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Circulation. 2007;116:2157-2164
Published online before print October 22, 2007, doi: 10.1161/CIRCULATIONAHA.107.699785
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(Circulation. 2007;116:2157-2164.)
© 2007 American Heart Association, Inc.


Stroke

Differences in Stroke Subtypes Between Black and White Patients With Stroke

The South London Ethnicity and Stroke Study

Hugh S. Markus, FRCP; Usman Khan, MRCP; Jonathan Birns, MRCP; Andrew Evans, MRCP; Lalit Kalra, FRCP; Anthony G. Rudd, FRCP; Charles D.A. Wolfe, FRCP; Paula Jerrard-Dunne, MRCP

From the Centre for Clinical Neuroscience, St George’s University of London (H.S.M., U.K., P.J.-D.); Departments of Stroke Medicine and Health and Social Care Research, Kings College London (J.B., A.E., L.K.); and Guy’s and St Thomas’ NHS Foundation Trust (A.G.R., C.D.A.W.), London, UK.

Correspondence to Professor Hugh Markus, Centre for Clinical Neuroscience, St George’s University of London, London, SW17 ORE, UK. E-mail hmarkus{at}sgul.ac.uk

Received February 28, 2007; accepted August 28, 2007.


*    Abstract
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Background— Determining whether the distribution of stroke subtypes differs between ethnic groups is important in understanding the mechanisms of the increased stroke incidence in black patients.

Methods and Results— In this study, 600 black and 600 white patients with stroke were prospectively and consecutively recruited to determine differences in stroke subtypes. The pathophysiological Trial of Org 10172 (TOAST) classification was used and compared with a clinical (Oxfordshire Community Stroke Project) subtype classification. Stroke subtypes were determined by one investigator by review of original imaging. Black patients with stroke were significantly younger and had higher prevalences of hypertension, diabetes, and obesity. They were less likely to be smokers and had lower prevalences of myocardial infarction and atrial fibrillation. In the black patients, 33% of stroke was due to cerebral small vessel disease compared with 14% in the white stroke cohort (odds ratio, 2.94; 95% confidence interval, 1.97 to 4.39; P<0.001, controlling for age, gender, cardiovascular risk factors, and social class). The black stroke cohort had less large vessel atherosclerosis (odds ratio, 0.49; 95% confidence interval, 0.29 to 0.82; P=0.007) and cardioembolic disease (odds ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P=0.002). Using a classification based on clinical syndrome alone gave a higher estimate of the frequency of small vessel disease stroke, particularly in white patients.

Conclusions— A relative excess of small vessel disease was observed in black patients with stroke compared with an excess of extracranial atherosclerosis and cardioembolic stroke in white patients with stroke that was independent of conventional risk factors and social class. Whether these excesses are due to differences in genetic susceptibility or as-yet undetermined differences in environmental risk remains to be determined.


Key Words: cerebral infarction • epidemiology • ethnicity • lacunar stroke • risk factors • stroke


*    Introduction
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Stroke mortality is increased among black compared with white patients. Population-based studies suggest that this excess mortality is due to an increased stroke incidence.1,2 Age-adjusted stroke incidence has been estimated to be 2.2 and 2.4 times higher in UK and US black patients, respectively, compared with the white population.3,4 A number of explanations for this excess incidence have been reported. Risk factor profiles differ between the ethnic groups, with hypertension, diabetes, and, in some studies, smoking and obesity occurring more frequently in black populations.5–7 Socioeconomic differences appear to account for some of the increased risk but do not explain all of it.8 Differing genetic susceptibility, particularly to hypertension and its effects on the cerebral vasculature, has been suggested.9

Editorial p 2099

Clinical Perspective p 2164

Stroke represents a heterogeneous syndrome caused by a number of different underlying pathologies. Different subtypes may have differing disease mechanisms and risk factor profiles. Few studies have compared the distribution of stroke subtypes between black and white patients with stroke. The available data suggest a higher proportion of lacunar (small vessel disease [SVD]) stroke and intracranial atherosclerosis in black patients, although not all studies have replicated these differences.10–14 Previous studies have had a number of limitations. The number of black patients with stroke in these studies has been small, <200 in all studies. Some studies10,13 have used a clinical classification (the Oxfordshire Community Stroke Project [OCSP] classification15) to derive information on subtypes. This system is less accurate and provides less pathophysiological information than classification systems based on investigation results.16 Investigation rates, particularly to exclude large artery disease, often have been insufficient to allow accurate subtyping.

