Transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) can identify intracranial atherosclerosis but have not been rigorously validated against the gold standard, catheter ...angiography. The WASID trial (Warfarin Aspirin Symptomatic Intracranial Disease) required performance of angiography to verify the presence of intracranial stenosis, allowing for prospective evaluation of TCD and MRA. The aims of Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial were to define abnormalities on TCD/MRA to see how well they identify 50 to 99% intracranial stenosis of large proximal arteries on catheter angiography.
SONIA standardized the performance and interpretation of TCD, MRA, and angiography. Study-wide cutpoints defining positive TCD/MRA were used. Hard copy TCD/MRA were centrally read, blind to the results of angiography.
SONIA enrolled 407 patients at 46 sites in the United States. For prospectively tested noninvasive test cutpoints, positive predictive values (PPVs) and negative predictive values (NPVs) were TCD, PPV 36% (95% CI: 27 to 46); NPV, 86% (95% CI: 81 to 89); MRA, PPV 59% (95% CI: 54 to 65); NPV, 91% (95% CI: 89 to 93). For cutpoints modified to maximize PPV, they were TCD, PPV 50% (95% CI: 36 to 64), NPV 85% (95% CI: 81 to 88); MRA PPV 66% (95% CI: 58 to 73), NPV 87% (95% CI: 85 to 89). For each test, a characteristic performance curve showing how the predictive values vary with a changing test cutpoint was obtained.
Both transcranial Doppler ultrasound and magnetic resonance angiography noninvasively identify 50 to 99% intracranial large vessel stenoses with substantial negative predictive value. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis trial methods allow transcranial Doppler ultrasound and magnetic resonance angiography to reliably exclude the presence of intracranial stenosis. Abnormal findings on transcranial Doppler ultrasound or magnetic resonance angiography require a confirmatory test such as angiography to reliably identify stenosis.
There are limited data on the relationship between patient and site characteristics and clinical outcomes after intracranial stenting.
We performed a multivariable analysis that correlated patient ...and site characteristics with the occurrence of the primary endpoint (any stroke or death within 30 days of stenting or stroke in the territory of the stented artery beyond 30 days) in 160 patients enrolled in this stenting registry. All patients presented with an ischemic stroke, TIA, or other cerebral ischemic event (e.g., vertebrobasilar insufficiency) in the territory of a suspected 50-99% stenosis of a major intracranial artery while on antithrombotic therapy.
Cerebral angiography confirmed that 99% (158/160) of patients had a 50-99% stenosis. In multivariable analysis, the primary endpoint was associated with posterior circulation stenosis (vs anterior circulation) (hazard ratio HR 3.4, 95% confidence interval CI 1.2-9.3, p = 0.018), stenting at low enrollment sites (< 10 patients each) (vs high enrollment site) (HR 2.8, 95% CI 1.1-7.6, p = 0.038), < or = 10 days from qualifying event to stenting (vs > or = 10 days) (HR 2.7, 95% CI 1.0-7.8, p = 0.058), and stroke as a qualifying event (vs TIA/other) (HR 3.2, 95% CI 0.9-11.2, p = 0.064). There was no significant difference in the primary endpoint based on age, gender, race, or percent stenosis (50-69% vs 70-99%).
Major cerebrovascular complications after intracranial stenting may be associated with posterior circulation stenosis, low volume sites, stenting soon after a qualifying event, and stroke as the qualifying event. These factors will need to be monitored in future trials of intracranial stenting.
Antithrombotic therapy for intracranial arterial stenosis was recently evaluated in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. A prespecified aim of WASID was to ...identify patients at highest risk for stroke in the territory of the stenotic artery who would be the target group for a subsequent trial comparing intracranial stenting with medical therapy.
