Benefit of carotid endarterectomy for patients with high-grade stenosis of the internal carotid artery.
National Institute of Neurological Disorders and Stroke (NINDS)
February 26, 1991
NIH's National Institute of Neurological Disorders and Stroke has reported findings from an ongoing randomized controlled clinical trial of carotid endarterectomy (CE) for patients with a recent hemispheric TIA or a mild stroke and ipsilateral severe stenosis of the internal carotid artery. In symptomatic patients with severe (70-99%) stenosis, CE resulted in a 17% (p<0.001) absolute reduction in stroke risk. In these patients, CE was beneficial in the prevention of stroke, even when strokes in other vascular territories were included in the analysis (corrected online March 25, 1991).
The 50-site study, conducted at research centers in the U.S. and Canada, involved patients under 80 years of age (median age: 66) with angiographic evidence of 30-99% stenosis in a carotid artery accessible to CE and a history of a hemispheric TIA or non-disabling stroke within the preceding 120 days.
Patients entered into the study were classified into two stenotic strata: 30-69% and 70-99%. A total of 595 patients were in the severe (70-99%) stenosis group, of which half received optimal medical care, including antiplatelet therapy (usually aspirin) and, as indicated, antihypertensive, antilipid, and antidiabetic therapy, and half received optimal care plus CE. Interim analysis shows that, in the latter group, CE reduces the overall risk of fatal and non-fatal ipsilateral carotid stroke, despite any perioperative risk of any stroke or death from any cause. Over 24% of medical patients, but only 7% of surgical patients, had experienced fatal or non-fatal ipsilateral stroke at 18 months.
Currently, conclusions cannot be drawn about possible benefits for symptomatic patients with moderate (30-69%) stenosis or for asymptomatic patients.
This trial will continue for symptomatic patients with moderate stenosis. Other trials are continuing to evaluate asymptomatic patients.
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The investigators of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) are reporting the results of an interim analysis of the findings of a randomized controlled clinical trial of carotid endarterectomy for patients with a recent hemispheric, transient ischemic attack (TIA) or a mild (non-disabling) stroke and ipsilateral narrowing of the internal carotid artery. Two groups in the Trial received best medical care, including antiplatelet therapy; one of the two groups also had endarterectomy. For patients with high-grade stenosis (70-99% narrowing in the luminal diameter), surgery was highly beneficial. Consequently, patients with high-grade stenosis are no longer being entered into the Trial. Since the question of surgical benefit for patients with moderate stenosis (30-69%) has not yet been answered, that part of the Trial dealing with symptomatic patients with moderate stenosis will continue. Since it is also not yet known whether asymptomatic patients will benefit from carotid endarterectomy, other trials for those patients will also continue.
The primary question of efficacy addressed by the Trial was: Among symptomatic patients with high-grade carotid stenosis (70-99%), does carotid endarterectomy, despite perioperative risk of any stroke or death from any cause, reduce the overall risk of fatal and non-fatal ipsilateral carotid stroke? The interim analysis to follow answers this question as well as the following question: Among symptomatic patients with high-grade stenosis, is the risk of any severe stroke or death from any cause reduced by carotid endarterectomy?
The Trial was conducted at 50 U.S. and Canadian centers, all of which had documented surgical and neurological expertise.
Patient Eligibility and Measurement of Stenosis
To be eligible for the trial, patients aged less than 80 years must have had a hemispheric TIA or a non-disabling stroke within 120 days and had to have angiographic evidence of 30-99% stenosis in a carotid artery (appropriate for the symptoms) that was accessible to endarterectomy. To measure stenosis, the investigators used the linear diameter at the site of greatest narrowing as the numerator (N) and the diameter of the normal artery distal to the bulb as the denominator (D). The degree (in %) of stenosis then becomes: (1 - N/D) x 100. Patients were classified into two pre-determined stenotic strata: 30-69% and 70-99%. The 595 patients with 70-99% narrowing were identified as the high-grade stenosis patients. Patients were excluded if they refused informed consent, had had a possible cardiac source of embolic stroke, uncontrolled hypertension, uncontrolled diabetes, mental incapacity, clinically important impairment of major organs, recent myocardial infarction, or other serious illnesses that would reduce their chances of survival to less than 50% during the next five years.
