BACKGROUND AND PURPOSE—The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (r-tPA; CLEAR) in Acute Ischemic Stroke (AIS) and CLEAR-Enhanced Regimen ...(CLEAR-ER) trials demonstrated safety of reduced dose r-tPA plus the glycoprotein 2b/3a inhibitor, eptifibatide, in AIS compared with r-tPA alone. The objective of the CLEAR-Full Dose Regimen (CLEAR-FDR) trial was to estimate the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients treated with the combination of full-dose r-tPA plus eptifibatide.
METHODS—CLEAR-FDR was a single-arm, prospective, open-label, multisite study. Patients aged 18 to 85 years treated with 0.9 mg/kg IV r-tPA within 3 hours of symptom onset were enrolled. After obtaining consent, eptifibatide (135 μg/kg bolus and 2-hour infusion at 0.75 μg/kg per minute) was administered. The primary end point was the proportion of patients who experienced sICH within 36 hours. An independent clinical monitor adjudicated if an sICH had occurred and an independent neuroradiologist reviewed all images. The stopping rule was 3 sICHs within the first 19 patients or 4 sICHs within 29 patients.
RESULTS—From October 2013 to December 2014, 27 patients with AIS were enrolled. Median age was 73 years (range, 34–85; interquartile range, 65–80) and median National Institute of Health stroke scale score was 12 (range, 6–26; interquartile range, 9–16). One sICH (3.7%; 95% confidence interval, 0.7%–18%) was observed.
CONCLUSIONS—These results demonstrate comparable safety of full-dose r-tPA plus eptifibatide with historical rates of sICH with r-tPA alone and support proceeding with a phase 3 trial evaluating full-dose r-tPA combined with eptifibatide to improve outcomes after AIS.
Objective
Hemorrhagic transformation (HT) is a major complication of ischemic stroke that worsens outcomes and increases mortality. Disruption of the blood–brain barrier is a central feature of HT ...pathogenesis, and leukocytes may contribute to this process. We sought to determine whether ischemic strokes that develop HT have differences in RNA expression in blood within 3 hours of stroke onset prior to treatment with thrombolytic therapy.
Methods
Stroke patient blood samples were obtained prior to treatment with thrombolysis, and leukocyte RNA was assessed by microarray analysis. Strokes that developed HT (n = 11) were compared to strokes without HT (n = 33) and controls (n = 14). Genes were identified (corrected p < 0.05, fold change ≥|1.2|), and functional analysis was performed. RNA prediction of HT in stroke was evaluated using cross‐validation, and in a second stroke cohort (n = 52).
Results
Ischemic strokes that developed HT had differential expression of 29 genes in circulating leukocytes prior to treatment with thrombolytic therapy. A panel of 6 genes could predict strokes that later developed HT with 80% sensitivity and 70.2% specificity. Key pathways involved in HT of human stroke are described, including amphiregulin, a growth factor that regulates matrix metalloproteinase‐9; a shift in transforming growth factor‐β signaling involving SMAD4, INPP5D, and IRAK3; and a disruption of coagulation factors V and VIII.
Interpretation
Identified genes correspond to differences in inflammation and coagulation that may predispose to HT in ischemic stroke. Given the adverse impact of HT on stroke outcomes, further evaluation of the identified genes and pathways is warranted to determine their potential as therapeutic targets to reduce HT and as markers of HT risk. Ann Neurol 2013;74:232–240
Orolingual angioedema is a rare adverse effect of tissue plasminogen activator (tPA), with an incidence of 1% to 5%. There are currently no published reports describing resolution of tPA-induced ...orolingual angioedema with complement inhibitor therapy. A 72-year-old man receiving home angiotensin-converting enzyme inhibitor therapy presented to the emergency department with newly developed orolingual angioedema after treatment with tPA for acute ischemic stroke. Therapy was initiated with intravenous methylprednisolone 125 mg, famotidine 20 mg, and diphenhydramine 50 mg, without significant improvement. Because of increased concern for airway protection, plasma-derived C1 esterase inhibitor was administered. Concerns about progressive and airway-threatening orolingual angioedema subsided 2 hours after administration, and invasive airway maneuvers were avoided. Orolingual angioedema is an infrequent, severe adverse effect of tPA for treatment of acute ischemic stroke. Complement inhibitors may be an additional therapeutic option for patients presenting with orolingual angioedema with potential airway compromise that is refractory to standard anaphylactic therapies.
