Early clinical and radiological predictors of fatal brain swelling in ischemic stroke.

BACKGROUND AND PURPOSE: Early identification of acute stroke patients at risk of fatal brain swelling is necessary to facilitate implementation of aggressive therapies. Initial clinical, laboratory, and CT characteristics that may be used as selection criteria were analyzed to determine predictors of herniation and neurological death. METHODS: Data from the placebo arm of the Lubeluzole-International-9 trial were reviewed to identify patients with fatal brain edema. Early clinical, laboratory, and radiographic parameters were evaluated in a case-control design. Initial CT scans were analyzed for early ischemic abnormalities by 2 blinded investigators. RESULTS: Twenty-three patients died from brain swelling, with minimum baseline National Institutes of Health Stroke Scale (NIHSS) scores of 20 (n=12; mean, 23.2+/-1.8) with left and 15 (n=11; mean, 17.6+/-2.2) with right hemispheric infarctions (P=0. 0001). A sample of 112 subjects with comparably severe strokes, but who did not die from brain swelling, was selected from the remaining population according to the same NIHSS scores. Among clinical and laboratory characteristics, nausea/vomiting within 24 hours after onset (odds ratio [OR], 5.1; 95% CI, 1.7 to 15.3; P=0.003) and 12-hour systolic blood pressure >/=180 mm Hg (OR, 4.2; 95% CI, 1.4 to 12.9; P=0.01) were independently associated with fatal brain swelling. Among radiographic factors, only hypodensity of >50% of the middle cerebral artery territory on initial CT scan was an independent predictor (OR, 6.1; 95% CI, 2.3 to 16.6; P=0.0004). CONCLUSIONS: Patients with baseline NIHSS score >/=20 with left or >/=15 with right hemispheric infarctions within 6 hours of symptom onset who also have nausea/vomiting or >50% middle cerebral artery territory hypodensity are at high risk for developing fatal brain swelling.

Pharmacokinetics of lubeluzole (Prosynap) after single intravenous doses in healthy subjects.

The single-dose pharmacokinetics of lubeluzole were investigated in 2 single-blind, placebo-controlled, dose-escalation studies in healthy male subjects. In the first study, 6 subjects received an intravenous infusion of 2.5, 5, and 10 mg lubeluzole. In the second study, a 15 mg dose of lubeluzole was administered to 6 subjects, of whom 5 also received 20 mg and 2 also 25 mg lubeluzole. Following the infusion, plasma lubeluzole concentrations decayed biphasically, with a mean distribution half-life (t1/2alpha) of 30 to 65 minutes and a mean terminal half-life (t1/2beta) of 15 to 24 hours. The results of the 2 studies indicate that lubeluzole exhibits linear kinetics over the dose range tested in healthy male subjects.

Cardiovascular safety of lubeluzole (Prosynap(R)) in patients with ischemic stroke.

The cardiovascular safety of lubeluzole was evaluated in patients with ischemic stroke in a double-blind, placebo-controlled trial. Forty-six patients were randomized to receive a continuous daily infusion of lubeluzole 5 mg (loading dose 3.75 mg over 1 h), lubeluzole 10 mg (loading dose 7.5 mg over 1 h), or placebo for 5 days within 24 h of stroke onset. The primary measure of cardiovascular safety was the QTc interval, derived from the continuous electrocardiogram (ECG) and measured during treatment and a 2-day follow-up. Compared with placebo. Neither dosage of lubeluzole had any statistically or clinically relevant effects on the QTc. Neither were there any significant differences among the three treatment groups in the area under the curve for heart rate, QT interval, QT dispersion, or QTlc. Lubeluzole did not increase the frequency of ECG abnormalities. No ventricular fibrillation, ventricular tachycardia, or torsades de pointes were observed in any of the treatment groups. During this trial, 3 patients in the placebo group and 2 patients in the lubeluzole 5-mg group died. There were no deaths in the lubeluzole 10-mg group. Adverse experiences were similar in all three treatment groups except that superficial thrombophlebitis was more frequent in the lubeluzole 10-mg group. In doses to 10 mg/day, lubeluzole has a favorable cardiovascular safety profile, as demonstrated by the lack of clinically relevant effects on heart rate, QT, QTc, and QTlc, and it was well tolerated by patients with ischemic stroke.

