Background and Purpose-We sought to report the occurrence and risk factors of intracranial hemorrhage during long-term follow-up of patients with internal carotid artery stenosis, with and without carotid endarterectomy.Methods-From the prospective data of the North American Symptomatic Carotid Endarterectomy Trial, 3 types of intracranial hemorrhage were recognized: petechiae within infarction (PTI), intracerebral hematoma (ICH), and subarachnoid hemorrhage (SAH). The 30-day and 5-year risks of intracranial hemorrhage (PTI or ICH) were estimated from Kaplan-Meier event-free survival curves. Cox proportional-hazards regression modeling was used to identify risk factors.Results-Of 1039 strokes that occurred in 749 of 2885 patients during an average follow-up of 5 years, there were 24 PTIs, 14 ICHs, and 1 SAH. The 5-year risk of intracranial hemorrhage was 1.7% in both medically and surgically treated patients, but the 30-day risk of 0.64% in surgically treated patients was 10 times higher than the risk of 0.07% in medically treated patients (P = 0.01). Approximately 50% of all intracranial hemorrhages were either disabling or fatal, and ICHs were more likely to be fatal than PTIs. Old age, a history of hypertension, intermittent claudication and smoking, and infarct on brain images were risk factors for intracranial hemorrhage in medically treated patients, whereas diabetes mellitus was the sole risk factor in surgically treated patients.Conclusions-Intracranial hemorrhages are uncommon in patients with internal carotid artery stenosis but are associated with high mortality and morbidity. The risk factors for intracranial hemorrhage are different between medically and surgically treated patients.

Results of randomized trials on carotid endarterectomy make it mandatory that therapeutic decisions for patients with carotid stenosis consider the degree of stenosis, presence of symptoms, skill of surgeon and time since the last ischemic event. Patients with severe (>70% by angiogram) stenosis should receive carotid endarterectomy, provided the operative risk is <6% and symptoms have recurred within 6 months. With moderate stenosis (50-69% by angiogram), and with similar low operative risk and time limit, males with hemispheric, nondisabling stroke and appropriate CT lesion will benefit from carotid endarterectomy. Patients with TIA only, retinal symptoms alone and who are women are not going to benefit in this range of stenosis. Particularly at risk with medical care alone are symptomatic patients with coexistent intracranial stenosis, widespread white-matter lesions, intraluminal thrombi, contralateral occlusion and absence of good collateral circulation. The same highrisk patients, enjoy good long-term results from endarterectomy. Lacunar syndromes at presentation respond to endarterectomy, but with less benefit. Symptomatic patients do as well, regardless of age, provided patients with serious cardiac disorders and with organ failure are avoided. Serious doubt exists about indications for endarterectomy in asymptomatic subjects. Even if the upper limit of 3% perioperative risk is exceeded land in large institutional databases and other studies, it usually is), the risk of large-artery strokes from the asymptomatic lesion is only slightly above the risk facing these subjects from lacunar and cardioembolic stroke. To prevent 1 large-artery stroke in 5 years in asymptomatic subjects requires that 111 subjects be submitted to endarterectomy. Copyright (C) 2001 S. Karger AG, Basel.

Two trials conducted in the 1960s for symptomatic patients were unable to detect benefit for carotid endarterectomy because of high perioperative rates of stroke and death [1, 2]. Despite these failed trials by the 1980s carotid endarterectomy had become one of the most frequently performed operations in the United States. As the popularity of the procedure grew so did concern about the appropriateness of its application. This combination of events set the stage for randomized clinical trials for both symptomatic and asymptomatic patients. Design flaws plagued two trials for asymptomatic patients [3, 4] and a third found benefit for endarterectomy only if transient ischemic attack (TIA) was included as an outcome event and perioperative stroke and death were overlooked [5]. If stroke and death alone were used to evaluate benefit, no difference was found between the medical and surgical groups in the short-term or in the extended follow-up. Subjects and Methods

BACKGROUND The causes of stroke in patients with asymptomatic carotid-artery stenosis have not been carefully studied. Information about causes might influence decisions about the use of carotid endarterectomy in such patients. METHODS We studied patients with unilateral symptomatic carotid-artery stenosis and asymptomatic contralateral stenosis from 1988 to 1997. The causes, severity, risk, and predictors of stroke in the territory of the asymptomatic artery were examined and quantified. RESULTS The risk of stroke at five years after study entry in a total of 1820 patients increased with the severity of stenosis. Among 1604 patients with stenosis of less than 60 percent of the luminal diameter, the risk of a first stroke was 8.0 percent (1.6 percent annually), as compared with 16.2 percent (3.2 percent annually) among 216 patients with 60 to 99 percent stenosis. In the group with 60 to 99 percent stenosis, the five-year risk of stroke in the territory of a large artery was 9.9 percent, that of lacunar stroke was 6.0 percent, and that of cardioembolic stroke 2.1 percent. Some patients had more than one stroke of more than one cause. In the territory of an asymptomatic occluded artery (as was identified in 86 patients), the annualized risk of stroke was 1.9 percent. Strokes with different causes had different risk factors. The risk factors for large-artery stroke were silent brain infarction, a history of diabetes, and a higher degree of stenosis; for cardioembolic stroke, a history of myocardial infarction or angina and hypertension; for lacunar stroke, age of 75 years or older, hypertension, diabetes, and a higher degree of stenosis. CONCLUSIONS The risk of stroke among patients with asymptomatic carotid-artery stenosis is relatively low. Forty-five percent of strokes in patients with asymptomatic stenosis of 60 to 99 percent are attributable to lacunes or cardioembolism. These observations have implications for the use of endarterectomy in asymptomatic patients. Without analysis of the risk of stroke according to cause, the absolute benefit associated with endarterectomy may be overestimated.

