Published online before print August 2, 2007, doi: 10.1161/STROKEAHA.107.485573
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(Stroke. 2007;38:2430.)
© 2007 American Heart Association, Inc.
Original Contributions |
Racial/Ethnic Differences in Longitudinal Risk of Intracranial Hemorrhage in Brain Arteriovenous Malformation Patients
From the Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care (H.K., K.Y.T.P., A.S.A., W.L.Y.), the Departments of Epidemiology and Biostatistics (C.E.M., S.C.J.), Neurological Surgery (M.T.L., W.L.Y.), Neurology (V.S., S.C.J., N.U.K., W.L.Y.), and Radiology (R.T.H.), University of California, San Francisco, Calif; and the Division of Research (S.S.), Kaiser Permanente Northern California, Oakland, Calif.
Correspondence to Helen Kim, PhD, University of California, San Francisco, Department of Anesthesia and Perioperative Care, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94115. E-mail kimhel{at}anesthesia.ucsf.edu
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Abstract |
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Background and Purpose— Race/ethnicity is associated with overall incidence of intracranial hemorrhage (ICH), but its impact in patients with brain arteriovenous malformation is unknown. We evaluated whether race/ethnicity was a risk factor for ICH in the natural course in a large, multiethnic cohort of patients with brain arteriovenous malformation followed longitudinally.
Methods— Data were collected prospectively for patients with brain arteriovenous malformation evaluated at the University of California, San Francisco (n=436) and retrospectively through databases and chart review in the 20 hospitals of the Kaiser Permanente Medical Care Program (n=1028). Multivariate Cox regression was performed to assess the influence of race/ethnicity on subsequent ICH, adjusting for risk factors. Cases were censored at first treatment, loss to follow-up, or death.
Results— Average follow up was 4.7±8.0 years for Kaiser Permanente Medical Care Program patients and 2.8±7.3 years for University of California, San Francisco patients with no difference in time to ICH between cohorts (log rank P=0.57). The annualized 5-year ICH rate was 2.1% (3.7% for ruptured at presentation; 1.4% for unruptured). Initial ICH presentation (hazard ratio: 3.0, 95% CI: 1.9 to 4.9, P<0.001) and Hispanic race/ethnicity (hazard ratio: 1.9, 95% CI: 1.1 to 3.3, P=0.02) were independent predictors of ICH, adjusting for age, gender, cohort, and a cohort–age interaction. The ICH risk for Hispanics versus whites increased to 3.1 (95% CI: 1.3 to 7.4, P=0.013) after further adjusting for arteriovenous malformation size and deep venous drainage in a subset of cases with complete data. Similar trends were observed for blacks (hazard ratio: 2.1, 95% CI: 0.9 to 4.8, P=0.09) and Asians (hazard ratio: 2.4, 95% CI: 0.8 to 7.1, P=0.11), although nonsignificant.
Conclusions— This study reports the first description of race/ethnic differences in brain arteriovenous malformation, with Hispanics at an increased risk of subsequent ICH compared with whites.
Key Words: brain arteriovenous malformation • hemorrhage • racial differences • risk factor • survival
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Introduction |
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The risk of intracranial hemorrhage (ICH) in the untreated course (natural history) of brain arteriovenous malformations (BAVM) has been estimated in retrospective studies to range from 2% to 6% per year.1,2 However, relatively few risk factors for ICH in the natural course of BAVM exist. Clinical presentation with ICH appears to be the strongest risk factor for subsequent ICH.3–5 Other risk factors include morphological attributes primarily obtained from MRI and catheter angiography such as venous drainage patterns and deep location.2,6–12 The risk of ICH in the untreated course has been reported to vary dramatically between 1% to 34% per year depending on the number of risk factors present.13
For primary intracerebral hemorrhage, it is well established that certain racial/ethnic groups are at higher risk, especially Hispanic and black patients, and that risk factors differ among these groups.14–16 However, it is not known whether risk of ICH in patients with BAVM varies by race/ethnicity. We sought to determine whether race/ethnicity was an independent risk factor for subsequent ICH in the natural course in a large, multiethnic cohort of patients with BAVM followed longitudinally.
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Methods |
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Patient Population
University of California, San Francisco Cohort
All patients with BAVM evaluated at the University of California, San Francisco (UCSF) from January 2000 through August 2006 were prospectively identified and enrolled in the UCSF BAVM registry. Patients with BAVM are identified using an active surveillance system of all medical and surgical services involved with BAVM management at UCSF, including neurology, neurosurgery, and interventional neuroradiology, as previously described.17 At enrollment, detailed demographic, clinical, and BAVM morphological data (size, location, and drainage) are collected after receiving informed consent from all patients. Follow-up information is obtained during routine clinic visits or annually by telephone after study enrollment.
