[Show abstract][Hide abstract] ABSTRACT: Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
The American Journal of Human Genetics 04/2014; 94(4):511-21. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leukocytosis is associated with hemorrhage volume and early neurologic deterioration after intracerebral hemorrhage (ICH). We examined total white blood cell (WBC) count, absolute monocyte count (AMC), and absolute neutrophil count (ANC) as potential readily available prognostic biomarkers in human ICH.
In a retrospective study, adult patients aged 18 years or older who presented to 1 of 2 local hospitals with nontraumatic ICH from July 2008 to December 2009 within 12 hours of symptom onset were identified. Demographics, Glasgow Coma Scale (GCS), ICH volume, ICH location, and 30-day case fatality rates were determined. Total WBC count, ANC, AMC, and hemoglobin concentration were determined. Linear and logistic regressions were used to evaluate factors associated with baseline ICH volume (log transformed) and 30-day case fatality, respectively.
Of the 186 patients, mean (±SD) age was 67.3 ± 14.8 years; 51% were men and 22% were black. Median (interquartile range) ICH volume was 12.8 (4.9, 29.4) mL. After adjusting for patient age and initial hemoglobin, higher initial WBC count (P = .0009) and higher ANC (P = .006) were associated with higher ICH volume, whereas AMC was not (P = .4). After adjusting for patient age, GCS, intraventricular hemorrhage (+/-), stroke location, and ICH volume, baseline AMC was associated with greater odds of 30-day case fatality (odds ratio 2.26, 95% confidence interval 1.10-4.65, P = .03).
The association of AMC with higher 30-day case fatality after ICH is hypothesis generating. Given the lack of association between presenting AMC and ICH volume, AMC may contribute to secondary injury after ICH (hematoma expansion and/or cerebral edema).
Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 10/2013;
[Show abstract][Hide abstract] ABSTRACT: Apolipoprotein E (ApoE) genotypes have been associated with lobar intracerebral hemorrhage (ICH). Although statins have been associated with an increased risk of ICH, meta-analyses have not consistently shown a statin-induced risk of ICH. Here, we test whether hypercholesterolemia (HC) and ApoE polymorphisms affect the risk of ICH by statin use.
The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study is a prospective, demographically matched case-control study of ICH. A similar study of ICH, Genetic Risks for Medication-Related Hemorrhagic Stroke (GOCHA), was used as a replication cohort. Subjects were classified as normocholesterolemia, HC without statin use, and HC with statin use. Statistical comparisons were performed using Fisher exact test, χ(2) tests, and the Breslow-Day test.
The discovery cohort consisted of 558 ICH cases and 1444 controls, and the replication cohort consisted of 1020 ICH cases and 382 controls. The association of lower risk for HC was not attenuated by statin use. Statin use was observed to confer a higher risk for lobar ICH in those carrying ApoE4/E4 and ApoE2/E4 genotypes in both discovery and replication cohorts, and a test for interaction showed a trend towards significance (P=0.11 for statin and ApoE4/E4).
Statin use does not seem to attenuate the association of HC with decreased risk for nonlobar ICH. Our data support a gene-by-drug effect for lobar ICH, but larger sample sizes are needed to confirm the association before any clinical change is warranted.
http://clinicaltrials.gov. Unique identifier: NCT00930280.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
[Show abstract][Hide abstract] ABSTRACT: DNA from buccal brush samples is being used for high-throughput analyses in a variety of applications, but the impact of sample type on genotyping success and downstream statistical analysis remains unclear. The objective of the current study was to determine laboratory predictors of genotyping failure among buccal DNA samples, and to evaluate the successfully genotyped results with respect to analytic quality control metrics. Sample and genotyping characteristics were compared between buccal and blood samples collected in the population-based Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study (https://gerfhs.phs.wfubmc.edu/public/index.cfm).
Seven-hundred eight (708) buccal and 142 blood DNA samples were analyzed for laboratory-based and analysis metrics. Overall genotyping failure rates were not statistically different between buccal (11.3%) and blood (7.0%, p = 0.18) samples; however, both the Contrast Quality Control (cQC) rate and the dynamic model (DM) call rates were lower among buccal DNA samples (p < 0.0001). The ratio of double-stranded to total DNA (ds/total ratio) in the buccal samples was the only laboratory characteristic predicting sample success (p < 0.0001). A threshold of at least 34% ds/total DNA provided specificity of 98.7% with a 90.5% negative predictive value for eliminating probable failures. After genotyping, median sample call rates (99.1% vs. 99.4%, p < 0.0001) and heterozygosity rates (25.6% vs. 25.7%, p = 0.006) were lower for buccal versus blood DNA samples, respectively, but absolute differences were small. Minor allele frequency differences from HapMap were smaller for buccal than blood samples, and both sample types demonstrated tight genotyping clusters, even for rare alleles.
