Carotid Artery Disease: Then and Now

Interventions for carotid revascularization have been pioneered over the past 70 years, and safety for those interventions has been achieved (Figure). Concurrently, drugs to prevent and treat atherosclerosis have been invented with improving safety, tolerability, and efficacy. The plummeting use of cigarettes and other cultural changes have complemented interventional and medical treatments, culminating in a decreasing burden from carotid disease and stroke. This overview focuses on those medical and interventional treatments. Optimal management for patients with high‐grade asymptomatic carotid stenosis remains to be defined.

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MEDICAL TREATMENTS

The safety and efficacy of medical treatment without revascularization have not been tested this century in a randomized clinical trial (RCT) focused on patients with high‐grade carotid stenosis. Only 113 patients were in the medical group in the SPACE‐2 (Stent‐Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy‐2) trial. ¹ The most recent comprehensive guideline statement recommends low‐dose aspirin, antihypertensive treatment for patients with hypertension, lipid‐lowering therapy with statins, ezetimibe, and PCSK‐9 (proprotein convertase subtilisin/kexin type 9) inhibitors, as needed, and optimal glycemic control of diabetes. ² Behavioral counseling to assist patients in achieving a healthy lifestyle is also recommended. In CREST‐2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial), ³ intensive medical treatment (IMT) is the experimental arm because carotid endarterectomy (CEA) and carotid artery stenting (CAS) have been compared with each other in preceding carotid RCTs. The CREST‐2 IMT protocol includes guideline medical treatment recommendations, behavioral counseling, and the option for PCSK‐9 inhibitors. ³ The systolic blood pressure goal is <130 mm Hg, and the goal for lipid control is low‐density lipoprotein <70 mg/dL. The medical groups in CREST‐2 now have >1000 patients. Accordingly, testing of safety and efficacy of IMT for patients with high‐grade asymptomatic carotid stenosis will be feasible.

CAROTID ARTERY ENDARTERECTOMY

CEA to prevent stroke in patients with high‐grade carotid stenosis was pioneered in the early 1950s. The first RCT reported in 1970 was inconclusive. ⁴ Larger US and international RCTs followed in the 1990s. These trials provided definitive support for CEA in preventing stroke compared with medical treatment alone. ⁴

For symptomatic patients, the North American Symptomatic Carotid Endarterectomy Trial showed an annual absolute risk reduction in ipsilateral stroke of 11.3% for CEA in patients with ≥70% stenosis and an annual absolute risk reduction of 1.3% for patients with 50% to 69% stenosis. ⁴ The ECST (European Carotid Surgery Trial) also showed efficacy for CEA. ⁴ However, a benefit for CEA was not shown for patients with 50% to 69% stenosis. ⁴

For asymptomatic patients, the RCTs of the 1990s consistently favored CEA in preventing ipsilateral stroke. ⁴ None of the asymptomatic RCTs showed a relationship of risk or benefit to the degree of carotid stenosis. ⁴ Results of these trials for symptomatic and asymptomatic patients form the basis for treatment guidelines and medical practice today. Appropriately powered contemporary RCTs have not been reported.

CAS FOR SYMPTOMATIC PATIENTS

CAS was pioneered in the 1990s to be less invasive than CEA. Safety of CAS comparable to CEA was reported from retrospective and registry studies. ⁵ In 2004, the SAPPHIRE (Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy) RCT ² reported that CAS performed in patients deemed at increased risk for CEA was noninferior to CEA at 30 days. In 2005, the Centers for Medicare and Medicaid Services approved reimbursement for CAS for high‐risk symptomatic patients with ≥70% stenosis and asymptomatic patients with ≥80% stenosis. ⁵ , ⁶ The Centers for Medicare and Medicaid Services did not approve reimbursement for conventional‐risk patients.

In the 2000s, 4 large RCTs compared CEA with CAS in conventional‐risk symptomatic patients with ≥70% stenosis. ⁵ All of these trials used first‐generation CAS technology. ⁵ The 3 trials with stroke as the primary outcome showed an advantage for CEA. ⁵ The interventionists in these trials had limited experience. The fourth RCT, the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), ⁵ randomized symptomatic and asymptomatic patients and incorporated rigorous credentialing. ⁵ Perioperative myocardial infarction was part of the primary end point. In both the symptomatic and asymptomatic patients, primary outcomes did not differ out to 10 years of follow‐up. ⁵ However, significantly more periprocedural strokes occurred in the CAS group (4.1% versus 2.3%), while fewer periprocedural myocardial infarctions occurred in the CAS group (1.1% versus 2.3%).

