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Stroke. 2007;38:2718-2725
Published online before print August 30, 2007, doi: 10.1161/STROKEAHA.107.487090
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(Stroke. 2007;38:2718.)
© 2007 American Heart Association, Inc.

Original Contributions

Risk Factors for Intracerebral Hemorrhage in a Pooled Prospective Study

Jared D. Sturgeon, PhD; Aaron R. Folsom, MD, MPH; W.T. Longstreth, Jr, MD, MPH; Eyal Shahar, MD, MPH; Wayne D. Rosamond, PhD Mary Cushman, MD, MSc

From the Division of Epidemiology & Community Health (J.D.S., A.R.F.), School of Public Health, University of Minnesota, Minneapolis; the Departments of Neurology and Epidemiology (W.T.L.), University of Washington, Seattle; the Division of Epidemiology and Biostatistics (E.S.), University of Arizona, Tucson; the Department of Epidemiology (W.D.R.), University of North Carolina, Chapel Hill; the Departments of Medicine and Pathology (M.C.), University of Vermont, Burlington.

Correspondence to Dr Aaron R. Folsom, Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, 1300 S Second Street, Suite 300, Minneapolis, MN 55454-1015. E-mail folsom{at}epi.umn.edu


*    Abstract
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Background and Purpose— Few prospective studies have reported risk factors for intracerebral hemorrhage (ICH), and results are inconsistent. We studied risk factors for ICH in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).

Methods— The ARIC cohort was recruited in 1987 to 1989 and involves 15 792 men and women, aged 45 to 64 years at baseline, sampled from 4 US communities. The CHS cohort was recruited in 1989 to 1993 and involves 5888 men and women, aged 65 or over at baseline, sampled from 4 US communities. Baseline measurements included many potential vascular risk factors. The cohorts were followed for incident stroke events.

Results— Over 263 489 person-years of follow-up, 135 incident ICH events occurred. In a multivariable model, age, African-American ethnicity (versus Whites), and hypertension were positively associated with incident ICH, whereas low-density lipoprotein cholesterol and triglycerides were inversely related to incident ICH. Participants with systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg had 5.55 (95% CI 3.07 to 10.0) times the rate of ICH as nonhypertensives. Sex, smoking, alcohol intake, body mass index, waist-to-hip ratio, waist circumference, and diabetes were not related to ICH.

Conclusions— In this pooled cohort the risk factors for ICH were older age, African-American ethnicity, hypertension, lower LDL-C, and lower triglycerides.


Key Words: cerebral hemorrhage • epidemiology • hypertension • risk factors • stroke


*    Introduction
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Stroke is the third leading cause of death in the United States.1 Intracerebral hemorrhage (ICH) is the most common cause of hemorrhagic stroke in the United States and has a higher case fatality than ischemic stroke.2

ICH has been strongly linked to age, race, and hypertension status. Associations have been less consistent with many other risk factors, including greater alcohol consumption, male sex, smoking, low physical activity, body mass index (both high and low), total cholesterol (both low and high), and diabetes. Age, male sex, high alcohol intake, and hypertension were statistically significantly associated with ICH in 1 recent meta-analysis.3 Another meta-analysis of studies from the Asian-Pacific region found high blood pressure, smoking, low cholesterol, and possibly diabetes associated with greater ICH risk.4

We examined major vascular disease risk factors in relation to incident ICH in a pooled study of 2 prospective population-based cohorts, the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).


*    Methods
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The ARIC study cohort consists of a population sample of 15 792 individuals from 4 communities: Jackson, Mississippi; Forsyth County, North Carolina; Washington County, Maryland; and the northwestern suburbs of Minneapolis, Minnesota. The Jackson sample comprised African-American residents only. The ARIC cohort was aged 45 to 64 years old at baseline when recruited between 1987 to 1989.5

CHS is a randomly selected population-based cohort study from 4 communities: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. CHS initially recruited 5201 participants from 1989 to 1990, and added 687 African-Americans from 1992 to 1993. Participants over the age of 65 were randomly sampled from the Health Care Financing Administration (HCFA or Medicare) eligibility lists.6 These studies received approval from relevant human subjects review boards and all participants gave voluntary consent.