We identified a buccal sample characteristic, a ratio of ds/total DNA <34%, which distinguished buccal DNA samples likely to fail high-throughput genotyping. Applying this threshold, the quality of final genotyping resulting from buccal samples is somewhat lower, but compares favorably to blood. Caution is warranted if cases and controls have different sample types, but buccal samples provide comparable results to blood samples in large-scale genotyping analyses.
[Show abstract][Hide abstract] ABSTRACT: Early deterioration is common in intracerebral hemorrhage (ICH). Treatment at tertiary care centers has been associated with lower ICH mortality. Guidelines recommend aggressive care for 24 hours irrespective of the initial outlook. We examined the frequency of and factors associated with transfer to tertiary centers in ICH patients who initially presented at nontertiary emergency departments (EDs). We also compared observed with expected mortality in transferred and nontransferred patients using published short-term mortality predictors for ICH.
Adult patients who resided in a 5-county region and presented to nontertiary EDs with nontraumatic ICH in 2005 were identified. Intracerebral hemorrhage score and ICH Grading Scale (ICH-GS) were determined. Of 16 local hospitals, 2 were designated tertiary care centers. Logistic regression was used to assess factors associated with transfer.
Of 205 ICH patients who presented to nontertiary EDs, 80 (39.0%) were transferred to a tertiary center. In multivariate regression, better baseline function (modified Rankin scale 0-2 versus 3-5; odds ratio, 0.42, 95% confidence interval, 0.21-0.85, P = .016) and black race (odds ratio, 2.28, 95% confidence interval 1.01-5.12, P = .046) were associated with transfer. A trend toward higher 30-day mortality was observed in nontransferred patients (32.5% versus 45.6%, P = .06). The ICH-GS overestimated mortality for all patients, while the ICH Score adequately predicted mortality.
We found no significant difference in mortality between transferred and nontransferred patients, but the trend toward higher mortality in nontransferred patients suggests that further evaluation of ED disposition decisions for ICH patients is warranted. Expected ICH mortality may be overestimated by published tools.
The American journal of emergency medicine 05/2011; 29(4):391-5. · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Warfarin-associated intracerebral hemorrhage (WICH) became more frequent in the past 2 decades. Interest in potential WICH treatment trials has grown, but the practicality of such trials has received less attention. We determined the number of patients that would be eligible for enrollment in hypothetical treatment trials for WICH using a population-based study.
We identified all patients aged 18 years or older from the Greater Cincinnati/Northern Kentucky region with nontraumatic intracerebral hemorrhage in 2005. Three hypothetical WICH treatment trial criteria sets were used to determine eligibility for enrollment, varying from relatively strict to broadly inclusive. For the hypothetical trials, we assumed the comparison of a standard therapy to an alternative therapy. Sample size calculations assumed different rates of poor outcome depending on the criteria set, various effect sizes, a 2-sided alpha of 0.05, and 80% power. Given 5 years of trial enrollment, the population base needed to enroll the required subjects was then calculated.
Warfarin-associated intracerebral hemorrhage accounted for 54 of 286 (19%) cases of intracerebral hemorrhage within the Greater Cincinnati/Northern Kentucky region in 2005. Eligibility rates ranged from 2 of 54 WICH patients (4% of cases, strictest set) to 11 of 54 WICH patients (20% of cases, most inclusive set). Given these rates, a population base of at least 67 million persons would be required to conduct a 5-year trial for WICH with a 10% effect size using a moderately strict criteria set.
Any planned treatment trial for WICH should anticipate significant challenges in successfully enrolling adequate numbers of patients.
[Show abstract][Hide abstract] ABSTRACT: To compare surgical management and case-fatality rates of intracerebral hemorrhage (ICH) in 1988 and 2005.
