Padmini Sekar

The increasing incidence of anticoagulant-associated intracerebral hemorrhage

Objective: 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. Methods: 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. Results: 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 ≥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. Conclusions: 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.

Warfarin use leads to larger intracerebral hematomas

Background: 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. Methods: 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. Results: 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). Conclusion: 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. GLOSSARY: AAICH = anticoagulant-associated intracerebral hemorrhage; GERFHS = Genetic and Environmental Risk Factors for Hemorrhagic Stroke; HR = hazard ratio; ICH = intracerebral hemorrhage; INR = international normalized ratio; IVH = intraventricular hemorrhage.

Racial Variations in Location and Risk of Intracerebral Hemorrhage

Background and Purpose— Risk factors for intracerebral hemorrhage (ICH) vary by location. Incidence rates of ICH are known to be higher in American blacks than whites, but how rates may differ by hemorrhage location is unknown. We sought to define incidence rates for different ICH locations in a biracial population. Methods— All hospitalized patients age ≥20 years with spontaneous ICH were identified in the Greater Cincinnati/Northern Kentucky metropolitan area from May 1998 to July 2001 and August 2002 to April 2003. Incidence rates per 100 000 persons were age, sex, and race adjusted as appropriate to the 2000 US population. Risk ratios (RRs) with 95% CIs were calculated from unadjusted incidence rates. Results— There were 1038 qualifying ICHs. Annual incidence rates per 100 000 persons ≥20 years of age were 48.9 for blacks and 26.6 for whites. Annual incidence rates per 100 000 blacks in lobar, deep cerebral, brain stem, and cerebellar locations were 15.2, 25.7, 5.1, and 2.9, respectively. Annual incidence rates per 100 000 whites in the same locations were 9.4, 13.0, 1.3, and 2.9. The greatest excess risk of ICH in blacks compared with whites was found among young to middle-aged (35 to 54 years) persons with brain stem (RR, 9.8; 95% CI, 4.2 to 23.0) and deep cerebral (RR, 4.5; 3.0 to 6.8) hemorrhage. Conclusions— The excess risk of ICH in American blacks is largely attributable to higher hemorrhage rates in young and middle-aged persons, particularly for deep cerebral and brain stem locations. Hypertension is the predominant risk factor for hemorrhages in these locations.

Effect of Untreated Hypertension on Hemorrhagic Stroke

Background and Purpose— Stroke is the third leading cause of death and the leading cause of disability in the United States. Intracerebral hemorrhage and subarachnoid hemorrhage represent ≈20% of all stroke cases and have a mortality rate of 40% to 50%. Hypertension is an important risk factor for these subtypes of stroke. We sought to determine whether untreated hypertension carries a different risk from treated hypertension for hemorrhagic stroke. Methods— Cases of hemorrhagic stroke in the greater Cincinnati region were identified by screening all area hospital emergency rooms, radiology reports, and International Classification of Diseases 9 codes. Medical records were reviewed for risk factors and medication use. Cases of hemorrhagic stroke were approached for enrollment into the genetic sampling and interview arm. If subjects agreed, the case was matched by age, race, and gender to population-based controls. Results— Between May 1997 and December 2002, we recruited 549 cases of hemorrhagic stroke, of which 322 were intracerebral hemorrhage and 227 were subarachnoid hemorrhage. Untreated hypertension was found to be a significant risk factor for hemorrhagic stroke (odds ratio [OR]= 3.5 [2.3 to 5.2]; P <0.0001) as was treated hypertension (OR = 1.4 [1.0 to 1.9]; P = 0.03). Insurance status of “self-pay” or Medicaid was a significant risk factor for untreated hypertension (OR = 2.7 [1.6 to 4.4]). We estimate that 17% to 28% of hemorrhagic strokes among hypertensive patients would have been prevented if they had been on hypertension treatment. Conclusion— Untreated hypertension is highly prevalent and an important risk factor for hemorrhagic stroke. We estimate that among hypertensive subjects, approximately one fourth of hemorrhagic strokes would be prevented if all hypertensive subjects received treatment.

Selective Serotonin Reuptake Inhibitors and Risk of Hemorrhagic Stroke

Background and Purpose— 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. Methods— We tested the hypothesis that SSRIs increase the risk for or potentiate the risk of hemorrhagic stroke associated with antiplatelets and anticoagulants. Results— 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. Conclusions— Further studies with larger populations would be needed to exclude a small increase in intracranial hemorrhage risk with SSRI use.

Combined IV and intra-arterial thrombolysis for acute ischemic stroke.

Combined IV and intra-arterial (IA) thrombolysis for acute ischemic stroke may offer advantages over either technique alone. Sixty-two nonrandomized patients with NIH Stroke Scale scores of ≥10 who met standard criteria for IV thrombolysis were treated with an IV/IA approach. Three-month modified Rankin Scale scores were 0 to 2 for 50% of patients, mortality was 18%, and symptomatic intracerebral hemorrhage occurred in 8%. IV/IA thrombolysis appeared safe and effective in this group.

Location and outcome of anticoagulant-associated intracerebral hemorrhage.

BackgroundThe characteristics of patients with anticoagulant-associated intracerebral hemorrhage (AAICH) have not been well characterized in a population-based setting.MethodsWe 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.ResultsAAICH 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).ConclusionsAAICH 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 accures 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.