Preplanned pooled analyses of individual patient data from the 4 trials of conventional‐risk symptomatic patients are informative. Both CAS and CEA showed robust clinical durability. ⁷ After the periprocedural period, the annual risk of stroke was 0.64% for CAS and 0.60% for CEA. Pooled analysis also confirmed the negative effect of advancing age on outcomes for CAS, previously reported by SPACE and CREST. Compared with CAS patients aged <60 years, the hazard ratio (HR) for periprocedural stroke and death in patients undergoing CAS aged 65 to 69 years was 2.16 (95% CI, 1.13–4.13) with a plateauing of risk for patients aged >70 years (HR, ≈4). ⁸

CAS AND CEA FOR ASYMPTOMATIC PATIENTS

CAS was compared with CEA in 2 large RCTs. ⁵ In CREST, no significant differences were reported for the 1181 asymptomatic patients out to 10 years. ⁵ The ACT‐1 (Asymptomatic Carotid Trial 1) ⁹ randomized 1453 patients and found CAS to be noninferior to CEA out to 5‐years. ACST‐2 (Asymptomatic Carotid Trial 2) ¹⁰ randomized 3625 patients to CAS or CEA and did not find significant differences in outcomes. In sum, these trials showed that CAS and CEA have achieved impressive, nearly equivalent safety. Efficacy cannot be inferred because a medical‐treatment‐only group was not included.

Because of the improvements in medical approaches to atherosclerosis and asymptomatic carotid disease, 3 RCTs comparing medical treatment to revascularization were initiated: ECST‐2, SPACE‐2, and CREST‐2. ⁵ SPACE‐2 ⁸ has reported primary and secondary outcomes: 203 patients were randomized to CEA, 197 to CAS, and 113 to medical treatment alone. The rate of periprocedural stroke and death plus ipsilateral stroke out to 5 years was 4.4% for CAS, 2.5% for CEA, and 3.1% for medical treatment. Superiority to medical treatment was not shown for either CAS or CEA. The investigators advised caution in interpretation because enrollment was well below the preplanned sample size.

Outcomes from CREST‐2 ⁸ will be available in 2026. CREST‐2 is 2 RCTs randomizing patients with ≥70% stenosis. One trial compares CEA plus IMT to IMT alone. The other trial compares CAS plus IMT to IMT alone. The prespecified cohorts of 1240 patients for each trial will be followed up to 4 years. CREST‐2 includes a centrally directed, protocol‐driven medical treatment program. ³ Cognitive trajectories will be compared in both trials. ⁸ An ancillary study, CREST‐H (Asymptomatic Carotid Stenosis Trial–Hemodynamics), ¹¹ will analyze cognitive function in patients with ipsilateral hemispheric hypoperfusion, a subgroup that may be more likely to derive cognitive benefit from revascularization.

TRANSCAROTID REVASCULARIZATION

Transcarotid Revascularization (TCAR) is another revascularization option. Arterial access is obtained directly via the common carotid artery and eliminates the risks posed by catheter manipulation through the aortic arch. Stent placement is done under conditions of retrograde flow, which may lessen anterograde propagation of embolic debris. ² Large registries with neurological examinations of patients before and after TCAR have reported immediate and later outcomes comparable to those reported for CAS.⁵ In the Vascular Quality Initiative registry, the 30‐day stroke and death rate was 1.6%. for 8104 symptomatic and asymptomatic patients. ² Acceptance of TCAR has been rapid and largely at the expense of CEA.

CURRENT STATUS AND RECOMMENDATIONS

In October 2023, the Centers for Medicare and Medicaid Services issued a new National Coverage Determination. ⁶ In in the United States. CAS will be reimbursed for symptomatic patients with ≥50% carotid stenosis and asymptomatic patients with ≥70% stenosis. TCAR will also be reimbursed.

A recent guideline provides recommendations for prevention and treatment for patients at risk for carotid artery disease and patients with established carotid artery disease. ² Our recommendations are similar. For symptomatic patients, revascularization is appropriate for patients with ≥50% stenosis and the clinical characteristics of the patients enrolled in the symptomatic RCTs. Treatment should be timely, though not emergent. ² For asymptomatic patients, evidence supports revascularization in patients with ≥70% stenosis, in addition to medical treatment. Medical treatment alone may be favored for patients averse to CEA and interventional procedures, primarily because of the low risk for stroke without revascularization. RCT evidence does not favor CEA over CAS, though CEA has had a consistent advantage over CAS in patients aged >75 years. TCAR has been deemed equivalent to CAS by US regulatory bodies, but RCT evidence is lacking and no RCTs have been initiated. Overall, we suggest that these general recommendations be applied only after considering characteristics of the individual patient, as discussed in comprehensive guideline statements. ¹¹ More guidance for management of asymptomatic patients will be forthcoming with the results from CREST‐2 and CREST‐H.

QUESTIONS FOR THE FUTURE

Questions remain for management. Symptomatic status and degree of carotid stenosis have guided patient selection for nearly 50 years. Other indicators of risk are needed to refine estimates of the hazard and benefit of treatment options. ² , ⁵ Studies of carotid plaque, brain perfusion, and prior brain injury by computed tomography, magnetic resonance, optical coherence tomography, and ultrasound imaging hold promise. The greatest yield of such studies may be for patients with asymptomatic carotid disease and potentially for patients with embolic stroke of unknown significance. ¹² Improvements in stent delivery systems, stent design including micromesh stents, and retrograde flow design will continue. ⁵ There is no doubt that the next iteration of a summary such as this one will include the use (and misuse?) of artificial intelligence.

Disclosures

No authors had any relevant financial conflicts of interest regarding this article. Each author is an investigator in CREST‐2.