CREST-2 Boosts Modern Medical Therapy for the Initial Treatment of Asymptomatic Carotid Stenosis

By Jeffrey Zimmet, MD, PhD

Synopsis: CREST-2 consisted of two parallel randomized trials in patients with ≥ 70% asymptomatic carotid stenosis, showing that intensive medical therapy alone produced very low stroke rates, with no significant additional benefit from carotid endarterectomy and a modest absolute risk reduction with carefully performed transfemoral carotid stenting over four years. These findings support intensive risk factor control as the default strategy and suggest reserving revascularization for highly selected patients at experienced centers.

Source: Brott TG, Howard G, Lal BK, et al. Medical management and revascularization for asymptomatic carotid stenosis. N Engl J Med. 2025; Nov 21. doi:10.1056/NEJMoa2508800. [Online ahead of print].

The management of high-grade asymptomatic carotid stenosis continues to evolve as advances in medical therapy, carotid endarterectomy (CEA), and carotid artery stenting (CAS) improve patient outcomes and influence procedural risk-benefit analyses. Previous landmark studies, primarily from the 1990s and early 2000s (such as ACAS and ACST-1) demonstrated benefit for CEA over then-contemporary medical therapy, but these were conducted before widespread adoption of statins, strict blood pressure targets, and aggressive risk factor modification.

The advent of intensive medical therapy has since reduced annual ipsilateral stroke rates in such patients to well below 1%. Transfemoral CAS came into practice later, with early studies suggesting efficacy comparable to CEA in symptomatic patients, although its benefit in asymptomatic disease with modern medical therapy remained unclear. At the same time, transcarotid artery revascularization (TCAR) has emerged as an alternative with perceived safety advantages, although published outcomes in the context of modern randomized trials are limited. CREST-2 was designed to address whether patients with high-grade (≥ 70%) asymptomatic carotid stenosis should receive revascularization in addition to best medical management.

The study was uniquely comprised of two parallel, observer-blinded, multicenter randomized trials: one comparing CEA to intensive medical therapy alone, the other comparing transfemoral CAS to medical therapy. All participants were treated with modern risk factor control protocols, including free access to blood pressure and cholesterol-lowering medications, with specific targets for systolic blood pressure (< 130 mmHg), low-density lipoprotein (LDL) (< 70 mg/dL), and diabetes control. Operators met strict certification standards for low perioperative complication rates, and the trials enrolled a robust population at 155 centers internationally between 2014 and 2025.

CREST-2’s stenting trial randomized 1,245 patients and found the four-year composite primary outcome (stroke or death within 44 days, or ipsilateral ischemic stroke thereafter) occurred in 6.0% of those assigned to medical management alone vs. 2.8% assigned to transfemoral CAS plus medical therapy (absolute difference 3.2%, P = 0.02). Notably, the periprocedural risk of stroke or death was 1.3% in the CAS group compared to 0% in the medical arm.

The parallel endarterectomy trial randomized 1,240 patients and showed a four-year primary event rate of 5.3% with medical management vs. 3.7% with CEA (absolute difference 1.6%, P = 0.24). Both forms of revascularization resulted in low annual postprocedural ipsilateral stroke rates (< 0.5%), but almost all disabling and major strokes were rare under modern medical management as well. Subgroup and secondary outcomes were consistent with primary results, demonstrating the overall durability of medical therapy and marginal additional benefit from revascularization.

The CREST-2 investigators concluded that, while transfemoral CAS plus intensive medical therapy produced a statistically significant absolute reduction in the composite event rate compared to medical therapy alone, the margin was modest (3.2%) and the benefit primarily accrued at the cost of periprocedural risk offset. CEA did not significantly reduce the primary endpoint vs. medical therapy alone, suggesting limited value in routine surgical revascularization for asymptomatic patients with well-controlled risk factors. The trial underscores the efficacy and safety of best medical therapy and highlights the importance of careful patient selection and operator proficiency if revascularization is considered.

Commentary

The CREST-2 results have immediate implications for management of asymptomatic carotid stenosis, affirming that intensive medical therapy alone suffices for most patients, with revascularization reserved for select cases. For practicing cardiologists, who often initiate vascular risk management, these findings highlight the primacy of aggressive secondary prevention: target systolic blood pressure < 130 mmHg (achieved in only 60% to 70% of CREST-2 participants), LDL < 70 mg/dL (70% to 80% adherence), and comprehensive lifestyle counseling, which halved event rates from historical trials. The lack of CEA benefit aligns with prior trials, including SPACE-2 and ECST-2, suggesting that routine surgery is not indicated for asymptomatic disease, as procedural risks (1.5%) now match or exceed long-term medical risks (1.3% annually). CAS’s modest advantage (absolute reduction 3.2%) must be weighed against its periprocedural hazard (1.3% stroke/death, none in the medical arm), fragility (three to four events could nullify significance), and applicability limited to expert centers, because real-world periprocedural events are significantly greater based on CREST-1 data.

CREST-2 does not address the role of TCAR, a newer technique in which access is gained via the common carotid artery with direct flow reversal to minimize embolic risk. TCAR has gained popularity in recent years, with real-world registry data and some observational studies suggesting that its periprocedural stroke and death rate may be at least as favorable as, or possibly lower than, transfemoral CAS, particularly in certain anatomic or high-risk patient subgroups. However, by the time TCAR gained wider use, approximately half of the CREST-2 patient cohort already had been enrolled and, thus, TCAR was not systematically studied or represented in the trial.

This limitation has important implications. The safety and efficacy of TCAR in comparison to both transfemoral CAS and CEA, especially in asymptomatic patients, has not been assessed in a contemporary, randomized controlled trial with intensive medical therapy as a comparator. Furthermore, the strict credentialing and operator experience requirements in CREST-2 are likely to minimize periprocedural risk beyond what might be achieved in routine practice. As such, while the results of CREST-2 provide vital evidence against routine CEA (and, arguably, CAS) in asymptomatic patients, they do not directly inform optimal use of TCAR, which may have a distinct risk profile and technical advantages in select populations.

For practicing cardiologists, the CREST-2 data affirm that modern intensive medical therapy should be first-line for asymptomatic carotid stenosis, reserving any revascularization — whether CEA, transfemoral CAS, or TCAR — for highly selected patients, such as those with progression, symptoms despite therapy, or specific anatomical indications. In the absence of high-quality, randomized TCAR data against contemporary medical therapy in this population, enthusiasm for adopting routine TCAR should be tempered, and its use individualized within a multidisciplinary framework and ideally studied in future clinical trials.

In summary, CREST-2 moves the field toward conservative management for asymptomatic high-grade carotid stenosis. Although emerging technologies such as TCAR remain promising, they have yet to be rigorously tested in the paradigm-shifting context of CREST-2’s methodology and population.

Jeffrey Zimmet, MD, PhD, is Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center.