Kaiser Permanente Medical Care Program Cohort
Using previously described methods,4,5 we identified all BAVM cases who were active members of the Kaiser Permanente Medical Care Program (KPMCP), a managed-care organization that includes approximately 3.3 million members or approximately 30% of the population of the geographical area covered. Member characteristics are representative of the northern California region with the exception of underrepresentation at both extremes of the socioeconomic spectrum. Eligible cases were ascertained through computerized search of all inpatient (physician-coded) and outpatient (analyst-coded) databases using International Classification of Diseases, 9th edition code 747.81 to identify cases with a diagnosis of intracranial vascular malformation, which includes BAVM. Additionally, for cases identified after 1998, complete text reports for all radiological procedures were searched using Current Procedural Terminology-4 codes for various neuroradiological procedures and screened for text strings germane to BAVM. A trained medical record abstractor reviewed all charts of potential cases to verify diagnosis and abstracted data on demographics and clinical course; BAVM morphological data were recorded when available in the narrative. Abstracts were reviewed by one or more of the study physicians (V.S., W.L.Y., S.C.J.) to confirm the diagnosis. Unique identifiers prevented recounting from multiple patient visits. Cases that were treated at both KPMCP and UCSF were excluded from the UCSF cohort and included with the KPMCP cohort.
Data Collection
Self-reported race/ethnicity information for each subject was recorded from the inpatient medical records (white, black/African American, Latino/Hispanic, Asian/Pacific Islander, American Indian/Alaska Native, more than one race, and unknown or not reported). Because there were so few BAVM cases of "American Indian/Alaska Native" race/ethnicity, these subjects were grouped with the "other" category for analyses along with "unknown or not reported" and "more than one race." Patient characteristics included initial ICH presentation (ICH versus no ICH), age at diagnosis (years), gender, history of high blood pressure (yes/no), current cigarette smoker at time of BAVM diagnosis (yes/no), and history of ICH before initial presentation (yes/no). It is unknown whether the history of ICH is related to the BAVM or to other vascular malformations. BAVM characteristics included venous drainage pattern (exclusively deep versus other) and size (maximum dimension in centimeters). Data on eloquence and location were not available for KPMCP patients.
Statistical Analysis
The primary outcome is time from diagnosis to subsequent ICH in the natural course; censoring occurred at first BAVM treatment, loss to follow-up, or death. Kaplan-Meier survival curves and log-rank test were used to describe hemorrhage-free survival rates between KPMCP and UCSF cohorts. Before constructing multivariate models, we evaluated whether the effect of each predictor on time to subsequent ICH differed between cohorts by including an interaction term with cohort in Cox regression models. No significant interactions were observed between cohort and multicategory race (P=0.692) or any other risk factors, except for age at diagnosis in decades (P=0.039). Moreover, our previous study indicated a nonproportional hazards effect for initial ICH presentation,5 in which ICH and non-ICH presentation rates converged over time. Therefore, multivariate Cox regression models were performed to evaluate the effect of race/ethnicity (primary predictor) on subsequent ICH in the 2 cohorts combined adjusting for known ICH risk factors, overall cohort effects, and accounting for the cohort–age interaction and time-varying effect of ICH presentation. Primary comparisons for race/ethnicity were among Hispanics, blacks, Asians, and whites (reference group) using a Bonferroni-adjusted significance level for 3 tests of P=0.017 (0.05/3).
Because of missing data for some clinical variables, we ran 3 different multivariate Cox regression models, which we refer to as models A, B, and C. Model A adjusted for age in decades, gender, ICH presentation and the time-varying covariate, cohort, and the cohort–age interaction, which was available on all 1464 patients with BAVM. Model B adjusted for all the variables in model A plus morphological attributes such as arteriovenous malformation size and exclusively deep venous drainage (included based on evidence from previous studies18) in the 497 cases (227 KPMCP and 270 UCSF) with complete data for these variables. Model C adjusted for model A variables in model B patients and was performed as a sensitivity analysis to determine if results in model B were attributable to adjustment of the morphological risk factors or to the subset of patients included.
Additionally, we ran a number of secondary analyses to account for disease severity, ie, ICH history before initial presentation, and secondary outcomes, including death and ICH as events, censoring at first treatment or last follow-up. We also examined follow-up distributions to further explore potential informative censoring by race/ethnicity and performed a time-to-treatment analysis censoring at ICH event, death, or last follow up. All statistical analyses were conducted using SPSS Version 12 (SPSS, Inc).
