On superficial review, CREST2 appears rigorous and its conclusions undeniable, especially since it is published in the highly reputable New England Journal of Medecine. However, a detailed analysis reveals that the study is poorly designed and has severe limitations, which were overlooked by its authors, the ethics committees and the journal reviewers. As a result, some of its conclusions are invalid and others are misleading.
Serious design flaws
The duration of the study is far too short
The authors of CREST2 have overlooked the most serious limitation of their trials: They compare three treatments with very different actuarial stroke curves. Two of which, carotid surgery and angioplasty, have a large part of their complications occurring in the first month of the study, while the third treatment, purely medical, which leaves the atherosclerotic plaque in place, has its complications occurring over time. Beyond the post-operative period, all patients have a risk of non-carotid stroke, mainly cardioembolic. But those only receiving medical treatment also have the risk of rupture of the fibrous cap of their atherosclerotic plaque or even of its evolution towards occlusion. The stroke rate of asymptomatic carotid stenoses is low, which considerably increases the time required for interventional treatments to neutralize the rate of postoperative complications.
Therefore, the shorter the study, the more it is biased against interventional procedures. Ideally, such research should track patients for at least as long as half the group survives, roughly 10 years.
In addition, this approach does not account for the portion of only medically treated patients who may live beyond four years and up to 30 years but still carry the high-risk atheromatous plaque.
Crest2 is made up of two separate trials
This has two serious drawbacks.
- It is not possible to compare surgery and angioplasty.
- If one of the trials proves that one treatment is superior to the other, that trial must be stopped.
Critical appraisal and commentary on the limitations of CREST2.
Critical appraisal and commentary on the conclusions of CREST2.
The conclusions reached by the authors.
Concluding that carotid endarterectomy does not demonstrate its superiority over medical treatment at four years sends a misleading message: surgery is not effective on asymptomatic stenoses, but carotid angioplasty is effective, although there is no real comparison between surgery and angioplasty.
Within 44 days post-procedure, the complication rates are similar. There were 9/617 post-surgery strokes and 8/616 post-angioplasty strokes.
The difference occurs later, related to the rate of stroke, which is partly cardioembolic.
Conclusions that should have been reached by the authors.
Medical treatment alone, even at 4 years, has a much higher stroke rate than angioplasty or surgery.
The trial of medical treatment alone versus angioplasty was stopped because angioplasty, combined with medical treatment, demonstrated its superiority over medical treatment alone.
Surgery has not demonstrated significant superiority over medical treatment alone, likely due to an insufficient follow-up period.
Pending longer-term results, it is always necessary to combine medical treatment with an interventional technique, depending on the indications and contraindications of each of these two complementary techniques.
Two important questions raised by the publication of CREST2
Is it ethical, given that in the angioplasty-medical treatment alone trial, angioplasty has demonstrated its superiority over medical treatment-alone, to continue this trial which will expose patients in the medical treatment-alone group to an increased risk of stroke?
What profit surplus will the stenting industry make after the publication of CREST2?
Conclusion
CREST2 trials should never have been published in its current form, and even worse, with these conclusions.
The main interest of CREST2 is to show the lack of short-term effectiveness of medical treatment alone and the remarkable progress of angioplasty, but it does not mention the cost of treatments, which is important when two treatments are equivalent.
Stroke rate of interventional treatments could be reduced by a better understanding of the mechanism of perioperative complications.
The continued monitoring of patients, which is planned in CREST2, will allow for more refined results and likely to be more in line with reality.
References
- Medical Management and Revascularization for Asymptomatic Carotid Stenosis. Brott TG, Howard G, Lal BK, et al; CREST-2 Investigators. N Engl J Med. 2025 Nov 21;394(3):219-231. doi: 10.1056/NEJMoa2508800. Epub 2025 Nov 21. PMID: 41269206
- Diabetes, stroke severity and hemodynamic cerebral ischemia. Petitjean C, Labreuche J. Cardiovasc Diabetol Endocrinol Rep. 2025 Dec 21;11(1):48. doi: 10.1186/s40842-025-00264-2. PMID: 41422063
- Hemodynamic Stroke: Emerging Concepts, Risk Estimation, and Treatment. Wegener S, Baron JC, Derdeyn CP, et al. Stroke. 2024 Jun;55(7):1940-1950. doi: 10.1161/STROKEAHA.123.044386. Epub 2024 Jun 12. PMID: 38864227