Determining whether the distribution of stroke subtypes differs between the ethnic groups and whether this difference is explained by conventional risk factors is important in understanding the mechanisms underlying the increased stroke incidence in black patients. We therefore carried out a prospective study of 600 black patients with stroke and compared them with 600 consecutively recruited white patients with stroke to determine differences in subtype, with both groups of patients undergoing extensive investigation to allow accurate subtyping.


*    Methods
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Study Population
The South London Ethnicity and Stroke Study (SLESS) is a prospective study begun in 1999 that has recruited consecutive black patients with stroke from a contiguous catchment area covered by 3 hospitals in South London (Guy’s and St Thomas’ Hospitals, King’s College Hospital, and St George’s Hospital). All hospitals have a specialized stroke unit and a rapid-access outpatient transient ischemic attack clinic, and patients are recruited from both of these sources. In addition, the prospective community-based South London Stroke Register3 is nested within the catchment area, and patients were identified from this register. Here, we present an analysis of the first 600 black patients with stroke recruited to SLESS between 1999 and 2005. All strokes presenting during this period, including recurrent strokes, were included. Consecutive recruitment of 600 white patients with stroke also was carried out from the same 3 centers over specified periods. All patients underwent standardized clinical assessment. Demographic data were collected, and all patients had brain imaging (computed tomography, 65.4%; magnetic resonance imaging, 8.3%; both computed tomography and magnetic resonance imaging, 26.3%). Imaging of the extracranial cerebral vessels was performed in 97% of ischemic patients with stroke. Echocardiography was performed when clinically indicated (56.7%). Its use was determined by the attending physician, but it was recommended in young patients with stroke (<60 years) and in patients in whom there were cardiac abnormalities on examination or ECG, cerebral infarcts in multiple cerebral artery territories, or no obvious other cause of stroke. Intracranial imaging was performed in 134 of the black ischemic patients with stroke (magnetic resonance angiography, 93; computed tomographic angiography, 13; transcranial Doppler, 26; intra-arterial angiography, 1) and 81 white ischemic patients with stroke. The study protocol had ethics approval, and informed consent was obtained from all participants.

Risk Factors
Risk factor information and other clinical and investigation details were collected on a standardized proforma. Hypertension was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg persisting >7 days after the acute event (World Health Organization classification) or prestroke treatment with antihypertensive drugs.17 Diabetes mellitus was defined as a previous diagnosis of type I or II diabetes, at least 2 random glucose readings of ≥11.1 mmol/L, or fasting blood glucose readings of ≥7.0 mmol/L after the acute phase of stroke to exclude acute transient elevation of glucose as a stress response after stroke.18 Hypercholesterolemia was defined as serum cholesterol >5.2 mmol/L or prestroke treatment with a cholesterol-lowering agent.19 A history of myocardial infarction, peripheral vascular disease, and atrial fibrillation also was recorded from clinical history, notes review, and family doctor referral letter when available. Raised body mass index was defined as >27 kg/m2.

Ethnicity was defined according to the Census 2001 definition.20 The Registrar General’s Social Scale (1990) was used to define social class as an estimate of socioeconomic status.21

