Carotid endarterectomy (CEA) has become the gold standard and the preferred method for treatment of symptomatic and asymptomatic patients with high-grade carotid stenosis, displacing optimal medical measures alone as an ethical alternative in managing these patients.1-5 However, carotid angioplasty-stenting (CAS) has been recommended by some clinicians as an alternative to CEA for patients who have extracranial carotid occlusive disease. Emergence of a position of clinical equipoise6 on the relatively equivalent value of these alternatives, as defined by different specialists who manage patients with cerebrovascular insufficiency by different procedures, has resulted in the initiation of a major European clinical trial, CAVATAS (Carotid and Vertebral Artery Transluminal Angioplasty Study)7 as well as planning in this country for a major effort sponsored by the National Institutes of Health (NIH).8 Funding has been approved by the National Institute of Neurological Disorders and Stroke (NINDS), NIH, and the randomized clinical trial in patients with symptomatic extracranial carotid occlusive disease, Carotid Revascularization Endarterectomy versus Stent Trial (CREST), was initiated in December 2000. Issues related to initiation of CREST have been described in prior publications.9-11
Stroke is the third most common cause of death in North America and approximately 600,000 new strokes are reported annually in the United States.12,13 Seventy-five percent of these occur in the distribution of the carotid arteries. Among strokes of a thromboembolic etiology, carotid occlusive disease is the most common cause. The 30-day and 5-year mortality rates for stroke occurring in the carotid distribution are 17% and 40%, respectively,12 while as many as 150,300 stroke-related fatalities are documented annually. The American Heart Association (AHA) estimated that the cost of stroke in the United States approximated $18 billion in 1993.14
CEA reduces the reported incidence of stroke alone as well as stroke and death in symptomatic patients with high-grade (> 70%) stenoses.1 In addition, recent data presented by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) investigators11 have confirmed the efficacy of CEA for carotid stenosis >50%. The procedure also reduces the incidence of combined neurological events in male patients with asymptomatic stenoses >50%,4 and ipsilateral stroke or any peri-procedural stroke or death in patients with asymptomatic stenoses >60%.5 Although CAS has been proposed as an alternative to CEA, the safety and clinical effectiveness of CAS have not been established and no prospective comparisons of CAS and CEA have been conducted in this country. Furthermore, a recently published Science Advisory from the American Heart Association15 concluded that “…with few exceptions, use of carotid stenting should be limited to well-designed, well-controlled randomized studies with careful dispassionate oversight.”
Carotid endarterectomy, performed with a low peri-procedural complication rate, is the only form of mechanical cerebral revascularization for which definitive evidence of clinical effectiveness has been reported. In the NASCET data,1 life-table estimates of the cumulative risk of stroke at 2 years were 26% in the medical group vs 9% in the surgical group (absolute risk reduction [+-SE]: 17+-3.5%, P<0.001). The corresponding estimates for major or fatal ipsilateral stroke were 13.1% vs 2.5% (absolute risk reduction [+-SE]: 10.6+-2.6%, P<0.001) and for any stroke or death were 32% vs 16% (absolute risk reduction: 16.5+-4.2%, P<0.001). Complementary findings were reported in the European Carotid Surgery Trial (ECST)2 and the VA symptomatic endarterectomy trial.3 Although recent presentation of data by the NASCET investigators on patients with symptomatic disease16 also has confirmed efficacy of CEA in male patients with 50-69% stenosis, the benefit was not confirmed in women with the same degree of stenosis. In the Asymptomatic Carotid Atherosclerosis Study (ACAS),5 after a median follow-up of 2.7 years, the aggregate risk over 5 years for ipsilateral stroke and any peri-procedural stroke or death was estimated to be 5.1% for surgical patients and 11% for patients treated medically (aggregate risk reduction: 53%; 95% CI, 22%-72%). Results from NASCET have provided the basis for current indications for CEA in symptomatic patients throughout this country and abroad.