ARIC and CHS measured many risk factors at baseline, as detailed elsewhere.7–9 The 2 studies used similar methods to assess most risk factors allowing for the pooling of the studies. In both studies a brief clinical examination measured height, weight in pounds, waist circumference at the umbilicus, and maximum hip circumference. A questionnaire assessed current smoking status (current/former/never), cigarettes smoked per day, packs of cigarettes smoked, and years of smoking. The usual intake of alcohol per week was reported and converted to grams per week. Coronary heart disease history was assessed by questions about previous physician-diagnosed myocardial infarction, coronary bypass, and coronary angioplasty, or an ECG evidence of previous myocardial infarction.

The studies used identical methods for the measurement of blood pressure. The participant was required to sit with uncrossed legs for 5 minutes before 3 measurements were taken by a random-zero sphygmomanometer. The mean of the second and third measurements were used for analysis. Hypertension status was assigned based on current use of antihypertensive medications or systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg. For the current study, blood pressure level was also categorized based on Joint National Committee 6 criteria: Normal or High Normal if systolic <140 mm Hg and diastolic <90 mm Hg; Stage I Hypertension if systolic was 140 to 159 mm Hg or diastolic 90 to 99 mm Hg; Stage II Hypertension if systolic 160 to 179 mm Hg or diastolic 100 to 109 mm Hg; Stage III Hypertension if systolic ≥160 mm Hg or diastolic ≥110 mm Hg.10

CHS adopted ARIC methods for blood collection, sample preparation, and laboratory quality assurance. Fasting plasma total cholesterol and triglycerides were measured enzymatically according to Centers for Disease Control and Prevention standards. Low-density lipoprotein (LDL) was calculated using the Friedwald equation, whereas high density lipoprotein (HDL) was measured after precipitation of other lipids. Hypercholesterolemia was defined as a total cholesterol ≥200 mg/dL (5.17 mmol/L) or taking anti-lipid medications at baseline.

Diabetes status was assessed using blood glucose measures and medication status. Participants with fasting glucose of 110 to 126 mg/dL (6.11 to 7 mmol/L), no medications, and no self-reported diabetes were categorized as having impaired fasting glucose status. Participants with a fasting glucose ≥126 mg/dL (7 mmol/L) or nonfasting glucose ≥200 mg/dL (11.1 mmol/L) or use of diabetes medications or self-report of diagnosed diabetes were categorized as having diabetes.11

ARIC outcomes were ascertained through yearly phone interviews, follow-up examinations, community hospital surveillance, and reported deaths. A reported hospitalization led to screening, and if eligible, to medical record abstraction and verification. Records were abstracted for acute stroke if the discharge diagnosis included a cerebrovascular disease code (International Classification of Diseases, 9th revision, code 430-438), if a cerebrovascular procedure was mentioned in the summary, or if the computed tomography or magnetic resonance report showed evidence of acute cerebrovascular disease.9 In ARIC, hospitalized strokes and out of hospital stroke deaths are included, but not nonfatal nonhospitalized strokes.

CHS surveillance and cerebrovascular event ascertainment have been described in detail previously.12,13 CHS participants were contacted every 6 months and asked detailed questions about interim medical events. Self-or proxy-reported stroke events were explored and medical records abstracted for verification. CHS also searched HCFA Medicare Utilization files for stroke ICD-9 codes (430-438) and on event identification abstracted suspected event records for complete verification. CHS also searched reported deaths for CHS participants. In CHS, fatal and nonfatal hospitalized and nonhospitalized strokes were ascertained.

