John W. Norris

Guidelines for Carotid Endarterectomy A Multidisciplinary Consensus Statement From the Ad Hoc Committee, American Heart Association

BACKGROUND AND PURPOSE Indications for carotid endarterectomy have engendered considerable debate among experts and have resulted in publication of retrospective reviews, natural history studies, audits of community practice, position papers, expert opinion statements, and finally prospective randomized trials. The American Heart Association assembled a group of experts in a multidisciplinary consensus conference to develop this statement. METHODS A conference was held July 16-18, 1993, in Park City, Utah, that included recognized experts in neurology, neurosurgery, vascular surgery, and healthcare planning. A program of critical topics was developed, and each expert presented a talk and provided the chairman with a summary statement. From these summary statements a document was developed and edited onsite to achieve consensus before final revision. RESULTS The first section of this document reviews the natural history, methods of patient evaluation, options for medical management, results of surgical management, data from position statements, and results to date of prospective randomized trials for symptomatic and asymptomatic patients with carotid artery disease. The second section divides 96 potential indications for carotid endarterectomy, based on surgical risk, into four categories: (1) Proven: This is the strongest indication for carotid endarterectomy; data are supported by results of prospective contemporary randomized trials. (2) Acceptable but not proven: a good indication for operation; supported by promising but not scientifically certain data. (3) Uncertain: Data are insufficient to define the risk/benefit ratio. (4) Proven inappropriate: Current data are adequate to show that the risk of surgery outweighs any benefit. CONCLUSIONS Indications for carotid endarterectomy in symptomatic good-risk patients with a surgeon whose surgical morbidity and mortality rate is less than 6% are as follows. (1) Proven: one or more TIAs in the past 6 months and carotid stenosis > or = 70% or mild stroke within 6 months and a carotid stenosis > or = 70%; (2) acceptable but not proven: TIAs within the past 6 months and a stenosis 50% to 69%, progressive stroke and a stenosis > or = 70%, mild or moderate stroke in the past 6 months and a stenosis 50% to 69%, or carotid endarterectomy ipsilateral to TIAs and a stenosis > or = 70% combined with required coronary artery bypass grafting; (3) uncertain: TIAs with a stenosis < 50%, mild stroke and stenosis < 50%, TIAs with a stenosis < 70% combined with coronary artery bypass grafting, or symptomatic, acute carotid thrombosis; (4) proven inappropriate: moderate stroke with stenosis < 50%, not on aspirin; single TIA, < 50% stenosis, not on aspirin; high-risk patient with multiple TIAs, not on aspirin, stenosis < 50%; high-risk patient, mild or moderate stroke, stenosis < 50%, not on aspirin; global ischemic symptoms with stenosis < 50%; acute dissection, asymptomatic on heparin. Indications for carotid endarterectomy in asymptomatic good-risk patients performed by a surgeon whose surgical morbidity and mortality rate is less than 3% are as follows. (1) Proven: none. As this statement went to press, the National Institute of Neurological Disorders and Stroke issued a clinical advisory stating that the Institute has halted the Asymptomatic Carotid Atherosclerosis Study (ACAS) because of a clear benefit in favor of surgery for patients with carotid stenosis > or = 60% as measured by diameter reduction. When the ACAS report is published, this indication will be recategorized as proven. (2) acceptable but not proven: stenosis > 75% by linear diameter; (3) uncertain: stenosis > 75% in a high-risk patient/surgeon (surgical morbidity and mortality rate > 3%), combined carotid/coronary operations, or ulcerative lesions without hemodynamically significant stenosis; (4) proven inappropriate: operations with a combined stroke morbidity and mortality > 5%.

Outcome in Patients with Asymptomatic Neck Bruits

Five hundred asymptomatic patients with cervical bruits were followed prospectively by clinical and Doppler examination for up to four years (mean, 23.2 months) to identify the variables predicting outcome. Thirty-six patients had strokes or transient ischemic attacks, 51 had cardiac ischemic events, and 45 died. At one year the incidence of cerebral ischemic events (transient ischemic attacks and strokes) was 6 percent, that of cardiac ischemic events was 7 percent, and that of death was 4 percent. The overall incidence of stroke at one year was 1.7 percent (1 percent in patients without previous transient ischemic attacks), but the incidence was 5.5 percent in patients with severe carotid-artery stenosis (greater than 75 percent). Cerebral ischemic events were most frequent in patients with severe carotid-artery stenosis (P less than 0.0001), progressing carotid-artery stenosis (P less than 0.0005), or heart disease (P less than 0.0005) and in men (P less than 0.025). The degree of carotid-artery stenosis on initial presentation was a powerful predictor of neurologic sequelae. Patients with asymptomatic cervical bruits have a higher risk of a cardiac ischemic event than of a stroke. Although the risk of cerebral ischemic events is highest in patients with severe carotid-artery stenosis, in most instances even these patients do not have strokes without some warning.

