Heather Meldrum

Benefit of Carotid Endarterectomy in Patients with Symptomatic Moderate or Severe Stenosis

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 causes and risk of stroke in patients with asymptomatic internal-carotid-artery stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators.

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.

Drugs and Surgery in the Prevention of Ischemic Stroke

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.

Risk, causes, and prevention of ischaemic stroke in elderly patients with symptomatic internal-carotid-artery stenosis

BACKGROUND Carotid endarterectomy benefits patients with symptomatic stenosis of 70-99% in the internal carotid artery, with smaller benefit for 50-69% stenosis. The benefit of carotid endarterectomy in patients of 75 years and older remains unclear. METHODS Patients aged 75 years or older from the North American Symptomatic Carotid Endarterectomy Trial were compared with those aged 65-74 years and less than 65 years for baseline characteristics and risk of ipsilateral ischaemic stroke at 2 years by degree of stenosis and treatment group. FINDINGS Among patients with 70-99% stenosis, the absolute risk reduction of ipsilateral ischaemic stroke with carotid endarterectomy was 28.9% (95% CI 12.9-44.9) for patients aged 75 years or older (n=71), 15.1% (7.2-23.0) for those aged 65-74 years (n=285), and 9.7% (1.5-17.9) for the youngest group (n=303). Among patients with 50-69% stenosis, the absolute risk reduction was significant only in those of 75 years and older (n=145; 17.3% [6.6-28.0]). The perioperative risk of stroke and death at any degree of stenosis was 5.2% for the oldest group, 5.5% for 65-74 years, and 7.9% for less than 65 years. The number of patients aged 75 years or older needed to treat to prevent one ipsilateral stroke within 2 years was three with 70-99% stenosis and six with 50-69% stenosis. INTERPRETATION In the prevention of ipsilateral ischaemic stroke, elderly patients with 50-99% symptomatic carotid stenosis benefited more from carotid endarterectomy than younger patients did. To achieve this treatment benefit, surgeons must be skilled and patients with other life-threatening illnesses must be excluded.

Do the facts and figures warrant a 10-fold increase in the performance of carotid endarterectomy on asymptomatic patients?

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.

Aspirin Dose in Stroke Prevention Beautiful Hypotheses Slain by Ugly Facts

Thomas Huxley wrote: “The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact.”1 Acceptance of several hypotheses has convinced many clinicians to use low-dose aspirin whenever thrombosis or thromboembolism arising in any critical arterial systems threatens vital organs. Two current communications support this concept.2 3 This editorial reflects upon the possibility that this insistence on low dose is not based on unassailable data and could have tragic consequences for stroke prevention. In the 1950s, the role of platelet-fibrin emboli was identified in patients with transient ocular and cerebral ischemic events.4 In 1965 and 1967 two drugs, sulfinpyrazone and aspirin, were observed to alter functions of blood platelets.5 6 Harrison et al7 reported on two patients whose attacks of frequent amaurosis fugax stopped with administration of 600 mg aspirin. Within 2 to 4 days the attacks would recur when the aspirin was replaced by either placebo or 150 mg dypyridamole. The mechanisms of action of aspirin on platelets or endothelial cells were not elucidated when the Canadian Cooperative Study group launched the first randomized trial using aspirin in thrombosis prevention. We selected an arbitrary dose of aspirin based on the dosage commonly used in pain relief and convenient to put in capsule form. The sulfinpyrazone dose used was the same as that for antigout therapy. The study design was double-blind 2×2 factorial; look-alike capsules of 325 mg aspirin, 200 mg sulfinpyrazone, both, or placebo were given four times daily.8 Subsequent trials were launched involving patients with TIA and nondisabling stroke and, together with the seminal Canadian and the abbreviated American trials, have recently been reviewed.9 They showed a relative risk reduction of stroke and death of 25% to 42% using 900 to 1300 mg aspirin daily. Patients with stable and …