ARIC adapted the National Survey of Stroke criteria for its stroke definition.14 These criteria require stroke to have evidence of sudden or rapid onset of neurological symptoms that persist for >24 hours or lead to death, and have no other apparent cause such as trauma, tumor, infection, or anticoagulation therapy. A definite ICH must have met one of the following criteria: (1) CT or MRI showing intraparenchymal hematoma; (2) Demonstration at autopsy or surgery of ICH; or (3) at least 1 major or 2 minor neurological deficits; and a bloody spinal fluid on lumbar puncture; and cerebral angiography demonstrates an avascular mass effect and no evidence of aneurysm or arteriovenous malformation; and no CT or MRI. A probable ICH met criteria (3), other than cerebral angiography, but had a decreased level of consciousness or coma lasting 24 hours or until the participant died. In ARIC, 98% of strokes received a CT or MRI. In ARIC, stroke criteria were implemented as a computer algorithm and reviewed by a physician blinded to the automated results. A second physician adjudicated disagreements between the computer and initial physician.

CHS adopted stroke criteria similar to the Systolic Hypertension in the Elderly Program (SHEP).8,15 Potential stroke events in CHS were referred to a Cerebrovascular Adjudication Committee. The committee consisted of a neurologist from each site, a neuroradiologist, and a neurologist or internist representing the coordinating center. A suspected event was classified as a stroke if there was a rapid onset neurological deficit (or subarachnoid hemorrhage) lasting >24 hours or until death. The event could not be caused by trauma, tumor, or infection, but in contrast to ARIC an ICH while on anticoagulation therapy did not preclude an ICH classification in CHS. Only 7 participants with an ICH in CHS were potentially taking anticoagulation medication. Their exclusion had little impact on results, as would be expected from the small numbers and because anticoagulation was only weakly correlated with exposures of interest. The CHS Committee has assessed its reliability by blindly reviewing 30 stroke cases reporting a kappa of 0.86 for stroke versus no stroke, and a kappa of 1.0 for stroke subtype (ICH versus SAH versus ischemic). A suspected hemorrhagic stroke was classified as an ICH if (1) there was CT or MRI evidence of ICH, or (2) bloody cerebrospinal fluid on lumbar puncture with a focal deficit, or (3) autopsy or surgical evidence indicated ICH. In CHS 86% of stroke events had brain imaging as part of their stroke work-up.

The combined cohort had 21 680 participants at baseline with follow-up through June 30, 2002 for CHS and December 31, 2002 for ARIC. For analysis, we excluded any participants who reported a history of stroke at baseline (n=582) or were not African-American or White (n=87). Participants who did not fast 8 hours before baseline blood draws were excluded from analysis involving triglycerides (n=560). The outcome of interest was definite or probable incident ICH. If a participant had more than one ICH after baseline only the first event was considered.

The association of baseline risk factors with incident ICH was assessed. Relative rates and incident rate estimates were calculated using Poisson regression as implemented in SAS 8.2 (SAS Institute). Power was 80% to detect a relative risk of 1.6 for a dichotomous exposure assuming 30% exposed. Two-way multiplicative interactions between all risk factors and study (ARIC, CHS), age, race, and hypertension (continuous systolic pressure and hypertension categories) were examined. Variables with univariate associations with ICH were entered stepwise into a Poisson model with ICH as the outcome and kept within the model if their contribution to the model was significant at the alpha=0.05 level after mutual adjustment. Variables that had not demonstrated a univariate association were then tested in the full model, and included if they met the same criteria.


*    Results
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As shown in Table 1, at baseline the mean age was 54 in ARIC and was 73 years in CHS. Because of the large sample size and differences in ages between cohorts, most other baseline variables differed significantly between ARIC and CHS.


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  		Table 1. Mean or Prevalence of Baseline Measures by Study, ARIC/CHS Cohort

Over 263 489 person-years of follow-up 135 incident ICH events occurred (61 in ARIC, 74 in CHS). The median follow-up time was 13.5 years for participants free of ICH, and median time to event was 8.0 years for participants experiencing an ICH. Table 2Down shows crude ICH incidence rates and age-adjusted relative rates by risk factor categories. Before multivariable adjustment, age, ethnicity, blood pressure, hypertension status, triglycerides, HDL cholesterol, and LDL cholesterol were significantly associated with ICH (P<0.05). ICH was not associated with sex, education, history of coronary heart disease, alcohol intake, smoking, total cholesterol, BMI, WHR, waist circumference, or diabetes status in either the univariable or multivariable models (P>0.05).