Early mortality following stroke: a prospective review.

Analysis of early deaths after stroke is important, since some deaths may be preventable. Previous studies have relied on retrospective and often incomplete clinical data, for comparison with pathological findings. The present study is based on 1073 consecutive stroke patients admitted to an intensive care stroke unit from a well-defined population. There were 212 deaths within the first 30 days, yielding a mortality rate of 20%. Clinical, radiological, and laboratory data were collected prospectively according to a standardized protocol. Autopsies were performed on 90 of the 212 patients, and CT scanning on a further 27. Early mortality after stroke exhibits a bimodal distribution. One peak occurs during the first week, and a second during the second and third weeks. The majority of deaths in the first week are due to transtentorial herniation. Of these, deaths due to hemorrhage usually occur within the first three days, whilst deaths due to infarction peak between the third and sixth day post ictus. After the first week, deaths due to relative immobility (pneumonia, pulmonary embolism and sepsis) predominate, peaking towards the end of the second week. Cardiac deaths occur throughout the first month, and unfortunately account for many deaths in patients with small functional deficits. Stroke VOL 15, No 3, 1984

Selfotel in Acute Ischemic Stroke Possible Neurotoxic Effects of an NMDA Antagonist

BACKGROUND AND PURPOSE Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies. METHODS Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit. RESULTS The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.

Carotid Plaque Pathology Thrombosis, Ulceration, and Stroke Pathogenesis

Background and Purpose— To determine the relationship between ulceration, thrombus, and calcification of carotid artery atherosclerotic plaques and symptoms of ipsilateral or contralateral stroke. Methods— We compared microscopic plaque morphology from patients with and without stroke symptoms ipsilateral or contralateral to the plaque. Plaques were characterized for ulceration, thrombus, and calcification. We analyzed plaques from 241 subjects: 170 patients enrolled in the Asymptomatic Carotid Atherosclerosis Study (ACAS) and 71 patients enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET); 128 subjects had no history of stroke symptoms, 80 subjects had ipsilateral symptoms, and 33 had contralateral symptoms. Results— Plaque ulceration was more common in plaques taken from symptomatic patients than those without symptoms (36% versus 14%; P<0.001); frequency of ulceration was similar for plaques associated with ipsilateral (34%) and contralateral (42%) symptoms. Thrombus was most common in plaques taken from patients with both ipsilateral symptoms and ulceration. The extent of calcification was unassociated with stroke symptoms. Conclusion— Carotid plaque ulceration and thrombosis are more prevalent in symptomatic patients. Ulceration is more common in symptomatic patients regardless of side of carotid symptoms, whereas thrombus is associated with ipsilateral symptoms and plaque ulceration. Preoperative identification of carotid ulceration and thrombus should lead to greater efficacy of stroke prevention by carotid endarterectomy.

Prognosis of acute stroke

We evaluated factors affecting mortality and quality of life in 1,013 patients with acute stroke followed for 2 to 8 years. In cerebral infarction, the major determinants for short-term mortality were impaired consciousness, leg weakness, and increasing age. The major determinants for long-term mortality were low level of activity at hospital discharge, advanced age, male sex, heart disease, and hypertension.

Cervical Arterial Dissection. Time for a Therapeutic Trial

Background and Purpose— Cervical arterial dissection is a major cause of stroke in young adults, yet despite standard treatment with anticoagulants or antiplatelet drugs, its management remains uncertain. The goal of this study was to assess the natural history of the disorder and to decide on the feasibility of a therapeutic trial. Methods— Collaborating members of the Canadian Stroke Consortium prospectively enrolled consecutively referred patients with angiographically proven acute vertebral or carotid arterial dissection. Data recorded included clinical and radiological details, recurrence of ischemic cerebral events, and medical or surgical treatment. Results— Of 116 patients, 67 had vertebral and 49 had carotid dissections, with no difference in age or sex. In 68 (59%), trauma occurred at the time of dissection. During the course of a 1-year follow-up, at least 17 patients (15%) had recurrent transient ischemic attacks, stroke, or death, mainly in the weeks immediately after the dissection. In 105 patients with complete follow-up, the event rate in those treated with anticoagulants was 8.3% and in those treated with aspirin was 12.4%, a nonsignificant difference of 4.1%. Using these data, we calculate that for a 2-arm trial (aspirin versus anticoagulants) with 80% power and 5% significance, 913 patients are needed in each group. Conclusions— From our data indicating an initial relatively high recurrence rate, a multicenter trial of anticoagulants versus aspirin involving a total of 2000 patients is feasible.