Stroke Subtyping
One investigator (H.M.) subtyped all patients using data that had been prospectively collected on a dedicated questionnaire, with additional review of all original brain imaging and original notes when necessary. Subtyping was not fully blinded to ethnicity because names were apparent on the brain imaging database system. The pathophysiological Trial of Org 10172 (TOAST) subtyping classification was used.22 To avoid any bias resulting from different rates of risk factors such as hypertension between the 2 groups, the presence of hypertension and diabetes was not used as a criterion in the diagnosis of SVD. SVD was defined as a clinical lacunar syndrome with a compatible lesion on magnetic resonance imaging or computed tomography. Exclusion criteria included subcortical infarction >15 mm diameter; cortical infarction of any size; carotid, vertebral, or intracranial artery stenosis >50%; and a potential cardiac source of embolism. Large vessel atherosclerotic disease was defined as carotid, vertebral, or major intracranial artery stenosis >50% in the arterial territory of the stroke. Cardioembolic stroke was defined on the basis of the presence of a potential source of cardiac embolism categorized as high or moderate risk according to the TOAST criteria. In infarction patients, if there was a cardioembolic source, the case was classified as cardioembolic even if the infarct was of lacunar type. When no cause of stroke was found, patients were assigned to an "unknown" category. When >1 potential stroke mechanisms were identified, patients were placed in a "tandem" category. Rare causes of stroke were designated "other." Primary intracerebral hemorrhage was defined as a separate category. Patients with primary subarachnoid hemorrhage were excluded. In patients with previous stroke, subtyping was performing on the current stroke. For an intracranial stenosis to be identified as the pathophysiological cause of the stroke, the stenosis had to be in the arterial territory of the stroke. However, we also looked at the prevalence of intracranial stenosis in any intracranial vessel; therefore, a separate analysis of the prevalence of intracranial stenosis (>50%) in any intracranial vessel, whether symptomatic or not, was performed.

To estimate the differing effects of using a pathophysiological (TOAST) versus a stroke subtype classification based purely on clinical syndrome, we used the OCSP15 to classify all patients into total anterior circulation stroke, partial anterior circulation stroke, lacunar stroke, and posterior circulation stroke.

Case Ascertainment
In the present study, 90.7% (544) of the black stroke cohort were recruited via hospital admission, and 9.3% (56) were recruited from the community or outpatient facilities. Part of our catchment area is covered by the South London Stroke Register, an ongoing population-based register that enrolls first-ever strokes through notification from hospital inpatient and outpatient facilities and community sources.3 Over the time period of our study, a similar proportion of black patients with stroke (89.6%) were entered into the South London Stroke Register through hospital admission and 10.4% through outpatient and community facilities. This suggests a very high level of case ascertainment of strokes within the community. Over the time period of our study, 87.4% of white patients with stroke were entered into the South London Stroke Register through inpatient facilities and 12.6% from outpatient and community sources. This suggests minimal case ascertainment bias in the study population.

Statistical Analysis
All statistical tests were performed with SPSS version 14 (SPSS Inc, Chicago, Ill). Single-variable and multivariable logistic regression analyses were used to calculate odds ratios (ORs), 95% confidence intervals (CIs), and probability values. Age, gender, hypertension, diabetes, hypercholesterolemia, smoking, raised body mass index, and socioeconomic status were controlled for in multivariable analysis. In view of the many comparisons made, a significance level of P=0.01 was used throughout the analysis. Sample size calculations performed with clinstat (Martin Bland; http://www-users. york.ac.uk/{approx}mb55/soft/soft.htm) showed that a sample size of 600 in each group would allow an increase in SVD from 15% in white patients with stroke to 23.7% in black patients with stroke with P=0.01 and power of 0.9.

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.


*    Results
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Subject Characteristics and Risk Factor Differences Between Black and White Patients With Strokes
Demographics and risk factor profiles in black and white patients with stroke are shown in Table 1. Of the 600 black patients, 502 (83.7%) presented with their first stroke, and 98 presented with a recurrent stroke, having had a previous stroke before the recruitment period or when living outside the catchment area. Black patients with stroke were significantly younger. On age-adjusted analysis, they had higher prevalences of hypertension, diabetes, and raised body mass index compared with white patients with stroke. Black patients with stroke were less likely to be smokers and had lower prevalences of previous myocardial infarction, peripheral vascular disease, and atrial fibrillation compared with white patients with stroke. After multivariable analysis, the significant differences in age, hypertension, diabetes, smoking, myocardial infarction, and atrial fibrillation persisted. Among hypertensive patients, there was a trend toward more hypertensive agents before stroke onset in the black patients (use of >1 agent, 44.6% versus 38.1%; OR, 1.30; 95% CI, 0.98 to 1.76; P=0.07). There were significant differences in social class between the 2 groups (Table 1). We found that 8.4% of the black stroke cohort were in the skilled nonmanual category of the 1990 Registrar General’s Social Scale compared with 21.9% of the white stroke cohort (P<0.001, age adjusted).