Patient delay in seeking treatment for acute coronary syndrome and stroke symptoms is the major factor limiting delivery of definitive treatment in these conditions. Despite decades of research and ...public education campaigns aimed at decreasing patient delay times, most patients still do not seek treatment in a timely manner. In this scientific statement, we summarize the evidence that (1) demonstrates the benefits of early treatment, (2) describes the extent of the problem of patient delay, (3) identifies the factors related to patient delay in seeking timely treatment, and (4) reveals the inadequacies of our current approaches to decreasing patient delay. Finally, we offer suggestions for clinical practice and future research.
Epidemiological studies suggest that sex has a role in the pathogenesis of cardioembolic stroke. Since stroke is a vascular disease, identifying sexually dimorphic gene expression changes in blood ...leukocytes can inform on sex-specific risk factors, response and outcome biology. We aimed to examine the sexually dimorphic immune response following cardioembolic stroke by studying the differential gene expression in peripheral white blood cells.
Blood samples from patients with cardioembolic stroke were obtained at ≤3 hours (prior to treatment), 5 hours and 24 hours (after treatment) after stroke onset (n = 23; 69 samples) and compared with vascular risk factor controls without symptomatic vascular diseases (n = 23, 23 samples) (ANCOVA, false discovery rate p≤0.05, |fold change| ≥1.2). mRNA levels were measured on whole-genome Affymetrix microarrays. There were more up-regulated than down-regulated genes in both sexes, and females had more differentially expressed genes than males following cardioembolic stroke. Female gene expression was associated with cell death and survival, cell-cell signaling and inflammation. Male gene expression was associated with cellular assembly, organization and compromise. Immune response pathways were over represented at ≤3, 5 and 24 h after stroke in female subjects but only at 24 h in males. Neutrophil-specific genes were differentially expressed at 3, 5 and 24 h in females but only at 5 h and 24 h in males.
There are sexually dimorphic immune cell expression profiles following cardioembolic stroke. Future studies are needed to confirm the findings using qRT-PCR in an independent cohort, to determine how they relate to risk and outcome, and to compare to other causes of ischemic stroke.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Transient ischemic attacks (TIAs) have been shown to be a strong predictor of subsequent stroke and death. We present the incidence and short-term prognosis of TIA within a large population with a ...significant proportion of minorities with out-of-hospital TIA.
TIA cases were identified between July 1, 1993 and June 30, 1994 from the Greater Cincinnati/Northern Kentucky population of 1.3 million inhabitants by previously published surveillance methods, including inpatient and out-of-hospital events. Incidence rates were adjusted to the 1990 population, and life-table analyses were used for prognosis.
The overall race, age, and gender-adjusted incidence rate for TIA within our population was 83 per 100,000, with age, race, and gender adjusted to the 1990 US population. Blacks and men had significantly higher rates of TIA than whites and women. Risk of stroke after TIA was 14.6% at 3 months, and risk of TIA/stroke/death was 25.2%. Age, race, and sex were not associated with recurrent TIA or subsequent stroke in our population, but age was associated with mortality.
Using our incidence rates for TIA in blacks and whites, we conservatively estimate that approximately 240 000 TIAs occurred in 2002 in the United States. Our incidence rate of TIA is slightly higher than previously reported, which may be related to the inclusion of blacks and out-of-hospital events. There are racial and gender-related differences in the incidence of TIA. We found a striking risk of adverse events after TIA; however, there were no racial or gender differences predicting these events. Further study is warranted in interventions to prevent these adverse events after TIA.
