Risk Factors for Intracerebral Hemorrhage
The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Background and Purpose—Risk factors for intracerebral hemorrhage (ICH) have been largely identified in case–control studies, with few longitudinal studies available.
Methods—Predictors of incident ICH among 27 760 black and white participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study were assessed.
Results—There were 62 incident ICH events during an average follow-up of 5.7 years. The increase in risk with age differed substantially between blacks and whites (P=0.006), with a 2.25-fold (95% confidence interval, 1.63–3.12) increase per decade in whites, but no age association with ICH risk in blacks (hazard ratio=1.09; 95% confidence interval, 0.70–1.68). We observed increased risk among men, those with higher systolic blood pressure, and warfarin users.
Conclusions—The racial differences in the impact of age contributed to a risk of ICH that was >5 times higher for blacks than whites at age 45, but only about one third as great by age 85. Confirming findings from other studies, men participants with elevated systolic blood pressure and warfarin users were also at greater risk. The contributors to the racial differences in ICH risk require additional investigation.
The low incidence of intracerebral hemorrhage (ICH) events makes the assessment of risk factors challenging. A decade ago, Ariesen et al1 reviewed largely case–control studies of ICH, concluding that age, male sex, and hypertension were the largest risk factors for ICH. A case–control study by Woo et al2 not only reported risk factors separately for lobar and nonlobar ICH, but also assessed risk factors for a pooled analysis, finding increased risk with hypertension, frequent alcohol use, anticoagulant use, history of ischemic stroke, and first-degree relative with ICH, but not finding associations with diabetes mellitus, smoking, drug use, education, or Apo E2/E4. In a secondary analysis of a case–control study of ICH assessing a potential role of phenylpropanolamine, hypertension, diabetes mellitus, postmenopausal status, current cigarette smoking, alcohol use (>2/d), use of caffeinated drinks (>5/d), and use of drugs containing caffeine were associated with higher risk for ICH.3
In one of the very few prospective examinations of risk factors for ICH, Sturgeon et al4 combined data from the Atherosclerosis Risk in Communities (ARIC) study with the Cardiovascular Health Study (CHS) cohort, reporting that older age, black, and hypertension were risk factors for incident ICH. This study also reported a race-by-age interaction, where at age 45, blacks had 5.8 times the risk of ICH compared with whites, a risk that was reduced to 0.94 times by age 75. The authors also reported a modest interaction between systolic blood pressure (SBP) and age. This report did not find associations of sex, smoking, diabetes mellitus, alcohol intake, and measures of obesity with ICH risk.
Although surveillance studies are powerful for calculating incident event rates, with the exception of demographic factors (age, race, and sex), they are not useful to assess clinical risk factors. However, a surveillance study was the first to show a differential impact of age on ICH risk by race, where between the ages of 55 and 74, the ICH risck for blacks was1.8 times (95% confidence interval [CI], 1.0–3.2) greaterthan whites, but above the age of 75, the risk ratio was only 0.23 (95% CI, 0.1–0.8).5 The report of Sturgeon et al4 is one of few confirmations of this age-by-race interaction, but the study included relatively few blacks, and confounded race with geographic disparities because the majority of blacks ≤65 years of age were enrolled at the Jackson (Mississippi) ARIC center.
Although elevated cholesterol was shown to be protective of ICH in the Multiple Risk Factor Intervention Trial (MRFIT) screenee population,6 clinical trial evidence of the association of lipid-lowering treatment is inconsistent, with some reports showing ICH risk increased7 and others decreased;8 furthermore, a meta-analysis of 182 803 patients in 31 trials failed to show an association.9
Herein, we assess risk factors for ICH in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a longitudinal cohort study of white and black community-dwelling participants.
