Racial Differences in Vascular Risk Factors and Outcomes of Patients With Intracranial Atherosclerotic Arterial Stenosis
Background and Purpose— Atherosclerotic intracranial stenosis is an important cause of stroke in blacks, yet there are limited data on vascular risk factors and outcome. We analyzed the vascular risk factors and outcomes of blacks and whites in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial.
Methods— Baseline characteristics and outcomes (ischemic stroke, brain hemorrhage, or vascular death combined and ischemic stroke alone) were compared between blacks (n=174) and whites (n=331) using univariate and multivariate analyses.
Results— Blacks were significantly (P<0.05) more likely than whites to be/have: female, hypertension history, diabetes history, higher LDL, higher total cholesterol, lower triglycerides, unmarried, unemployed, nonprivate insurance, no insurance, stroke as qualifying event, <70% stenosis, symptomatic anterior circulation vessel, no antithrombotic medication before qualifying event, and no family history of myocardial infarction. Blacks more frequently reached an end point of ischemic stroke, brain hemorrhage or vascular death (28% versus 20%; hazard ratio of 1.49, 95% CI 1.03 to 2.17, P=0.03), had a higher 2-year event rate (0.28 versus 0.19), and reached the end point of ischemic stroke alone (25% versus 16% at 2 years; hazard ratio of 1.62, P=0.017). In multivariate analysis, race was associated with ischemic stroke (P=0.0488) but not with the end point ischemic stroke, brain hemorrhage or vascular death (P=0.188).
Conclusions— Blacks with intracranial stenosis are at higher risk of stroke recurrence than whites. This risk warrants additional study of factors contributing to stroke in blacks and highlights the need for aggressive risk factor management in blacks to prevent recurrence.
Intracranial atherosclerosis results in nearly 10% of ischemic strokes in the United States and disproportionately affects blacks, Hispanics, and Asians.1–4 Intracranial stenosis is associated with multiple modifiable risk factors including smoking, hypertension, hyperlipidemia, and diabetes. A few prospective studies have evaluated these risk factors in patients with intracranial stenosis and found that blacks were more often than whites to be hypertensive, smokers, or diabetic. However, there are limited data on the outcome of blacks versus whites with intracranial stenosis.4,5
The Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial, which is the first large clinical trial in patients with intracranial arterial stenosis, provided a unique opportunity to study the presence and management of risk factors (at baseline and 1 year) and outcomes in different racial groups with intracranial stenosis.6
Materials and Methods
Study Design and Patient Eligibility
The design of the the WASID trial has been previously published.6–8 Briefly, WASID was a double-blind, multicenter trial that enrolled 569 participants from 59 North American sites (58 sites in the United States and 1 in Canada) from 1999 until 2003. Patients that were 40 years of age or older with angiographically proven symptomatic intracranial atherosclerotic stenosis (50% to 99%) of the carotid, middle cerebral, vertebral, or basilar artery were randomized to aspirin (1300 mg daily) or warfarin (international normalized ratio goal of 2.0 to 3.0). Only patients with a nondisabling stroke (modified Rankin Scale score of <3) or transient ischemic attack occurring within 90 days were eligible. Patients were excluded if they had a contraindication to aspirin or warfarin, tandem extracranial stenosis with 50% to 99% stenosis, source of cardiac embolism, required heparin, or comorbid condition with predicted survival of <5 years. Participants self-identified race and ethnicity and only the results of those identified as either non-Hispanic white or blacks are in this study.
Assessments and Follow-Up
At the time of enrollment, information regarding race/ethnicity (American Indian, Asian, black, Hispanic, white, or other), vascular risk factors, lifestyle, and medications was collected in a standardized format. Additional information included self-reported baseline medical history, age, family history, social factors, physical activity, employment, insurance type, smoking status and alcohol use. History of coronary artery disease was defined as having a history of myocardial infarction, angina, coronary angioplasty, or coronary artery bypass surgery. Values for lipid levels were obtained from the medical record if they had been measured within 90 days before trial enrollment. If this condition had not been met, measurements had to be taken within 48 hours of the qualifying event or between 6 weeks and 4 months after the qualifying event because cholesterol levels may fall after acute stroke. Blood pressure was obtained from the right arm while seated. History of hypertension was defined as a systolic blood pressure >150 mm Hg, or diastolic blood pressure >90 mm Hg, or use of antihypertensive medication. History of diabetes was defined as at least 2 fasting venous serum glucose levels >125 mg/dL, or oral hypoglycemic medication use, or insulin therapy.