Assessment scales for the evaluation of stroke patients.

The approval of tissue plasminogen activator to treat acute ischemic stroke and the continuing need to evaluate new neuroprotective drugs and thrombolytic agents in clinical trials have focused interest on the quantitative evaluation of stroke patients. Emphasizing outcomes management in clinical practice has also heightened the importance of quantitative evaluation using assessment scales. Investigators who evaluate, revise, and use assessment scales for the measurement of stroke impairment, disabilites, and handicaps face many challenges. These problems include the heterogeneity of stroke and the need to determine appropriate outcome measures, to use neurological deficit scales that can accurately predict disability, to ensure adequate follow-up, and to use scales that can be used outside of clinical trials by all health care professionals. Such scales should be easily and quickly administered, responsive, valid, and reliable. The most important categories of stroke scales are neurological deficit scales (e.g., Canadian Neurological Scale, European Stroke Scale, and National Institutes of Health [NIH] Stroke Scale), functional outcome scales (e.g., Barthel Index), and global outcome scales (e.g., Modified Rankin Scale). Although stroke-specific, health-related quality-of-life (HRQL) scales have yet to be developed and validated, general HRQL scales such as the Nottingham Health Profile, the Medical Outcomes Study Short Form-36, the Sickness Impact Profile, and the Health Utilities Index may be used to assess stroke patients. Lacking the ideal single stroke outcome scale, we continue to recomend a combination of scales: the NIH Stroke Scale (or similar deficit scale), the Barthel Index, and the Rankin Scale.

The safety and tolerability of single intravenous doses of lubeluzole (Prosynap) in healthy volunteers.

The safety and tolerability of single escalating doses of lubeluzole were evaluated in healthy male volunteers in 2 studies. In the first of 2 randomized, single-blind, placebo-controlled, dose-escalation studies, 6 subjects received single 30-minute infusions of 2.5, 5, and 10 mg of lubeluzole, and 2 additional subjects received placebo. In the second study 6 different subjects received a 1-hour infusion of 15 mg of lubeluzole, 5 of whom received the 20-mg dose, and 2 received 25 mg of lubeluzole. Two additional subjects received placebo. Small increases and decreases in PQ, QRS, QT, QTc, and QTm intervals were noted after infusion of all lubeluzole doses and placebo, however, these changes were within the normal ranges for these values except for the QTc for the 25-mg dose of lubeluzole. Significant prolongation of the QTc interval was observed at the end of the 1-hour infusion in both subjects receiving the 25-mg dose of lubeluzole. No clinically relevant changes in systolic time intervals, heart rate, blood pressure, and clinical laboratory values were noted in subjects receiving 2.5-25 mg of lubeluzole or placebo. Adverse experiences, predominantly lightheadedness and dizziness, were reported by subjects receiving doses of lubeluzole greater than or equal to 10 mg. Lubeluzole, administered as single intravenous doses of 2.5-15 mg, is safe and well tolerated in healthy male volunteers.

Safety and pharmacokinetics of the neuroprotective drug lubeluzole in patients with ischemic stroke.