The goals of the REGARDS study are to advance the understanding of racial and geographic differences in stroke mortality, including assessing risk factors for ischemic stroke and ICH. The study recruited 30 239 community-dwelling participants across the United States between 2003 and 2007. The study oversampled the stroke belt (56%), including North Carolina, South Carolina, Georgia, Tennessee, Alabama, Mississippi, Arkansas, and Louisiana; with the remainder of the participants from the other 40 contiguous US states. The study also oversampled blacks (44%). Of the eligible participants contacted, the cooperation rate was 49%. A cardiovascular risk survey was completed by telephone and an in-home physical assessment conducted ≈2 to 3 weeks later. Participants were followed up at 6-month intervals by telephone, and medical records were retrieved and physician-adjudicated for suspected strokes. Details of the study methods are provided elsewhere.10
During the in-home assessment, 2 blood pressure measures were taken after the participant had been seated for 5 minutes, and average SBP was used in analyses. Hypertension was defined as SBP ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or self-reported use of antihypertensive medications. Diabetes mellitus was defined as fasting glucose ≥126 mg/dL (or ≥200 mg/dL for participants who failed to fast) or self-reported use of diabetic medications. Chronic kidney disease (CKD) was defined by estimated glomerular filtration rate (using the CKD Epi equation)11 of <60 mL/min per 1.73 m2 or albumin/creatinine ratio greater than 30 mg/mmol. High sensitivity C-reactive protein, total cholesterol, high-density lipoprotein, and triglycerides were measured centrally, and low-density lipoproteins calculated using the Friedewald formula.12 Smoking, current alcohol use, current aspirin use, and use of nonsteroidal anti-inflammatory drugs were all defined from the telephone interview. Warfarin use was defined by medication inventory performed in the participant’s home.
Suspected stroke was identified by hospitalization for stroke or stroke-like symptoms that were solicited during follow-up telephone interviews. Medical records were retrieved for each suspected stroke, and stroke end points (including the determination of stroke subtype of infarction versus ICH) were determined by physician review. Details of this process are available elsewhere.13
Proportional hazards analysis was used to assess associations between risk factors and incident ICH events through April 1, 2012. Hypothesized interactions (age-race and age-SBP) were assessed. A priori, main effects were assessed at α=0.05, whereas interactions were assessed at α=0.10. Because some medical records could not be retrieved and other records remained in the adjudication process at the time of analysis (≈10% each), multiple imputation14 techniques were used in the analysis to reduce the potential bias arising from undocumented stroke events. Details of the multiple imputation approach used are provided elsewhere,15 and sensitivity analysis repeating analyses showed no differences in interpretation of the impact of any factors.
Follow-up was available on 29 653 of the 30 239 (98%) study participants, of whom 27 760 participants (94%) were stroke-free at baseline (Table 1). There were 62 ICH events over a follow-up averaging 5.7 years.
The crude event rates are shown for 3 age strata: 45 to 64 years, 65 to 74 years, and 75+ years (Table 2). For whites, there was a marked increased risk across the age strata (0.10% to 0.31% to 0.47%), but this was not seen for blacks across the age strata (0.21% to 0.17% to 0.25%). When age was modeled as a continuous variable (Table 3), the age-by-race interaction was highly significant (P=0.0062) and not substantially mediated by other predictors of ICH risk. Because of this significant interaction, the remaining results focus on the impact of race and age on ICH risk (Table 3). Table 4 displays the association of potential predictive variables. The estimated black-to-white hazard ratio in the fully adjusted model is also shown in the Figure, where ICH risk in blacks is ≈5 times greater than whites at age 45 but only one third as great at age 85. For each 10-year difference in age, the risk of an ICH was 2.25 (95% CI, 1.63–3.12) times greater for whites and was modestly attenuated to 2.03 (95% CI, 1.44–2.86) by adjustment for other significant factors (Table 3). In contrast, for blacks, for each 10-year difference in age, there was only a 1.09 times (95% CI, 0.70–1.68) increase in ICH risk, and this was almost completely attenuated (HR=1.01; 95% CI, 0.65–1.58) by adjustment for other factors.