WASID was a randomized, double-blinded, multicenter trial involving 569 patients with transient ischemic attack or ischemic stroke due to 50% to 99% stenosis of a major intracranial artery. Median time from qualifying event to randomization was 17 days, and mean follow-up was 1.8 years. Multivariable Cox proportional hazards models were used to identify factors associated with subsequent ischemic stroke in the territory of the stenotic artery. Subsequent ischemic stroke occurred in 106 patients (19.0%); 77 (73%) of these strokes were in the territory of the stenotic artery. Risk of stroke in the territory of the stenotic artery was highest with severe stenosis > or =70% (hazard ratio 2.03; 95% confidence interval 1.29 to 3.22; P=0.0025) and in patients enrolled early (< or =17 days) after the qualifying event (hazard ratio 1.69; 95% confidence interval 1.06 to 2.72; P=0.028). Women were also at increased risk, although this was of borderline significance (hazard ratio 1.59; 95% confidence interval 1.00 to 2.55; P=0.051). Location of stenosis, type of qualifying event, and prior use of antithrombotic medications were not associated with increased risk.
Among patients with symptomatic intracranial stenosis, the risk of subsequent stroke in the territory of the stenotic artery is greatest with stenosis > or =70%, after recent symptoms, and in women.
There are limited data on the relationship between control of vascular risk factors and vascular events in patients with symptomatic intracranial arterial stenosis.
We utilized the Warfarin Aspirin ...Symptomatic Intracranial Disease study database to analyze vascular and lifestyle risk factors at baseline and averaged over the course of the trial. Cutoff levels defining good control for each factor were prespecified based on national guidelines. Endpoints evaluated included 1) ischemic stroke, myocardial infarction, or vascular death or 2) ischemic stroke alone. Univariate associations were assessed using the log-rank test and multivariable analysis was done using Cox proportional hazards regression.
From baseline until year 2 follow-up, there was not a significant improvement in blood pressure control. During the same period, there were improvements in patients with total cholesterol <200 mg/dL (54.6% to 79.2%, p < 0.001) or low-density lipoprotein <100 mg/dL (28.7% to 55.9%, p < 0.001). Multivariable analysis showed that systolic blood pressure >or=140 mm Hg (HR = 1.79, p = 0.0009, 95% confidence limits 1.27 to 2.52), no alcohol consumption (HR 1.69, 1.21 to 2.39, p = 0.002), and cholesterol >or=200 mg/dL (HR 1.44, 1.004 to 2.07, p = 0.048) were associated with an increased risk of stroke, myocardial infarction, or vascular death. The same risk factors were predictors of ischemic stroke alone in multivariable analysis.
Elevated blood pressure and cholesterol levels in symptomatic patients with intracranial stenosis are associated with an increased risk of stroke and other major vascular events.
The WASID trial showed no advantage of warfarin over aspirin for preventing the primary endpoint of ischemic stroke, brain hemorrhage, or vascular death. In analyses of selected subgroups, there was ...no definite benefit from warfarin. Warfarin reduced the risk of the primary endpoint among patients with basilar artery stenosis, but there was no reduction in stroke in the basilar artery territory or benefit for vertebral artery stenosis or posterior circulation disease in general.
Atherosclerosis of the major intracranial arteries is an important cause of ischemic stroke. We established measurement criteria to assess percent stenosis of a major intracranial artery (carotid, ...middle cerebral, vertebral, basilar) and determined the interobserver/intraobserver agreements and interclass/intraclass correlations of these measurements.
We defined percent stenosis of an intracranial artery as follows: percent stenosis = (1 - (D(stenosis)/D(normal))) x 100, where D(stenosis) = the diameter of the artery at the site of the most severe stenosis and D(normal) = the diameter of the proximal normal artery. If the proximal segment was diseased, contingency sites were chosen to measure D(normal): distal artery (second choice), feeding artery (third choice). Using a hand-held digital caliper, three neuroradiologists independently measured D(stenosis) and D(normal) of 24 stenotic intracranial arteries. Each observer repeated the readings 4 weeks later. We determined how frequently two observers' measurements of percent stenosis of each of the 24 diseased arteries differed by 10% or less.
