Understanding the CREST results. Carotid stenting vs surgery: Parsing the risk of stroke and MI
ABSTRACTThe Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) is the largest randomized prospective study to date to compare carotid artery stenting and carotid endarterectomy in a patient population similar to that seen in everyday practice. CREST showed stenting and surgery to be equivalent in terms of the composite end point of stroke, myocardial infarction (MI), or death within 30 days, as well as for the rate of stroke at up to 4 years (N Engl J Med 2010; 363:11–23). Importantly, the risk of major stroke was low with either intervention. However, the results need to be considered in the context of the impact of each procedure on stroke and MI.
KEY POINTS
- In CREST, stenting and surgery had similar combined rates of stroke, MI, and death when performed by highly qualified interventionalists and surgeons in carefully selected patients.
- The risk of periprocedural stroke was higher with stenting; most of those strokes were nonmajor. Both major and nonmajor strokes were associated with decreased quality of life in long-term follow-up.
- Endarterectomy was associated with higher rates of periprocedural MI than stenting.
- Endarterectomy carried a significantly higher rate of cranial nerve damage than stenting.
The case for percutaneous intervention
While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.
So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.20,21
Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.20
With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.21
SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)22 was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.
The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.23 The benefit persisted up to 2 years.22
The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.
SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),24 conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.
EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),25 in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.
Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.26 Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.
ICSS (the International Carotid Stenting Study)27 compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.
An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).
In a substudy of ICSS,28 the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.
Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.
Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.
CREST STUDY DESIGN
CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.
Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.
CREST included patients with or without symptoms
CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.
Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.
Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.
Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.
Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.
