CLINICAL PERSPECTIVE

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(Circulation. 2006;113:555-563.)
© 2006 American Heart Association, Inc.

Stroke

Predictors of Ischemic Stroke in the Territory of a Symptomatic Intracranial Arterial Stenosis

Scott E. Kasner, MD; Marc I. Chimowitz, MBChB; Michael J. Lynn, MS; Harriet Howlett-Smith, RN; Barney J. Stern, MD; Vicki S. Hertzberg, PhD; Michael R. Frankel, MD; Steven R. Levine, MD; Seemant Chaturvedi, MD; Curtis G. Benesch, MD; Cathy A. Sila, MD; Tudor G. Jovin, MD; Jose G. Romano, MD; Harry J. Cloft, MD, PhD, for the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) Trial Investigators^*

From the Department of Neurology, University of Pennsylvania Medical Center (S.E.K.), Philadelphia; Department of Neurology (M.I.C., H.H.-S., B.J.S., M.R.F.) and Department of Biostatistics (M.J.L., V.S.H.), Rollins School of Public Health, Emory University School of Medicine, Atlanta, Ga; Department of Neurology, University of Maryland (B.J.S.), Baltimore; Department of Neurology, Mount Sinai School of Medicine (S.R.L.), New York, NY; Department of Neurology, Wayne State University (S.C.), Detroit, Mich; Department of Neurology, University of Rochester School of Medicine (C.G.B.), Rochester, NY; Department of Neurology, Cleveland Clinic Foundation (C.A.S.), Cleveland, Ohio; Department of Neurology, University of Pittsburgh School of Medicine (T.G.J.), Pittsburgh, Pa; Department of Neurology, University of Miami Medical School (J.G.R.), Miami, Fla; and Department of Radiology, Mayo Clinic (H.J.C.), Rochester, Minn.

Correspondence to Scott E. Kasner, MD, Department of Neurology, University of Pennsylvania, 3 W Gates Bldg, 3400 Spruce St, Philadelphia, PA 19104. E-mail kasner{at}mail.med.upenn.edu

Received July 25, 2005; revision received November 21, 2005; accepted November 23, 2005.

	Abstract

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Background— 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.

Methods and Results— 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 70% (hazard ratio 2.03; 95% confidence interval 1.29 to 3.22; P=0.0025) and in patients enrolled early (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.

Conclusions— Among patients with symptomatic intracranial stenosis, the risk of subsequent stroke in the territory of the stenotic artery is greatest with stenosis 70%, after recent symptoms, and in women.

Key Words: stroke • atherosclerosis • cerebrovascular circulation

	Introduction

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Atherosclerotic stenosis of the major intracranial arteries is an important cause of ischemic stroke, especially in blacks, Asians, and Hispanics.^1,2 In the United States, intracranial stenosis causes 8% to 10% of ischemic strokes, and the risk of recurrent stroke in these patients may be as high as 15% per year.^3–8 The Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) study was a randomized clinical trial that compared warfarin and aspirin for preventing stroke and vascular death in patients with stenosis of a major intracranial artery.⁹ The study determined that warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin for preventing stroke and vascular death. Another therapeutic strategy is intracranial angioplasty or stenting, but there are no studies on the comparative safety and efficacy of angioplasty or stenting versus medical therapy.

Clinical Perspective p 563

A few retrospective studies have suggested that there are subgroups of patients with intracranial arterial stenosis at particularly high risk of stroke in the territory of the stenotic artery who may be the target population for intracranial angioplasty or stenting. These include patients with severe stenosis (70% to 99%),⁸ those with vertebrobasilar disease,^8,10,11 and those who had an ischemic event while undergoing antithrombotic therapy.¹² Furthermore, studies of extracranial carotid stenosis have suggested that stroke rather than transient ischemic attack (TIA)¹³ and recent symptoms¹⁴ may portend greater risk. These 5 potential high-risk features require validation in a prospective study to have clinical utility for patients with intracranial stenosis.