Table 4 provides the outcome of the model-building, where univariately male sex was associated with a nearly 3 times higher risk of ICH (HR=2.83; 95% CI, 1.63–4.91). For each 10 mm Hg higher difference in SBP, there was a 24% increased risk of ICH (HR=1.24; 95% CI, 1.10–1.40), with prevalent CKD more than a doubling of risk (HR=2.26; 95% CI, 1.28–3.98), and with warfarin use >3 times increased risk (HR=3.54; 95% CI, 1.63–7.67). No other factors were significantly associated with ICH risk (P>0.05), whereas a univariate association for CKD was mediated and was becoming insignificant after adjustment for SBP (P=0.12). We were unable to demonstrate the age-by-SBP interaction as observed by Sturgeon et al4 to be significant.
Race played a major role in the ICH risk pattern with increasing age, whereas for white participants, there was more than a doubling of risk per decade of age but virtually no change in risk across age periods for blacks. These race-specific differences had a profound impact on the black-to-white relative risk of ICH, with blacks having >5 times increased risk at age 45, but only one third the risk at age 85. Our findings of a race–age interaction were strikingly similar to those reported by Sturgeon,4 who reported a black-to-white relative risk of 5.8 at age 45 (compared with 5.41 in our data), a risk of 1.7 times at age 65 (compared with 1.25 in our data), and 0.94 at age 75 (compared with 0.60 in our data). These findings were also generally concordant with the surveillance study observations made by Broderick et al5, where the black ICH risk was 1.8 times greater than whites between the ages of 55 and 74 but was only 0.23 that of whites over the age of 75. We have previously reported that the relative risk at age 45 for all stroke events was 2.90 times (95% CI, 1.72–4.89) greater among blacks relative to whites.13,16 With black-to-white risk of ICH at age 45 being 5.41 times (95% CI, 1.48–19.93) greater, it seems likely that black-to-white differences in ICH risk at young ages are larger than the overall excess of stroke events, and contributing to the higher all stroke risk.
We also confirmed SBP and male sex as powerful predictors of risk of ICH events. Unlike other reports,1–4 we failed to detect an association with hypertension status. We defined hypertension by elevated SBP or diastolic blood pressure levels or use of antihypertensive medications. Of the 16 017 hypertensive participants in this report, 13 867 participants (87%) were on current treatment. Compared with studies recruiting subjects during earlier years, it is possible we failed to show hypertension as a risk factor, because at the time of our baseline visit (2003–2007), a larger proportion of hypertensive participants were on treatment, and those who were treated had better blood pressure control than study participants in earlier studies. Supporting this possibility, in the case–control study of Woo et al,17 there was a higher odds ratio of 3.5 (95% CI, 2.3–5.2) for ICH risk with untreated hypertension but a much more modest odds ratio of 1.4 (95% CI, 1.0–1.9) for treated hypertension.
Bleeding is one of the expected sideeffects of warfarin use, with an estimated hazard ratio of 1.71 (95% CI, 1.21–2.41) for oral anticoagulation relative to aspirin therapy in a pooled analysis of 6 randomized clinical trials.18 Furthermore, recent results of the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial confirmed excess cerebral hemorrhage risk among warfarin users (relative risk=2.05; CI, 1.36–3.12), although there was not a significant difference in risk of intracerebral or intracranial hemorrhage between the groups.19 However, literature documenting higher ICH risk for warfarin use in population-based studies is surprisingly sparse. There are 2 case–control studies reported by Woo et al2,17 showing a univariate odds ratio 3 to 4 times greater for users of anticoagulants than nonusers (P<0.0001). We also observed a univariate 3.54-times increased risk associated with warfarin use, a difference that was attenuated to 2.24 times greater by adjustment for other risk factors (including SBP). Warfarin use was not examined in the reviews by Ariesen et al1 and Sturgeon et al,4 and no association was seen in the large case–control series reported by Feldman.3