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  		Table 2. Age-Adjusted Associations Between Classic Risk Factors and Incident Intraparenchymal Hemorrhage, Combined ARIC/CHS Cohort


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  		Table 2. Continued

Table 3 shows the final multivariable model. Study (ARIC/CHS) did not contribute to the model beyond age and did not confound the other variables. Greater age, more severe hypertension, African-American ethnicity, lower triglycerides, and lower LDL-C (lower 3/4 versus top quarter) were associated with greater incidence of ICH after mutual adjustment. The risk of ICH doubled every decade and African-Americans had 1.89 (95% CI 1.28, 2.80) times the risk of Whites.


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  		Table 3. Multivariable Adjusted Independent Associations of Baseline Risk Factors With Intraparenchymal Hemorrhage, Combined ARIC/CHS Cohort

The risk of ICH increased most dramatically with increasing hypertension stage. Sixty percent of participants with an ICH had elevated blood pressure, compared with 39% of those remaining free of ICH. The relative rates of ICH doubled from Stage 1 to Stage 2, and then doubled again from Stage 2 to Stage 3 hypertension. Participants with Stage 3 hypertension at baseline were more than 5 times more likely to experience an ICH than those with Normal or High Normal blood pressure. The adjusted rate of ICH increased 22% (95% CI 13% to 31%) for every 10-mm Hg increment of systolic blood pressure.

Plasma LDL-C and triglycerides both had an inverse relation with ICH. LDL-C, modeled as the top 1/4 versus lower 3/4 of the distribution, and increasing triglycerides per log unit were both associated with about half the risk of ICH. LDL cholesterol was modeled as a threshold variable, however it demonstrated a consistent risk trend when expressed in quartiles as seen in Table 2Up. At baseline, 3.5% of participants reported using lipid-lowering medications.

We detected 2 interactions, and did not find any interactions with study (ARIC/CHS). The association of systolic blood pressure (or hypertension status) with ICH was weakly negatively modified by age (probability value=0.01). That is, the rate ratio of ICH per 10 mm Hg systolic blood pressure diminished by 8% per 10 years greater age.

The Figure illustrates an interaction between ethnicity and age (probability value=0.001). As age increased the differences in ICH incidence between Whites and African-Americans decreased and eventually reversed so that the oldest Whites had higher ICH rates than did African-Americans. As shown in the Figure, our model estimates that at age 45 African-Americans had 5.8 times the ICH rate of Whites, whereas that relative rate decreased to 1.7 by age 65, and to 0.94 by age 75.


Figure 1487090
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  		Figure. Ethnicity by age interaction in relation to incident intracerebral hemorrhage-predicted rates by baseline age, ARIC, and CHS pooled cohort.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
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 up arrowResults
 *Discussion
down arrowReferences
 
In this prospective study assessing baseline risk factors and subsequent occurrence of ICH, increasing age, African-American ethnicity, high blood pressure, low triglycerides, and low LDL cholesterol were risk factors for incident ICH.

Age and non-White ethnicity have both been consistently positively associated with ICH. The risk of ICH in our study doubled every decade, a result that closely mirrors other research.3,16–18 The relative rate of 1.89 for African-Americans versus Whites was also similar to estimates reported in the literature.16,17,19–22 Qureshi et al examined the relation between ethnicity and ICH in NHANES I and reported that much of the association with ethnicity was mediated through hypertension and education.20 In our study the association between ethnicity and ICH was moderately positively confounded by hypertension, but was not confounded by education status in a separate model. The reasons for the increased rate of ICH in African-Americans are not well understood. This difference may reflect less health care coverage among African-Americans; however, Iribarren et al reported African-Americans had greater ICH rates than Whites among Kaiser Permanente enrollees, all of whom had health care coverage.17 Neaton et al did not find a significant association between median income, a surrogate for socioeconomic status, and ICH mortality rates in the MRFIT study.16