BACKGROUND AND PURPOSE—The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial demonstrated safety of recombinant tissue-type ...plasminogen activator (r-tPA) plus eptifibatide in acute ischemic stroke (AIS). CLEAR-ER randomized AIS patients (5:1) to 0.6 mg/kg r-tPA plus eptifibatide versus standard r-tPA (0.9 mg/kg). Interventional Management of Stroke III randomized AIS patients to r-tPA plus endovascular therapy versus standard r-tPA. Albumin in Acute Stroke Part 2 randomized patients to albumin±r-tPA versus saline±r-tPA. Our aim was to compare outcomes in CLEAR-ER combination arm patients to propensity score-matched r-tPA only subjects in Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III.
METHODS—The primary outcome was 90-day severity-adjusted modified Rankin score (mRS) dichotomization based on baseline National Institutes of Health Stroke Scale. Secondary outcomes were 90-day mRS dichotomization as excellent (mRS, 0–1); mRS dichotomization as favorable (mRS, 0–2); and nonparametric analysis of the ordinal mRS.
RESULTS—Eighty-five combination arm CLEAR-ER subjects were matched with 169 Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III trials’ r-tPA only patients (controls). Median age in CLEAR-ER and control subjects was 68years; median National Institutes of Health Stroke Scale in the CLEAR-ER subjects was 11 and in control subjects 12. At 90 days, CLEAR-ER subjects had a nonsignificantly greater proportion of patients with favorable outcomes (45% versus 36%; unadjusted relative risks, 1.24; 95% confidence intervals, 0.91–1.69; P=0.18). Secondary outcomes were 52% versus 34% excellent outcomes (relative risks, 1.51; 95% confidence intervals, 1.13–2.02; P=0.007); 60% versus 53% favorable outcome (relative risks, 1.13; 95% confidence intervals, 0.90–1.41; P=0.31); and ordinal Cochran–Mantel–Haenszel P=0.10.
CONCLUSION—r-tPA plus eptifibatide showed a favorable direction of effect that was consistent across multiple approaches for AIS outcome evaluation. A phase III trial to establish the efficacy of r-tPA plus eptifibatide for improving AIS outcomes is warranted.
Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a ...glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination.
The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke-funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 microg/kg bolus followed by 0.75 microg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy.
Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA-only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group.
The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.
CONTEXT.— Decreasing the time from stroke onset to hospital arrival and improving
control of stroke risk factors depend on public knowledge of stroke warning
signs and risk factors. OBJECTIVE.— To ...assess current public knowledge of stroke warning signs and risk
factors. DESIGN.— A population-based telephone interview survey using random digit dialing
conducted in 1995. SETTING.— The Greater Cincinnati, Ohio, metropolitan area, the population of which
is similar to that of the United States overall in age, sex, percentage of
blacks, and economic status. PARTICIPANTS.— Respondents with age, race, and sex that matched the population of patients
with acute stroke. MAIN OUTCOME MEASURES.— Knowledge of risk factors for stroke and warning signs of stroke as
defined by the National Institute of Neurological Disorders and Stroke. RESULTS.— Telephone calls were made to 17634 households, which yielded 2642 demographically
eligible individuals. Interviews were completed by 1880 respondents (response
rate, 71.2%). A total of 1066 respondents (57%) correctly listed at least
1 of the 5 established stroke warning signs, and of all respondents, 1274
(68%) correctly listed at least 1 of the established stroke risk factors.
Of the respondents, 469 (57%) of 818 respondents with a history of hypertension
listed hypertension, 142 (35%) of 402 respondents who were current smokers
listed smoking, and 32 (13%) of 255 respondents with diabetes listed diabetes
as a risk factor for stroke. Compared with those younger than 75 years, respondents
75 years or older were less likely to correctly list at least 1 stroke warning
sign (60% vs 47%, respectively; P<.001) and were
less likely to list at least 1 stroke risk factor (72% vs 56%, respectively; P<.001). CONCLUSION.— Considerable education is needed to increase the public's awareness
of the warning signs and risk factors for stroke. Respondents with self-reported
risk factors for stroke are largely unaware of their increased risk. The population
at greatest risk for stroke, the very elderly, are the least knowledgeable
about stroke warning signs and risk factors.
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