Olcay Aksoy, MD Department of Cardiovascular Medicine, Cleveland Clinic
Samir R. Kapadia, MD Department of Cardiovascular Medicine, Cleveland Clinic
Christopher Bajzer, MD Department of Cardiovascular Medicine, Cleveland Clinic
Wayne M. Clark, MD Department of Neurology, Oregon Health & Science University, Portland; Investigator, Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
Mehdi H. Shishehbor, DO, MPH, PhD Department of Cardiovascular Medicine, Cleveland Clinic
Address: Mehdi H. Shishehbor, DO, MPH, Heart & Vascular Institute, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail shishem@gmail.com
Dr. Shishehbor has disclosed teaching and speaking for Abbott Vascular.
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.
Patients received antiplatelet agents
Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.
Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.
Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).
End points: Stroke, MI, death
The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.
Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.
Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.
MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.29
Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.
The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.
Intention-to-treat analysis
Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.
Most patients enrolled were available for analysis
From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.
A ‘conventional-risk’ patient population
The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:
35% were women
47% had asymptomatic carotid disease
86% had carotid stenosis of 70% or greater
86% had hypertension
30% had diabetes mellitus
83% had hyperlipidemia
26% were current smokers
42% had a history of cardiovascular disease
21% had undergone coronary artery bypass grafting surgery.
The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.
The interventionalists and surgeons were highly experienced
Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.
The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.
CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY
Periprocedural outcomes
Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).
Outcomes at 4 years
Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.
Figure 2. Kaplan-Meier analysis of the primary outcome (stroke, myocardial infarction, or death during the periprocedural period or any ipsilateral stroke within 4 years after randomization) for patients undergoing carotid artery stenting or carotid endarterectomy.
The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.
The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.
Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.
Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.
