Carotid Landmark Trials
CEA has its clearest benefit in recently symptomatic 70–99% stenosis without near-occlusion; delay reduces that benefit. In asymptomatic disease, comparing two procedures does not establish whether intervention is needed.
Written August 10, 2026 · Mr Razhan K Ali
At a glance
CEA has its clearest benefit in recently symptomatic 70–99% stenosis without near-occlusion; delay reduces that benefit. In asymptomatic disease, comparing two procedures does not establish whether intervention is needed. [1,4,5,17,18]
CEA = carotid endarterectomy; CAS = carotid artery stenting; MI = myocardial infarction. Read each result with its population, comparator, endpoint and follow-up. A stroke/MI/death composite is not the same as stroke alone.
1. Symptomatic stenosis: who benefits, and how soon?
Clinical question: Does adding CEA to medical treatment prevent stroke, and how does benefit change with stenosis severity and delay?
| Trial / population | Result to know | What it means |
| NASCET, 1991 Randomised trial; recent retinal or hemispheric symptoms and 70–99% stenosis. |
Two-year ipsilateral stroke: 26% medical treatment vs 9% CEA; absolute reduction 17 percentage points. [1] | Large benefit in severe symptomatic stenosis. These are historical trial risks, not estimates for every patient receiving current medical treatment. |
| ECST final, 1998 Randomised trial; symptomatic stenosis measured using the ECST method. |
Benefit was concentrated above approximately 80% ECST. Operative major stroke/death was 7.0%. [2] | Supports CEA in severe symptomatic disease, but ECST and NASCET percentages are not interchangeable. |
| NASCET moderate stenosis, 1998 Randomised trial; symptomatic stenosis below 70%. |
For 50–69%, five-year ipsilateral stroke: 22.2% medical treatment vs 15.7% CEA; number needed to treat (NNT) 15. No significant benefit below 50%. [3] | Benefit in 50–69% stenosis is smaller: patient selection and timing matter. |
| Pooled CEA trials, 2003 Individual-patient analysis of NASCET, ECST and the Veterans Affairs trial, using standardised measurements and outcomes. |
Five-year absolute reduction in ipsilateral ischaemic stroke, including operative stroke/death: 16.0 percentage points for ≥70% without near-occlusion; 4.6 for 50–69%. [4] | No routine CEA benefit below 50%. Near-occlusion is a separate category, not ordinary severe stenosis; clear five-year benefit was not demonstrated. |
| Rothwell timing analysis, 2004 Pooled NASCET/ECST analysis; symptomatic stenosis ≥50%. |
NNT to prevent one ipsilateral stroke over five years: 5 when randomised within two weeks of the last event vs 125 when randomised after more than 12 weeks. [5] | Delay reduces benefit. This was an analysis by time to randomisation, not a trial assigning patients to early or late surgery. |
2. CEA or stenting: what is the trade-off?
Clinical question: Once revascularisation is appropriate, how do the procedures compare for early harm and later stroke prevention?
| Trial / population | Result to know | What it means |
| SAPPHIRE, 2004 Randomised non-inferiority trial; high surgical risk, with symptomatic ≥50% or asymptomatic ≥80% stenosis. |
Protected CAS vs CEA: 12.2% vs 20.1% for death/stroke/MI within 30 days, plus death or ipsilateral stroke from day 31 to one year. Non-inferiority was met. [6] | A selected high-risk population. Non-inferiority is not proof of superiority, and this was not the usual standard-risk symptomatic CEA population. |
| EVA-3S, 2006 Randomised trial; symptomatic stenosis ≥60%. |
Thirty-day stroke/death: 9.6% CAS vs 3.9% CEA. Stopped early for safety and futility. [7] | Higher early stroke/death with CAS in this symptomatic population. |
| SPACE, 2006 Randomised non-inferiority trial; symptomatic stenosis. |
Death or ipsilateral ischaemic stroke from randomisation to 30 days after treatment: 6.84% CAS vs 6.34% CEA. Non-inferiority was not demonstrated. [8] | Similar event rates do not, by themselves, establish equivalence or non-inferiority. |
| ICSS early report, 2010 Randomised trial; symptomatic stenosis. |
Stroke, death or procedural MI within 120 days of randomisation: 8.5% CAS vs 5.2% CEA. [9] | Favoured CEA for early safety. Do not quote these as 30-day procedural rates. |
| CREST, 2010; symptomatic analysis, 2011 Randomised trial; symptomatic and asymptomatic patients. |
The four-year composite of periprocedural stroke/MI/death plus later ipsilateral stroke did not differ significantly. In the symptomatic subgroup, periprocedural stroke/death was 6.0% CAS vs 3.2% CEA. [10,11] | CAS caused more periprocedural strokes; CEA caused more MI and cranial nerve injury. A similar composite can conceal clinically different complications. |
| ICSS long-term report, 2015 Follow-up of the symptomatic randomised cohort. |
Five-year fatal/disabling stroke: 6.4% CAS vs 6.5% CEA. Any stroke: 15.2% vs 9.4%, respectively. [12] | Similar fatal/disabling stroke estimates, but more strokes overall with CAS, mainly non-disabling. These intention-to-treat estimates include early events. |
| Carotid Stenting Trialists’ Collaboration age analysis, 2016 Pooled individual-patient data from four symptomatic trials. |
CAS procedural stroke/death risk increased with age. At 70–74 years, the CAS vs CEA hazard ratio was 2.09 (95% confidence interval 1.32–3.32). [13] | Supports preferring CEA in older symptomatic patients; do not extrapolate this subgroup estimate to every age or asymptomatic patient. |
| CREST long-term report, 2016 Follow-up of the mixed symptomatic/asymptomatic cohort. |
No significant difference in postprocedural ipsilateral stroke over ten years. [14] | Both treatments can provide durable protection. Similar later outcomes do not remove the importance of early procedural harm. |