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Table 1. Conventional Risk Factor Comparisons Between Black and White Stroke Populations: ORs for Each Risk Factor

Differences in Stroke Subtype Between Black and White Populations
A comparison of the prevalence of cardioembolic sources, large artery stenoses, and lacunar infarcts between the 2 groups is shown in Table 2. Cardioembolic sources and large artery stenosis were more common in white patients; lacunar infarcts were more common in black patients.


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Table 2. Differences in the Results of Cardiac, Large Vessel, and Brain Investigations Between Black and White Patients With Ischemic Stroke: ORs for Abnormal Findings

Differences in TOAST stroke subtype between the black and white cohorts are shown in Table 3. In black patients, 33.2% of stroke was due to cerebral SVD compared with 14.0% in the white stroke cohort. This difference was significant after controlling for age, gender, cardiovascular risk factors, and social class (OR, 2.94; 95% CI, 1.97 to 4.39; P<0.001). The black stroke cohort had significantly less large vessel atherosclerotic disease (OR, 0.49; 95% CI, 0.29 to 0.82; P=0.007) and cardioembolic disease (OR, 0.54; 95% CI, 0.37 to 0.80; P=0.002) compared with the white stroke cohort.


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Table 3. Differences in Stroke Subtype Between Black and White Populations Using the TOAST Classification: ORs for Each Subtype

Stroke classification using the OCSP clinical classification is shown in Table 4. Although lacunar stroke (SVD stroke) is still increased in black stroke patients, the OR is 1.94 (95% CI, 1.39 to 2.73; P<0.001) on multivariable analysis, less than that found with the TOAST classification. This difference was attributable largely to white patients who presented with a clinical lacunar syndrome but were subsequently found to have large vessel carotid disease.


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Table 4. Differences in OCSP Stroke Subtypes Between Black and White Patients With Stroke: ORs for Stroke Subtypes

Risk factor profiles for the different stroke subtypes in the 2 ethnic groups are shown in Table 5Down. All differences are after multivariable analysis controlling for age, gender, and cardiovascular risk factors. The most striking differences are increased hypertension and diabetes but reduced smoking in black compared with white patients with SVD.


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Table 5. Risk Factor Comparison Between Stroke Subtypes in Black and White Cohorts: ORs for Each Risk Factor


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Table 5. Continued

Risk Factor Differences Between Black African and Black Caribbean Strokes
Demographics and risk factor profiles in black African and black Caribbean patients are shown in Table 6. Black Caribbean patients were older and more likely to smoke compared with black African patients on both single-variable and multivariable analysis. Single-variable analysis demonstrated a significantly increased prevalence of diabetes and peripheral vascular disease in black Caribbean patients, which weakened after controlling for risk factors and social class.


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Table 6. Conventional Risk Factor Differences Comparison Between Black African and Black Caribbean Stroke Cohorts: ORs for Each Risk Factor

Differences in Stroke Subtype Between Black African and Black Caribbean Populations
Intracerebral hemorrhage was more common in the black African compared with black Caribbean patients with stroke both before and after controlling for age and gender (OR, 2.17; 95% CI, 1.29 to 3.68; P=0.004). This difference remained but was attenuated and no longer reached the 0.01 significance level after controlling for risk factors and social class (OR, 2.12; 95% CI, 1.04 to 4.33; P=0.039; Table 7Down).


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Table 7. Differences in Stroke Subtypes Between Black African, Black Caribbean, and White Cohorts


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Table 7. Continued

Intracranial Stenosis Between Black and White Stroke Cohorts
Intracranial stenosis was present in 24 of the 134 black patients with ischemic stroke (17.9%) in whom imaging was performed and 2 of 81 white patients with ischemic stroke (2.1%) (OR, 8.62; 95% CI, 1.99 to 37.53; P=0.004) and after adjustment for age, risk factors, and social class (OR, 9.68; 95% CI, 1.58 to 59.33; P=0.014).