Currently, some information is available from two7,17 randomized clinical trials comparing the efficacy of CAS and CEA. In Europe, the CAVATAS investigators7 are comparing surgical intervention and angioplasty for treatment of carotid and vertebral occlusive lesions. Martin Brown, MD, principal investigator, CAVATAS, presented the results from Phase I of his multi-centered trial during the AHA’s International Stroke meeting in New Orleans on February 2000. Among 504 randomized patients primarily to angioplasty alone and considered suitable candidates for CEA, 30-day stroke and death rates were comparable, 10.3% for CEA and 10.4% for the CAS group. These are the only data available on cases randomized to CEA or CAS; however, their influence may be blunted by the somewhat higher than expected complication rate in the CEA group. Phase II reportedly was initiated in July 2000 and will utilize angioplasty-stenting in all symptomatic carotid cases. Alberts and coauthors17 described the methodology of the other randomized clinical trial comparing carotid stenting versus endarterectomy in symptomatic patients (stenoses 50-99%) as sponsored by a manufacturer. The stated aim of this trial was to determine whether or not CAS was equivalent to CEA in the prevention of any ipsilateral stroke, peri-procedural death (within 30 days), or vascular death within 1 year of treatment. However, this trial has been discontinued because of recruitment and management difficulties.
Conclusions regarding initially positive results of prospectively collected registries18,19 and clinical reports20,21 as well as initial clinical trial data7,8 await further review. However, it now appears that in selected patients, CAS can be used to treat extracranial carotid stenosis in NASCET-eligible patients with peri-procedural complications that may approach those reported for CEA.22
CREST ORGANIZATIONAL PLAN
The CREST investigators submitted a grant application and have received approval for funding from the NINDS for a trial to compare efficacy of CEA and CAS in symptomatic patients with extracranial carotid stenoses >50%. However, recognizing that CAS is a relatively new procedure, each participating center will be required to complete a credentialing phase so as to reassure clinicians that the safety of these procedures has been reviewed and established before proceeding with the randomized phase of the trial. Assuming that a credentialing phase, which requires performance of up to 20 interventional procedures at each of 50 or more participating centers, is completed to the satisfaction of the study’s Interventional Management Committee, randomization of patients between the two treatments will then proceed. The primary outcome events for this clinical trial will include: (1) any stroke, myocardial infarction, or death during the 30-day peri-operative or peri-procedural period, or (2) ipsilateral stroke after 30 days. Endpoints will be reviewed by an Adjudication Committee blinded to the assigned treatment. Stroke will be determined by a positive transient ischemic attack/stroke questionnaire confirmed by an evaluation of a neurologist. Myocardial infarction will be determined by ECG and enzyme abnormalities. Secondary goals include: (1) describe differential efficacy of the two treatments in men and women, (2) contrast peri-operative procedural (30-day) morbidity and postprocedural (after 30 days) mortality for CEA and CAS, (3) estimate and contrast the restenosis rates for the two procedures, (4) identify subgroups of participants at differential risk for the two procedures, and (5) evaluate differences in health-related quality of life issues and cost- effectiveness.
Differential efficacy assessment of CEA and CAS based on gender is a secondary goal for CREST. In patients with high-grade asymptomatic stenosis reported by ACAS, CEA offered a 66% reduction in events over a 5-year period for men, but only a 17% reduction for women.5 In NASCET, while no differential gender effects were reported among symptomatic patients with stenoses greater than 70%, male patients demonstrated greater benefit after CEA than women for stenoses of 50-69%.16 While the causes for these examples of differential efficacy between genders are not well understood, the effect may be attributed to a higher complication rate for CEA in women, possibly caused by their reported smaller arterial sizes and greater surgical morbidity. Unfortunately, neither ACAS nor NASCET suspected the possibility of a differential gender effect. However, given the results of these two randomized clinical trials, a requirement for a priori plans to evaluate the possibility of a differential gender effect has become an important component of CREST. Centers are being selected with the goal of recruiting up to 50% women in the randomized sample of patients, while the minimal goal is 40% recruitment of women.
Patients will be evaluated at baseline, 24-hours post-procedure, 30 days, 6 months, and thereafter at 6-month intervals. Baseline procedures will include a brief medical history and physical examination, a risk factor evaluation, performance of neurological status questionnaires, a neurological examination, ECG, and a baseline carotid duplex scan. The 30-day follow-up will include evaluation of the neurological status through questionnaires, ECG, and a follow-up carotid duplex scan. All 6-month follow-up visits will include a brief physical, completion of the neurological questionnaire, risk factor evaluation, and carotid duplex scan. All patients with a positive neurological status questionnaire will be evaluated by a neurologist. The sample size for the study is approximately 2,500 symptomatic patients, which will be sufficient to detect a relative difference of 25-30% between treatment groups. Lesser differences would be considered sufficiently small to declare the treatments equivalent.