We identified all adult residents (age, >or=18 years) from the 5-county Greater Cincinnati region who were hospitalized with ICH in 1988 and 2005. Demographics, severity of illness, ICH volume, ICH location, rates and timing of surgery, and 30-day case-fatality rate were compared between the groups.
In 1988, 171 ICH patients (67 lobar, 80 deep cerebral, 10 brainstem, and 14 cerebellar) met the study criteria; in 2005, 259 ICH patients (91 lobar, 123 deep cerebral, 19 brainstem, and 26 cerebellar) met the study criteria. In 1988, 16% of the patients had surgical removal of their ICH versus 7% in 2005 (P = 0.003). In both 1988 and 2005, patients treated with surgery were younger (P < 0.001) and had a higher percentage of cerebellar hemorrhages than nonsurgical patients. The timing of surgery was similar in 1988 and 2005. In 1988, the 30-day case-fatality rate was 32% in surgical patients versus 50% in nonsurgical patients (P = 0.06). In 2005, the 30-day case-fatality rate was 16% (surgical) versus 45% (nonsurgical) (P = 0.02).
The frequency of surgery for ICH was lower in 2005 than in 1988, which may reflect the influence of recent clinical trial data showing no benefit for surgery rather than medical management. The ICH case-fatality rate was essentially the same in 1988 and 2005. Innovative clinical trials to improve ICH outcomes are warranted.
[Show abstract][Hide abstract] ABSTRACT: Among patients with intracerebral hemorrhage (ICH), warfarin use before onset leads to greater mortality. In a retrospective study, we sought to determine whether warfarin use is associated with larger initial hematoma volume, one determinant of mortality after ICH.
We identified all patients hospitalized with ICH in the Greater Cincinnati region from January through December 2005. ICH volumes were measured on the first available brain scan by using the abc/2 method. Univariable analyses and a multivariable generalized linear model were used to determine whether international normalized ratio (INR) influenced initial ICH volume after adjusting for other factors, including age, race, sex, antiplatelet use, hemorrhage location, and time from stroke onset to scan.
There were 258 patients with ICH, including 51 patients taking warfarin. In univariable comparison, when INR was stratified, there was a trend toward a difference in hematoma volume by INR category (INR <1.2, 13.4 mL; INR 1.2-2.0, 9.3 mL; INR 2.1-3.0, 14.0 mL; INR >3.0, 33.2 mL; p = 0.10). In the model, compared with patients with INR <1.2, there was no difference in hematoma size for patients with INR 1.2-2.0 (p = 0.25) or INR 2.1-3.0 (p = 0.36), but patients with INR >3.0 had greater hematoma volume (p = 0.02). Other predictors of larger hematoma size were ICH location (lobar compared with deep cerebral, p = 0.02) and shorter time from stroke onset to scan (p < 0.001).
Warfarin use was associated with larger initial intracerebral hemorrhage (ICH) volume, but this effect was only observed for INR values >3.0. Larger ICH volume among warfarin users likely accounts for part of the excess mortality in this group.
[Show abstract][Hide abstract] ABSTRACT: No proven treatments exist for intracerebral hemorrhage (ICH). Carefully selected patients may benefit from surgery, and an international multicenter trial is ongoing. We sought to determine how many patients in a population-based ICH cohort would have been eligible for surgery using the Surgical Trial in Intracerebral Hemorrhage II (STICH II) criteria.
We identified all patients aged > or =18 years residing in the five-county Greater Cincinnati region who were hospitalized with first-ever nontraumatic ICH in 2005. STICH II trial criteria were used to determine eligibility for treatment and reasons for exclusion.
During 2005, 286 ICH patients were identified (103 lobar, 126 deep cerebral, 23 brainstem, 28 cerebellar, and 6 IVH). Non-lobar hemorrhages are not eligible for STICH II. Among patients with lobar hemorrhage, 22 had no exclusions. The most common (not mutually exclusive) reasons for exclusion were volume <10 cc or >100 cc (n = 46) and presence of IVH (n = 27). No significant age, gender or racial differences existed between eligible and ineligible patients with lobar ICH. Only one (4.5%) of the 22 STICH II eligible patients in our population had surgery, compared with eight of 81 (9.9%) ineligible lobar ICH patients (P = 0.43). Mortality at 180 days in STICH II eligible patients was 36% vs. 49% for ineligible lobar ICH patients (P = 0.19).
