Impact of individual clinical outcomes on trial participants' perspectives on enrollment in emergency research without consent.

BACKGROUND: Evidence suggests that patients are generally accepting of their enrollment in trials for emergency care conducted under exception from informed consent. It is unknown whether individuals with more severe initial injuries or worse clinical outcomes have different perspectives. Determining whether these differences exist may help to structure post-enrollment interactions. METHODS: Primary clinical data from the Progesterone for the Treatment of Traumatic Brain Injury trial were matched to interview data from the Patients' Experiences in Emergency Research-Progesterone for the Treatment of Traumatic Brain Injury study. Answers to three key questions from Patients' Experiences in Emergency Research-Progesterone for the Treatment of Traumatic Brain Injury study were analyzed in the context of enrolled patients' initial injury severity (initial Glasgow Coma Scale and Injury Severity Score) and principal clinical outcomes (Extended Glasgow Outcome Scale and Extended Glasgow Outcome Scale relative to initial injury severity). The three key questions from Patients' Experiences in Emergency Research-Progesterone for the Treatment of Traumatic Brain Injury study addressed participants' general attitude toward inclusion in the Progesterone for the Treatment of Traumatic Brain Injury trial (general trial inclusion), their specific attitude toward being included in Progesterone for the Treatment of Traumatic Brain Injury trial under the exception from informed consent (personal exception from informed consent enrollment), and their attitude toward the use of exception from informed consent in the Progesterone for the Treatment of Traumatic Brain Injury trial in general (general exception from informed consent enrollment). Qualitative analysis of interview transcripts was performed to provide contextualization and to determine the extent to which respondents framed their attitudes in terms of clinical experience. RESULTS: Clinical data from Progesterone for the Treatment of Traumatic Brain Injury trial were available for all 74 patients represented in the Patients' Experiences in Emergency Research-Progesterone for the Treatment of Traumatic Brain Injury study (including 46 patients for whom the surrogate was interviewed due to the patient's cognitive status or death). No significant difference was observed regarding acceptance of general trial inclusion or acceptance of general exception from informed consent enrollment between participants with favorable neurological outcomes and those with unfavorable outcomes relative to initial injury. Agreement with personal enrollment in Progesterone for the Treatment of Traumatic Brain Injury trial under exception from informed consent, however, was significantly higher among participants with favorable outcomes compared to those with unfavorable outcomes (89% vs 59%, p = 0.003). There was also a statistically significant relationship between more severe initial injury and increased acceptance of personal exception from informed consent enrollment ( p = 0.040) or general exception from informed consent use ( p = 0.034) in Progesterone for the Treatment of Traumatic Brain Injury trial. Many individuals referenced personal experience as a basis for their attitudes, but these references were not used to support negative views. CONCLUSION: Patients and surrogates of patients with unfavorable clinical outcomes were somewhat less accepting of their own inclusion in the Progesterone for the Treatment of Traumatic Brain Injury trial under exception from informed consent than were patients or surrogates of patients with favorable clinical outcomes. These findings suggest a need to identify optimal strategies for communicating with patients and their surrogates regarding exception from informed consent enrollment when clinical outcomes are poor.

Recombinant tissue-type plasminogen activator plus eptifibatide versus recombinant tissue-type plasminogen activator alone in acute ischemic stroke: propensity score-matched post hoc analysis.

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.

Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial.

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.

Patients' perspectives of enrollment in research without consent: the patients' experiences in emergency research-progesterone for the treatment of traumatic brain injury study.

OBJECTIVE: Research in acute illness often requires an exception from informed consent. Few studies have assessed the views of patients enrolled in exception from informed consent trials. This study was designed to assess the views of patients and their surrogates of exception from informed consent enrollment within the context of a randomized, placebo-controlled trial of an investigational agent for traumatic brain injury. DESIGN: Interactive interview study. SETTING: Nested within the Progesterone for the Treatment of Traumatic Brain Injury trial, a Phase III randomized controlled trial in acute traumatic brain injury. SUBJECTS: Patients and surrogates (for patients incapable of being interviewed) enrolled in Progesterone for the Treatment of Traumatic Brain Injury under exception from informed consent at 12 sites. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Interviews focused on respondents' acceptance of exception from informed consent enrollment in Progesterone for the Treatment of Traumatic Brain Injury, use of placebo and randomization, understanding of major study elements, and views regarding regulatory protections. Descriptive statistical analysis was performed; textual data were analyzed thematically. Eighty-five individuals were interviewed. Eighty-four percent had positive attitudes toward Progesterone for the Treatment of Traumatic Brain Injury inclusion. Seventy-eight percent found their inclusion under exception from informed consent acceptable, and 72% found use of exception from informed consent in Progesterone for the Treatment of Traumatic Brain Injury acceptable in general. Only two respondents clearly disagreed with both personal and general exception from informed consent enrollment. The most common concerns (26%) related to absence of consent. Eighty percent and 92% were accepting of placebo use and randomization, respectively. Although there were few black respondents (n = 11), they were less accepting of personal exception from informed consent enrollment than white respondents (55% vs 83%; p = 0.0494). CONCLUSIONS: Acceptance of exception from informed consent in this placebo-controlled trial of an investigational agent was high and exceeded acceptance among community consultation participants. Exception from informed consent enrollment appears generally consistent with patients' preferences.

RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke.

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-ß 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.

A matched comparison of eptifibatide plus rt-PA versus rt-PA alone in acute ischemic stroke.

BACKGROUND: The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator (rt-PA) in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial found that intravenous rt-PA plus eptifibatide (combination arm) in acute ischemic stroke (AIS) was safe and had a direction of effect that would justify a phase III trial. CLEAR-ER had unanticipated imbalances between treatment groups. We compared the rates of symptomatic intracranial hemorrhage (sICH) and good outcomes for combination therapy patients in the CLEAR-ER trial to a matched cohort of rt-PA patients from the National Institute of Neurological Disorders and Stroke (NINDS) trial. METHODS: CLEAR-ER was a multicenter, double-blind, randomized study; rt-PA-eligible AIS patients were randomized to .6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and .75mcg/kg/min two-hour infusion) versus standard rt-PA (.9 mg/kg). For this analysis, we matched 1:1 CLEAR-ER combination therapy patients with rt-PA arm NINDS trial patients. Patients were matched by age, gender, race, baseline modified Rankin Scale score, baseline National Institutes of Health Stroke Scale (NIHSS) score, and stroke onset to rt-PA time. RESULTS: Fifty-four matches were made. One (1.8%) sICH occurred in each group (odds ratio [OR] 1.00, 95% confidence interval [CI] .01-78.50). At 90 days, 51.8% of the CLEAR-ER group had good outcomes versus 46.3% in the NINDS rt-PA group (OR 1.30, 95% CI .57-2.96). For subjects with baseline NIHSS score > 12 (CLEAR-ER median NIHSS score), 38.5% of the CLEAR-ER group had good outcomes versus 23.1% in the NINDS group (OR 2.33, 95% CI .60-9.02). CONCLUSIONS: The safety and direction of effect of eptifibatide plus rt-PA were confirmed. A phase III trial is needed to determine the efficacy of eptifibatide plus rt-PA for improving long-term outcomes after AIS.

Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial.

BACKGROUND AND PURPOSE: In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial. METHODS: CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression. RESULTS: Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01-1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70-4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51-3.76; P=0.52). CONCLUSIONS: The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00894803.

Do either corticosteroids or antiviral agents reduce the risk of long-term facial paresis in patients with new-onset Bell's palsy?

BACKGROUND: The cause of Bell's palsy remains uncertain, although accumulating evidence suggests a viral etiology. To date, treatment to minimize long-term deficits from this disorder typically includes anti-inflammatory or antiviral medication. CLINICAL QUESTION: Do corticosteroids or antiviral agents, either alone or in combination, reduce the risk of long-term facial paresis in patients with new-onset Bell's palsy? EVIDENCE REVIEW: Three multicenter, randomized, controlled trials enrolled over 1,500 adult patients with paroxysmal, unilateral paresis of cranial nerve VII and treated them with varying regimens and combinations of prednisolone, antiviral agents, and placebo, and evaluated complete recovery up to 12 months later. RESULTS: The two larger, most recent trials incorporated similar factorial designs to allow for comparisons between steroids, antivirals, both combined, and placebo, and assessed recovery using validated measures of facial nerve function. In the larger, blinded trial, the numbers needed to treat to achieve complete recovery for patients in the prednisolone and acyclovir groups at 9 months were 7.8 (95% confidence interval [CI] 5.9-13.7) and 18.7 (95% CI 9.5-infinity), respectively. The number needed to treat to achieve complete recovery for patients in the valacyclovir plus prednisolone group vs. the prednisolone alone group in the second trial was 14.8 (95% CI 9.1-744.8). CONCLUSIONS: Current evidence suggests that prednisolone, an inexpensive and readily available medication, is effective for this common condition, but there was no statistically significant difference observed with acyclovir. Valacyclovir provides minimal added benefit to prednisolone alone.