A total of 22 patients with acute ischemic stroke participated in two randomized, single-masked, placebo-controlled studies that evaluated the safety and pharmacokinetics of single escalating intravenous doses of lubeluzole. The first dose of study medication in all patients was given within 6 hours of the first sign of stroke onset. In the first study, 6 patients received a single 1-hour intravenous infusion of 5 mg of lubeluzole; 4 of these patients received an additional 10-mg dose 3 to 4 days later. Two additional patients received placebo. In the second study, 4 patients received a single 1-hour infusion of 10 mg of lubeluzole, and 2 patients received placebo. After a safety evaluation of the second study, 6 additional patients received 15 mg of lubeluzole, and 2 other patients received placebo. Lubeluzole had no clinically relevant effects on any cardiovascular variable compared with placebo. The majority of adverse experiences were mild to moderate and resolved during treatment. No unexpected electroencephalogram abnormalities were observed, and no evidence of epileptiform discharges was found in any of the patients. At the end of the infusion, plasma lubeluzole concentrations decayed biphasically, with mean distribution half-lives of 46.3 to 101.0 minutes and mean terminal half-lives of 20.8 to 27.7 hours. Comparisons of the dose-normalized value of the individual plasma concentrations at the end of the infusion and the total area under the curve from time 0 to infinity suggested that lubeluzole exhibited linear kinetics over the dose range evaluated in patients with ischemic stroke. In the small number of patients studied, lubeluzole's favorable safety profile was demonstrated by the lack of clinically relevant effects on cardiovascular variables and by neurologic examination and clinical laboratory findings.

Lubeluzole in acute ischemic stroke. A double-blind, placebo-controlled phase II trial. Lubeluzole International Study Group.

BACKGROUND AND PURPOSE: We aimed to assess the safety and efficacy of lubeluzole in patients with a clinical diagnosis of acute (< 6 hours) ischemic stroke in the carotid artery territory. METHODS: A randomized, double-blind, placebo-controlled multicenter trial was conducted in 232 patients. Because treatment was administered within 6 hours and a CT scan was not mandatory before the start of treatment, 39 patients with either an intracerebral hemorrhage or ischemic stroke in the vertebrobasilar circulation were excluded from the primary efficacy analysis as prespecified in the protocol. Of the 193 patients with acute ischemic stroke in the carotid artery territory (target population), 61 received placebo, 66 lubeluzole 7.5 mg over 1 hour followed by 10 mg/d for 5 days, and 66 lubeluzole 15 mg over 1 hour followed by 20 mg/d for 5 days. RESULTS: The trial, initially aimed at a patient inclusion of 270, was terminated prematurely according to the advice of the Safety Committee because of an imbalance in mortality between the treatment groups. Mortality rates at the final follow-up of 28 days for placebo, lubeluzole 10 mg/d, and lubeluzole 20 mg/d were, respectively, 18%, 6%, and 35% in the target population, results that were confirmed in the intent-to-treat population. Multivariate logistic regression analysis showed that the lower mortality in the lubeluzole 10 mg/d group was significantly in favor of the 10 mg/d treatment (P = .019). The higher mortality rate in the 20 mg/d group could be explained, at least in part, by an imbalance at randomization that led to a higher number of patients in that group with severe ischemic stroke. A total of 26 of 66 patients (39%) who received lubeluzole 10 mg/d had a score on the Barthel Index of > 70 at day 28, indicating no or mild disability, compared with 21 of 61 (34%) in the placebo group and 19 of 66 (29%) in the lubeluzole 20 mg/d group (P = NS). CONCLUSIONS: In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.

Flunarizine in stroke treatment (FIST): a double-blind, placebo-controlled trial in Scandinavia and the Netherlands.