Although CKD was strongly (HR=2.26; P=0.0052) associated with ICH risk in univariate models, adjustment for other risk factors substantially attenuated the association (HR=1.54; P=0.15), suggesting a confounding of CKD with these factors was responsible for the substantial univariate effect. Others have suggested higher ICH risk with heavy alcohol intake.1–3 Using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) classification scheme,20 only 4% of the participants of the REGARDS study reported heavy drinking (≥7 drinks/week for women, ≥ drinks/week for men). Because of the small proportion of participants reporting heavy drinking, we were compelled to examine any alcohol use rather than heavy use, and as such, an association with heavy drinking could not be ruled out. Although we did observe a higher risk among current smokers and diabetic participants, the differences failed to reach statistical significance; however, the pattern for these risk factors was consistent with other studies.1,3,4
We failed to observe an association for total cholesterol or any of the subclasses (P>0.10). Most reports assessing lipids as a risk factor for ICH focused on the association with total cholesterol, failing to find an association.9 A report by Ariesen1 showed significant evidence of heterogeneity (P=0.001) of a lipid effect between studies and little evidence of a pooled effect (odds ratio=1.22; 95% CI, 0.56–2.67). The studies included in that meta-analysis bridged the advent of neuroimaging, and 1 potential contributor to the heterogeneity (and hence to the lack of a finding) is the absence of advanced diagnostic imaging in the early studies included in his analysis. There was also no evidence of an association between total cholesterol and ICH risk in the subsequent report of Feldmann et al3 or Sturgeon et al.4 A meta-analysis of treatment for lipid lowering in randomized trials conducted primarily for secondary coronary risk reduction also failed to show a significant association with ICH risk.7 Our findings may suggest that the effect of lipids on ICH risk is absent or quite small.
In general, we suggest caution in the interpretation of risk factors for which associations with ICH were not detected. Although we had 156 876 person-years of exposure, we accrued only 62 ICH events, for a crude incidence rate of 39.5 events per 100 000 person-years. This incidence rate was only slightly lower than the crude rate of 51.2 per 100 000 person-years (135 events in 263 489 years of exposure) reported by Sturgeon et al.3 However, the relatively small number of events in the REGARDS study limits statistical power. Specifically, for risk factors that are ≈50% prevalent (such as hypertension or aspirin use), 62 events provides 80% power to detect a hazard ratio of 2.04. For risk factors such as diabetes mellitus or CKD that are 20% prevalent, a hazard ratio of 2.43 can be detected with 80% power. Hence, a risk factor would have to present at least a moderate impact on ICH risk to have a high probability of detection in our study.
As the REGARDS study continues to accrue stroke events, we look forward to having a sufficient number of ICH events to perform risk function analyses focusing on risk factors for ICH in specific brain regions and assess the racial differences in ICH risk in specific brain regions.
The study has several substantial strengths and a few limitations. A major strength of the REGARDS cohort is its substantial sample size and prospective design, allowing the assessment of risk factors for the relatively rare ICH events to be estimated in a single cohort under a single protocol. In addition, the oversampling of blacks in the cohort provides an unprecedented opportunity to evaluate racial differences in ICH risk. The study design of the REGARDS cohort, in which participants are dispersed across ≈60% of the counties in the continental United States, makes the ongoing monitoring of factors assessed at baseline (such as warfarin use) infeasible, and requires the analysis to depend on assessments made at baseline. Also, as noted above, statistical power is limited by a relatively small number of events (62).
In conclusion, we report that age and race have a dynamic interplay in the risk of ICH, with substantial increases in risk with increasing age for whites, a pattern that was not present in blacks. At young ages, blacks had >5 times the risk of ICH compared with their white counterparts; however, at older ages, their risk was only about one third that of whites. We also confirm male sex and elevated SBP as major risk factors for ICH and have confirmed the increased risk among warfarin users in the general population. Clearly, the contributors to the substantial age-by-race interaction need further investigation.
The authors thank the investigators, staff, and participants of the REGARDS study for their valuable contributions.
Sources of Funding
This research was supported by a grant from the National Institutes of Health (National Institute of Neurological Disorders and Stroke cooperative agreement U01 NS041588) to Dr Howard.
- Received December 17, 2012.
- Accepted February 14, 2013.
- © 2013 American Heart Association, Inc.
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