Matthew L. Flaherty

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.

Age at stroke: Temporal trends in stroke incidence in a large, biracial population

Objectives: We describe temporal trends in stroke incidence stratified by age from our population-based stroke epidemiology study. We hypothesized that stroke incidence in younger adults (age 20–54) increased over time, most notably between 1999 and 2005. Methods: The Greater Cincinnati/Northern Kentucky region includes an estimated population of 1.3 million. Strokes were ascertained in the population between July 1, 1993, and June 30, 1994, and in calendar years 1999 and 2005. Age-, race-, and gender-specific incidence rates with 95 confidence intervals were calculated assuming a Poisson distribution. We tested for differences in age trends over time using a mixed-model approach, with appropriate link functions. Results: The mean age at stroke significantly decreased from 71.2 years in 1993/1994 to 69.2 years in 2005 (p < 0.0001). The proportion of all strokes under age 55 increased from 12.9% in 1993/1994 to 18.6% in 2005. Regression modeling showed a significant change over time (p = 0.002), characterized as a shift to younger strokes in 2005 compared with earlier study periods. Stroke incidence rates in those 20–54 years of age were significantly increased in both black and white patients in 2005 compared to earlier periods. Conclusions: We found trends toward increasing stroke incidence at younger ages. This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable.

The Unchanging Incidence and Case-Fatality of Stroke in the 1990s A Population-Based Study

Background and Purpose— Many advances were made in stroke prevention strategies during the 1990s, and yet temporal trends in stroke incidence and case-fatality have not been reported in the United States. Blacks have a 2-fold higher risk of stroke; however, there are no data over time showing if any progress has been made in reducing racial disparity in stroke incidence. The objective of this study was to examine temporal trends in stroke incidence and case-fatality within a large, biracial population during the 1990s. Methods— Within a biracial population of 1.3 million, all strokes were ascertained at all local hospitals using International Classification of Diseases, 9th Revision codes during July 1993 to June 1994 and again in 1999. A sampling scheme was used to ascertain cases in the out-of-hospital setting. Race-specific incidence and case-fatality rates were calculated and standardized to the 2000 US Census population. A population-based telephone survey regarding stroke risk factor prevalence and medication use was performed in 1995 and 2000. Results— There were 1954 first-ever strokes in 1993–1994 and 2063 first-ever strokes in 1999. The annual incidence of first-ever hospitalized stroke did not significantly change between study periods: 158 per 100 000 in both 1993–1994 and 1999 (P=0.97). Blacks continue to have higher stroke incidence than whites, especially in the young; however, case-fatality rates continue to be similar between races and are not changing over time. Medication use for treatment of stroke risk factors significantly increased in the general population between study periods. Conclusions— Despite advances in stroke prevention treatments during the 1990s, the incidence of hospitalized stroke did not decrease within our population. Case-fatality also did not change between study periods. Excess stroke mortality rates seen in blacks nationally are likely the result of excess stroke incidence and not case-fatality, and the racial disparity in stroke incidence did not change over time.

Stroke Incidence is Decreasing in Whites, but Not in Blacks: A Population-Based Estimate of Temporal Trends in Stroke Incidence from the Greater Cincinnati/Northern Kentucky Stroke Study

Background and Purpose— Although other studies (in largely white populations) have found that stroke incidence declined during the 1990s, we previously reported that stroke incidence in our population (18% of which was black) did not change during that decade and that incidence rates in blacks were significantly higher than in whites. We sought to update temporal trends in stroke incidence by adding new data obtained from our large, biracial population in 2005. The objective of this study was to examine temporal trends in stroke incidence and case-fatality within a large biracial population over time by comparing stroke incidence rates from 1993 to 1994, 1999, and 2005. Methods— Within the Greater Cincinnati/Northern Kentucky population of 1.3 million, all strokes among area residents were ascertained at all local hospitals during July 1993 to June 19/94 and calendar years 1999 and 2005. A sampling scheme was used to ascertain cases in the out-of-hospital setting. Only first-ever strokes were included in this analysis. Race-specific incidence rates, standardized to the 2000 US Census population, and case-fatality rates were calculated. Results— The number of physician-confirmed first-ever strokes in patients ≥20 years of age was 1942 in 1993 to 1994, 2041 in 1999, and 1921 in 2005. In all study periods, blacks had higher stroke incidence than whites, and case-fatality rates were similar between races. In contrast to previous study periods, we found a significant decrease in overall stroke incidence in 2005. When stratified by race and stroke subtype, this change was driven by a decrease in ischemic stroke incidence among whites, whereas ischemic stroke incidence in blacks was unchanged. Hemorrhagic stroke incidence was unchanged in both races. Conclusions— For the first time, we report a significant decrease in stroke incidence within our population, which is consistent with other reports in the literature. This decrease was found only among whites, which suggests a worsening of the racial disparity in stroke incidence.

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.

Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes.

Background: Hematoma expansion (HE) is a surrogate marker in intracerebral hemorrhage (ICH) trials. However, the amount of HE necessary to produce poor outcomes in an individual is unclear; there is no agreement on a clinically meaningful definition of HE. We compared commonly used definitions of HE in their ability to predict poor outcome as defined by various cutpoints on the modified Rankin Scale (mRS). Methods: In this cohort study, we analyzed 531 patients with ICH from the Virtual International Stroke Trials Archive. Primary outcome was mRS at 90 days, dichotomized into 0–3 vs 4–6. Secondary outcomes included other mRS cutpoints and mRS “shift analysis.” Sensitivity, specificity, and predictive values for commonly used HE definitions were calculated. Results: Between 13% and 32% of patients met the commonly used HE definitions. All definitions independently predicted poor outcome; positive predictive values increased with higher growth cutoffs but at the expense of lower sensitivities. All HE definitions showed higher specificity than sensitivity. Absolute growth cutoffs were more predictive than relative cutoffs when mRS 5–6 or 6 was defined as “poor outcome.” Conclusion: HE robustly predicts poor outcome regardless of the growth definition or the outcome definition. The highest positive predictive values are obtained when using an absolute growth definition to predict more severe outcomes. Given that only a minority of patients may have clinically relevant HE, hemostatic ICH trials may need to enroll a large number of patients, or select for a population that is more likely to have HE.