To assess for potential occurrence of an end point, participants or family members were called monthly by the study coordinator and seen every 4 months by a neurologist blinded to the participant’s treatment group. During the course of the study, atherosclerosis risk factors were managed by the blinded neurologist and the patient’s primary care physician. Study physicians were provided with national guidelines for the management of hypertension, diabetes, and hyperlipidemia.9–11 Participating sites were provided with reminders regarding risk factor management and periodic updates of the guidelines.
All patients were to be followed to a common termination date or until the WASID primary end point of ischemic stroke, brain hemorrhage, or death from a vascular cause other than stroke (myocardial infarction, pulmonary embolism, subdural or subarachnoid hemorrhage, limb or organ ischemia, or major systemic hemorrhage) was reached. Independent committees of neurologists and cardiologists, who were blinded to study group assignments, adjudicated all study end points. In this study, we evaluate the end points of: (1) ischemic stroke, brain hemorrhage or vascular death; (2) ischemic stroke alone; or (3) stroke in the territory of the enrollment vessel.
Differences in demographic, vascular risk factors, medical history, family history, social and employment factors, stroke and angiographic characteristics, and outcomes were compared between blacks and whites. We examined these factors using a χ2 test to compare percentages for categorical variables and an independent groups t test to compare means of continuous variables. The Kaplan-Meier method was used to estimate cumulative outcome probabilities which were compared between groups using the log-rank test. P≤0.05 was considered statistically significant. Cox proportional hazards models were used to assess multivariate significance. Four consecutively nested hierarchical regression analyses were used to assess the hazards ratio of race (calculated as blacks relative to whites) for ischemic stroke and for the combined end point of stroke, brain hemorrhage or vascular death. Model 1 included race only. Model 2 included known risk factors for stroke and atherosclerosis: age; gender; or history of hypertension, lipid disorder, diabetes, and smoking. Model 3 included factors from Model 2 and factors that were significantly different in the univariate analysis of race verses sociodemographic and baseline characteristics: marital status, alcohol use, physical activity, education level, private insurance, unemployment status, antithrombotic medication use at qualifying event, and qualifying-event characteristics (transient ischemic attack or stroke, anterior versus posterior circulation event, National Institutes of Health Stroke Scale score). (Lipid values were not used in this model because 15% of the participants did not have lipids checked at the time of enrollment.) Model 4 included all elements from Model 3 and factors that were significantly associated with stroke in WASID: severity of stenosis and time from qualifying event to enrollment.12 Statistical significance was set at an α level of 0.05. Analyses were performed using SAS version 8.2 (SAS Institute).
Of the 569 randomized patients, 174 were self-identified as black and 331 were self-identified as white. There was no significant difference in randomization to warfarin or aspirin between blacks and whites: 52% of blacks and 51% of whites were randomized to warfarin. A comparison of sociodemographic and baseline characteristics between blacks and whites is shown in Table 1. We found that on average blacks were younger than whites and more likely to be female. Blacks were more likely to be unmarried and have fewer years of formal education. Blacks and whites also had significant differences in employment, with the major differences being that blacks were less likely to have full-time employment and more likely to be unemployed. Regarding insurance status, the black-white differences were most notable in that blacks were more likely to have Medicare/Medicaid as well as no insurance whereas a lower percentage of blacks had private insurance.
In Table 2, lifestyle, comorbid conditions, and family history of stroke and myocardial infarction are analyzed by race. We found that blacks were more likely to not drink alcohol and were more likely to have a sedentary lifestyle than whites. Blacks were more likely to have higher measured HDL, higher LDL, total cholesterol, and lower triglycerides. Blacks were more likely to have a history of hypertension than whites; however, measured mean blood pressures were not statistically different at the time of enrollment between the 2 groups. Blacks were significantly more likely to have a history of diabetes. Even though blacks were equally likely to have a family history of stroke as whites, they were less likely to have a family history of myocardial infarction.
Regarding stroke and vessel characteristics (Table 3), blacks were less likely than whites to take an antithrombotic agent at the time of the qualifying event, were more likely than whites to have had a stroke rather than a transient ischemic attack, more likely to have the symptomatic vessel in the anterior circulation than whites. The degree of stenosis of the symptomatic vessel was less likely to be 70% to 99% in blacks than in whites.
QE indicates qualifying event; TIA, transient ischemic attack; NIHSS, National Institutes of Health Stroke Scale.
