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Risk factors have been described for spontaneous intracerebral hemorrhage (ICH); their relative contribution to lobar vs nonlobar hemorrhage location is less clear. Our purpose here was to investigate risk factors by hemorrhage location.
This case-control study prospectively enrolled subjects with first-ever spontaneous ICH and matched each with up to 3 controls by age, race, and gender. Conditional stepwise logistic regression modeling was used to determine significant independent risk factors for lobar and nonlobar ICH.
From December 1997 through December 2006, 597 cases and 1,548 controls qualified for the analysis. Hypertension, warfarin use, first-degree relative with ICH, personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype were more common in ICH cases. Hypercholesterolemia and moderate alcohol consumption (≤2 drinks per day) were less common in ICH cases. The associations of hypertension and hypercholesterolemia were specific for nonlobar ICH. Conversely, the association of APOE ε2 or ε4 genotype was specific for lobar ICH.
APOE ε2 or ε4 genotype was associated specifically with lobar ICH. Hypertension was associated specifically with nonlobar ICH. A protective association was seen between hypercholesterolemia and nonlobar ICH; no such association was identified for lobar ICH.
Intracerebral hemorrhage (ICH) accounts for approximately 20% of strokes worldwide, with 30-day mortality estimates of 32%–50%.1–4 Of patients who survive, only 28%–35% are independent at 3 months.5,6 Prior reports from our group and others support the hypothesis that risk factors for ICH vary according to hemorrhage location.7–10 The Genetic and Environmental Risk Factors in Hemorrhagic Stroke (GERFHS) Study is designed to examine the genetic and environmental variables associated with hemorrhagic stroke in the biracial population of the Greater Cincinnati/Northern Kentucky (GCNK) region (population 1.3 million, 16% black). In 2002, our preplanned interim analysis examined the hypothesis that risk factors for ICH varied according to hemorrhage location. Hypertension had the highest attributable risk for nonlobar ICH (e.g., basal ganglia, thalamus, brainstem, cerebellum, or periventricular white matter), whereas APOE alleles ε2 and ε4 had the highest attributable risk for lobar ICH7—findings that have been replicated in other studies.8–10 That report had a limited sample size and therefore limited ability to differentiate risk factors by subgroup. The current report, with over 3 times the sample size of our interim report, re-examines the hypothesis that risk factors for ICH vary in prevalence and attributable risk for lobar vs nonlobar ICH.
GERFHS is a case-control study of hemorrhagic stroke that used population-based case ascertainment.
We prospectively surveyed hospital admission logs in an attempt to identify all patients presenting to one of the 16 adult hospitals serving the GCNK region with potential cerebral hemorrhage from December 1997 to August 2001, and July 2002 to December 2006. Methods have been previously described.7,11 GERFHS defined ICH as the nontraumatic abrupt onset of severe headache, altered level of consciousness, or focal neurologic deficit associated with a focal collection of blood within the brain parenchyma as observed on CT, on other neuroimaging, or at autopsy (adapted from Classification of Cerebrovascular Disease III ).7 We abstracted data from medical charts of all individuals with possible hemorrhagic stroke, and followed individuals with hemorrhagic stroke until hospital discharge (up to 30 days).
The Institutional Review Board for each hospital system approved the study. We obtained a Certificate of Confidentiality from the Department of Health and Human Services. Study personnel obtained informed consent for all subjects who underwent interview and genetic analysis.
Eligibility criteria include age ≥18 years, residence within 50 miles of the University of Cincinnati, and enrollment within 90 days of the index event. Hemorrhages associated with trauma, brain tumor, encephalitis, endarterectomy, hemorrhagic cerebral infarction, or thrombolytic treatment of ischemic stroke did not meet study criteria. The GERFHS study collected data for subarachnoid hemorrhage (SAH) as well as ICH. This analysis of first-ever spontaneous ICH excludes primary SAH and ICH due to a structural cause (arteriovenous malformation, aneurysm, cavernous angioma, venous angioma, dural fistula). We also excluded patients with prior ICH and those not of white or black race. We included patients with anticoagulant-associated ICH, pure intraventricular hemorrhage, and prior ischemic stroke. Study neurologists reviewed clinical and neuroimaging information for each patient and made the final decision about case eligibility.
To assess completeness of ICH event ascertainment, we compared the ICH events ascertained by the GERFHS study in 2005 with those ascertained independently by a population-based study of all stroke subtypes in our region, the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS). The GCNKSS used hospital discharge ICD-9 codes and outpatient-based ascertainment. We found 324 cases ascertained by both studies, 7 ascertained only by GERFHS, and 33 ascertained only by GCNKSS (including 8 coroner's cases and 1 identified in an outpatient clinic).