Some previous studies have reported a positive association between male sex and ICH; however, our study failed to detect an association. In a meta-analysis, Ariesen et al estimated an odds ratio for the risk of men for ICH compared with women for 2 case–control studies as 1.35 (95% CI 0.99 to 1.80).3 Ariesen et al estimated a crude risk ratio of 4.64 (95% CI 4.02 to 5.40) for men relative to women in their meta-analysis of cohort studies, but problems exist with that estimate. Of the 6 studies Ariesen et al cite, only 2 included both males and females. Of the studies with both sexes, the first reported only 11 events,23 and the second study, by Iribarren et al, had a crude relative risk of 1.27 for men compared with women.17 Among the studies in the meta-analysis that included only men, 1 was a male Korean population,18 and 1 was a study of male smokers.24 The reports with only women were both from the Nurses’ Health Study.25,26 Given the higher risk of ICH in Koreans, the propensity of smokers to have greater rates of hypertension, and the potential that women in the Nurses’ Health Study are healthier than the general population, a crude relative risk from this meta-analysis would overestimate risk for men. Two population-based studies of ICH reported relative rates in men compared with women of 1.1 (95% CI 0.9 to 1.2)21 and 1.5 (95% CI 1.2 to1.8),22 which more closely match our finding. These 2 case–control studies also showed that the relations of race and sex with ICH differ by whether the ICH was lobar or deep; for example, the male increase may be only for deep ICH.22 We unfortunately did not classify location of hemorrhage, and it is possible that our rate ratios were affected by a different mix of ICH locations compared with previous studies.

High blood pressure has consistently been reported as a major risk factor for ICH.4,16,24,27,28 The meta-analysis and review by Areisen et al estimated a crude odds ratio of 3.68 for hypertension and ICH compared with normotensives. We reported a dramatically increasing risk of ICH with increasing levels of hypertension. This observation has been reported by Suh et al, who found the relative risk of ICH for Stage III hypertensive Korean men was 33.3 (95% CI 22.7 to 49.0) relative to normotensives.18 Leppalla et al reported, in a clinical trial of men, that those with systolic blood pressure ≥160 mm Hg had 3.78-fold (95% CI 2.28 to 6.25) risk of ICH compared with those with normal blood pressure.24

Corroborating previous findings examining ICH and cholesterol,4,27,29–34 we observed a moderate inverse association between LDL-C and ICH. Triglyceride levels were also inversely and independently associated with ICH, which is consistent with the only previous study of triglycerides and hemorrhagic stroke in the U.S.,7 but it contrasts with the lack of association in the Asian-Pacific region.4 Cholesterol and triglycerides play important structural roles in cell membranes. There is increased erythrocyte fragility in vitro and in vivo with reduced levels of cholesterol.35 It has been proposed that lower cholesterol results in a weakened endothelium that more readily leads to arterial fragility, hemorrhage, or slower repair after small hemorrhages.36,37 Potentially weakened endothelium may be more susceptible to microaneurysms—the chief pathological finding of cerebral hemorrhages.37 This also may be true for low triglyceride levels. Despite the link between low cholesterol and ICH, statin therapy has increased ICH risk in clinical trials,38 but did not increase risk in other reports.39

The relation between smoking and ICH tends to be weak and inconsistent in individual studies. In a meta-analysis,3 the relative risk of ICH from current smoking versus never smoking was 1.31 (95% CI 1.09 to 1.58). In a large Asian-Pacific pooling project, this relative risk was 1.23 (95% CI 1.01 to 1.49). A review of the literature suggested that studies were more likely not to observe a relation between ICH and smoking when studies collected smoking information as general categories such as current/former/never,18,27,28 and more likely to observe a relation if studies reported on pack-years.16,40,41 Our study modeled smoking in several ways, yet we did not find any consistent or independent relation between smoking and ICH. Thrift et al also examined the risk of ICH with smoking by several categorical designations and also failed to find a significant association.42 Potentially, smoking exerts an effect on ICH risk that our study was underpowered to detect because of low smoking rates.