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Results |
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A total of 1464 patients with BAVM were identified in the 2 cohorts (1028 KPMCP and 436 UCSF) and differed on a number of demographic, clinical, and medical characteristics (Table 1
). On average, BAVM cases in the KPMCP cohort were older and had longer follow-up than cases seen at UCSF (P<0.001). The race/ethnic distribution varied between cohorts (P<0.001); a greater percentage of BAVM cases at KPMCP were reported to be black and white, whereas at UCSF, a greater percentage was Hispanic and Asian. A greater frequency of BAVM cases at KPMCP also had a history of ICH (P=0.013) or were current cigarette smokers (P<0.001) compared with UCSF cases at the time of diagnosis. As expected, because UCSF is a referral center, treatment (by embolization, surgery, or radiosurgery) was conducted more frequently in patients seen at UCSF compared with KPMCP (P<0.001). No significant differences were observed between the cohort for the major ICH risk factors, including initial presentation of ICH (P=0.962), BAVM size (P=0.163), and exclusively deep venous drainage (P=0.632). However, anatomic risk factors were missing from over half of KPMCP patients (Table 1).
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Overall, 6.8% of patients experienced an ICH (75 KPMCP, 25 UCSF) during 6011 patient-years of follow-up, corresponding to a 5-year annualized ICH rate of 2.1% (2.0% KPMCP and 2.8% UCSF). Cumulative hemorrhage-free survival curves and number at risk entering each 5-year interval are shown in the Figure. No differences in hemorrhage-free survival between KPMCP and UCSF cohorts were observed (Figure, A, log rank P=0.57). We examined potential interactions between cohort and individual predictors and only age at diagnosis (in decades) was found to differ between cohorts (P=0.039). For example, the hazard ratio for increasing age by a decade was 0.61 in UCSF and 1.01 in KPMCP. Therefore, the 2 cohorts were combined for further analyses but allowing for overall cohort differences and cohort-specific age effects.
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Univariate Cox regression analysis (Table 2) identified ICH presentation (P<0.001), exclusively deep venous drainage (P=0.006), and Hispanic versus white race/ethnicity (P=0.023) as predictors of subsequent ICH in the natural course. The Kaplan-Meier hemorrhage-free survival after diagnosis grouped by initial presentation (Figure, B, log rank P<0.001) confirmed that hemorrhagic presentation has a higher ICH rate than presentation with an unruptured BAVM; the 5-year annualized ICH rate was 3.7% for ruptured and 1.4% for unruptured patients at presentation. Hispanic patients with BAVM also had worse hemorrhage-free survival rates compared with non-Hispanic whites (Figure, C, log rank P=0.016). The hazard ratio (HR) for ICH in Hispanics versus whites was 1.9 (95% CI: 1.09 to 3.18) in the combined cohort: 3.7 (95% CI: 1.4 to 9.7, P=0.01) in UCSF, and 1.4 (95% CI: 0.7 to 2.8, P=0.39) in KPMCP.
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To evaluate whether Hispanic race/ethnicity remained a predictor of subsequent ICH independent of traditional risk factors, we ran 2 different multivariate Cox regression models (Table 3). Model A includes all 1464 patients with BAVM adjusting for age, gender, race, ICH presentation and the time-varying covariate, cohort, and the cohort–age interaction. Model B adjusts for all the variables in model A plus BAVM size and deep venous drainage in the 497 cases with data available on these variables, which included 227 patients from KPMCP and 270 from UCSF.
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ICH presentation (HR: 3.0, 95% CI: 1.9 to 4.9, P<0.001) was the strongest independent predictor of subsequent ICH in the natural course in both multivariate models (Table 3); the HR was 3.0 (95% CI: 1.9 to 4.9, P<0.001) in model A and 3.5 (95% CI: 1.5 to 8.6, P=0.005) in model B. However, the effect of ICH presentation decreased by a factor of 0.54 (P=0.020, model A) or 0.58 (P=0.201, model B), respectively, for each additional decade of follow up. Qualitatively, the risk of subsequent ICH was higher for patients presenting with ICH at the beginning, but the ICH and non-ICH rates tended to converge over time.