The Dilemma of Surgical Treatment for Patients with Asymptomatic Carotid Disease

Prophylactic carotid endarterectomy in persons with asymptomatic carotid stenosis became common when practitioners began listening for bruits, when noninvasive imaging methods identified the lesions with increasing accuracy, and when many surgeons became increasingly skilled at the procedure. The search for the riskbenefit ratio of endarterectomy for persons who are otherwise perfectly well has led to many published case series. Unfortunately, these case series lack the credibility of randomized, controlled trials, even though they established that some surgeons have sufficient skill to remove plaques with a perioperative stroke-related morbidity and mortality of 3% or less. Most deaths that occurred in these cases series were from myocardial infarction [1-3]. More recently, the results from four randomized, controlled trials involving a total of 3355 patients have been published [4-7]. The results of the CASANOVA (Carotid Artery Stenosis with Asymptomatic Narrowing: Operation versus Aspirin) [4] and Mayo Asymptomatic Carotid Endarterectomy [5] randomized trials were negative. Both trials had design problems and unacceptably high rates of perioperative complications. The Veterans Affairs trial found benefit only when transient ischemic attacks were included with stroke as a primary outcome event [6]. When the transient events were omitted from the analyses, endarterectomy did not improve the occurrence of perioperative stroke and death or long-term stroke-free survival. Reduction in the number of transient ischemic events is not an adequate exchange for the more serious perioperative risk for stroke and death. The Asymptomatic Carotid Artery Study (ACAS), a multicenter trial conducted in 39 centers in the United States and Canada, randomly assigned half of the 1662 asymptomatic patients to receive the best medical care plus endarterectomy and the other half to receive only the best medical care [7]. In this issue of Annals, two of the ACAS investigators comment on this study [8]. On the basis of the statistical results of this study, Drs. Brott and Toole urge physicians to consider endarterectomy in asymptomatic persons with carotid artery stenosis of 60% or greater. In our view, a closer look at the ACAS results yields a much more cautious interpretation of their data. The reported 53% relative risk reduction is much less impressive when converted into an absolute risk reduction of 5.9% over 5 years. This is an average stroke reduction of slightly more than 1% per year. If this positive, albeit slight, benefit could be accomplished with a smaller associated surgical complication rate, there would be no concern that its statistical significance was being interpreted as a matter of clinical importance. Even in ACAS, however, the dramatically low perioperative rate of 2.3% is the same as the annual risk for stroke in the persons in the control group. Asymptomatic patients for whom carotid endarterectomy is recommended must be advised that they face a higher risk for stroke in the first year than if they continue to receive medical treatment alone. Several more years may pass before these patients can be shown to benefit from the procedure. In other reported studies of asymptomatic patients, the average perioperative rate was 4.5% [4, 5, 9, 10]. An acceptable risk-benefit ratio is not achieved by such an average perioperative rate. The 3% rate recommended by an American Heart Association Committee as the maximum perioperative risk in asymptomatic patients is three times higher than the average annualized risk difference of ACAS [11]. According to the ACAS results, the numbers of patients needed to be treated by endarterectomy to prevent 1 stroke in 2 and 5 years are high: 67 and 17, respectively. By contrast, in the symptomatic patients studied by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) [12], 10 patients needed to be treated by endarterectomy to prevent 1 stroke in 1 year and 6 patients to prevent 1 stroke in 2 years. For patients in NASCET with the highest degree of stenosis (90% to 99%), only 3 patients needed to have endarterectomy to prevent 1 stroke in 2 years [12]. See also the preceding Perspective as well as pp 649-55 and the editorial note on p 729. In the ACAS trial, women were not shown to benefit from endarterectomy. The facts that only 565 women were studied in the trial and that the reported perioperative complication rate (3.6%) was more than double the rate in men (1.7%) probably account for this anomalous finding. It is particularly disappointing that no difference was seen in the occurrence of disabling strokes between the surgical and medical arms of ACAS. Patients must be advised that major disability faces them just as often when they elect endarterectomy as when they elect medical therapy and that major stroke is an immediate risk. Physicians who would recommend carotid endarterectomy for the asymptomatic patient must recognize that the economic burden and the personal and family anguish of a disabling stroke will not be diminished. Many previous observations have affirmed that patients with the highest degree of asymptomatic stenosis ( 80%) are more vulnerable to stroke than those with lesser degrees ( 75% to 80%) [13-16]. It is disappointing that ACAS included too few patients to support this theory. Only 85 outcome events of ipsilateral stroke or perioperative death occurred in the median 2.7 years of follow-up. A larger sample size for this type of study, on the order of 7000 persons, has been recommended on the basis of observed outcome events in population case series [17]. In addition, because ACAS depended on Doppler ultrasound as the primary imaging technique, the patients could not be stratified by deciles of stenosis. The beneficial results for endarterectomy from ACAS are too modest to be applied to all persons with stenosis greater than 60%. The published data cannot be used to formulate guidelines to advise which asymptomatic persons with what amount of stenosis and what combination of risk factors should have the procedure. None of the studies of asymptomatic patients that were done before ACAS depended on ultrasound except to screen potential candidates for angiography. Even when ultrasound is perfected to the point at which the degree of extracranial stenosis can be determined with complete accuracy, it will not identify many important intracranial pathologic processes (such as stenosis, occlusion, and aneurysm). Ultrasound is ineffective in the presence of extensive calcification and tortuosity, and it does not image lesions that extend beyond the carotid bulb or identify near-occlusion and soft thrombi within the arteries. All these features add to the risk for stroke and of endarterectomy [18]. Another caveat to the use of ultrasound relates to a technical point: The measurements from Doppler studies are commonly reported as a percentage that reflects an area rather than a linear measurement. A 60% area stenosis seen by ultrasound is only a 45% to 55% linear stenosis seen by angiography. Consequently, the description of a 60% stenosis from a Doppler report may be misinterpreted in clinical practice. In ACAS, 60% is meant to reflect a conversion to linear stenosis by a comparison of peak frequencies on Doppler with arteriographic linear measurements. The 60% value is only equivalent to a linear measurement on an arteriogram if the cut-point formula of ACAS is applied [19]. Because no data confirm the benefit of endarterectomy at levels of 45% to 55% linear stenosis, area measurement by Doppler must not be equated with linear measurement by angiography. The published results from the studies in asymptomatic patients are not sturdy enough to lead to the abandonment of conventional arteriography and its small inherent risk. It is hoped that the perfection of ultrasound and magnetic resonance angiography will make conventional arteriography unnecessary; however, these refinements are still ahead of us. The results from all trials of asymptomatic carotid stenosis are disappointingly inconclusive. With further study, patients with the most severe stenosis will probably be shown to benefit from carotid endarterectomy. When this benefit is known, the procedure should be done by the most skilled surgeons whose results have been validated by independent audit. We and others [20, 21] worry that premature uncritical acceptance of the reports will lead to many inappropriate endarterectomies. A result that is exalted for its statistical significance must also have compelling clinical importance before patients are urged to seek investigation leading to a treatment that imposes risks for major stroke or death. We do not recommend mass screening of populations to detect asymptomatic carotid artery lesions. In the Asymptomatic Carotid Surgery Trial, a much larger randomized, controlled trial of this problem [22], investigators plan to have enough patients in all deciles of asymptomatic stenosis to confirm or deny that there are subgroups of patients who will clearly benefit from carotid endarterectomy. The results of this trial are not expected for 3 or more years. In the meantime, we and our patients must wait for clearer guidelines of the kind demanded by evidence-based medicine.