Controls were selected from the general population by random digit dialing. We attempted to match 3 controls of the same gender, race, and age (±5 years) to each case.
Study neurologists classified hemorrhages as lobar (involving predominantly the cortex and underlying white matter of the cerebral hemisphere), deep (involving predominantly the basal ganglia, periventricular white matter, thalamus, or internal capsule), cerebellar, or brainstem. When location was unclear, a group of study neurologists adjudicated the films. For the current analysis, we categorized hemorrhage location as lobar or nonlobar (all other categories).
Study nurses interviewed each consented case (or proxy) and control face-to-face in a highly structured, identical manner.7 To determine ability to be interviewed, every case passed a screening test consisting of 7 questions regarding orientation, ability to follow commands, and attention; 31% did not pass the test and required proxy interview. The first choice for a proxy was the spouse/live-in companion or designated power of attorney, followed by adult child, parent, sibling, or close friend (in this order).
Race and risk-factor variables were determined by self-report. Among the interview questions, participants were asked whether a doctor had ever told them they had high blood pressure/were hypertensive (yes, no, or unknown) or elevated cholesterol/blood lipids (yes, no, or unknown). We elected to use self-report because physiologic variables may be altered as a result of the hemorrhage. Study nurses asked about alcohol consumption (amount, frequency, and type), cigarette smoking (never, former, or current smoker; number of pack-years), and education (less than high school, high school or greater). We also recorded medication use by cases (immediately prior to ICH onset) and controls.
For APOE genotyping, we obtained 4 buccal brush samples or whole blood from each case and control at the time of interview. APOE genotype was determined by a PCR-based method to determine genotype at single nucleotide polymorphisms rs429358 and rs7412.12,13 Our controls showed no significant departure from Hardy-Weinberg expectations (p = 0.3357 for white controls, and p = 0.0345 for black controls; a p value that rejects Hardy-Weinberg equilibrium is <0.0001).
Categorical variables are reported as proportions. Variables with yes/no/unknown responses were analyzed dichotomously as “reported” (“yes” responses) and “not reported” (“no” or “unknown” responses, or missing data); tables e-1, e-2, and e-3 on the Neurology® Web site at www.neurology.org contain responses for each variable by hemorrhage location. APOE genotype was analyzed in an additive model.10 Continuous variables are reported as mean with standard deviation. Univariate analyses that examine the association of independent variables with ICH are reported as odds ratios (ORs) with 95% confidence intervals (CIs).
We conducted multivariate analysis using stepwise elimination. APOE genotype was analyzed as a 3-level continuous variable. We analyzed hemorrhage location subgroups (lobar vs nonlobar) separately; an exploratory analysis stratified subjects by race. An additional exploratory analysis examined hemorrhage location subgroups by hypercholesterolemia, statin use, and APOE genotype. We calculated attributable risk using the multivariate OR and the prevalence rate from the matched controls.
Of the 7,133 potential cerebral hemorrhage events screened between 1997 and 2006, we identified 2,850 cases of ICH, of which 597 subjects with first-ever spontaneous ICH underwent interview and genetic testing (figure). To determine whether these 597 interviewed cases were representative of all the verified ICH cases ascertained, we compared the abstracted data from interviewed cases vs noninterviewed cases. Noninterviewed cases were significantly older. After adjusting for age, interviewed cases had significantly lower mortality and higher documented histories of smoking and hypercholesterolemia. There were no significant differences for the other documented risk factors (table 1).
We matched controls 3:1 for 385 of the 597 cases, 2:1 for 181 cases, and 1:1 for 31 cases, for a total of 1,548 controls. Although age was a criterion for matching, the cases were, on average, 3 years older than the controls (65.2 ± 15.5 vs 62.2 ± 14.6), which resulted in a small but significant age effect (OR 1.13 per year, 95% CI 1.08–1.17; p < 0.001); thus, all multivariate analyses were adjusted for age.
ICH cases were more likely to have a history of hypertension, current warfarin use, a first-degree relative with ICH, a personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype. Conversely, ICH cases were less likely to have a history of hypercholesterolemia or moderate alcohol consumption (≤2 drinks per day; table 2).
Independent risk factors associated with lobar ICH were warfarin use, a prior history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype. Less than a high school education carried the highest attributable risk for lobar ICH (table 3).
Nonlobar ICH cases had an increased likelihood of hypertension, warfarin use, first-degree relative with ICH, prior history of ischemic stroke, and less than a high school education. Hypercholesterolemia was less frequent in nonlobar ICH cases (table 4).