INTRODUCTION: An international, multicenter trial was conducted in 331 patients to determine the effect of a large dose of flunarizine (a calcium entry blocker) in the treatment of acute ischemic stroke in the territory of the Middle cerebral artery. METHODS: The administration of the trial medication should start within 24 h after the initial symptoms of stroke. According to a random schedule, the patients were assigned to a 4-weeks double-blind treatment with either flunarizine (n = 166) or placebo (n = 165): one week intravenous administration (50 mg daily), followed by 3 weeks oral treatment (week 2, 21 mg daily; week 3-4, 7 mg daily). All patients had to be investigated by computerized tomography (CT) within 7 days after stroke onset; 36 patients were secundarily excluded because the CT showed another pathology. During the treatment period, other "stroke therapies" were not allowed. Patients were followed up for 24 weeks. RESULTS: After the 24 weeks trial period, the percentage of patients who were dead or pendent (modified Rankin score 3-5) was similar in both treatment groups (flunarizine 67%, placebo 65%). During the trial, the scores for handicap severity (modified Rankin scale), neurological status (Orgogozo) and activities of daily living (modified Barthel index) strongly improved in both treatment groups, but no differences were found between the treatment groups. In this trial, the administration of trial treatment started relatively late after stroke onset (flunarizine group: mean time interval 13.5 h; placebo 12.3 h). A subgroup of patients received trial medication within 6 h after stroke onset (flunarizine n = 31; placebo n = 29). Also in this subgroup, no differences were found between the flunarizine and placebo group. CONCLUSION: Flunarizine did not improve neurologic and functional outcome in patients with acute ischemic stroke.

The European Stroke Scale.

BACKGROUND AND PURPOSE: For detecting therapeutic effect and matching of treatment groups in stroke trials, a scale that meets the clinimetric criteria is of the utmost importance. METHODS: The European Stroke Scale consists of 14 items selected for their specificity and their prognostic value. It is designed for patients with middle cerebral artery stroke. Interrater reliability, internal consistency, and time for completion were investigated in 74 patients. Intrarater reliability was studied in 38 patients. To establish concurrent validity, two trials were performed in 20 and 44 patients. The scale was correlated with the MCA Neurological Scale, the Canadian Stroke Scale, the Scandinavian Stroke Scale, the Barthel Index, and the Rankin Scale. Correlations were calculated by means of Spearman's correlation coefficient. The trial in 44 patients also investigated the prognostic validity of the scale for 1-month and 8-month neurological, functional, and handicap status. These data were analyzed by linear regression. RESULTS: Interrater (kappa value range, 0.62 to 0.85) and intrarater (kappa value range, 0.65 to 1.00) reliability for each item was good, and internal consistency was excellent (Cronbach's alpha coefficient, 0.92). Mean time for completion was 8.2 minutes (range, 4 to 14 minutes). Correlations of the European Stroke Scale with other neurological scales ranged from 0.93 to 0.95. The correlation with the Barthel Index and the Rankin Scale was 0.84 and -0.86. The R2 values for prognostic validity ranged from 0.45 to 0.81 (P < or = .0001). CONCLUSIONS: The European Stroke Scale has been developed according to the clinimetric criteria.

Hospital referral of stroke patients: a survey of attitudes in general practice, and consideration of entry times for clinical trials.

Two major issues in clinical trials in stroke are the criteria used for the selection of patients expected to benefit from the proposed treatment, and the entry time of those patients. We surveyed 507 Belgian general practitioners (GPs) on their opinions on referral of stroke patients to hospital and also on their actual referral behaviour. The feasibility of a 6-hour entry time was included in the investigation. Stroke is considered to require an urgent response: 88% of GPs visited the patient immediately on concluding that such an event had occurred. The mean time between the onset of the first clinical symptoms and the arrival of the GP at the patient's residence was about 30 minutes. Within 6 h of the insult, 95% of the patients referred to hospital had been admitted. Information on the GP's most recent stroke patient revealed that 72.4% of these stroke patients were admitted to hospital. Patients referred to hospital were significantly younger, had a significantly more severe stroke, and were significantly more likely to have had a first stroke and to have lived independently before the insult than patients not admitted to hospital. We think that Belgian GPs need to change their referral behaviour with respect to stroke patients and refer more of those who have suffered more mildly. There is every reason to be optimistic about this re-education, since the patients whom GPs do refer to hospital are referred rapidly enough to profit from a possibly efficacious treatment.