Among the three pairs of observers, interobserver agreements were 88% (observer 1 versus observer 2), 79% (observer 1 versus observer 3), 75% (observer 2 versus observer 3) for the first reading and were 75% (observer 1 versus observer 2), 100% (observer 1 versus observer 3), and 71% (observer 2 versus observer 3) for the second reading. Intraobserver agreement for each of the observers was 88%, 83%, and 100%. Interclass correlation was 85% (first reading) and 87% (second reading). Intraclass correlation was 92% (first and second readings combined).
This method shows good interobserver and intraobserver agreements for the measurement of intracranial stenosis of a major artery. If validated in subsequent studies, this method may serve as a standard for the measurement of percent stenosis of an intracranial artery.
Atherosclerotic intracranial arterial stenosis is an important cause of stroke. Warfarin is commonly used in preference to aspirin for this disorder, but these therapies have not been compared in a ...randomized trial.
We randomly assigned patients with transient ischemic attack or stroke caused by angiographically verified 50 to 99 percent stenosis of a major intracranial artery to receive warfarin (target international normalized ratio, 2.0 to 3.0) or aspirin (1300 mg per day) in a double-blind, multicenter clinical trial. The primary end point was ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.
After 569 patients had undergone randomization, enrollment was stopped because of concerns about the safety of the patients who had been assigned to receive warfarin. During a mean follow-up period of 1.8 years, adverse events in the two groups included death (4.3 percent in the aspirin group vs. 9.7 percent in the warfarin group; hazard ratio for aspirin relative to warfarin, 0.46; 95 percent confidence interval, 0.23 to 0.90; P=0.02), major hemorrhage (3.2 percent vs. 8.3 percent, respectively; hazard ratio, 0.39; 95 percent confidence interval, 0.18 to 0.84; P=0.01), and myocardial infarction or sudden death (2.9 percent vs. 7.3 percent, respectively; hazard ratio, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.02). The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group (P=0.16); the rate of death from nonvascular causes was 1.1 percent and 3.8 percent, respectively (P=0.05). The primary end point occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent of those in the warfarin group (hazard ratio, 1.04; 95 percent confidence interval, 0.73 to 1.48; P=0.83).
Warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin in this trial. Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.
We conducted a retrospective, multicenter study to compare the efficacy of warfarin with aspirin for the prevention of major vascular events (ischemic stroke, myocardial infarction, or sudden death) ...in patients with symptomatic stenosis of a major intracranial artery. Patients with 50 to 99% stenosis of an intracranial artery (carotid; anterior, middle, or posterior cerebral; vertebral; or basilar) were identified by reviewing the results of consecutive angiograms performed at participating centers between 1985 and 1991. Only patients with TIA or stroke in the territory of the stenotic artery qualified for inclusion in the study. Patients were prescribed warfarin or aspirin according to local physician preference and were followed by chart review and personal or telephone interview. Seven centers enrolled 151 patients; 88 were treated with warfarin and 63 were treated with aspirin. Median follow-up was 14.7 months (warfarin group) and 19.3 months (aspirin group). Vascular risk factors and mean percent stenosis of the symptomatic artery were similar in the two groups, yet the rates of major vascular events were 18.1 per 100 patient-years of follow-up in the aspirin group (stroke rate, 10.4/100 patient-years; myocardial infarction or sudden death rate, 7.7/100 patient-years) compared with 8.4 per 100 patient-years of follow-up in the warfarin group (stroke rate, 3.6/100 patient-years; myocardial infarction or sudden death rate, 4.8/100 patient-years). Kaplan-Meier analysis showed a significantly higher percentage of patients free of major vascular events among patients treated with warfarin (p = 0.01).
Atherosclerotic disease of the major intracranial arteries is a frequent cause of stroke. In addition, many patients who have symptomatic intracranial stenosis are at very high risk for recurrent ...stroke. Preliminary studies suggest that angioplasty and stenting may reduce the risk of stroke in patients who have severe stenosis of intracranial arteries. Data for angioplasty and stenting, however, consist of case series; no randomized studies have been completed to date. This article reviews these data and discusses the rationale for a randomized trial of angioplasty and stenting versus best medical management for patients who have symptomatic intracranial stenosis.
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