We performed an exploratory analysis of nonlobar ICH predictors, stratified by race. Black cases were 6 times more likely to have had a history of hypertension than black controls (OR 6.15, 95% CI 2.78–13.57, p < 0.0001); white cases were twice as likely to have had hypertension as white controls (OR 2.42, 95% CI 1.74–3.37; p < 0.0001). Among cases, black cases (n = 93) were more likely to have had hypertension than their white counterparts (n = 287; p < 0.0001). Given the 59.8% prevalence of hypertension in black controls and the 47.2% prevalence in white controls, the risk of ICH attributable to hypertension was 75.4% in black subjects and 40.1% in white subjects.
We performed an exploratory analysis of hypercholesterolemia with respect to statin use and APOE genotype, in addition to hemorrhage location. We found no association between statin use and ICH, regardless of hemorrhage location or APOE genotype. Moreover, the protective association between high cholesterol and nonlobar ICH was of similar magnitude in statin users and nonusers (table e-4).
Our data add to the growing body of literature assessing risk factors for ICH and lend support to the concept that lobar and nonlobar ICH result from different pathophysiologic factors.
We found hypercholesterolemia less frequently in nonlobar ICH cases compared to controls, but found no difference between lobar ICH cases and controls. The protective association between hypercholesterolemia and all ICH is supported by several studies.8,14–16 Our results suggest that this finding is driven specifically by the association of hypercholesterolemia with nonlobar ICH. The Rotterdam Scan Study found that those with the highest quartile of triglycerides had the lowest rate of deep or infratentorial microbleeds; no such relationship was seen with lobar microbleeds.17 Hypercholesterolemia may therefore play a more relevant pathophysiologic role in maintenance of deep penetrating arterioles than in cortical arterioles. The mechanism of hypercholesterolemia's association with nonlobar ICH is unclear, but low cholesterol has been hypothesized to contribute to vascular fragility.18 We found no association between statin use and ICH, regardless of hemorrhage location or APOE genotype. This lack of association would seem to be at odds with the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial, which found an increased risk of ICH among subjects randomized to atorvastatin 80 mg vs placebo.19 Further research on statin dosage and target low-density lipoprotein would help clarify the relationship between statin usage and ICH.
We found self-reported hypertension more frequently in ICH cases compared to controls. Nonlobar ICH cases appear to drive this association, for we found no such association with lobar ICH. Other studies also found hypertension more frequently in nonlobar compared to lobar ICH, but did not collect hypertension frequency in the population as a whole, preventing calculation of attributable risk.9,11 In the current analysis, we determined the attributable risk for hypertension in nonlobar ICH, and found the attributable risk to be significantly higher for black than for white subjects. The higher attributable risk in black subjects is related in part to the higher frequency of hypertension in black controls, but may also be related to blood pressure control, which could not be determined from our data. Given the relatively small sample size of nonlobar ICH among black subjects, variables beyond hypertension may not have reached significance due to limited power. The absence of such variables in a multivariate model may overestimate the influence of hypertension as a risk factor among black subjects.
APOE alleles ε2 and ε4 appear to play a role in the pathogenesis of amyloid angiopathy.20,21 Most studies have found APOE alleles ε2, ε4, or both more frequently in lobar ICH cases, although other studies have found no association.10,12,22–25 The largest and most detailed analysis of APOE genotype and ICH was a meta-analysis that included our cases as well as those from 6 other studies. That study found that alleles ε2 and ε4 were both associated with lobar ICH in white subjects, most strongly in subjects with a high probability of cerebral amyloid angiopathy.10 Here we similarly found APOE alleles ε2 and ε4 to be associated with lobar ICH.
Our analysis confirms that use of warfarin is associated with both lobar and nonlobar ICH.26 Warfarin use increased the odds of ICH in our present analysis by 3- to 4-fold; however, the frequency of warfarin use in the population is relatively low so the attributable risk for anticoagulation was less than 10%. The frequency of anticoagulation has increased over time,27 as studies have consistently demonstrated the superiority of warfarin over antiplatelet agents for stroke prevention in high-risk patients with atrial fibrillation.28,29 The risk of anticoagulant-associated ICH in recent clinical trials has ranged from 0.38 to 0.47% per patient year, and was lower (0.10%–0.24% per patient year) for the newer anticoagulants dabigatran and apixiban.30,31 Our results can serve as a baseline for ongoing and future studies of ICH in the setting of anticoagulation. As the newer anticoagulants are adopted, the per-person risk of anticoagulant-associated ICH would be expected to decline if real-world experience with these agents mirrors that of the clinical trials.
Alcohol intake has been variably reported to be associated with ICH.15,16 Here we found a small protective association of moderate alcohol consumption (≤2 drinks/day) with ICH. This association was no longer significant when analyzed by ICH location, likely reflecting loss of power after stratification. We found no association of heavy alcohol use with ICH. Studies are difficult to compare because of the varying definitions of alcohol use, but alcohol has not been consistently found to play a role in ICH.