Combination pharmacotherapy for achievement and maintenance of vascular patency.

Acute ischemic stroke results from an abrupt interruption of focal cerebral blood flow. In the majority of cases, this interruption is caused by an acute thromboembolism. Arising from the clinical trials in acute myocardial infarction, combination pharmacotherapy is gaining significant interest as a potential method to improve current thrombolytic treatment in acute ischemic stroke. This article reviews the scientific rationale and available evidence for the potential options to improve current pharmacologic therapy for achieving and maintaining vascular patency in acute ischemic stroke.

Hyperfibrinogenemia and functional outcome from acute ischemic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies have found strong correlations between elevated plasma fibrinogen levels and both ischemic stroke incidence and stroke mortality. Little is known about the influence of fibrinogen levels on functional stroke outcome. METHODS: Placebo data from the Stroke Treatment with Ancrod Trial (STAT) and European Stroke Treatment with Ancrod Trial (ESTAT) were analyzed. Fibrinogen levels were determined within 3 hours (STAT) or 6 hours (ESTAT) of stroke onset and at preset intervals throughout 5 days of intravenous infusions. Barthel Index scores at 90 days quantified functional outcomes. The association between initial fibrinogen levels and functional outcomes was evaluated using a multiple logistic regression analysis. RESULTS: Fibrinogen levels increased gradually over the first 24 hours from a pretreatment median value of 340 mg/dL to a 24-hour median value of 376 mg/dL. In a univariate analysis, the proportion of patients with good functional outcome decreased with increasing quartiles of initial fibrinogen levels in both STAT (36.0% to 26.2%) and ESTAT (53.8% to 24.8%). In a multifactorial analysis, the same trend was observed. Patients with initial fibrinogen levels <450 mg/dL had better outcomes in both studies; the difference (42.0% versus 21.6%) was significant in ESTAT (P=0.0006), even when corrected for age and initial stroke severity. CONCLUSIONS: The independent association of higher initial fibrinogen levels with poor outcome needs to be verified using a larger acute stroke dataset. Even in the present small populations, the apparent association of these 2 variables suggests that treatments designed to reduce fibrinogen levels could potentially be important in treating acute ischemic stroke.

Ancrod in acute ischemic stroke: results of 500 subjects beginning treatment within 6 hours of stroke onset in the ancrod stroke program.

BACKGROUND AND PURPOSE: Previous studies of multiple-day dosing with the defibrinogenating agent, ancrod, in acute ischemic stroke yielded conflicting results but suggested that a brief dosing regimen might improve efficacy and safety. The Ancrod Stroke Program was designed to test this concept in subjects beginning ancrod or placebo within 6 hours of the onset of acute ischemic stroke. METHODS: Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score ("responder analysis"). Safety variables included mortality, major bleeding, and intracranial hemorrhage. RESULTS: Although the desired changes in fibrinogen level were seen in >90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects (P=0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; P=0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects (P=0.19), was approximately twice as high (3.9% vs 2.0%; P=0.19). CONCLUSIONS: These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia.

Effect of low frequency ultrasound on combined rt-PA and eptifibatide thrombolysis in human clots.

INTRODUCTION: Fibrinolytics such as recombinant tissue plasminogen activator (rt-PA) are used to treat thrombotic disease such as acute myocardial infarction (AMI) and ischemic stroke. Interest in increasing efficacy and reducing side effects has led to the study of adjuncts such as GP IIb-IIIa inhibitors and ultrasound (US) enhanced thrombolysis. Currently, GP IIb-IIIa inhibitor and fibrinolytic treatment are often used in AMI, and are under investigation for stroke treatment. However, little is known of the efficacy of combined GP IIb-IIIa inhibitor, fibrinolytic and ultrasound treatment. We measure the lytic efficacy of rt-PA, eptifibatide (Epf) and 120 kHz ultrasound treatment in an in-vitro human clot model. MATERIALS AND METHODS: Blood was drawn from 15 subjects after IRB approval. Clots were made in 20 microL pipettes, and placed in a water tank for microscopic visualization during lytic treatment. Clots were exposed to control, rt-PA (rt-PA), eptifibatide (Epf), or rt-PA+eptifibatide (rt-PA + Epf), with (+US) or without (-US) ultrasound for 30 minutes at 37 degrees C in human plasma. Clot lysis was measured over time, using a microscopic imaging technique. The fractional clot loss (FCL) and initial lytic rate (LR) were used to quantify lytic efficacy. RESULTS AND CONCLUSIONS: LR values for (- US) treated clots were 0.8+/-0.1(control), 1.8+/-0.3 (Epf), 1.5+/-0.2 (rt-PA), and 1.3+/-0.4 (rt-PA + Epf) (% clot width/minute) respectively. In comparison, the (+ US) group exhibited LR values of 1.6+/-0.2 (control), 4.3+/-0.4 (Epf), 6.3+/-0.4 (rt-PA), and 4.6+/-0.6 (rt-PA + Epf). For (- US) treated clots, FCL was 6.0+/-0.8 (control), 9.2+/-2.5 (Epf), 15.6+/-1.7 (rt-PA), and 28.0+/-2.2% (rt-PA + Epf) respectively. FCL for (+ US) clots was 13.5+/-2.4 (control), 20.7+/-6.4 (Epf), 44.4+/-3.6 (rt-PA) and 30.3+/-3.6% (rt-PA + Epf) respectively. Although the addition of eptifibatide enhances the in-vitro lytic efficacy of rt-PA in the absence of ultrasound, the efficacy of ultrasound and rt-PA is greater than that of combined ultrasound, rt-PA and eptifibatide exposure.