Hispanic race/ethnicity also remained an independent predictor of subsequent ICH after multivariate adjustment (Table 3). Compared with whites, Hispanics were at 1.9-fold risk of ICH (95% CI: 1.1 to 3.3, P=0.02, model A) and at 3.1-fold risk (95% CI: 1.3 to 7.4, P=0.013) after further adjustments for BAVM size and deep venous drainage (model B). This increased risk survived Bonferroni correction for the 3 major race/ethnic comparisons (Bonferroni-adjusted P=0.017). Black patients with BAVM had a nonsignificant increased risk of ICH in both multivariate models, although the sample size was much smaller for this group. Asian/Pacific Islander patients had an estimated reduced risk of ICH in the entire cohort (Table 3, model A) compared with whites but an estimated increased risk in the subset with data available on morphological attributes (Table 3, model B, both not statistically significant).
Because 66% of cases were missing data on both BAVM size and deep venous drainage, we performed a sensitivity analysis (model C) restricted to the 497 cases included in the subset analysis (model B). Multivariate Cox regression excluding size and deep venous drainage (ie, model A) in these cases yielded HRs for blacks (2.19), Hispanics (3.04), and Asians (2.37) similar to those reported in model B (Table 3).
Approximately 5% of the overall cohort had a history of ICH before presentation (Table 1
); 47% of these cases (36 of 77) did not present initially with ICH at the time of diagnosis. To account for disease severity, we ran 2 different analyses. First, we included history of ICH as a predictor in the multivariate model. Second, we recoded all patients with a positive history of ICH as presenting initially with ICH. Both analyses resulted in similar, slightly higher, risk estimates for all race/ethnic groups (data not shown) and did not change the overall results presented in Table 3.
We also examined the effect of history of hypertension or cigarette smoking on risk of ICH. No significant associations were observed for either hypertension or smoking (Table 2), and addition of these covariates to the multivariate model did not change the risk estimates for race/ethnicity (data not shown). Finally, we included death with ICH as an end point in the survival analysis, which increased the total number of events to 140 (112 KPMCP, 28 UCSF). Race/ethnic associations still remained when using this composite end point.
We further examined distribution of follow-up times by race/ethnicity. Overall, Hispanics had shorter mean±SD years of follow-up (2.4±5.3) compared with whites (4.5±8.3), Asians (3.4±7.9), and blacks (5.8±9.1), although the distributions overlap. Correspondingly, Hispanics (HR: 1.3, 95% CI: 1.1 to 1.5) and Asians (HR: 1.3, 95% CI: 1.1 to 1.6) were more likely and blacks (HR: 0.86, 95% CI: 0.68 to 1.10) less likely to receive treatment compared with whites when performing a time-to-treatment analysis, censoring at ICH, death, or last follow-up.
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Discussion |
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Patients with BAVM from our referral center (UCSF) and the defined HMO population of KPMCP were similar with respect to the main outcome of interest—ICH in the natural course before any treatment and the known predictors of ICH. These results confirm and extend our previous findings4,5 and those of other referral centers3 that ICH presentation is the strongest independent risk factor for subsequent ICH in the natural, untreated course. This effect appears to be highest in the time period after diagnosis and approximately halves for each additional decade of follow-up, which is also consistent with our previous study.5
To our knowledge, this is the first report of race/ethnic differences in ICH risk in either BAVM epidemiology or predisposition to BAVM hemorrhage. This is most likely because there is a lack of large, multiethnic BAVM cohorts available for study or, because of the rarity of the disease, a focus on more image-derived ICH risk factors such as size and venous drainage patterns. For primary intracerebral hemorrhage, however, there is a large body of literature documenting that Hispanics, blacks, and Asians are at higher risk than whites and that risk factors differ among these racial/ethnic groups.14–16,19 For instance, compared with whites, the risk of primary intracerebral hemorrhage was 2.9-fold higher in Hispanics from the Northern Manhattan Stroke Study20 and 2.1-fold higher in Mexican Americans from Texas.21 We found that compared with whites, Hispanic patients with BAVM from the San Francisco Bay area were at approximately 2-fold increased risk of ICH (P=0.024) independent of ICH presentation (model A, Table 3) and 3-fold increased risk (P=0.013) after we adjusted for morphological risk factors (model B, Table 3); Bonferroni correction for the 3 major race/ethnic comparisons was P=0.017. Importantly, the magnitude of risk was found to be almost as high as that for ICH presentation. A trend was also observed for black patients, although the sample size in this group was much smaller and the result not statistically significant.