*    Discussion
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*Discussion
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The present study shows clear differences in the distribution of stroke subtypes between black and white patients with stroke that are not fully explained by differences in conventional risk factors or socioeconomic status. SVD stroke was markedly more common in black patients, whereas large vessel disease stroke, predominantly extracranial, and cardioembolic stroke were more common in white patients. In those patients in whom intracranial imaging was performed, intracranial stenosis was more frequent in black compared with white patients.

The most striking finding is the increase in lacunar stroke in black patients with stroke. This has been reported in some but not all previous studies comparing stroke subtypes between the 2 ethnic groups.10–14 The pathogenesis of SVD is incompletely understood, but hypertension is the major risk factor. A small vessel arteriopathy affecting the perforating arteries occurs, and endothelial dysfunction has been implicated.23 In the present study, hypertension was significantly more common in the black subjects, but the difference in stroke subtypes persisted after hypertension and other risk factors were controlled for. It is also possible that increased severity of hypertension in the black patients could contribute to the increased risk of SVD. There was a suggestion that the severity of hypertension was greater in black patients, with a trend for an increased number of antihypertensive agents before stroke. However, the number of agents also will be influenced by the quality and use of health services, which may be influenced by factors such as socioeconomic status and education. It also has been proposed that there is an increased susceptibility of the small cerebral vessels to hypertensive damage in black individuals. A genetic basis of the latter has been suggested,9 and impaired endothelial function has been reported in black individuals without stroke.24

The differing distribution in atherosclerotic disease between the 2 populations was striking. Consistent with some but not all previous studies, we found that large artery disease was almost twice as common among white as black individuals. This finding is consistent with studies demonstrating that the carotid endarterectomy rate is lower in black individuals.25 In contrast to the excess of extracranial atherosclerotic disease in white patients, preliminary data from a subgroup demonstrated a marked excess of intracranial stenosis, presumably resulting from atherosclerosis, in black patients with stroke. These differences were not explained by differences in risk factor profiles, and the mechanisms remain uncertain.

Consistent with previous studies from the United Kingdom and the United States, we found marked differences in conventional risk factor profiles between black and white individuals.5–7 The black patients with stroke were {approx}8 years younger. After adjustment for age, gender, conventional risk factors, and socioeconomic status, hypertension and diabetes were {approx}3 times as common among black individuals. In contrast, smoking, myocardial infarction, and atrial fibrillation all were more common among white subjects. Socioeconomic differences have been suggested as an explanation for the excess stroke risk found among black patients, but the subtype differences in this study persisted after accounting for social class. These risk factor differences are certainly likely to contribute significantly to the approximate doubling of stroke risk reported in population-based studies from both our South London Stroke register and the United States2–4 but did not account for the differing distribution of stroke subtypes between the 2 populations.

All our black patients with stroke were first-generation migrants from either Africa or the West Indies. This is in contrast to US studies that included many black patients with stroke whose families have been living in the United States for generations. Most of our patients were black Caribbean, but almost 200 were black African. There were significant differences between the 2 cohorts in both risk factors and stroke subtypes. Black African patients with stroke were {approx}7 years younger, were more likely to be male, and had a lower incidence of smoking on multivariable analysis. They also were more likely to have intracerebral hemorrhage as a stroke subtype, although this difference was reduced when hypertension was controlled for. In contrast, intracerebral hemorrhage was no more frequent in black Caribbean stroke patients compared with the white control subjects. Some previous studies have found intracerebral hemorrhage to be more frequent in black compared with white patients with stroke. This might be expected because subcortical hemorrhage is believed to be caused often by a small vessel arteriopathy secondary to hypertension by a mechanism similar to that causing ischemic SVD. However, despite finding a marked excess of ischemic SVD in the black patients with stroke as a whole, we found no overall difference in intracerebral hemorrhage rates, although the frequency did appear to be increased in the smaller African subgroup.