In this population-based ICH cohort, 7.7% (22 of 286) of ICH patients would have qualified for STICH II enrollment. Other treatment options need to be explored for most ICH patients.
Neurocritical Care 01/2008; 9(2):237-41. · 3.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Selective serotonin reuptake inhibitors (SSRI) are widely prescribed. Several reports have observed an increased bleeding risk associated with SSRI use, which is hypothesized to be secondary to their antiplatelet effect.
We tested the hypothesis that SSRIs increase the risk for or potentiate the risk of hemorrhagic stroke associated with antiplatelets and anticoagulants.
In multivariate analysis, we found no increased risk associated with SSRI use for intracerebral hemorrhage (odds ratio=1.1, 95% CI: 0.7 to 1.8; P=0.63) or subarachnoid hemorrhage (odds ratio=0.6, 95% CI: 0.4 to 1.0; P=0.054). In addition, potentiation of risk with warfarin or antiplatelets was not observed.
Further studies with larger populations would be needed to exclude a small increase in intracranial hemorrhage risk with SSRI use.
[Show abstract][Hide abstract] ABSTRACT: Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However, replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW. Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes, hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P=0.019 and P<10(-4), respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks.
Human Genetics 07/2007; 121(5):601-7. · 4.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Blacks have higher mortality rates from aneurysmal subarachnoid hemorrhage (SAH) than Caucasians. The time to treatment for aneurysmal SAH has been found to correlate with mortality and outcome. Therefore, we examined racial differences in the time to treatment of aneurysmal SAH among patients from the Greater Cincinnati area.
We evaluated data from 439 adult aneurysmal SAH patients prospectively identified from May 1997 to August 2001 and July 2002 to March 2005. The primary outcome measure was time to treatment, defined as elapsed time from arrival in the emergency department to aneurysm treatment. A multivariable model was constructed to determine the role of potential variables, including race, on time to treatment for SAH.
In univariate analysis, Caucasian patients were significantly older than black patients (P < 0.0001) and were more likely to be male (P = 0.014), insured (P < 0.0001), and transferred from emergency departments of presentation to other hospitals (P < 0.0001). Black patients were more likely to have anterior circulation aneurysms (P = 0.009) and preexisting hypertension (P < 0.001). In univariate analysis, anterior circulation aneurysms showed a trend toward earlier treatment than posterior circulation aneurysms (P = 0.07). In multivariable models, race was not associated with time to treatment or case-fatality rate. Patients transferred from other facilities were treated more expeditiously than patients who presented directly to the emergency department (P = 0.003), and a history of diabetes mellitus was associated with delay in treatment (P = 0.05).
Race was not associated with time to treatment after aneurysmal SAH in the Greater Cincinnati area. Reducing the increased burden of SAH mortality among blacks must be addressed at the prevention stage.
[Show abstract][Hide abstract] ABSTRACT: With the advent of genome-wide genotyping, the utility of stored buccal brushes for DNA extraction and genotyping has been questioned. We sought to describe the genomic DNA yield and concordance between stored buccal brushes and blood samples from the same individuals in the context of Affymetrix 500 K Human GeneChip genotyping.
Buccal cytobrushes stored for approximately 7 years at -80 degrees C prior to extraction yielded sufficient double stranded DNA (dsDNA) to be successfully genotyped on the Affymetrix approximately 262 K NspI chip, with yields between 536 and 1047 ng dsDNA. Using the BRLMM algorithm, genotyping call rates for blood samples averaged 98.4%, and for buccal samples averaged 97.8%. Matched blood samples exhibited 99.2% concordance, while matched blood and buccal samples exhibited 98.8% concordance.
Buccal cytobrushes stored long-term result in sufficient dsDNA concentrations to achieve high genotyping call rates and concordance with stored blood samples in the context of Affymetrix 500 K SNP genotyping. Thus, given high-quality collection and storage protocols, it is possible to use stored buccal cytobrush samples for genome-wide association studies.
[Show abstract][Hide abstract] ABSTRACT: To define temporal trends in the incidence of anticoagulant-associated intracerebral hemorrhage (AAICH) during the 1990s and relate them to rates of cardioembolic ischemic stroke.