E gaz Moniz, 1 the pioneer of angiography, in the 1920s identified carotid artery lesions in patients who had experienced a stroke. In the early 1940s, Hultquist 2 published early pathological observations. It remained for C. Miller Fisher's 3 meticulous observations in the 1950s to focus attention on the importance of the extracranial portion of the carotid arteries as a prominent cause of ischemic stroke. Quickly the concept evolved of transient ischemic attacks as forerunners of ischemic infarction. Because surgeons had learned to repair arteries in the battlefields of World War II, it was predictable that pioneers would attempt to remove offending carotid arterial lesions. First to publish was the English team of Eastcott et al. 4 An Argentinean and Americans missed the accolades of primacy by delaying publication.

Stroke is the second most common cause of death worldwide, exceeded only by heart disease.1 Coincident with the emergence of prevention strategies, incidence of stroke is declining dramatically in developed countries. The prevention of stroke is an obligation facing everyone involved with delivering health care. ### Summary points Managing the risk factors of hypertension, tobacco, and hyperglycaemia reduces the risk of stroke Managing hyperglycaemia will diminish the severity of strokes Warfarin prevents stroke in non-valvular atrial fibrillation Aspirin is the first choice of platelet inhibitors for stroke prevention Endarterectomy prevents stroke when symptoms are due to severe stenosis;with moderate stenosis the benefit is muted Endarterectomy is of uncertain benefit for asymptomatic carotid stenosis Prospective population studies and retrospective case series have identified modifiable risk factors important for ischaemic and haemorrhagic stroke. The Four Horsemen of the Apocalypse of stroke display the banners of hypertension, tobacco, diabetes mellitus, and hyperlipidaemia.2 All are responsible for cerebral arteriosclerosis. Transient ischaemic events are powerful predictors of stroke. Coronary artery disease and atrial fibrillation increase stroke risk. Compounds lowering cholesterol, the “statins,” reduce the risk of myocardial infarction and stroke.3 At no age and in neither sex is a systolic blood pressure above 160 mm Hg and a diastolic pressure above 90 mm Hg acceptable. Even elderly subjects and heavy smokers reduce the risk of stroke by abandoning cigarettes.4 Control of insulin dependent diabetes has not been shown to reduce stroke.5 A stroke in the presence of hyperglycemia is more disabling. Family history of stroke requires the Four Horsemen be sought and managed in the early decades of life. Fatalistic attitudes are wrong. Genetics deals the cards. The play can be determined by environmental influences. Coagulation abnormalities and homocysteinaemia add to the likelihood of early stroke but are manageable.6 Seven randomised trials …

BACKGROUND Previous studies have shown that carotid endarterectomy in patients with symptomatic severe carotid stenosis (defined as stenosis of 70 to 99 percent of the luminal diameter) is beneficial up to two years after the procedure. In this clinical trial, we assessed the benefit of carotid endarterectomy in patients with symptomatic moderate stenosis, defined as stenosis of less than 70 percent. We also studied the durability of the benefit of endarterectomy in patients with severe stenosis over eight years of follow-up. METHODS Patients who had moderate carotid stenosis and transient ischemic attacks or nondisabling strokes on the same side as the stenosis (ipsilateral) within 180 days before study entry were stratified according to the degree of stenosis (50 to 69 percent or <50 percent) and randomly assigned either to undergo carotid endarterectomy (1108 patients) or to receive medical care alone (1118 patients). The average follow-up was five years, and complete data on outcome events were available for 99.7 percent of the patients. The primary outcome event was any fatal or nonfatal stroke ipsilateral to the stenosis for which the patient underwent randomization. RESULTS Among patients with stenosis of 50 to 69 percent, the five-year rate of any ipsilateral stroke (failure rate) was 15.7 percent among patients treated surgically and 22.2 percent among those treated medically (P=0.045); to prevent one ipsilateral stroke during the five-year period, 15 patients would have to be treated with carotid endarterectomy. Among patients with less than 50 percent stenosis, the failure rate was not significantly lower in the group treated with endarterectomy (14.9 percent) than in the medically treated group (18.7 percent, P=0.16). Among the patients with severe stenosis who underwent endarterectomy, the 30-day rate of death or disabling ipsilateral stroke persisting at 90 days was 2.1 percent; this rate increased to only 6.7 percent at 8 years. Benefit was greatest among men, patients with recent stroke as the qualifying event, and patients with hemispheric symptoms. CONCLUSIONS Endarterectomy in patients with symptomatic moderate carotid stenosis of 50 to 69 percent yielded only a moderate reduction in the risk of stroke. Decisions about treatment for patients in this category must take into account recognized risk factors, and exceptional surgical skill is obligatory if carotid endarterectomy is to be performed. Patients with stenosis of less than 50 percent did not benefit from surgery. Patients with severe stenosis (> or =70 percent) had a durable benefit from endarterectomy at eight years of follow-up.