Association of Apolipoprotein E4 and Haplotypes of the Apolipoprotein E Gene With Lobar Intracerebral Hemorrhage

Background and Purpose— Conflicting reports in the literature exist with regard to the association of apolipoprotein E (apo E) alleles and lobar intracerebral hemorrhage (ICH). We genotyped 12 single-nucleotide polymorphisms in the 5′ upstream regulatory, exonic, and intronic regions of the apo E gene and performed genotype and haplotype association analyses. Methods— We prospectively enrolled subjects with hemorrhagic stroke and matched them with 2 controls based on age, race, and sex. Each case was reviewed by a physician to determine case status and location of the ICH. Multivariate logistic-regression modeling with backward elimination was used to determine significant risk factors for lobar ICH. Associations at the genotype and haplotype levels and linkage disequilibrium were conducted according to standard statistical methods. Results— Between May 1997 and December 2002, 315 cases of ICH were recruited, of whom 107 were lobar ICH cases matched to 205 controls. No association was found for apo E2, E3, or E4 with nonlobar ICH. Independent, significant risk factors for lobar ICH included apo E4, untreated hypertension, anticoagulant use, a first-degree relative with ICH, and ≤high school education (compared with >high school education). Treated hypercholesterolemia compared with “no history of hypercholesterolemia” was associated with a decreased risk of lobar ICH. Haplotype association analysis demonstrated a significant association of the apo E gene with lobar ICH among whites (P<0.0001) and blacks (P=0.0024). Conclusions— Apo E4 is independently associated with lobar ICH but not nonlobar ICH. Haplotypes of the apo E gene are associated with lobar ICH. Untreated hypertension is a risk factor for lobar ICH.

Smoking and family history and risk of aneurysmal subarachnoid hemorrhage

Objective: Smoking and family history of aneurysmal subarachnoid hemorrhage (aSAH) are independent risk factors for aSAH. Using a population-based case-control study of hemorrhagic stroke, we hypothesized that having both a first-degree relative with a brain aneurysm or SAH (+FH) and current smoking interact to increase the risk of aSAH. Methods: Cases of aneurysmal SAH were prospectively recruited from all 17 hospitals in the five-county region around the University of Cincinnati. Controls were identified by random digit dialing. Controls were matched to cases of aSAH by age (±5 years), race, and sex. Conditional multiple logistic regression was used to identify independent risk factors. For deviation from the additive model, the interaction constant ratio test was used. Results: A total of 339 cases of aSAH were matched to 1,016 controls. Compared to current nonsmokers with no first-degree relatives with aSAH (−FH), the odds ratio (OR) for aSAH for current nonsmokers with +FH was 2.5 (95% confidence interval [CI] 0.9–6.9); for current smokers with −FH, OR = 3.1 (95% CI 2.2–4.4); and for current smokers with +FH, OR = 6.4 (95% CI 3.1–13. 2). The interaction constant ratio, which measured the deviation from the additive model, was significant: 2.19 (95% CI 0.80–5.99). The lower bound of the 95% CI >0.5 signifies a departure from the additive model. Conclusion: Evidence of a gene–environment interaction with smoking exists for aneurysmal subarachnoid hemorrhage. This finding is important to counseling family members and for screening of intracranial aneurysm (IA) as well as the design and interpretation of genetic epidemiology of IA studies.

Infection After Intracerebral Hemorrhage: Risk Factors and Association With Outcomes in the Ethnic/Racial Variations of Intracerebral Hemorrhage Study

Background and Purpose— Risk factors for infections after intracerebral hemorrhage (ICH) and their association with outcomes are unknown. We hypothesized there are predictors of poststroke infection and infections drive worse outcomes. Methods— We determined prevalence of infections in a multicenter, triethnic study of ICH. We performed univariate and multivariate analyses to determine the association of infection with admission characteristics and hospital complications. We performed logistic regression on association of infection with outcomes after controlling for known determinants of prognosis after ICH (volume, age, infratentorial location, intraventricular hemorrhage, and Glasgow Coma Scale). Results— Among 800 patients, infections occurred in 245 (31%). Admission characteristics associated with infection in multivariable models were ICH volume (odds ratio [OR], 1.02/mL; 95% confidence interval [CI], 1.01–1.03), lower Glasgow Coma Scale (OR, 0.91 per point; 95% CI, 0.87–0.95), deep location (reference lobar: OR, 1.90; 95% CI, 1.28–2.88), and black race (reference white: OR, 1.53; 95% CI, 1.01–2.32). In a logistic regression of admission and hospital factors, infections were associated with intubation (OR, 3.1; 95% CI, 2.1–4.5), dysphagia (with percutaneous endoscopic gastrostomy: OR, 3.19; 95% CI, 2.03–5.05 and without percutaneous endoscopic gastrostomy: OR, 2.11; 95% CI, 1.04–4.23), pulmonary edema (OR, 3.71; 95% CI, 1.29–12.33), and deep vein thrombosis (OR, 5.6; 95% CI, 1.86–21.02), but not ICH volume or Glasgow Coma Scale. Infected patients had higher discharge mortality (16% versus 8%; P=0.001) and worse 3-month outcomes (modified Rankin Scale ≥3; 80% versus 51%; P<0.001). Infection was an independent predictor of poor 3-month outcome (OR, 2.6; 95% CI, 1.8–3.9). Conclusions— There are identifiable risk factors for infection after ICH, and infections predict poor outcomes.Background and Purpose Risk factors for infections after intracerebral hemorrhage (ICH) and their association with outcomes are unknown. We hypothesized there are predictors of post-stroke infection and infections drive worse outcomes.