥342 cm/sec), hypertension, diabetes, dyslipidemia, smoking, CHA2DS2-VASc score (0-3, ≥4), symptomatic status of target artery, symptomatic status of contralateral artery. Results appeared consistent across subgroups in both trials. Median infarct volume was 1.55 mL (IQR 0.27-7.81) and appeared similar between treatment groups in both trials
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
Funding
National Institute of Neurological Disorders and Stroke, National Institutes of Health (grants U01 NS080168, U01 NS080165); Centers for Medicare and Medicaid Services, Department of Health and Human Services; NIH StrokeNet (grant U01 NS086872). Alirocumab donated by Regeneron Pharmaceuticals after 2018
Based on: CREST-2 (New England Journal of Medicine, 2025)
Authors: T.G. Brott, G. Howard, B.K. Lal, ..., for the CREST-2 Investigators
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
Reviewed by: Ahmed Koriesh, MD
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