The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.

Reducing delay in seeking treatment by patients with acute coronary syndrome and stroke: a scientific statement from the American Heart Association Council on cardiovascular nursing and stroke council.

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.

Reducing delay in seeking treatment by patients with acute coronary syndrome and stroke: a scientific statement from the American Heart Association Council on Cardiovascular Nursing and Stroke Council.

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.

Supplemental oxygen use in ischemic stroke patients: does utilization correspond to need for oxygen therapy?

BACKGROUND: In 1994, the American Heart Association Stroke Council concluded that there were no data to support the routine use of supplemental oxygen in patients who had a stroke. More recently, supplemental oxygen has been suggested to be potentially detrimental. The purpose of this study was to determine the extent of oxygen use in ischemic stroke patients and whether patients receiving oxygen had indications for its use. METHODS: A literature search was performed to generate a comprehensive list of explicit criteria for supplemental oxygen use. When the literature disagreed, the criteria were included in the list to overestimate rather than underestimate the justification for oxygen use. A retrospective chart review of consecutive, nonintubated, ischemic stroke patients admitted to a university hospital was performed. Statistical tests and logistic regression models were constructed to identify the presence of unjustified oxygen use within the sample. Hospital charges were used to quantify opportunities for resource conservation. RESULTS: A total of 167 patient charts were reviewed yielding a total of 600 inpatient days abstracted. One hundred two patients (61.1%) received oxygen during some portion of their hospitalization. Of the 322 days that patients received oxygen, 147 (45.6%) met at least 1 criterion for oxygen use. Of the 278 days that patients did not receive oxygen, 69 (24.8%) met at least 1 of the criteria for oxygen use. There were 384 days for which no criteria were met. Of these, a patient still received oxygen 45.6% of the time (175 days). Factors associated with oxygen use included the presence of at least 1 justifying criteria as well as increasing age and male sex. Withholding oxygen from those not medically justified by the criteria could produce resource savings of roughly 45%. CONCLUSIONS: Using a literature-based list of criteria for supplemental oxygen use, only 45.6% of days of oxygen use were justified in our ischemic stroke population. This study demonstrates that oxygen therapy is commonly given to ischemic stroke patients without clear indication, and opportunities exist for substantial resource conservation.

Prevalence of atrial fibrillation and antithrombotic prophylaxis in emergency department patients.

BACKGROUND AND PURPOSE: The emergency department (ED), as the point of first medical contact for many complaints referable to atrial fibrillation (AF) and a common source of primary care, occupies a unique position to identify AF patients at risk of stroke. This study evaluates that potential by determining the prevalence of AF in an ED population and assessing antithrombotic use in those patients with recurrent AF. METHODS: This was a multicenter, retrospective, cross-sectional study of consecutive records of ED patients with AF identified by ECG between January and June 1998. American Heart Association and modified Stroke Prevention in Atrial Fibrillation criteria established high-risk patients and contraindications to anticoagulation, respectively. RESULTS: We identified 866 records with ECG-proven AF in 78 787 patient visits for an estimated prevalence of 1.10% (95% CI, 1.03 to 1.17). We found that 556 records had a prior history of AF; of these, 221 (40%) used warfarin alone, 155 (28%) had antiplatelet therapy alone, 28 (5%) used both, and 152 (27%) had no antithrombotic therapy identified. Sixty-eight patients (12%; 95% CI, 0.10 to 0.15) were warfarin eligible and without antithrombotic therapy. An additional 64 (12%; 95% CI, 0.09 to 0.14) had antiplatelet therapy alone. In warfarin-eligible patients, no differences were identified between the anticoagulated and nonanticoagulated groups on the basis of age, sex, or race. Of patients on warfarin with a measured international normalized ratio, 61% (95% CI, 0.55 to 0.67) were outside the AHA-recommended range of 2.0 to 3.0. CONCLUSIONS: AF is a common finding in an ED population. Many are warfarin eligible and untreated or undertreated. Methods to increase anticoagulant use in this at-risk population warrant further investigation.