The WASID study provided a unique opportunity to identify predictors of stroke in the territory of a stenotic intracranial artery. As such, a prespecified aim of WASID was to identify patients at sufficiently high risk of stroke in the territory of the stenotic artery who would be the target group for a subsequent trial comparing intracranial stenting with medical therapy.

	Methods

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Study Design and Patient Eligibility
Details of the WASID study design and results of the comparison of warfarin and aspirin have been published previously.^7,9 Briefly, WASID was an investigator-initiated, randomized, double-blind, multicenter clinical trial conducted at 59 sites in North America that was funded by the National Institute of Neurological Disorders and Stroke (NINDS). The study protocol was approved by the institutional review board at each site, and all patients gave written informed consent to participate. Patients were enrolled between February 1999 and July 2003.

Inclusion criteria included TIA or nondisabling stroke within 90 days of randomization that was attributable to angiographically verified 50% to 99% stenosis of a major intracranial artery (internal carotid, middle cerebral, vertebral, or basilar artery), modified Rankin score 3, and age 40 years. Exclusion criteria included extracranial internal carotid stenosis (50% to 99%) tandem to an intracranial carotid or middle cerebral artery stenosis; nonatherosclerotic stenosis; a cardiac source of embolism (eg, atrial fibrillation); contraindication to aspirin or warfarin; and a comorbid condition that limited the outlook for survival to <5 years. Patients were randomly assigned treatment with warfarin (target international normalized ratio [INR] between 2.0 and 3.0) or aspirin (1300 mg daily). Study subjects and investigators were blinded to treatment allocation.

Angiographic Evaluation
Patients were enrolled in WASID on the basis of local interpretation of angiograms that demonstrated 50% to 99% stenosis of a major intracranial artery. One copy of the angiogram frame that best depicted the symptomatic stenosis was sent for central reading. The central neuroradiologist (HJC), blinded to the site reading, measured percent diameter stenosis according to the WASID measurement technique.⁷ On the same angiographic image, the length of stenosis was measured and then normalized by dividing by the diameter of the normal referent arterial segment. The measurements used in this analysis were those of the central neuroradiologist. On the basis of the intent-to-treat principle, patients whose central readings indicated <50% stenosis or complete 100% occlusion were included in this analysis.

Follow-Up and Assessment of End Points
Patients were contacted monthly to determine whether any events had occurred. Every 4 months, patients were examined by a neurologist blinded to treatment allocation. If a stroke was suspected, patients underwent brain computerized tomography (CT) or magnetic resonance imaging (MRI). Patients were to be followed up to a primary end point, death, or a common termination date. The primary end point for the comparison of warfarin and aspirin in WASID was ischemic stroke (in any vascular territory), brain hemorrhage, or nonstroke vascular death.

For the present analysis, the end point of interest was ischemic stroke in the territory of the symptomatic intracranial stenosis. Ischemic stroke was defined as a new focal neurological deficit of sudden onset that lasted 24 hours and was not caused by hemorrhage on brain imaging. Ischemic stroke was considered to be definitely in the same territory of the symptomatic artery when the neurological signs correlated with a new infarct on CT or MRI in an area of the brain supplied by that artery. Ischemic stroke was considered probably in the territory of the symptomatic artery when the neurological signs were localized to an area of the brain supplied by that artery but there was no new infarct on brain imaging. Ischemic stroke was considered in an indeterminate territory when the neurological signs could localize to 2 or more distinct vascular territories and there was no new infarct on brain imaging. Ischemic stroke could likewise be classified as probably not or definitely not in the territory of the symptomatic artery. For the purpose of the present analysis, ischemic strokes that were definitely or probably in the territory of the stenotic artery were considered in the territory.

The local investigator classified the location of the end-point ischemic stroke. In addition, the locations of all ischemic strokes were independently determined by a central investigator (MIC) at the end of the study. In cases in which there was disagreement, a second central investigator (BJS) independently determined the location, and the classification made by 2 of the 3 investigators was used.