All patients were given optimal medical care, including antiplatelet treatment (usually aspirin) and, as indicated, antihypertensive, antilipid, and antidiabetic therapy. More than 99% of both medical and surgical patients were on some anti-thrombotic drug during the trial. Patients randomly allocated to surgery underwent carotid endarterectomy by neurosurgeons or vascular surgeons who met strict performance standards and had previously demonstrated expertise in the procedure. Surgery was performed an average of two days after randomization. Surgical technique, including anesthetic method, the use of intra-operative monitoring, shunting, and patch-grafting were at the discretion of the surgeon.
Main Outcome Measures
Medical, neurological, and functional status was assessed by participating neurologists for all patients one month after entry, every 3 months for the following year, then every 4 months for the remainder of the Trial. All perioperative complications were reported, and all deaths in the first month after randomization were included for both groups, along with the main study outcome measure of stroke.
The results reported here apply only to symptomatic patients who were entered in the high-grade stenosis group. (There are no conclusive results at this time for the patients with moderate stenosis.) Randomization created balanced treatment groups of medical (295) and surgical (300) patients with respect to important prognostic characteristics and underlying vascular lesions. The median age of patients was 66 years (range 35 - 80), and one third were women. The qualifying event was a non-disabling stroke in 32% and one or more TIAs for the remainder of the group.
No patient was lost to follow-up, none was withdrawn, and the average duration of follow-up among surviving patients was 18 months. Among the medical patients, 16 (5.4%) crossed over and underwent carotid endarterectomy on the same side as the lesion for which they were randomized (5 after a stroke, 6 after a TIA, 2 as preliminary to other required surgery, and 3 for miscellaneous reasons). Of the 300 patients randomized to surgery, all but one underwent carotid endarterectomy.
The perioperative period was defined as the period from randomization to 30 days after surgery. There was a total perioperative stroke morbidity and mortality rate of 5% (including a major stroke and mortality rate of just over 2% and a mortality rate alone of less than 1%). During a period of similar duration (32 days), just over 3% of the medical group had stroke morbidity or mortality.
Interim analysis shows that among symptomatic patients with high-grade carotid stenosis (70-99%), carotid endarterectomy does indeed reduce the overall risk of fatal and non-fatal ipsilateral carotid stroke, despite any perioperative risk of any stroke or death from any cause. Including perioperative morbidity and mortality, or its equivalent time in the medical group, over 24% of medical patients, but only 7% of surgical patients, had experienced fatal or non-fatal ipsilateral stroke at 18 months. This result yields an absolute risk reduction of 17% (p<0.001). Furthermore, carotid endarterectomy remained beneficial overall in the prevention of stroke, even when strokes in other vascular territories were included in the analysis.
The investigators also found that among symptomatic patients with high-grade stenosis, the risk of any severe stroke or death from any cause was indeed reduced by carotid endarterectomy. By 18 months, more than 12% of medical patients, but only 5% of surgical patients, had experienced major or fatal stroke in any territory or death from any cause. This result yielded an absolute risk reduction of over 7% (p<0.01).
The early risk of perioperative stroke and death is rapidly overcome by endarterectomy, with benefit to the patient appearing within 3 months after the surgery. Moreover, benefit of surgery increases for as long as 30 months, which suggests that the beneficial effects of surgery persist at least that long.
A secondary analysis determined that a finer division of the degree of high-grade carotid stenosis (70-79%, 80-89%, 90-99%) correlated with the degree of relative risk reduction after surgery in symptomatic patients. This analysis reinforces the imperative need to continue to study the efficacy of carotid endarterectomy for carotid stenosis in the 30-69% range.
Carotid endarterectomy is highly beneficial for patients with recent hemispheric, transient ischemic attacks or non-disabling strokes and ipsilateral high-grade (70-99%) stenosis. At this time, conclusions cannot be drawn about possible benefits for symptomatic patients with moderate stenosis (30-69%) or for asymptomatic patients; these patients will continue to be studied in this and other trials.