Sensitivity analysis (model C) restricted to the subset of cases included in model B found that the HR for Hispanics, blacks, and Asians were all greater than 2.0 when excluding BAVM size and deep venous drainage from the multivariate model, suggesting potential bias attributable to missing data. We also observed differences in follow-up time by race/ethnicity with Hispanics having an overall shorter mean follow up and greater likelihood of being treated compared with whites. However, standard survival analysis methods appropriately account for the unequal censoring time distribution between racial groups,22 and the overlap in follow-up allows comparison of hazard rates over a reasonable range for time to ICH. It is possible that our results could be biased if there was differential informative censoring by race/ethnicity. However, this would require knowledge of hemorrhage-free survival times for censored patients in the different race/ethnic groups, which is unknown and difficult to ascertain.
Most natural history studies of BAVM have reported that small arteriovenous malformation size, although associated with ICH presentation, is not associated with subsequent ICH,1,3,5,23–25 consistent with our findings. In contrast, deep venous drainage was not found to be an independent predictor of ICH as reported by others.26 This may be explained by a fundamentally weaker association of anatomic factors with ICH or more likely because of variability in interpretation of imaging studies.27–29 For example, Al-Shahi et al27–29 studied descriptors determined by catheter angiography and found interobserver agreement ranging from 14% to 62%, generally worse for characteristics associated with more complex angioarchitecture. Of note was low interobserver agreement involving the measurement of Spetzler-Martin grade (47%) and the presence of aneurysms (40%), 2 variables that arguably bear some importance in patient management decisions. More recent studies incorporating MRI findings found only modest improvement in interobserver agreement with kappas ranging from 38% to 90%.28,29 Furthermore, we did not adjust for BAVM location or associated aneurysms in our multivariate model because these data were not available for KPMCP patients at the time of analysis, which may also explain some differences from previous natural history studies of BAVM.
Hypertension may be associated with ICH presentation in BAVM30 and is more prevalent in blacks than whites or Mexican Americans in the United States.31 However, no significant association was observed with hypertension and subsequent ICH in the natural course of BAVM, and adjustment for hypertension did not change the risk estimates for race/ethnic groups. Similarly, no association was observed for current smoking status and ICH, although this is an important risk factor for other hemorrhagic diseases of the brain, including primary ICH32 and subarachnoid hemorrhage.33,34
Among all risk factors examined, only the effect of age at diagnosis (decades) on time to subsequent ICH differed between cohorts. This finding is likely attributable to differences in case detection at UCSF and KPMCP rather than underlying physiological differences. Because no other interactions were significant, including race by cohort (P=0.69), we combined the data together for evaluating the primary effect of race/ethnicity on ICH risk controlling for cohort and cohort-specific age effects. However, we acknowledge that qualitative differences may still exist in the 2 cohorts from any unmeasured confounders. When stratifying the results by cohort, the univariate risk of ICH in Hispanics versus whites was increased, although much stronger in UCSF (HR: 3.7, 95% CI: 1.4 to 9.7) than in KPMCP (HR: 1.4, 95% CI: 0.7 to 2.8). The presence of different Hispanic subgroups in the 2 cohorts may explain the observed differences. For example, studies of race/ethnic differences may be confounded by population stratification if the sample population includes subgroups of different genetic ancestry. Hispanics are known to be an admixed population of white, Native American, and African American ancestry with wide variation in estimated ancestry proportions both within and between Hispanic subgroups.35–38 Association studies of asthma conducted among Puerto Ricans and Mexican Americans, for example, have shown that substantial confounding by population stratification can occur, even when recruiting ethnically matched cases and controls from the same clinic.35,39 The lack of detailed race/ethnic information (ie, such as whether a patient is Mexican American, Central American, and so on) remains a limitation of the study.
Despite these limitations, we observed a significant increased risk of ICH in Hispanics independent of known ICH predictors in the natural, untreated course in a large, multiethnic cohort of patients with BAVM. Differences in the prevalence of risk factors such as systemic medical comorbidity or in nontraditional risk factors such as genetic variation or ancestry may explain the increased risk of subsequent ICH observed in Hispanics and merits further investigation.
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Acknowledgments |
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We thank Nancy Quinnine, Brad Dispensa, Philippe Jolivalt, Voltaire Gungab (UCSF), and April Manns and Mike Sorel (KPMCP) for assistance with patient recruitment, data management, and manuscript preparation. We also gratefully acknowledge the contributions of other members of the UCSF and KPMCP BAVM Study Projects (http://avm.ucsf.edu).
Sources of Funding
Supported in part by NIH grants R01 NS34949 (to W.L.Y.), P01 NS044155-P1 (to W.L.Y.), and an AHA Scientist Development Grant (0735242N) awarded to H.K.
Disclosures
None.
Received February 16, 2007; accepted March 20, 2007.
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[Abstract/Free Full Text]
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