Statistical Methods
The original power analysis to address the main hypothesis pertinent to this study (in the best medical therapy group, patients with 70% to 99% stenosis would have a significantly higher rate of ischemic stroke in the territory of the stenotic artery than patients with 50% to 69% stenosis) assumed a sample size of 403 patients followed up for an average of 2.5 years. Assuming a 60:40 ratio in patients with moderate versus severe stenosis, the power was 94% to detect a difference in rates similar to that observed in the retrospective WASID pilot study,⁸ 18% with severe stenosis versus 6% with moderate stenosis over 3 years. In addition, we calculated that there was 80% power to detect hazard ratios (HRs) between 2.0 and 2.3 for other risk factors (eg, anterior versus posterior circulation stenosis).

WASID was halted after 569 patients had been enrolled and followed up for an average of 1.8 years. Because no difference was discerned between the 2 treatment arms, all patients were included in the present analysis. We determined the power of the study with 569 patients to detect HRs of 2 using the method of Lachin and Foulkes¹⁵ for the log-rank test. Among all 569 patients, the probability of ischemic stroke in the territory of the stenotic artery at 2 years was 0.14. To estimate the detectable differences between groups of patients, we determined the proportions with an event by 2 years in each of 2 groups that would yield an overall proportion of 0.14 when 1 proportion was twice the other proportion and when the sample size varied with 33%, 50%, or 67% of the 569 patients in the group with the smaller proportion. The smaller proportion at 2 years was translated to a hazard rate, and the power to detect a hazard rate twice as large was determined for the 3 sets of sample sizes. With a type I error of 0.05, the power was 0.76, 0.86, and 0.88 when the sample size in the group with the smaller hazard rate was 33%, 50%, and 67% of the 569 patients, respectively. Thus, the study had adequate power to detect HRs of 2 when the sample size of the smaller of 2 groups was at least 190.

Univariate analyses to assess the effect of each baseline factor were done with Cox proportional hazards regression. A series of nested multivariable Cox proportional hazards models were considered. The primary model was based on the 5 hypothesized contributors to the risk of stroke in the territory of the symptomatic artery: type of qualifying event (stroke versus TIA), location of vessel (anterior versus posterior circulation), percent stenosis, treatment with antithrombotic medications at the time of the qualifying event, and time from qualifying event to enrollment. A second model incorporated these 5 variables and was also adjusted for age, gender, and race. Additional variables were considered for inclusion in a third exploratory multivariable model if they were associated with stroke in the territory in univariate analysis at the P<0.05 level.

The cumulative probability of a stroke in the territory of the stenotic intracranial artery versus time was estimated by the product-limit method. The relationship between degree of stenosis and the risk of stroke in the territory of the stenotic artery was tested with the Cochran-Armitage test.¹⁶ Patients lost to follow-up were censored at the last contact date. Baseline characteristics were compared between patients with and without stroke in the territory with a ² test (for proportions) or independent groups t test (for means). All reported probability values are 2-sided, without adjustment for multiple testing; probability values <0.05 were considered statistically significant.

	Results

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In WASID, 569 patients were enrolled a median of 17 days after the qualifying TIA or ischemic stroke. The mean duration of follow-up was 1.8 years. Thirteen patients (2.3%) were lost to follow-up (6) or withdrew consent (7) at an average of 6 months after enrollment. The primary WASID end point of ischemic stroke, brain hemorrhage, or nonstroke vascular death occurred in 125 patients (22%).

Ischemic stroke accounted for the majority of events in WASID and occurred in 106 patients (19.0%); 77 (73%) of these strokes were in the territory of the stenotic artery (51 definite, 26 probable). Sixty (78%) of these 77 strokes occurred within the first year. Table 1 summarizes the baseline characteristics for patients with and without a stroke in the territory of the symptomatic stenotic artery. Table 2 shows event rates and univariate relationships between baseline characteristics and the rates of stroke in the territory of the stenotic artery. Univariate analysis (Table 2) showed that severity of stenosis (70% versus <70%; Figure), time from qualifying event to enrollment (17 days versus >17 days), female gender, National Institutes of Health (NIH) stroke scale (>1 versus 1), and history of diabetes mellitus were significantly associated (P0.05) with stroke in the territory of the stenotic artery, whereas body mass index was of borderline significance (P=0.068). Age, race, location of stenosis, length of stenosis, other vascular risk factors, comorbidities, treatment with antithrombotic agents at the time of the qualifying event, and treatment assignment were not significantly associated with an increased risk of stroke in the territory of the stenotic artery.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of Patients With and Without Subsequent Stroke in the Territory of the Symptomatic Stenotic Artery

