Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. Long-term follow-up after extracranial internal carotid artery dissection. Danish very-low-dose aspirin after carotid endarterectomy trial. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
The efficacy of carotid endarterectomy in patients with asymptomatic carotid stenosis has not been confirmed in randomized clinical trials, despite the widespread use of operative intervention in such patients.
                We conducted a multicenter clinical trial at 11 Veterans Affairs medical centers to determine the effect of carotid endarterectomy on the combined incidence of transient ischemic attack, transient monocular blindness, and stroke. We studied 444 men with asymptomatic carotid stenosis shown arteriographically to reduce the diameter of the arterial lumen by 50 percent or more. The patients were randomly assigned to optimal medical treatment including antiplatelet medication (aspirin) plus carotid endarterectomy (the surgical group; 211 patients) or optimal medical treatment alone (the medical group; 233 patients). All the patients at each center were followed independently by a vascular surgeon and a neurologist for a mean of 47.9 months.
                The combined incidence of ipsilateral neurologic events was 8.0 percent in the surgical group and 20.6 percent in the medical group (P < 0.001), giving a relative risk (for the surgical group vs. the medical group) of 0.38 (95 percent confidence interval, 0.22 to 0.67). The incidence of ipsilateral stroke alone was 4.7 percent in the surgical group and 9.4 percent in the medical group. An analysis of stroke and death combined within the first 30 postoperative days showed no significant differences. Nor were there significant differences between groups in an analysis of all strokes and deaths (surgical, 41.2 percent; medical, 44.2 percent; relative risk, 0.92; 95 percent confidence interval, 0.69 to 1.22). Overall mortality, including postoperative deaths, was primarily due to coronary atherosclerosis.
                Carotid endarterectomy reduced the overall incidence of ipsilateral neurologic events in a selected group of male patients with asymptomatic carotid stenosis. We did not find a significant influence of carotid endarterectomy on the combined incidence of stroke and death, but because of the size of our sample, a modest effect could not be excluded. Without strong evidence of benefit, the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s, then declined. Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis.
                We conducted a randomized trial at 50 clinical centers throughout the United States and Canada, in patients in two predetermined strata based on the severity of carotid stenosis--30 to 69 percent and 70 to 99 percent. We report here the results in the 659 patients in the latter stratum, who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery. All patients received optimal medical care, including antiplatelet therapy. Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons. All patients were examined by neurologists 1, 3, 6, 9, and 12 months after entry and then every 4 months. End points were assessed by blinded, independent case review. No patient was lost to follow-up.
                Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients--an absolute risk reduction (+/- SE) 17 +/- 3.5 percent (P less than 0.001). For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1 percent and 2.5 percent--an absolute risk reduction of 10.6 +/- 2.6 percent (P less than 0.001). Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis (P less than 0.001).
                Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery. To evaluate long-term outcome after extracranial internal carotid artery dissection (eICAD) in consideration of the applied antithrombotic therapy.
                Among 33 consecutive eICAD patients initially treated either with anticoagulation (n = 25) or with antiplatelets (n = 8), a standardized interview was performed after 28 +/- 22.1 months to analyze risks and benefits of both agents. Ischemic and hemorrhagic complications, occurrence of seizure and rates of arterial recanalization were compared and long-term clinical outcome was assessed using the modified Rankin Scale (mRS) and Barthel Index (BI).
                Among anticoagulated patients, 1 died due to brain herniation. In 3 patients stroke (n = 2) or TIA (n = 1) recurred. In the antiplatelet group, none died and no subsequent ischemic events happened. Hemorrhagic complications were noted in neither treatment group. Functional outcome among anticoagulated patients was BI 92 +/- 21.6 and mRS 1.48 +/- 1.50, which did not differ from patients initially treated with antiplatelets (BI 89 +/- 18.9, mRS 1.50 +/- 1.41, p > 0.05). Four anticoagulated patients developed seizures, compared to 2 patients with antiplatelets (p > 0.05). Arterial recanalization occurred in 16 of 22 antico- agulated patients with ultrasound follow-up, compared to 6 of 6 patients with antiplatelets (p > 0.05).
                In the absence of iatrogenic side effects, both anticoagulation and antiplatelets seem to be safe for eICAD. The rates for death and stroke were low and outcome ratings did not differ between both agents. These findings may indicate that a controlled randomized trial comparing anticoagulation and antiplatelets is ethically justified.
                Copyright 2000 S. Karger AG, Basel The effect of very-low-dose aspirin as an antithrombotic agent was evaluated blindly in 301 patients who had recently undergone carotid endarterectomy. After randomization, 150 patients received aspirin and 151 received placebo. The two groups were comparable with regard to age, sex, blood pressure, previous cerebrovascular events, and smoking habits. The effect of the study medication on platelet aggregation was measured twice in each patient during the first 2 months and at each follow-up visit; the dose was individually adjusted. In 76% of the patients receiving aspirin, 50 mg/day gave satisfactory platelet inhibition, 13% needed 60 mg/day, 8% needed 70 mg/day, and 3% needed 100 mg/day. Platelet aggregation was found to be inhibited in only 1.2% of the measurements in the patients receiving placebo. Observation during treatment averaged 21 months; total intention-to-treat follow-up averaged 25 months. For the combined outcome events of transient ischemic attack, stroke, acute myocardial infarction, and vascular death, aspirin reduced risk by 11% (95% confidence limits: -38% to 48%, p greater than 0.1). Thus, there was no significant effect of very-low-dose aspirin in our trial. To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.
                Collaborative meta-analyses (systematic overviews).
                Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen.
                287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens.
                "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death.
                Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000.
                Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed. Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy.
                The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470.
                The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006). Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197).
                Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
                Medical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union.
                Copyright 2010 Elsevier Ltd. All rights reserved.
Our results may indicate that antiplatelet drugs did not significantly change the odds of death but reduce the outcome 'stroke of any cause' in patients undergoing carotid endarterectomy. However, it can not be excluded that the beneficial effect in reducing stroke is due to chance. There is a suggestion that antiplatelets may increase the odds of haemorrhage, but there are currently too few data to quantify this effect.