Univariate analysis revealed that blacks were significantly more likely to have an ischemic stroke, brain hemorrhage or vascular death (hazard ratio 1.49, P=0.034) or ischemic stroke alone than whites, (hazard ratio 1.62, P=0.017), respectively (Table 4). When stroke in the territory of the entry vessel was evaluated, there was no difference between blacks and whites (hazard ratio 1.30, P=0.282). The difference between blacks and whites increased as the length of time from enrollment increased, with blacks having a higher event rate for ischemic stroke, brain hemorrhage, or vascular death as well as ischemic stroke alone than whites at 2 year follow-up; 28% of blacks versus 19% of whites had an ischemic stroke, brain hemorrhage or vascular death at 2 years whereas 25% of blacks and 15% of whites had an ischemic stroke alone (Table 4 and the Figure).
We noted in the univariate analyses that although blacks were less likely than whites to have 70% to 99% stenosis, their risk of both end points was higher (Tables 3 and 4⇑). The effect of race on the risk of the 2 end points was investigated when stratified by degree of stenosis (Table 5). In those patients with <70% stenosis, there were no differences in blacks versus whites for ischemic stroke alone (P=0.241), ischemic stroke in the territory of enrollment vessel (P=0.416), or for ischemic stroke, brain hemorrhage or vascular death (P=0.286). However, in those patients with ≥70% stenosis, blacks had a greater risk than whites for both ischemic stroke alone (P=0.0028) and for ischemic stroke, brain hemorrhage or vascular death (P=0.0066), but not for stroke in the territory of enrollment vessel (P=0.147). Although the stratified analysis showed that race had a different effect in the group with <70% stenosis than the group with ≥70% stenosis, in a proportional hazards model with the factors race, percent stenosis and the interaction, we found the interaction was not statistically significant for ischemic stroke alone (P=0.1726) or for ischemic stroke, brain hemorrhage or vascular death (P=0.1925).
We also found that risk-factor control results were not different between blacks and whites at 1 year. Specifically, there was no difference between blacks and whites in blood pressure ≥140/90 (P=0.6866), active smoking (P=0.1188), or cholesterol >200 (P=0.1483). Additionally, both blacks and whites were equally compliant with the assigned antithrombotic therapy in the trial as measured by permanent withdrawal of antithrombotic therapy: 20.7% of blacks had permanent withdrawal versus 22.4% of whites (P=0.6663).
To further investigate the role of the significant factors identified in this analysis as well as those associated with atherosclerosis and stroke outcome from the literature, we estimated the effect of race on outcome when adjusted for other factors in consecutively nested hierarchical regression models (Table 6). These models showed that being black increased the likelihood of having a recurrent ischemic stroke as compared to whites by 1.62 times when adjusting for the variables in models 2 to 4, which was statistically significant (P=0.0488). This is not true for the combined end point of ischemic stroke, brain hemorrhage or vascular death, which was the primary end point for WASID in which the risk of being black versus white was 1.35 after adjusting for the variables in models 2 to 4, which was not significant (P=0.185). Even though the unadjusted risk of being black versus white was 1.49 (P=0.043), this significance was diminished after adjusting for the variables in model 2 and remained nonsignificant with additional variables in models 3 to 4.
We found that blacks are significantly more likely than whites to reach the end point of ischemic stroke, brain hemorrhage or vascular death as well as the end point of ischemic stroke in our univariate analysis. In addition, adjusted results from the multivariate analysis showed that race was an independent contributing predictor of ischemic stroke but not the end point of ischemic stroke, brain hemorrhage or vascular death (P=0.185). As well, our data indicated that there are marked disparities in the frequency of major stroke risk factors in blacks as compared to whites with symptomatic intracranial stenosis that may contribute to the observed differences in end point and outcome. Given these data, aggressive risk-factor management and strategies to overcome the social factors influencing health care in the black population is of utmost importance in preventing secondary events.
Racial differences in stroke incidence and outcome have undergone recent scrutiny in epidemiological studies with blacks being observed to have both an increased incidence and mortality from stroke as well as stroke occurrence at an earlier age.13–15 Several prospective epidemiological studies include whites with relatively little contribution to the cohort size by minority populations. However, studies that have included at least a biethnic population were restricted by imaging or stroke classification schemes to confirm intracranial stenosis.16 Our study overcomes both of these obstacles by capitalizing on the enrollment of a biethnic population as well as use of angiography to accurately discern the presence and degree of intracranial stenosis. Blacks and whites represent the vast majority of participants enrolled in our multicenter trial with 89% of them self-described as either white or black; of these, 34% were black. The present study demonstrates the clear differences in vascular risk factors and outcomes between blacks and whites with intracranial stenosis.