View this table: [in this window] [in a new window]   TABLE 1. Continued

View this table: [in this window] [in a new window]   TABLE 2. Univariate Associations of Baseline Characteristics With Stroke in the Territory of the Symptomatic Stenotic Artery

View larger version (17K): [in this window] [in a new window]   Product-limit estimate of the cumulative probability of an ischemic stroke in the territory of the stenotic artery vs years after randomization, according to percent stenosis (70% stenosis shown as solid line, <70% stenosis as dashed line); log-rank test P<0.0010.

In the primary multivariable model, severe stenosis 70% resulted in a significantly higher subsequent risk of stroke in the territory of a symptomatic intracranial stenotic artery than stenosis <70% (HR 2.03; 95% confidence interval [CI] 1.29 to 3.22; P=0.0025). Risk increased linearly (P for trend=0.0026) with greater percent stenosis but may have declined when stenosis was 90% to 99% (Table 3). Furthermore, risk was significantly greater for patients enrolled 17 days after the qualifying event (HR 1.69; 95% CI 1.06 to 2.72; P=0.028). Type of qualifying event (stroke or TIA) was not statistically associated with risk of stroke in the territory of the symptomatic stenosis (HR 1.50; 95% CI 0.90 to 2.49; P=0.12). However, when we stratified the qualifying event according to severity of stenosis, we observed a low rate of stroke in patients with initial TIA and stenosis <70% and a very high rate of stroke in patients with initial stroke and stenosis 70% (Table 4), but there was no statistical evidence of interaction (P=0.11). There was also no interaction between type of qualifying event and time from qualifying event to enrollment (P=0.46). Among the 342 patients whose qualifying event was stroke, lacunar versus nonlacunar type had no impact (P=0.20). Location of stenosis (posterior versus anterior circulation) was not associated with risk (HR 1.05; 95% CI 0.66 to 1.68; P=0.97) nor was treatment with antithrombotic medications at the time of the qualifying event (HR 1.06; 95% CI 0.66 to 1.69; P=0.83).

View this table: [in this window] [in a new window]   TABLE 3. Risk of Stroke in the Territory of the Stenotic Intracranial Artery According to Percent Stenosis

View this table: [in this window] [in a new window]   TABLE 4. Probability of Stroke in the Territory of the Symptomatic Stenotic Artery Related to Severity of Stenosis and Type of Qualifying Event

In the second multivariable model adjusted for age, sex, and race (Table 5), the hazard estimates of the 5 putative risk factors were not significantly altered, which suggests no major confounding by demographic characteristics. However, female gender was marginally associated with greater risk of stroke in the territory of the symptomatic artery (HR 1.59; 95% CI 1.00 to 2.55; P=0.051).

View this table: [in this window] [in a new window]   TABLE 5. Multivariable Model of Characteristics Hypothesized to Be Associated With Subsequent Risk of Stroke in the Territory of the Symptomatic Stenotic Artery, Adjusted for Age, Gender, and Race

Additional variables identified as possibly associated with stroke in the territory of an intracranial stenosis in univariate analysis were diabetes mellitus and the NIH Stroke Scale. When incorporated into the exploratory third multivariable model (Table 6), diabetes was no longer associated with risk (HR 1.18; 95% CI 0.74 to 1.90; P=0.49), but NIH Stroke Scale scores greater than the median score of 1 were associated with subsequent risk (HR 2.16; 95% CI 1.26 to 3.70; P=0.0051). The NIH Stroke Scale strongly correlated with the type of qualifying event (P<0.001), and its inclusion in the model completely negated the marginal trend associated with the type of qualifying event. The HRs and probability values for the other parameters of the second model were essentially unchanged by the inclusion of these 2 additional variables.