3. Asymptomatic stenosis: what did the earlier trials establish?
Clinical question: Did CEA add benefit to older medical treatment, and how did CAS compare with CEA when intervention had already been chosen?
| Trial / comparison | Result to know | What it means |
| ACAS, 1995 Randomised trial; asymptomatic ≥60% stenosis. CEA plus medical treatment vs medical treatment alone. |
Estimated five-year ipsilateral stroke plus any perioperative stroke/death: 11.0% medical treatment vs 5.1% CEA. [15] | Benefit depended on low procedural risk. The medical-treatment arm predates contemporary prevention. |
| ACST-1 ten-year report, 2010 Randomised trial; asymptomatic stenosis. Immediate vs deferred CEA. |
Ten-year net stroke risk, including perioperative stroke/death: 17.9% deferred vs 13.4% immediate CEA. Perioperative stroke/death was 3.0%. [16] | A modest long-term benefit, dependent on procedural risk and sufficient life expectancy. |
| ACT I, 2016 Randomised non-inferiority trial; asymptomatic severe stenosis, age ≤79, standard surgical risk. CAS vs CEA. |
Thirty-day death/stroke/MI plus ipsilateral stroke through one year: 3.8% CAS vs 3.4% CEA; non-inferiority met. No significant difference in the reported five-year stroke or survival outcomes. [17] | Compared two procedures, not intervention against medical treatment alone. |
| ACST-2, 2021 Randomised trial; asymptomatic severe stenosis for which patient and clinician had already decided on intervention. CAS vs CEA. |
Procedural disabling stroke/death was about 1% in each group; five-year non-procedural fatal/disabling stroke was 2.5% in each group. More non-disabling procedural strokes occurred with CAS. [18] | Helps choose a procedure after deciding to intervene. It does not establish who needs intervention. |
4. Does intervention add benefit to modern medical treatment?
ECST-2: selected lower-risk disease
Design and population: A randomised trial of optimised medical therapy (OMT) alone vs OMT plus CEA or CAS. The 429 participants had stenosis ≥50%, with or without symptoms, and a predicted five-year ipsilateral stroke risk below 20% using the Carotid Artery Risk score. [19]
Outcome and result: The two-year interim analysis used a hierarchical outcome covering death, stroke, MI and new silent brain infarction. The win ratio was 1.01 (95% confidence interval 0.60–1.70; p=0.97). This compares prioritised outcomes, not simply stroke rates. [19]
Interpretation: No added benefit from revascularisation was demonstrated at two years. This does not prove equivalence, and should not be generalised to all recently symptomatic severe stenoses. The population was selected for lower predicted risk, and this was an interim analysis. [19]
CREST-2: asymptomatic high-grade stenosis
Design and population: Two parallel randomised trials in asymptomatic stenosis ≥70%: CAS plus intensive medical management (IMM) vs IMM alone, and CEA plus IMM vs a separate IMM-alone group. Published online in 2025 and in the 2026 journal issue. [20]
Primary outcome: Any stroke or death through day 44 after randomisation, followed by ipsilateral ischaemic stroke through four years. [20]
| Trial | IMM alone | Procedure + IMM | Four-year comparison |
| CAS trial | 6.0% | 2.8% | Significant reduction; p=0.02 |
| CEA trial | 5.3% | 3.7% | Reduction not statistically significant; p=0.24 |
Both rows report the primary composite outcome, not stroke alone. [20]
Interpretation: CAS added benefit in its trial; a statistically significant benefit of CEA was not demonstrated in its trial. CREST-2 did not randomise CAS against CEA. It therefore does not establish that CAS is superior to CEA, or that CEA can never benefit an asymptomatic patient. Apply the results to comparable patients and procedural performance. [20]
Why this matters in UK training
Keep the trial result separate from the recommendation. ESVS 2023 recommends intervention as soon as possible, preferably within 14 days of symptom onset, when intervention is appropriate for symptomatic 50–99% stenosis. [21]
NICE recommends urgent CEA assessment for patients with stable neurological symptoms after a non-disabling stroke or TIA and 50–99% NASCET stenosis, alongside medical treatment. [22]
Timing difference to recognise: The UK and Ireland National Clinical Guideline for Stroke specifies CEA as soon as possible and within one week of first presentation, in neurologically stable patients fit for surgery. These are different time anchors, not interchangeable deadlines. Early-treatment evidence should not be applied automatically to a large or disabling stroke. [23]
These guideline editions predate the ECST-2 and CREST-2 results above. Present the newer evidence explicitly rather than implying that it is already incorporated into their recommendations. [19–23]
Remember
NASCET/ECST: who benefits. Rothwell: why delay matters. CEA–CAS trials: early harm versus later protection. Modern trials: what intervention adds to medical treatment.