Our most striking finding is that race is an independent contributor to outcome in intracranial stenosis. Factors contributing to these racial differences in intracranial atherosclerosis and outcome may be broad in spectrum and include complex interactions between genetic, biological and social variables when compared to whites. The role of genetic background of blacks, novel genetic variants, or genetic susceptibility compared to whites and its contribution to stroke, atherosclerosis, as well as the risk factors associated with atherosclerosis are largely unknown and are beyond the scope of this article. However, we are able to analyze several biological and social factors that have been shown to be associated with atherosclerosis and stroke risk.
Biological factors such as hypertension, increased LDL, smoking, and diabetes have been shown to be critical to the development of atherosclerosis and stroke. We found that blacks had significantly higher rates of history of hypertension, history of diabetes and increased measured LDL. Even though there was no significant difference in smoking habits between blacks and whites when considering no use and any use, blacks were more likely to smoke at the time of enrollment. The paucity of data regarding intracranial stenosis does not allow us to compare our population to other major intracranial stenosis populations. However, when compared to other epidemiological stroke studies there are striking similarities.17–21 In the Northern Manhattan Stroke Study, the prevalence of hypertension and diabetes were found to be higher in blacks than in whites.17 Analysis of the WASID data previously showed that hypertension and hyperlipidemia were associated with an increased risk of stroke or other vascular events.22
Social and environmental conditions also contribute to the development of stroke directly and through complex interactions with biological factors. Through behaviors that may be based on cultural norms, economic and educational opportunities which are tied to employment and insurance, social conditions can influence outcome. Several studies have shown that the risk factors for atherosclerosis are inversely related to socioeconomic status (SES).23,24 In our study, blacks were more likely to have less formal education and nonprivate health insurance. SES may contribute to outcome, risk-factor development, and risk-factor management through several mechanisms including access to care, prescription choices, dietary choices, and healthcare delivery biases. The role of SES has been demonstrated to impact mortality and some health services in the timing of delivery of care.23,24 Another mechanism may be the failure to reach low-income communities through public health education campaigns or the failure of low-income people to adopt the recommendations of existing campaigns.
Another intriguing finding is that the suggestion that the difference in outcome between blacks and whites depends on the degree of stenosis. An analysis of risk factors for ischemic stroke in the territory of the entry vessel12 among WASID patients identified high-grade stenosis as a significant predictor. Because of the lack of data in intracranial stenosis, we compared our finding to that of a symptomatic extracranial stenosis trial. In the North American Symptomatic Carotid Endarterectomy Trial, patients with a higher degree of stenosis were at greatest risk of stroke recurrence with medical treatment alone.25 In the current study, in univariate analyses, blacks as a group were more likely to have recurrent events despite a lower degree of stenosis at study entry. However, in stratified analyses, we found that although outcome did not differ between blacks and whites with <70% stenosis, blacks with stenosis ≥70% had higher risk of both ischemic stroke and the combination of ischemic stroke, brain hemorrhage or vascular death.
There are several limitations to this analysis. Our study relied on the self-report of comorbid conditions, risk factors, family history of disease, and report of SES factors for which there are biases including under-reporting bias. Even though our sample size and study design do not allow us to further explore the complex interplay of biological differences (such as endothelial function, vascular stiffness, inflammation, genetics) and social factors, this study does provide evidence that novel mechanisms that are associated with race may be important and should be further studied. Our analysis does provide compelling information regarding the racial differences in risk-factor occurrence and racial differences in outcome and highlights the importance of inclusion of minority populations in clinical trials. As well, implications of our study highlight the need for clinical trials to address both risk factors and SES limitations in clinical trial. Predetermined strategies may be required in trials to ensure optimal medical treatment and management of stroke and atherosclerosis risk factors. Results from our analysis illustrate the need to design future studies that incorporate genetic, biological, and social factors.
Sources of Funding
The study was supported by the 1R01 NS36643 grant to Dr Chimowitz from the US Public Health Service, National Institute of Neurological Disorders and Stroke (NINDS). In addition, the following General Clinical Research centers, funded by the National Institutes of Health, provided local support for the evaluation of patients in the trial: Emory University (M01 RR00039), Case Western University, Metro-Health Medical Center (5M01 RR00080), San Francisco General Hospital (M01 RR00083-42), Johns Hopkins University School of Medicine (M01 RR00052), Indiana University School of Medicine (5M01 RR000750-32), Cedars-Sinai Hospital (M01 RR00425), and the University of Maryland (M01 RR165001).
Dr Chaturvedi reports being paid fees by Pfizer. Dr Chimowitz 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 Corp for consulting on a medical device (an intracranial stent) that was not evaluated in WASID. The remaining authors report no conflicts.
- Received May 21, 2008.
- Revision received July 24, 2008.
- Accepted July 31, 2008.
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