We identified all patients hospitalized with first-ever intracerebral hemorrhage (ICH) in greater Cincinnati during 1988, from July 1993 through June 1994, and during 1999. AAICH was defined as ICH in patients receiving warfarin or heparin. Patients from the same region hospitalized with first-ever ischemic stroke of cardioembolic mechanism were identified during 1993/1994 and 1999. Incidence rates were calculated and adjusted to the 2000 US population. Estimates of warfarin distribution in the United States were obtained for the years 1988 through 2004.
AAICH occurred in 9 of 184 ICH cases (5%) in 1988, 23 of 267 cases (9%) in 1993/1994, and 54 of 311 cases (17%) in 1999 (p < 0.001). The annual incidence of AAICH per 100,000 persons was 0.8 (95% CI 0.3 to 1.3) in 1988, 1.9 (1.1 to 2.7) in 1993/1994, and 4.4 (3.2 to 5.5) in 1999 (p < 0.001 for trend). Among persons aged > or =80, the AAICH rate increased from 2.5 (0 to 7.4) in 1988 to 45.9 (25.6 to 66.2) in 1999 (p < 0.001 for trend). Incidence rates of cardioembolic ischemic stroke were similar in 1993/1994 and 1999 (31.1 vs 30.4, p = 0.65). Warfarin distribution in the United States quadrupled on a per-capita basis between 1988 and 1999.
The incidence of anticoagulant-associated intracerebral hemorrhage quintupled in our population during the 1990s. The majority of this change can be explained by increasing warfarin use. Anticoagulant-associated intracerebral hemorrhage now occurs at a frequency comparable to subarachnoid hemorrhage.
[Show abstract][Hide abstract] ABSTRACT: Apolipoprotein E (APOE) and elastin (ELN) are plausible candidate genes involved in the pathogenesis of stroke. We tested for association of variants in APOE and ELN with subarachnoid hemorrhage (SAH) in a population-based study. We genotyped 12 single nucleotide polymorphisms (SNPs) on APOE and 10 SNPs on ELN in a sample of 309 Caucasian individuals, of whom 107 are SAH cases and 202 are age-, race-, and gender-matched controls from the Greater Cincinnati/Northern Kentucky region. Associations were tested at genotype, allele, and haplotype levels. A genomic control analysis was performed to check for spurious associations resulting from population substructure.
At the APOE locus, no individual SNP was associated with SAH after correction for multiple comparisons. Haplotype analysis revealed significant association of the major haplotype (Hap1) in APOE with SAH (p = 0.001). The association stemmed from both the 5' promoter and the 3' region of the APOE gene. APOE epsilon2 and epsilon 4 were not significantly associated with SAH. No association was observed for ELN at genotype, allele, or haplotype level and our study failed to confirm previous reports of ELN association with aneurysmal SAH.
This study suggests a role of the APOE gene in the etiology of aneurysmal SAH.
BMC Medical Genetics 02/2007; 8:49. · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To characterize long-term mortality following intracerebral hemorrhage (ICH) in two large population-based cohorts assembled more than a decade apart.
All patients age > or = 18 hospitalized with nontraumatic ICH in the Greater Cincinnati/Northern Kentucky area were identified during 1988 (Cohort 1) and from May 1998 to July 2001 and August 2002 to April 2003 (Cohort 2). Mortality was tabulated using actuarial methods and compared with a log-rank test.
There were 183 patients with ICH in Cohort 1 and 1,041 patients in Cohort 2. Patients in Cohort 1 were more likely to be white (p = 0.024) and undergo operation for their ICH (p = 0.002), whereas patients in Cohort 2 were more commonly on anticoagulants (p < 0.001). Among patients in Cohort 1, mortality at 7 days, 1 year, and 10 years was 31, 59, and 82%. Among patients in Cohort 2, mortality at 7 days and 1 year was 34 and 53%. Mortality rates did not differ between cohorts by log-rank test (p = 0.259).
Intracerebral hemorrhage (ICH) mortality did not improve significantly between study periods. Operation for ICH became less frequent, whereas anticoagulant-associated ICH became more common.
[Show abstract][Hide abstract] ABSTRACT: The Phosphodiesterase 4D (PDE4D) gene was reported recently to be associated with ischemic stroke in an Icelandic population. The association was found predominately with large vessel and cardioembolic stroke. However, 2 recent reports were unable to confirm this association, although a trend toward association with cardioembolic stroke was reported. None of the reports included significant proportions of blacks. We tested for genotype and haplotype association of polymorphisms of the PDE4D gene with ischemic stroke in a population-based, biracial, case-control study.