View this table: [in this window] [in a new window]   TABLE 6. Multivariable Model of Characteristics Hypothesized to Be Associated With Subsequent Risk of Stroke in the Territory of the Symptomatic Stenotic Artery, Adjusted for Age, Gender, and Race, Including Variables Statistically Significant in Univariate Analysis

To further evaluate the relationship between the type of qualifying event and NIH Stroke Scale, we compared subsequent risk between patients with single versus multiple ischemic events before randomization. Multiple prior events were not associated with a greater risk of stroke in the territory of the stenotic artery than was a single event (HR 1.31; 95% CI 0.828 to 2.06; P=0.25). All the above analyses were repeated with the exclusion of patients with centrally measured <50% stenosis (n=70) or complete occlusion (n=3), and no substantive changes in the primary results were observed.

	Discussion

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Patients with symptomatic intracranial stenosis are at high risk of subsequent stroke, predominantly in the territory of the stenotic artery. Despite the use of either warfarin or aspirin and vascular risk factor modification, the overall rates of stroke in the territory of the stenotic artery were 11% at 1 year and 14% at 2 years. Given the high risk of stroke in the territory of a symptomatic intracranial stenosis, alternative therapies are needed. In this regard, intracranial angioplasty and stenting have emerged as promising treatments for intracranial stenosis that are increasingly being used in clinical practice in the United States^17–20 and other countries.^21–25 However, these therapies have not been evaluated in a controlled clinical trial.

One recent uncontrolled multicenter phase I study, Stenting of Symptomatic atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA), with similar eligibility criteria to WASID, showed that the frequency of stroke in the territory of a stented intracranial artery was 7.2% at 30 days and 10.9% at 1 year.⁶ Two (4.7%) of 43 patients had strokes during the stenting procedure. Notably, the point estimates of the 1-year rates of stroke in WASID and SSYLVIA were virtually identical. Given the inherent risks of intracranial stenting, it is likely that the role, if any, for stenting will emerge from randomized controlled trials of patients at particularly high risk of stroke in the territory despite medical treatment.

In the present study, we identified risk factors associated with stroke in the territory of a stenotic intracranial artery. The major high-risk features were stenosis 70% to 99% and recent symptoms. The increased risk with severe stenosis validates the findings of the retrospective WASID pilot study and parallels the findings of symptomatic extracranial carotid artery stenosis trials.^13,14 Furthermore, risk increased linearly with percent stenosis, except perhaps among patients with stenosis 90% to 99%. This again parallels findings with severe extracranial carotid stenosis and may be related to low flow in the severely stenotic vessel with little potential for thromboembolism or the development of collateral blood supply.²⁶

Similarly, the association between recent symptoms and the risk of subsequent stroke in the territory of the stenotic artery has also been observed with extracranial carotid disease.¹⁴ It is possible that a time-selection bias existed in WASID, because some patients deemed to be at high risk of stroke may not have been enrolled early after the initial event to allow for a period of observation, and then were enrolled later after they were thought to be stable enough to participate in a randomized trial. This could have resulted in preferential inclusion of those subjects who remained stroke-free into the latter part of the enrollment period, and they may have represented a lower-risk population. However, this seems relatively unlikely, because the impact of timing was not confounded by the other characteristic most robustly tied to subsequent risk, namely, stenosis 70%. Although timing cannot be regarded as a factor that can discriminate among high- and low-risk patients during evaluation of the initial event, our observations suggest that potential intervention should be considered very soon after clinical presentation, unless early intervention also increases the short-term risk.²⁷ In contrast, if a patient presents for evaluation relatively late after the initial symptom, without intercurrent events, then perhaps a more conservative approach is warranted.