Hypercholesterolemia, HMG-CoA reductase inhibitors, and risk of intracerebral hemorrhage: a case-control study.

BACKGROUND AND PURPOSE: Several studies have demonstrated an association between hypocholesterolemia and intracerebral hemorrhage (ICH). We tested the hypothesis that hypercholesterolemia or use of HMG-CoA reductase inhibitors (statin) agents, or both, are associated with ICH. METHODS: This study was part of the preplanned midway analysis of an ongoing, population-based, case-control study of the genetic and environmental risk factors of hemorrhagic stroke. Conditional stepwise logistic regression modeling was used to determine if self-reported hypercholesterolemia or statin use, or both, were independent risk factors for ICH. RESULTS: Between December 1, 1997, and June 30, 2000, 188 cases of ICH and 366 age-, race-, and gender-matched controls were enrolled. Hypercholesterolemia and statin use were less common among cases than controls: 25% versus 38% (P=0.003) and 9% versus 17% (P=0.03), respectively. Hypercholesterolemia with statin use was associated with less risk of ICH (OR=0.30; P=0.0008) in multivariable analysis after controlling for alcohol use, hypertension, previous stroke, first-degree relative with ICH, education level, and apolipoprotein E alleles. CONCLUSIONS: Hypercholesterolemia was associated with a lower risk of ICH. We have not found an increased risk of ICH with the widespread use of statins in our population. Given the lack of cholesterol levels in the current study, further studies are needed to determine if lower cholesterol levels secondary to statin use bear the same risk as low cholesterol levels for ICH.

Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) has a 30-day mortality rate of 40% to 50% and lacks a proven treatment. We report a preplanned, midpoint analysis of the first population-based, case-control study that examines both genetic and environmental risk factors of ICH. METHODS: We prospectively identified cases of hemorrhagic stroke at all 16 hospitals in the Greater Cincinnati/Northern Kentucky region. All cases underwent medical record and neuroimaging review. Cases enrolled in the direct interview and genetic sampling arm of the study were matched to population-based control subjects by age, race, and sex. Multivariable logistic regression was performed to identify significant independent risk factors. RESULTS: We enrolled 188 cases of ICH (67 lobar, 121 nonlobar) and 366 control subjects in the direct interview arm of the study. Significant independent risk factors for lobar ICH included the presence of an apolipoprotein E2 or E4 allele, frequent alcohol use, prior stroke, and first-degree relative with ICH. Significant independent risk factors for nonlobar ICH were hypertension, prior stroke, and first-degree relative with ICH. An increasing level of education was associated with a decreased risk of nonlobar ICH. The attributable risk of apolipoprotein E2 or E4 for lobar ICH was 29%, and the attributable risk of hypertension for nonlobar ICH was 54%. CONCLUSIONS: There is significant epidemiological evidence that the pathophysiology of ICH varies by location. We estimate that a third of all cases of lobar ICH are attributable to possession of an apolipoprotein E4 or E2 allele and that half of all cases of nonlobar ICH are attributable to hypertension.

Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in acute ischaemic stroke: scientific rationale and available evidence.

Acute ischaemic stroke is the result of an abrupt interruption of focal cerebral blood flow. In the majority of cases, this interruption is caused by an acute thromboembolism. Based on clinical experience in the treatment of acute coronary syndromes, platelet glycoprotein (GP) IIb/IIIa receptor antagonists alone, in combination with reduced doses of thrombolytic agents, or as complementary therapy for short-term mechanical interventions merit consideration as a class of agents with potential use in ischaemic stroke. Research to date and extrapolation from the cardiac literature suggest significant, but as yet unproven, potential for the use of GP IIb/IIIa receptor antagonists in the treatment of acute ischaemic stroke. This potential exists both at the site of the thromboembolic occlusion and at the distal microvascular level. This article reviews the scientific rationale and available evidence for the potential use of platelet GP IIb/IIIa receptor antagonists in acute ischaemic stroke.