Opinions have varied about the participation of surgeons and interventionalists in randomized clinical trials comparing CEA and CAS. While the value of clinical participation has been recommended,8 the emergence of clinical equipoise6 between treatment groups as supported by a rigorous credentialing phase of CREST should reassure our colleagues about their participation as well as the ethical conduct of this trial.
Robert W. Hobson II, MD, is principal investigator, CREST (Carotid Revascularization Endarterectomy vs Stent Trial), professor of surgery and physiology, and director of the division of vascular surgery, University of Medicine and Dentistry of New Jersey (UMDNJ), New Jersey Medical School (NJMS), Newark.
- North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991; 325:445-453.
- European Carotid Surgery Trialists’ Collaborative Group. MCR European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet. 1991;337:1235-1243.
- Mayberg MR, Wilson SE, Yatsu F and the VA Symptomatic Carotid Stenosis Group. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA. 1991;266:3289-3294.
- Hobson RW, Weiss DG, Fields WS, et al, and the Veterans Affairs Cooperative Study Group. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. N Engl J Med. 1993;328:221 227.
- Executive Committee for the Asymptomatic Carotid Atherosclerosis Study: Endarterectomy for asymptomatic carotid stenosis. JAMA. 1995;273:1421 1428.
- Friedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987; 317:141-145.
- Major ongoing stroke trials: carotid and vertebral artery transluminal angioplasty study (CAVATAS). Stroke. 1996;27:358.
- Hobson RW, Brott T, Ferguson R, et al. Statement regarding carotid angioplasty and stenting [letter]. J Vasc Surg. 1997;25:1117.
- Hobson RW, Ferguson R. Status Report on the Carotid Revascularization Endarterectomy versus Stent Trial. Techniques in Vascular and Interventional Radiology. 2000;3(2):1-4.
- Hobson RW II. Indications for carotid angioplasty and stenting in carotid stenosis. In: Yao JST, Pearce WH, eds. Modern Vascular Surgery. New York: McGraw-Hill; 2000:127-136.
- Hobson RW II. Current role of percutaneous carotid angioplasty and stenting. In: Ernst CB, Stanley JC, eds. Current Therapy in Vascular Surgery. 4th ed. St Louis: Mosby Inc; 2001:59-60.
- Chambers BR, Norris JW, Shurvell BL, Hachinski V. Prognosis of acute stroke. Neurology. 1987;37:221-225.
- Wolf PA, Kannel WB, McGee DL. Epidemiology of strokes in North America. In: Barnett HJM, Stein BM, Mohr JP, Yatsu FM, eds. Stroke: Pathophysiology, Diagnosis and Management. New York: Churchill Livingstone; 1986:19-29.
- 1993 Heart and Stroke Facts Statistics. Dallas: American Heart Association; 1992: 18.
- Bettmann, MA, Katzen BT, Whisnant J et al. Carotid stenting and angioplasty; a statement from the Councils on Cardiovascular Radiology, Stroke, Cardio-thoracic and Vascular Surgery, Epidemiology and Prevention, and Clinical Cardiology, American Heart Association. Stroke. 1998;29:336-346.
- Barnett HJM, Taylor DW, Eliasziw M, et al, for the North American Symptomatic Carotid Endarterectomy Trial Collaborators. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339:1415-1425.
- Alberts MJ, McCann R, Smith TP, et al. A randomized trial: carotid stenting versus endarterectomy in patients with symptomatic carotid stenosis, study designs. J Neurovas Dis. November-December 1997:228-234.
- NACPTAR investigators. Update of the immediate angiographic results and in hospital central nervous system complications of cerebral percutaneous transluminal angioplasty. Circulation. 1995;92:I-383.
- NACPTAR Investigators: Ferguson R, Schwarten D, Purdp, et al. Restenosis following cerebral percutaneous transluminal angioplasty. Stroke. 1995;26:186.
- Diethrich EB, Ndiye M, Reid DB. Stenting in the carotid artery: initial experience in 110 patients. J Endovasc Surg. 1996; 3:42-62.
- Roubin GS, Yadav S, Iyer SS, et al. Carotid stent-supported angioplasty: a neurovascular intervention to prevent stroke. Am J Cardiol. 1996;78:8-12.
- Mathur A, Roubin GS, Piamsomboom C, Liu MW, Gomex CR, Iyer SS. Predictors of stroke following carotid stenting: univariate and multivariate analysis. Circulation. 1997;96:A1710.