Although the qualifying event type was not a statistically independent predictor of recurrent stroke in the territory of the stenotic artery, patients with stroke and 70% to 99% stenosis seemed to be at particularly high risk, whereas patients with TIA and 50% to 69% stenosis were at low risk. Other studies of patients with symptomatic extracranial carotid stenosis have suggested that initial stroke carries a higher risk of subsequent stroke than TIA,^13,14 although other studies of patients with medically treated carotid stenosis²⁸ and those with undefined vascular pathology^29,30 suggested that TIA could pose greater risk than stroke.

Our empiric finding of an independent association of the baseline NIH Stroke Scale score with increased risk of subsequent stroke suggests that patients with stroke-related deficits are more prone to subsequent stroke than patients presenting with TIA or stroke without residual deficits, although the reason for this is unclear. We suggest caution in the interpretation of the NIH Stroke Scale impact because it was not a prespecified variable, it can be influenced by preexisting and nonstroke factors (such as cognitive deficits or arthritis), and it may be insensitive to brain stem findings that are common in patients with vertebrobasilar stenosis, the circulation involved in nearly half of the patients in the present study.

The trend toward greater risk in women is an interesting finding that is not readily explained.³¹ In some studies of extracranial carotid stenosis, women had a lower risk of stroke than men and reaped a smaller benefit from intervention.¹⁴ This remains controversial, and potential explanations for the gender gap with extracranial disease include differential arterial anatomy,³² body size and habitus,³³ and hormonal factors, although considerable uncertainty remains. Women may also have smaller intracranial arteries, which could pose greater risk, as has been suggested in studies of patients with coronary or femoral artery disease in which smaller body size and smaller arteries were associated with greater risk of vascular events.^34,35 Further research is needed to determine why women with intracranial disease appear to be at greater risk than men.

Numerous other factors including age, race, location of stenosis, length of stenosis, antithrombotic agent at time of qualifying event, vascular risk factors, prior cerebrovascular events, comorbidities, and treatment assignment were considered, but none of these had a large impact on the risk of stroke in the territory of the stenotic artery. Of note, patients with intracranial stenosis of the vertebral and basilar arteries were not at higher risk of stroke in the territory than those with stenosis of the internal carotid or middle cerebral artery, which contradicts findings of previous retrospective studies.^8,10,11 Additionally, patients who had their qualifying event while they were undergoing antithrombotic therapy had virtually the same rate of stroke in the territory as patients who were not taking antithrombotic therapy at the time of their qualifying event. This finding is also in contrast with the results of a previous retrospective study that suggested that patients taking antithrombotic medications at the time of presentation were at substantially higher risk of recurrent stroke.¹²

Potential limitations of the present analysis are related primarily to statistical power and generalizability. We had enough power to detect relatively large effects of baseline characteristics on subsequent risk of stroke in the territory of the stenotic intracranial artery, but smaller effects such as those potentially related to the type of qualifying event and interactions among variables may not have been statistically evident. Furthermore, randomized clinical trials such as WASID may have limited generalizability, because patients were carefully selected for enrollment according to strict eligibility criteria. It is therefore possible that some patients may have been systematically excluded from the trial who had different clinical courses. This seems unlikely to be a major drawback, because WASID was the largest study of symptomatic intracranial stenosis to date and included patients with a wide variety of baseline characteristics. Ultimately, randomized trials still provide the best evidence for establishing clinical practice recommendations.

The results of the present study have important implications for clinical practice and for future research. Given the high risk of stroke in patients who were randomized soon after their qualifying events, early identification of intracranial stenosis is important for prognosis and possible intervention. Patients with 70% to 99% stenosis and recent symptoms are at particularly high risk of stroke and should constitute the target group for a future randomized trial comparing stenting with medical therapy. Conversely, some patients face a relatively low risk of stroke in the territory of the stenotic artery, and the exclusion of such patients from trials of intracranial stenting may be justified because the upfront risk of this procedure may exceed any potential subsequent benefit. Women may also represent a high-risk group that should be aggressively recruited to participate in intracranial stenting trials.