Previous studies have reported a positive association between HDL cholesterol and ICH or hemorrhagic stroke,24,31,43 inconsistent associations between BMI and ICH,4,17,19,27,32,44,45 inconsistent associations between alcohol and ICH,3,46 and no association17,32,47 or a weak association4 between diabetes and ICH. As mentioned, our study did not find an association of ICH with HDL cholesterol, BMI, diabetes, alcohol, or for WHR, for which there are no previous reports.

Previous manuscripts have reported that the inverse association between total cholesterol and ICH may be stronger for hypertensive than normotensive subjects,33,34 suggesting low-cholesterol may be more important in deep than lobar ICH. However, we did not observe any interactions involving lipids. Curb et al found a negative interaction between hypertension status (yes/no) and age in the Honolulu Heart Study of Asian American men.48 Our study found a similar interaction. As seen in other cardiovascular diseases, the relative impact of a risk factor often decreases with age.49 Potentially, the impact of hypertension in the etiology of ICH decreases with age attributable to the relative increased importance of other biological effects related to the aging process.

We observed an interaction with ethnicity and age in relation to incident ICH that has been previously suggested in the literature.21,50 While African-Americans had almost twice the risk of ICH as Whites, this excess risk was much greater at a younger age. The interaction has several possible explanations. First, African-Americans are at higher risk than Whites for other cardiovascular diseases and potentially those who live longer have inherently less risk of vascular disease than those who do not survive to older ages. Second, African-Americans more often than Whites have increased blood pressure at a young age; therefore the cumulative effects of hypertension may be manifested early in life in susceptible African-Americans. This could relate to race differences in location of ICH (deep versus lobar).21,22 Third, an ethnic disparity in health care coverage may lessen as participants age and become eligible for Medicare. Finally, it remains possible that different African-American recruitment strategies between ARIC and CHS account for this observed interaction.

This study has several strengths. It involved large biracial population-based cohorts from 6 US communities. This study covers a wide age range and ICH were incident events with a high proportion of brain imaging.

Despite the relatively large number of events, this study still had limited power to detect weak associations. Despite the relative similarity in ICH classifications in CHS and ARIC, differences in classification could impact the results. Although the methods of measurement for baseline risk factors were similar between ARIC and CHS, unidentified differences could exist. These differences could result in misclassification of the exposures that would bias results in unpredictable ways. Baseline ages for ARIC and CHS did not overlap, resulting in age and study being confounded. Although, in analysis, study (ARIC versus CHS) was not independently related to ICH and did not confound the reported associations, there is the possibility of residual confounding or study interactions due to methodological or population differences. This is especially true for the reported interactions of systolic blood pressure with age and of ethnicity with age. In a supplemental analysis (not shown), study did not modify the effect of ethnicity, giving some assurance that age, and not study, was the meaningful relation.

In conclusion, greater age, hypertension, African-American ethnicity, low LDL cholesterol, and low triglycerides increased the risk of ICH in this pooled cohort. Hypertension stage was dramatically related to ICH with those with Stage 3 Hypertension at baseline having 5 times the risk as those without hypertension. Hypertension remains the most important modifiable risk factor for ICH.


*    Acknowledgments
 
Sources of Funding

The National Heart, Lung, and Blood Institute funds the Atherosclerosis Risk in Communities Study (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022) and the Cardiovascular Health Study (N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, and U01 HL080295), with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at www.chs-nhlbi.org. Dr Sturgeon was funded through NHLBI T32-HL07779 and National Institutes of Health MSTP grant GM008244.

Disclosures

None.

Received March 5, 2007; revision received March 29, 2007; accepted April 4, 2007.


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