A total of 357 cases of ischemic stroke and 482 stroke-free controls from the same community were examined. Single nucleotide polymorphisms (SNPs) were chosen based on significant associations reported previously. Linkage disequilibrium (LD), SNP, and haplotype association analysis was performed using PHASE 2.0 and Haploview 3.2.
Although several univariate associations were identified, only 1 SNP (rs2910829) was found to be significantly associated with cardioembolic stroke among both whites and blacks. The rs152312 SNP was associated with cardioembolic stroke among whites after multiple comparison corrections. The same SNP was not associated with cardioembolic stroke among blacks. However, significant haplotype association was identified for both whites and blacks for all ischemic stroke, cardioembolic stroke, and stroke of unknown origin. Haplotype association was identified for small vessel stroke among whites.
PDE4D is a risk factor for ischemic stroke and, in particular, for cardioembolic stroke, among whites and blacks. Further study of this gene is warranted.
[Show abstract][Hide abstract] ABSTRACT: The characteristics of patients with anticoagulant-associated intracerebral hemorrhage (AAICH) have not been well characterized in a population-based setting.
We attempted to ascertain all patients with ICH in Greater Cincinnati from May 1998 to July 2001 and August 2002 to April 2003 via retrospective review of ICD-9 codes 430-438.9 at all area hospitals and prospective surveillance at tertiary centers. Cases of ICH without coagulopathy and AAICH were compared with multivariate logistic modeling and survival analysis.
AAICH occurred in 190 of 1041 ICH cases (18%). In multivariate analysis, predictors of AAICH were cerebellar location of hemorrhage (p = 0.01) and a history of coronary artery disease (p < 0.001), ischemic stroke (p < 0.001), atrial fibrillation (p < 0.001) and DVT or PE (p < 0.001). Relative to other ICH locations, only cerebellar ICH showed an excess risk of anticoagulant-associated hemorrhage (OR 2.2, 95% CI 1.2 to 4.0). In multivariate modeling the only predictor of cerebellar location of ICH was anticoagulation (p < 0.001). Patients with AAICH were more likely to die than other ICH patients. The difference in morality occurred by day one (mortality 33.2% vs 16.3%, p < 0.001) and remained stable through one year (mortality 66.3% vs 50.3%, p < 0.001).
AAICH preferentially affects the cerebellum. Despite its association with amyloid angiopathy, lobar ICH was no more likely to be anticoagulant-associated than deep cerebral ICH. The excess mortality among AAICH patients accrues within one day of hemorrhage. Patients with AAICH have a high burden of vascular risk factors. New treatments for AAICH with prothrombotic potential should be evaluated in randomized controlled trials before routine use.
Neurocritical Care 02/2006; 5(3):197-201. · 3.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To date, there are no proven, effective treatments for intracerebral hemorrhage (ICH) beyond supportive medical care. A recent randomized, blinded, placebo-controlled trial of recombinant factor VIIa (rFVIIa) administered intravenously within 4 hours of ICH onset reported a reduction in morbidity and mortality compared with placebo. We sought to determine the potential applicability of rFVIIa in a large, population-based cohort of ICH patients.
All of the patients age > or =18 years hospitalized with nontraumatic ICH in the Greater Cincinnati region were identified from May 1998 to July 2001 and August 2002 to April 2003. Patient demographics were compared with the inclusion and exclusion criteria from the rFVIIa trial to determine eligibility for treatment and reasons for exclusion. Mortality in the eligible patient group was compared with the placebo group in the rFVIIa trial.
Over 4 calendar years, 1018 ICH patients were identified; of these, 133 (13.1%) had no exclusions and presented within the prescribed time window. An additional 45 patients (4.4%) may have been eligible but had uncertain onset or computed tomography scan times. The most common reasons for exclusion (not mutually exclusive) were late presentation (n=398), vaso-occlusive disease (n=369), deep coma (n=219), and prolonged international normalized ratio or partial thromboplastin time (n=200). Mortality at 90 days among potentially eligible patients was the same as for the placebo group in the rFVIIa trial (29% versus 29%; P=0.99).
In this large, population-based ICH cohort, 13.1% to 17.5% of patients would have qualified for treatment with rFVIIa by trial criteria.