Termination of Acute Stroke Studies Involving Selfotel Treatment

Selfotel, a selective competitive N-methyl-D-aspartate antagonist, has neuroprotective efficacy in animal models of focal and global ischaemia and traumatic brain injury. In these models, selfotel was shown to reduce ischaemia-induced neuronal cell death and infarct size, and to attenuate neuronal injury. In a phase II study, an intravenous bolus dose of 1·5 mg/kg administered within 6 h of onset of acute ischaemic stroke was safe and potentially effective. To determine whether selfotel improved the outcome of acute ischaemic stroke and severe traumatic brain injury, two multinational placebo-controlled trials for each indication were initiated. After review of the aggregate data from the four trials and considering both safety and potential benefit, an independent Data and Safety Monitoring Board (DSMB) recommended that enrolment in the selfotel programme be suspended and that the trials be terminated. We report the results from these two stroke trials. The ASSIST (Acute Stroke Studies Involving Selfotel Treatment) programme involved two trials, one conducted in Europe, Australia, Argentina, and Canada (Protocol 10 IC/STE1), and the other in the USA and Israel (Protocol 07). The hypothesis tested in these double-blind, randomised, placebo-controlled trials was that 1·5 mg/kg selfotel administered intravenously within 6 h of stroke onset would improve functional outcome at 3 months defined as the proportion of patients reaching a score of at least 60 on the Barthel Index (BI). Patient accrual began in September, 1994. By December, 1995, 509 patients had been enrolled in the two trials and data from 476 patients (389 in Protocol 10 IC/STE1 and 87 in Protocol 07) were in the database. Of these, 328 patients had 3-month outcome data available for analysis (274 in Protocol 10 IC/STE1 and 54 in Protocol 07). Comparison of baseline demographic variables showed that the treatment groups were well-matched for sex, initial stroke severity (based on the Scandinavian Stroke Scale [SSS]), and time from stroke onset to therapy: 4000 mg/dL). Small bowel enteroclysis was normal. Body weight was 38 kg (height 171 cm). After 3 months of tetracycline an increase of weight of 25 kg was noted. However, duodenal and intra-abdominal lymphoma were unchanged and IgA did not return to normal. Seven courses of polychemotherapy (cychophosphamide, doxorubicin, vincristine, prednisone) from November, 1992, to June, 1993, did not cause lymphoma regression. IgA did, alone, return to normal. Furthermore, the lymphoma was still detectable after administration of four courses of vinblastine, etoposide, epirubicin, and prednisone, and after abdominal irradiation (18 Gy). Diagnostic re-evaluation in May, 1995, showed gastric metaplasia in the duodenal bulb infected with Helicobacter pylori and infiltrates of IPSID with monoclonal heavy-chain rearrangement. Omeprazole, amoxicillin, and clarithromycin were given for 7 days. For the first time the patient became symptom-free. Diagnostic work-up including endoscopic ultrasound and abdominal computed tomography in November, 1995, and March, 1996, confirmed complete lymphoma regression. Alkan and colleagues reported in this journal the disappearance of salivary gland MALT lymphoma after Helicobacter pylori eradication. Contrary to their findings, in our study Helicobacter pylori infection was located in (metaplastic) gastric mucosa where it is known to be associated with the development of MALT-type lymphoma.

High dose steroid treatment in cerebral infarction

Steroid treatment is widely used in acute cerebral infarction yet its value is controversial. High dose dexamethasone (480 mg over 12 days) was given in a double blind, randomised controlled trial to 113 consecutive eligible patients with acute cerebral infarction admitted to an acute stroke unit. Those with stroke for more than 48 hours, known embolic sources, diabetes, and infection were excluded. Death and quality of survival were recorded over 21 days. The active drug group (54 patients) matched the placebo group (59 patients) for age, initial stroke score, delay in beginning treatment, and other relevant variables. The two groups did not differ significantly in death rate or quality of survivorship. The small difference in mortality between the two groups may have represented a marginal therapeutic effect, which might reach significance in a larger sample. The widespread use of steroids in response to such a marginal therapeutic gain would expose large numbers of patients with stroke to more serious hazards of steroid treatment and convert patients who would otherwise have died into neurovegetative survivors. High dose steroid treatment was ineffective in ischaemic stroke, and the data suggest that further evaluation by a larger multicentre trial is not justified.

The case against surgery for asymptomatic carotid stenosis.

Asymptomatic cervical bruits with their implication of underlying carotid artery disease, carry an established but low risk of stroke. In spite of the rising numbers of patients subjected to carotid endarterectomy for this condition, there is little evidence that the benefits outweigh the risks. Outcome data from community studies and the current prospective Toronto study of patients with asymptomatic neck bruits indicate that the annual stroke rate is 1-2%, and the annual cardiac death rate is 2-4%. Published data of the results of carotid surgery suggest that surgical risks outweigh any possible benefits, unless a subgroup with spontaneous stroke risk of at least 5% can be identified. Stroke Vol 15, No 6, 1984