Before quoting a trial in a viva or MDT, give the patient group, the comparison, the outcome and the time point. Then explain what the trial does—and does not—justify.
References
1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–453. PMID: 1852179.
2. European Carotid Surgery Trialists’ Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998;351:1379–1387. PMID: 9593407.
3. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339:1415–1425. PMID: 9811916.
4. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet. 2003;361:107–116. PMID: 12531577.
5. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet. 2004;363:915–924. PMID: 15043958.
6. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med. 2004;351:1493–1501. doi:10.1056/NEJMoa040127. PMID: 15470212.
7. Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med. 2006;355:1660–1671. PMID: 17050890.
8. SPACE Collaborative Group. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet. 2006;368:1239–1247. PMID: 17027729.
9. Ederle J, Dobson J, Featherstone RL, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet. 2010;375:985–997. PMID: 20189239.
10. Brott TG, Hobson RW, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363:11–23. doi:10.1056/NEJMoa0912321. PMID: 20505173.
11. Silver FL, Mackey A, Clark WM, et al. Safety of stenting and endarterectomy by symptomatic status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Stroke. 2011;42:675–680. doi:10.1161/STROKEAHA.110.610212. PMID: 21307169.
12. Bonati LH, Dobson J, Featherstone RL, et al. Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. Lancet. 2015;385:529–538. PMID: 25453443.
13. Howard G, Roubin GS, Jansen O, et al. Association between age and risk of stroke or death from carotid endarterectomy and carotid stenting: a meta-analysis of pooled patient data from four randomised trials. Lancet. 2016;387:1305–1311. PMID: 26880122.
14. Brott TG, Howard G, Roubin GS, et al. Long-term results of stenting versus endarterectomy for carotid-artery stenosis. N Engl J Med. 2016;374:1021–1031. doi:10.1056/NEJMoa1505215. PMID: 26890472.
15. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421–1428. PMID: 7723155.
16. Halliday A, Harrison M, Hayter E, et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet. 2010;376:1074–1084. PMID: 20870099.
17. Rosenfield K, Matsumura JS, Chaturvedi S, et al. Randomized trial of stent versus surgery for asymptomatic carotid stenosis. N Engl J Med. 2016;374:1011–1020. PMID: 26886419.
18. Halliday A, Bulbulia R, Bonati LH, et al. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy. Lancet. 2021;398:1065–1073. PMID: 34469763.
19. Donners SJA, van Velzen TJ, Cheng SF, et al. Optimised medical therapy alone versus optimised medical therapy plus revascularisation for asymptomatic or low-to-intermediate risk symptomatic carotid stenosis (ECST-2): 2-year interim results of a multicentre randomised trial. Lancet Neurol. 2025;24:389–399. doi:10.1016/S1474-4422(25)00107-3. PMID: 40252662.
20. Brott TG, Howard G, Lal BK, et al. Medical management and revascularization for asymptomatic carotid stenosis. N Engl J Med. 2026;394:219–231. Published online 21 November 2025. doi:10.1056/NEJMoa2508800. PMID: 41269206.
21. Naylor R, Rantner B, Ancetti S, et al. Editor’s Choice—European Society for Vascular Surgery (ESVS) 2023 Clinical Practice Guidelines on the Management of Atherosclerotic Carotid and Vertebral Artery Disease. Eur J Vasc Endovasc Surg. 2023;65:7–111. doi:10.1016/j.ejvs.2022.04.011. Guideline.
22. National Institute for Health and Care Excellence. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. NG128. Recommendations. Accessed 30 September 2026.
23. Intercollegiate Stroke Working Party. National Clinical Guideline for Stroke for the UK and Ireland. 2023. Long-term management and secondary prevention. Accessed 30 September 2026.