Long-Term Clinical and Angiographic Outcomes in Symptomatic Patients With 70% to 99% Carotid Artery Stenosis

Background and Purpose In 1991, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) reported the benefit of carotid endarterectomy for 659 patients with 70% to 99% stenosis. Follow-up continued until 1997. Methods The present study examined the risks and causes of ipsilateral stroke in the randomized groups and in those who had delayed endarterectomy or continued on medical therapy and also examined the evolution of carotid disease on follow-up imaging. Results By on-treatment (efficacy) analysis, the risk of any ipsilateral stroke at 3 years was 28.3% for medically randomized and 8.9% for surgically randomized patients (19.4% absolute risk reduction, P <0.001). For combined disabling or fatal ipsilateral stroke, the risks were 14.0% and 3.4%, respectively (10.6% absolute risk reduction). In medical patients, >80% of the first strokes at 3 years were of large-artery origin. After February 1991, 116 suitable medical patients underwent endarterectomy within 6 months, and 115 continued on medical therapy. The 3-year risk of any ipsilateral stroke in the groups of 116 and 115 patients was 7.9% and 15.0%, respectively (7.1% absolute risk reduction). During follow-up, 81 patients had angiograms comparable to the baseline images. Progression by ≥10% occurred in 7 patients; regression, in 8; no change, in 39; and occlusion, in 27. By use of both angiography and ultrasound, 63 (25.5%) of the 247 medically treated patients progressed to occlusion, of whom 31.7% had an ipsilateral stroke before or on the day of occlusion. Conclusions Endarterectomy for patients with 70% to 99% stenosis and recent symptoms was efficacious in the long term. Compared with patients who continued on medical therapy, medical patients with delayed endarterectomy experienced a moderate benefit. Medically treated patients experienced a high risk of occlusion.

Evidence based cardiology: Prevention of ischaemic stroke

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 …

Risk, Types, and Severity of Intracranial Hemorrhage in Patients With Symptomatic Carotid Artery Stenosis

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.