Our study has a number of strengths. It is the largest study of well-phenotyped black patients with stroke. Previous studies have included <200 black patients.10–14 All patients were prospectively recruited, and all stroke subtyping was performed by the same individual by review of all original imaging. There was a high rate of investigation, with all patients having brain imaging and 97% having either carotid duplex or magnetic resonance angiography to image the extracranial vessels. This is important because recent studies have demonstrated that clinical lacunar syndromes can, not infrequently, be caused by large artery disease.26 We demonstrated this by classifying stroke not only by the TOAST system based on investigation results but also by subtyping based on clinical syndrome using the OCSP classification. The latter gave a higher estimate of the frequency of SVD stroke in white patients. It should be noted that we did not take into account imaging findings when applying this purely clinical classification; the use of these findings would be expected to include accuracy. The importance of using a method of stroke subtyping based on the results of investigations also is emphasized by a comparison between our results and those from a previous smaller study from the South London Stroke Register, which was nested within the SLESS. Here, with the OCSP, an increased incidence in all stroke subtypes was seen without the marked increase in small artery disease apparent in our study.10

Previous population-based studies have reported significantly higher rates of stroke of undetermined cause in black patients.12,14 These studies were limited by incomplete evaluation (carotid imaging was unavailable in 30% to 40% of subjects), and the results may have been attributable to a lack of uniformity of test use within the population. Extensive and uniform investigation of both study groups is an advantage of our study, in which the proportion of subjects with an unknown or undetermined cause of stroke was similar in both the black and white study groups.

A potential limitation of the present study is that it was not truly population based. However, the catchment areas of the 3 hospitals covered a contiguous defined area. Patients were recruited not only from hospital admissions but also from outpatient stroke services. The community-based South London Stroke Register is nested within the geographical catchment area of SLESS. This allowed us to determine the proportion of our black and white patients with stroke in the community who were admitted to hospital. Our proportion of both black and white patients admitted was very similar to that found in the South London Stroke Register population over the same period, suggesting at most a very small case ascertainment bias in our study population. A further limitation is that only 56% of patients received echocardiography. Our results on intracranial stenosis are interesting but preliminary because intracranial imaging was performed only in a subgroup of patients. There were no obvious differences between patients in whom it was and was not performed, specifically, in the OCSP subgroup or in the proportion with cortical versus subcortical infarcts. Nevertheless, we cannot exclude bias in the selection of subjects undergoing this imaging. Further studies are required in which intracranial imaging is performed in all subjects to assess its true importance in black patients with stroke. Subtyping was not blinded to ethnicity because original imaging and case notes were reviewed at the time of subtyping; however, a standard questionnaire was used, with prospectively collected data making any bias introduced here less likely.

There are important considerations in interpreting differences in disease between different ethnic groups.27 The assignment of ethnicity is not always reliable and can vary, depending on the definition and who applies it. In this study, we used self-report, which has been suggested to be the optimal method.27 Individuals of mixed ethnicity were not included. Although our results show differences between the 2 ethnic groups, ethnicity itself may be a risk marker rather than a risk factor. An important potential confounder is socioeconomic differences, although we controlled for them in all analyses.


*    Conclusions
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*Conclusions
down arrowReferences
 
In a prospective well-characterized stroke population, we found a relative excess of SVD in black patients with stroke compared with an excess of extracranial atherosclerosis and cardioembolic stroke in white patients with stroke. These differences were not fully explained by conventional risk factors or social class. Whether they are due to differences in genetic susceptibility or as-yet undetermined differences in environmental risk remains to be determined.


*    Acknowledgments
 
Source of Funding

This work was supported by a Stroke Association (UK) Programme Grant (PROG 3).

Disclosures

None.


*    References
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*References
 

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CLINICAL PERSPECTIVE

Stroke incidence in black populations in the United States and Europe is high, but the causes are incompletely understood. This large prospective study from London, UK, evaluated the spectrum of stroke subtypes in black compared with white patients with stroke. Small vessel disease (lacunar) stroke accounted for 33% of strokes in black patients compared with 14% of strokes in white patients. In contrast, extracranial large vessel disease stroke and cardioembolic stroke were twice as common in white patients compared with black patients with stroke. These differences may provide insights into etiologic differences in stroke incidence in black versus white patients and may be of relevance to the practicing clinician when investigating black patients with stroke.


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