Our finding that less than a high school education is associated with approximately double the risk of ICH is consistent with the findings from the National Health and Nutrition Examination Survey (NHANES I) study.32 Conversely, combined analysis of Atherosclerosis Risk in Communities (ARIC) and the Cardiovascular Health Studies (CHS) found only a nonsignificant trend toward higher risk of ICH with lower education levels.15 Low education level is thought to reflect socioeconomic status and associated issues such as health care access,33 thus the strength of its association with disease is likely to vary among populations. Notably the NHANES I study was designed to oversample individuals of lower socioeconomic status, whereas the ARIC and CHS studies were not.
We found no association between smoking and ICH, and this lack of association persisted regardless of hemorrhage location. The ARIC and CHS studies similarly found no association between ICH and smoking, even when stratified by current smoking status and pack-years.15 Conversely, the INTERSTROKE study found a small association between current smoking and ICH.16 Thus, if smoking is a risk factor for ICH, its effect is weak.
Our study is not without limitations. Cohort study design offers advantages over case-control design; however, a cohort study with 597 cases at an incidence rate of 20 per 100,000 per year4 would require 3 million patient years of follow-up. Potential limitations of our case-control study include inadequate capture of cases, survival bias, and recall bias. Comparison with the GCNKSS34,35 suggests that our method captures >90% of primary ICH cases that occur in our region. Despite our aggressive prospective enrollment, the difference in mortality between interviewed and noninterviewed subjects reveals a significant survival bias. Nevertheless, the minimal differences in risk factors between the interviewed and noninterviewed cases support the external validity of our results. In fact, the lower frequency of hypercholesterolemia in noninterviewed cases suggests that the data presented here may be an underestimate of the true effect size of hypercholesterolemia. Similarly, the trend toward more frequent anticoagulation in noninterviewed cases suggests that our results may underestimate the effect size of anticoagulation. Our structured interview assesses variables by self-report, which raises the possibility of recall bias, creating the potential for misclassification of exposure. Furthermore, self-report does not account for the severity of the hypertension or hypercholesterolemia. Sensitivities for self-report of hypertension, hypercholesterolemia, tobacco use, and alcohol consumption in prior studies ranged from 51%–86%, and specificities ranged from 57%–95%.36–38 Cases and controls had risk factor assessment by the same methodology, however, and common atherosclerotic risk factors such as diabetes and cigarette smoking did not show significant differences between cases and controls, which suggests that recall bias was not a significant factor in our analysis.
This is the largest study with population-based ascertainment of ICH cases that analyzes genetic and environmental risk factors by hemorrhage location and provides attributable risk estimates. We confirmed that APOE ε2 or ε4 genotype is associated with lobar ICH, whereas hypertension and high cholesterol are associated with nonlobar ICH, suggesting that lobar and nonlobar hemorrhages result from different pathophysiologic processes. Furthermore, ours is the first study to suggest that the protective association of hypercholesterolemia varies by hemorrhage location. Ongoing studies will further advance our knowledge of risk factors for ICH, and will allow assessment of risk factors by both race and hemorrhage location.
Supplemental data at www.neurology.org
Dr. Martini: drafting and revising the manuscript for content, data acquisition, analysis and interpretation of the data. Dr. Flaherty: revising the manuscript for content, study concept/design, analysis and interpretation of data, acquisition of data. Mr. Brown: statistical analysis, analysis and interpretation of the data, revising the manuscript for content. Ms. Haverbusch: acquisition of data, analysis and interpretation of the data, study coordination. Mrs. Comeau: statistical analysis, revising the manuscript for content. Ms. Sauerbeck: acquisition of data, study coordination. Dr. Kissela: revising the manuscript for content, data acquisition. Dr. Deka: acquisition of data, analysis and interpretation of data. Dr. Kleindorfer: revising the manuscript for content, data acquisition. Dr. Moomaw: revising the manuscript for content, analysis and interpretation of data, data management. Dr. Broderick: study concept/design, analysis and interpretation of data, revising the manuscript for content, study supervision, obtaining funding. Dr. Langefeld: analysis and interpretation of data, statistical analysis, revising the manuscript for content. Dr. Woo: study concept/design, acquisition of data, analysis and interpretation of data, revising the manuscript for content, study supervision, obtaining funding.
S. Martini, M. Flaherty, and M. Brown report no disclosures. M. Haverbusch receives salary support from grant NS 36695. M. Comeau reports no disclosures. L. Sauerbeck received salary support from grant NS 36695. B. Kissela, R. Deka, D. Kleindorfer, C. Moomaw, J. Broderick, and C. Langefeld report no disclosures. D. Woo serves as the PI of the grant (NS36695) from which the data are derived. Go to Neurology.org for full disclosures.