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.

Temporal Trends in Public Awareness of Stroke Warning Signs, Risk Factors, and Treatment

Background and Purpose— Delay in seeking medical attention after stroke symptom onset is the most important reason for low rates of thrombolytic use for ischemic stroke (IS) in the United States. This may be related to poor recognition of stroke symptoms, or to lack of awareness of time-sensitive stroke treatments. We describe public knowledge of t-PA as a treatment for IS, as well as changes over time in knowledge of stroke warning signs (WS) and risk factors (RF). Methods— Survey respondents were drawn from our biracial population of 1.3 million using random-digit dialing in 1995, 2000, and 2005 to reflect the age, race, and gender distribution of stroke patients, based on an ongoing stroke incidence study in the same region. They were asked open-ended questions regarding stroke WS, RF, and, in 2005, specific questions regarding t-PA. Comparisons over time were made using &khgr;2 analysis, and were corrected for multiple comparisons. Results— Over the 10-year study period, 6209 surveys were completed. Knowledge of WS and RF improved between 1995 and 2000. Between 2000 and 2005, knowledge did not improve significantly; however, there was a significant improvement in knowledge of 3 warning signs (12% in 1995 vs 16% in 2005, P=0.0004). In 2005, only 3.6% of those surveyed were able to independently name t-PA or “clot buster” when asked: “Suppose you were having a stroke. Do you know of any medication your doctor could give you into the vein to increase your chance of recovering from a stroke?”-although 19% claimed to have heard of t-PA once it was mentioned to them. Conclusion— Despite numerous national stroke public awareness campaigns, public knowledge of stroke WS and RF has not improved over the last 5 years. In addition, knowledge of t-PA as a treatment for IS is extremely poor. Public awareness messages in the future should focus on the possibility of urgent treatments, in addition to stroke WS and RF, so the public can translate their knowledge into action and present to medical attention more quickly. This may be the highest yield approach to increasing rates of treatment of IS with t-PA.

Designing a Message for Public Education Regarding Stroke Does FAST Capture Enough Stroke

Background and Purpose— Previous studies have shown poor public knowledge of stroke warning signs. The current public education message adopted by the American Heart Association lists 5 stroke warning signs (“suddens”). Another message called FAST (face, arm, speech, time) could be easier to remember, but it does not contain as many stroke symptoms. We sought to assess the percentage of stroke/transient ischemic attack (TIA) patients identified by both public awareness messages by examining presenting symptoms of all stroke/TIA patients from a large, biracial population in 1999. Methods— Cases of stroke who presented to an emergency department or were directly admitted were ascertained at all local hospitals by screening of ICD-9 codes 430 to 436, and prospective screening of emergency department admission logs, in 1999. Study nurses abstracted initial presenting symptoms from the medical record. All-cause 30-day case-fatality was calculated. Results— During 1999, 3498 stroke/TIA patients (17% black, 56% female) presented to an emergency department. Of these events, 11.1% had presenting symptoms not included in FAST, whereas 0.1% had presenting symptoms not included in the suddens. The FAST message performed much better for ischemic stroke and TIA than for hemorrhage, missing 8.9% of the ischemic strokes and 8.2% of the TIAs, versus 30.6% of intracerebral hemorrhage/subarachnoid hemorrhage cases. Case-fatality in patients missed by FAST was similar to patients with FAST symptoms (9.0% versus 11.6%, P=0.15). Conclusions— Within our population, we found that the FAST message identified 88.9% of stroke/TIA patients. The FAST message performed better for ischemic stroke and TIA than for hemorrhagic stroke. Whether the FAST message is easier to recall for the public than the “suddens” message has yet to be determined.

Greater Rupture Risk for Familial as Compared to Sporadic Unruptured Intracranial Aneurysms

Background and Purpose— The risk of intracranial aneurysm (IA) rupture in asymptomatic members of families who have multiple affected individuals is not known. Methods— First-degree unaffected relatives of those with a familial history of IA who had a history of smoking or hypertension but no known IA were offered cerebral MR angiography (MRA) and followed yearly as part of a National Institute of Neurological Diseases and Stroke-funded study of familial IA (Familial Intracranial Aneurysm [FIA] Study). Results— A total of 2874 subjects from 542 FIA Study families were enrolled. After study enrollment, MRAs were performed in 548 FIA Study family members with no known history of IA. Of these 548 subjects, 113 subjects (20.6%) had 148 IAs by MRA of whom 5 subjects had IA ≥7 mm. Two subjects with an unruptured IA by MRA/CT angiography (3-mm and 4-mm anterior communicating artery) subsequently had rupture of their IA. This represents an annual rate of 1.2 ruptures per 100 subjects (1.2% per year; 95% CI, 0.14% to 4.3% per year). None of the 435 subjects with a negative MRA have had a ruptured IA. Survival curves between the MRA-positive and -negative cohorts were significantly different (P=0.004). This rupture rate of unruptured IA in the FIA Study cohort of 1.2% per year is approximately 17 times higher than the rupture rate for subjects with an unruptured IA in the International Study of Unruptured Aneurysm Study with a matched distribution of IA size and location 0.069% per year. Conclusions— Small unruptured IAs in patients from FIA Study families may have a higher risk of rupture than sporadic unruptured IAs of similar size, which should be considered in the management of these patients.