The detailed results of the Asymptomatic Carotid Atherosclerosis Study (ACAS) have been published. Electrifying reports in the media suggested that 53% fewer strokes would occur if individuals with 60% or greater stenosis were submitted to endarterectomy. The burning question is whether the evidence from this trial, and those preceding it, is sufficiently compelling to persuade any or all individuals with carotid stenosis, but free of any hemisphere and retinal symptoms, to have carotid endarterectomy. Based on a variety of population samplings, it is reasonable to estimate that approximately two million people are living in North America and Europe with asymptomatic lesions comparable with those studied in the ACAS.

Randomized clinical trials have proved that warfarin therapy decreases the risk of stroke in patients with nonvalvular atrial fibrillation and in those who have had a myocardial infarction. In patients who are not candidates for long-term anticoagulant therapy, aspirin is beneficial, but the reduction in risk is smaller with aspirin than with warfarin. In patients with cerebral ischemic symptoms of noncardiac origin, aspirin and ticlopidine reduce the risk of stroke, but the benefit is modest. Given alone, neither dipyridamole nor sulfinpyrazone prevents stroke. The question remains whether either of these drugs plus aspirin is better than aspirin alone. The optimal dose of aspirin for stroke prevention has not been established. Carotid endarterectomy reduces the risk of stroke in symptomatic patients with at least 70 percent stenosis, as determined by arteriography. Current trials are addressing the question of whether endarterectomy is beneficial for patients with moderate degrees of carotid stenosis. The benefit of endarterectomy for patients with asymptomatic carotid lesions remains unclear.

Progress in therapeutic decision-making for patients with carotid artery disease has come from evaluations made by several major randomized clinical trials. For patients who are symptomatic and have arteriographically proven stenoses of 70% or more, endarterectomy is clearly established as the treatment of choice. Symptomatic patients with stenoses of less than 70% remain the subject of ongoing study. Asymptomatic patients are at low risk of stroke save for those with the highest (80% to 90%) degrees of stenosis, and even for these subjects the annual stroke rate is close to the operative risk. Four trials have been reported but the practicing physician is still without clear guidelines. The appropriateness of endarterectomy remains unsettled for any group of patients with narrowing of the carotid artery in the absence of symptoms. The decision to apply endarterectomy to symptomatic and to asymptomatic patients must attend to not only the prognostic importance of the degree of stenosis, but also to the vascular risk profile of the individual patient.

Several case series have suggested that endarterectomy is beneficial in asymptomatic carotid artery disease. Four randomized trials have been done in this area, the most recent of which is the Asymptomatic Carotid Atherosclerosis Study (ACAS). Results of the first three trials were negative, and ACAS produced a tantalizing, statistically significant finding that does not translate into clinical importance. Disabling strokes have not been reduced by surgical therapy, and the benefit for women has not been shown.It is unclear from this study whether persons with the greatest stenosis and the highest vascular risk profiles are appropriate candidates for endarterectomy. In patients in whom carotid artery disease is incidentally discovered, the benefits of the prophylactic addition of carotid endarterectomy to coronary bypass grafting or other major surgical procedure in patients are still unknown. Excellent surgical skill is of paramount importance for the future use of this procedure. Mass population screening to detect asymptomatic carotid disease will only be justified when and if future studies identify patients in whom the risk for disabling stroke after the procedure is clearly reduced.

Several randomized trials have recently reported on the benefit of carotid endarterectomy for symptomatic or asymptomatic patients. A positive benefit has been found for symptomatic patients with > or = 70% stenosis measured by angiogram with a particular formula and performed with high surgical skill. Symptomatic patients with < 70% stenosis continue to be randomized and followed. The answer for this group is expected in the next two years. The randomized trials of asymptomatic patients have not established the benefit for carotid endarterectomy clearly. The most recent trial shows the absolute risk reduction at 5 years is only 5.9% or less than 1.5% risk reduction per year. A fifth trial continues in Europe.

Overwhelmingproof exists that ischemie stroke can be prevented, or at least delayed, for a large number of individuals. Many strokes that resulted from severe symptomatic carotid artery stenosis need happen no longer. Effective treatments have been established by the time-consuming and expensive process of randomized clinical trials. Alas, all other methods seeking the truth about therapeutic benefit are less perfect and frequently misleading. Paradoxically, endarterectomy is complicated by stroke, the very disaster that it effectively reduces. This paradox demands of the practitioner that the indications for this therapy and the care with which it is administered must be precisely defined and scrupulously monitored. This communication will discuss who should and who should not undergo carotid endarterectomy (CE) by focusing on the arterial imaging methods that will provide the essential preoperative information to help ensure appropriate selection of candidates.1 PATIENTS PROVEN TO BENEFIT FROM CE The proven indications for