A phase 2 study of tramiprosate for cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: No treatments have been identified to lower the risk of intracerebral hemorrhage due to cerebral amyloid angiopathy (CAA). A potential approach to prevention is the use of agents that interfere with the pathogenic cascade initiated by the beta-amyloid peptide (Abeta). Tramiprosate (3-amino-1-propanesulfonic acid) is a candidate molecule shown in preclinical studies to reduce CAA in a transgenic mouse model. METHODS: We performed a 5-center phase 2 double-blinded trial to evaluate the safety, tolerability, and pharmacokinetics of tramiprosate in subjects with lobar intracerebral hemorrhage. Twenty-four subjects age > or =55 years with possible or probable CAA were randomized to receive 12 weeks of tramiprosate at 1 of 3 oral doses (50, 100, or 150 mg twice daily). Subjects were followed for clinical adverse effects, laboratory, vital sign, electrocardiogram, cognitive, or functional changes, appearance of new symptomatic or asymptomatic hemorrhages, and pharmacokinetic parameters. RESULTS: Enrolled subjects were younger (mean age 70.8+/-5.4, range 61 to 78) and had more advanced baseline disease (measured by number of previous hemorrhages) than consecutive subjects in a CAA natural history cohort. No concerning safety issues were encountered with treatment. Nausea and vomiting were the most common adverse events and were more frequent at high doses. Nine subjects had new symptomatic or asymptomatic hemorrhages during treatment; all occurred in subjects with advanced baseline disease, with no apparent effect of drug dosing assignment. CONCLUSIONS: These data suggest that tramiprosate can be given safely to subjects with suspected CAA and support future efficacy trials.

Validity of a retrospective National Institutes of Health Stroke Scale scoring methodology in patients with severe stroke.

OBJECTIVE: Quantifying stroke severity is essential for interpreting outcomes in stroke studies; severity impacts outcomes. Because outcome studies often enroll patients some time after stroke and there is little standardization of the history and physical examination, objective measurement of stroke severity is limited. A method for retrospectively scoring the National Institutes of Health Stroke Scale (NIHSS) based on history and physical examination has been proposed, but has yet to be validated in patients with higher NIHSS score. We evaluate the validity of this scoring method across the spectrum of the NIHSS scores. METHODS: The retrospective scoring algorithm was applied to history and physical examinations documented for 58 patients with ischemic stroke presenting to any of 17 regional acute care facilities who had a NIHSS score recorded by a stroke team physician. The retrospective NIHSS score was obtained by standardized chart review. Linear regression was used to estimate scale-dependent and scale-independent bias. Limits of agreement quantify deviation of the retrospective NIHSS score from the prospective NIHSS score. RESULTS: Mean (SD) age at stroke was 66 (14) years; 27 (46.6%) patients were men, and 38 (65.5%) were white. The mean (SD) prospective NIHSS score was 13.6 (7.8); the mean (SD) retrospective NIHSS score was 13.7 (7.8). There were 23 (40%) prospective NIHSS scores above 15, and 13 scores (22%) above 20. The linear regression constant was 0.290 (95% confidence interval -0.107, 0.687); the slope was 0.987 (95% confidence interval 0.962, 1.013). The R(2) for the model was 0.991. Limits of agreement were -1.35 and 1.59. CONCLUSION: The retrospective NIHSS appears valid across the entire spectrum of scores.

Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites.

BACKGROUND AND PURPOSE: Blacks have an excess burden of stroke compared with whites; however, data comparing ischemic stroke subtypes among the 2 groups are limited and typically involve relative frequencies. The objective of this study is to compare the incidence rates of ischemic stroke subtypes between blacks and whites within a large, representative, biracial population. METHODS: The Greater Cincinnati/Northern Kentucky Stroke Study is designed to measure incidence rates and trends of all strokes within a well-defined, large, biracial population. Hospitalized cases were ascertained by International Classification of Disease (9th revision; ICD-9) discharge codes. Out-of-hospital events were ascertained by prospective screening of emergency department admission logs, review of coroners' cases, and monitoring all public health and hospital-based primary care clinics. A sampling scheme was used to ascertain events from nursing homes and all other primary care physician offices. All potential cases underwent detailed chart abstraction and confirmed by physician review. Based on all available clinical, laboratory, and radiographic information, ischemic stroke cases were subtyped into the following categories: cardioembolic, large-vessel, small-vessel, other, and stroke of undetermined cause. Race-specific incidence rates were calculated and compared after adjusting for age and gender, and standardizing to the 1990 US population. RESULTS: Between July 1, 1993, and June 30, 1994, 1956 first-ever ischemic strokes occurred among blacks and whites in the study population. Small-vessel strokes and strokes of undetermined cause were nearly twice as common among blacks. Large-vessel strokes were 40% more common among blacks than whites, and there was a trend toward cardioembolic strokes being more common among blacks. CONCLUSIONS: The excess burden of ischemic strokes among blacks compared with whites is not uniformly spread across the different subtypes. Large-vessel strokes are more common and cardioembolic stroke are as common among blacks, traditionally thought to be more common among whites.

Trends in community knowledge of the warning signs and risk factors for stroke.

CONTEXT: Poor public knowledge of stroke warning signs and risk factors limits effective stroke intervention and prevention. OBJECTIVE: To examine temporal trends in public knowledge of stroke warning signs and risk factors. DESIGN AND SETTING: Population-based random-digit telephone survey conducted in July-November 2000 among individuals in the greater Cincinnati, Ohio, region. PARTICIPANTS: A total of 2173 survey respondents (69% response rate) were randomly identified based on their demographic similarities to the ischemic stroke population with regard to age, race, and sex. MAIN OUTCOME MEASURES: Spontaneous recall of at least 1 important stroke warning sign and 1 established stroke risk factor in comparison with findings from the same survey in 1995. RESULTS: In 2000, 70% of respondents correctly named at least 1 established stroke warning sign vs 57% in 1995 (P<.001), and 72% correctly named at least 1 established stroke risk factor vs 68% in 1995. Groups of individuals with the highest risk and incidence of stroke, such as persons at least 75 years old, blacks, and men, were the least knowledgeable about warning signs and risk factors. Television was the most frequently cited source of knowledge, 32% in 2000 vs 24% in 1995 (P<.001). CONCLUSIONS: Public knowledge of stroke warning signs within the greater Cincinnati region has significantly improved from 1995 to 2000, although knowledge of stroke risk factors did not improve significantly during the same time period. Public education efforts must continue and should focus on groups at the highest risk of stroke.