	Acknowledgments

 
This study was funded by a research grant (1R01 NS36643, Principal Investigator: Dr Chimowitz) from the US Public Health Service, NINDS. In addition, the following General Clinical Research centers, funded by the NIH, provided local support for the evaluation of patients in the trial: Emory University (M01 RR00039), Case Western University, MetroHealth Medical Center (5M01 RR00080), San Francisco General Hospital (M01 RR00083-42), Johns Hopkins University School of Medicine (M01 RR000052), Indiana University School of Medicine (5M01 RR000750-32), Cedars-Sinai Hospital (M01 RR00425), and the University of Maryland (M01 RR165001). Bristol-Myers-Squibb (after incorporating DuPont Pharma) supplied the warfarin (Coumadin) and placebo warfarin tablets, and Bayer supplied the aspirin and placebo aspirin tablets for the trial. Neither of these companies supplied direct funding for the trial. The Food and Drug Administration assigned an IND number of 57,138 for Coumadin (warfarin sodium) for this trial.

Disclosures

Dr Kasner reports having received grant support from NINDS and Boehringer Ingelheim, consulting fees from Boehringer Ingelheim and the Sankyo/Lilly Partnership, and lecture fees from Boehringer Ingelheim and Bristol-Myers Squibb; all corporate affiliations are with companies that make antithrombotic agents not evaluated in this study. Dr Chimowitz is the recipient of research grants (R01 NS36643 and R01 NS051688) from the US Public Health Service NINDS to fund this trial. He is also supported by grant 1 K24 NS050307 from the NIH/NINDS and reports being paid fees by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Astra-Zeneca, and the Sankyo/Lilly Partnership for consulting on antithrombotic agents that were not evaluated in this trial, and from Guidant Corporation and Cine-Med for consulting on medical devices not evaluated in this trial. M.J. Lynn reports receiving grant support from NINDS and the National Eye Institute (grant U10EY013287). Dr Stern reports receiving grant support from NINDS and has been paid fees by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Dr Hertzberg reports receiving grant support from NINDS. Dr Frankel reports receiving grant support from NINDS and the Centers for Disease Control and Prevention and has been paid lecture fees by Boehringer Ingelheim and Sanofi Pharmaceuticals, makers of antithrombotic agents not evaluated in this trial. Dr Levine reports receiving grant support from NINDS (grant K24NS43392), Ono Pharmaceuticals, and the Gaisman Frontiers of Biomedical Research; he also has received fees from AstraZeneca and lecture fees from Boehringer Ingelheim and Inspire for consulting on issues unrelated to this study. Dr Chaturvedi reports receiving grant support from Boehringer Ingelheim and has been paid lecture fees by Bristol-Myers Squibb, Sanofi Pharmaceuticals and Boehringer Ingelheim. Dr Sila reports receiving grant support from NINDS for participating in various multicenter stroke trials and has been paid lecture fees by Bristol-Myers Squibb. Dr Romano reports receiving grant support from the American Heart Association and has been paid lecture fees by Bristol-Myers Squibb and Boehringer Ingelheim. The other authors report no conflicts.

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CLINICAL PERSPECTIVE

Antithrombotic therapy for intracranial arterial stenosis was evaluated recently in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial, which showed that warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin for preventing stroke and vascular death. Importantly, the risk of future stroke in the territory of the stenotic intracranial artery was 14% at 2 years with either antithrombotic therapy. This prompts the question whether new treatment modalities such as intracranial angioplasty and stenting should become first-line therapies for this disease. In this regard, a prespecified aim of WASID, described in the current report, 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. The risk of subsequent stroke in the territory of the stenotic artery was highest with severe stenosis 70% and in patients enrolled early (17 days) after an initial transient ischemic attack or ischemic stroke. Women also appeared to be at increased risk. Variables previously believed to be associated with greater risk, including vertebrobasilar stenosis, type of qualifying event, and prior use of antithrombotic medications, had no significant impact in this study. Future trials of intracranial angioplasty and stenting should target recently symptomatic patients with severe stenosis 70%, and women should be actively recruited to participate.

	Footnotes

 
*For a list of the WASID Investigators, see the Appendix in the online-only Data Supplement, available at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.105.578229/DC1.

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