Intravenous valproate, levetiracetam, and fosphenytoin stopped status epilepticus that was resistant to initial treatment with lorazepam in approximately half the patients and did not differ ...significantly in effectiveness. Hypotension was numerically — but not significantly — more frequent with fosphenytoin.
In this international, randomized trial, patients with minor stroke or TIA who received clopidogrel plus aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 ...days than those who received aspirin alone.
Summary Background Preclinical models of stroke have shown that intravenous glyburide reduces brain swelling and improves survival. We assessed whether intravenous glyburide (RP-1127; glibenclamide) ...would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction. Methods For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18–80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82–300 cm3 on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous glyburide group. Intravenous glyburide was given as a 0·13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0·16 mg/h for the first 6 h and then 0·11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0–4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov , number NCT01794182. Findings Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous glyburide group and 14 (39%) in the placebo group had an mRS score of 0–4 at 90 days without decompressive craniectomy (adjusted odds ratio 0·87, 95% CI 0·32–2·32; p=0·77). Ten (23%) of 44 participants in the intravenous glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0·76), and four of 20 had serious adverse events (two in the intravenous glyburide group and two in the placebo group, p=1·00). One cardiac death occurred in each group (p=1·00). Interpretation Intravenous glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous glyburide. Funding Remedy Pharmaceuticals.
IMPORTANCE: Dual antiplatelet therapy with clopidogrel and aspirin is effective for secondary prevention after minor ischemic stroke or transient ischemic attack (TIA). Uncertainties remained about ...the optimal duration of dual antiplatelet therapy for minor stroke or TIA. OBJECTIVE: To obtain precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA. DESIGN, SETTING, AND PARTICIPANTS: This analysis pooled individual patient–level data from 2 large-scale randomized clinical trials that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor stroke or high-risk TIA. The Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) trial enrolled patients at 114 sites in China from October 1, 2009, to July 30, 2012. The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial enrolled patients at 269 international sites from May 28, 2010, to December 19, 2017. Both were followed up for 90 days. Data analysis occurred from November 2018 to May 2019. INTERVENTIONS: In the 2 trials, patients with minor stroke or high-risk TIA were randomized to clopidogrel-aspirin or aspirin alone within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was a major ischemic event (ischemic stroke, myocardial infarction, or death from ischemic vascular causes). The primary safety outcome was major hemorrhage. RESULTS: The study enrolled 5170 patients (CHANCE) and 4881 patients (POINT). Analysis included individual data from 10 051 patients (5016 in the clopidogrel-aspirin treatment group and 5035 in the control group) with a median age of 63.2 (interquartile range, 55.0-72.9) years; 6106 patients (60.8%) were male. Clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (328 of 5016 6.5% vs 458 of 5035 9.1%; hazard ratio HR, 0.70 95% CI, 0.61-0.81; P < .001), mainly within the first 21 days (263 of 5016 5.2% vs 391 of 5035 7.8%; HR, 0.66 95% CI, 0.56-0.77; P < .001), but not from day 22 to day 90. No evidence of heterogeneity of treatment outcome across trials or prespecified subgroups was observed. Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was nonsignificant. CONCLUSIONS AND RELEVANCE: In this analysis of the POINT and CHANCE trials, the benefit of dual antiplatelet therapy appeared to be confined to the first 21 days after minor ischemic stroke or high-risk TIA.
Guidelines for benzodiazepine dosing are based on high-quality data from randomised controlled trials.1–3 Status epilepticus, treated according to guidelines, can be expected to resolve in about 70% ...of patients after first-line treatment with benzodiazepines.3 In those 30% of patients with seizures that do not respond to first-line treatment with benzodiazepines, guidelines recommend treatment with any of several second-line anticonvulsants.4,5 Unfortunately, guidelines for second-line anticonvulsants in patients with status epilepticus have had to rely on scant and relatively low-quality data from observational studies or very limited trials. Subjectivity not only complicates clinical determination of cessation of seizures but also complicates subsequent clinical decision making about when to use additional rescue doses of anticonvulsants and when to proceed to endotracheal intubation.10 Similar clinical outcomes with both drugs in these trials might indicate a similar pharmacological effect on seizures but alternatively might show that clinical factors other than the drugs might be driving the clinical outcome more strongly. Burger/Phanie/Science Photo Library We are both Principal Investigators of the ESETT clinical trial, which is funded by the US National Institutes of Health, with overlapping goals to the reported trials.
BACKGROUND AND PURPOSE—Although the modified Rankin Scale (mRS) is the most commonly used primary end point in acute stroke trials, its power is limited when analyzed in dichotomized fashion and its ...indication of effect size challenging to interpret when analyzed ordinally. Weighting the 7 Rankin levels by utilities may improve scale interpretability while preserving statistical power.
METHODS—A utility-weighted mRS (UW-mRS) was derived by averaging values from time-tradeoff (patient centered) and person-tradeoff (clinician centered) studies. The UW-mRS, standard ordinal mRS, and dichotomized mRS were applied to 11 trials or meta-analyses of acute stroke treatments, including lytic, endovascular reperfusion, blood pressure moderation, and hemicraniectomy interventions.
RESULTS—Utility values were 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. For trials with unidirectional treatment effects, the UW-mRS paralleled the ordinal mRS and outperformed dichotomous mRS analyses. Both the UW-mRS and the ordinal mRS were statistically significant in 6 of 8 unidirectional effect trials, whereas dichotomous analyses were statistically significant in 2 to 4 of 8. In bidirectional effect trials, both the UW-mRS and ordinal tests captured the divergent treatment effects by showing neutral results, whereas some dichotomized analyses showed positive results. Mean utility differences in trials with statistically significant positive results ranged from 0.026 to 0.249.
CONCLUSIONS—A UW-mRS performs similar to the standard ordinal mRS in detecting treatment effects in actual stroke trials and ensures the quantitative outcome is a valid reflection of patient-centered benefits.
OBJECTIVEIn this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints.
...METHODSBlinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined.
RESULTSIn the per-protocol sample, 41 patients received glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 58.5% in IV glyburide vs n = 23 63.9% in placebo, p = 0.91) or the incidence of malignant edema (n = 19 46% in IV glyburide vs n = 17 47% in placebo, p = 0.94). However, treatment with IV glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 2.4% with IV glyburide vs n = 8 22.2% with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV glyburide had less midline shift (p < 0.01) and reduced MMP-9 (matrix metalloproteinase 9) levels (p < 0.01). The glyburide treatment group had lower rate of NIH Stroke Scale (NIHSS) increase of ≥4 during the infusion period (n = 7 37% in IV glyburide vs n = 12 71% in placebo, p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 58% vs n = 15 94%, p = 0.016).
CONCLUSIONIV glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV glyburide in large hemispheric infarction are warranted to corroborate these findings.
CLINICALTRIALS.GOV IDENTIFIERNCT01794182.
LEVEL OF EVIDENCEThis study provides Class II evidence that for patients with large hemispheric infarction, IV glyburide improves some edema-related endpoints.
To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women ...with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial.
Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning).
1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p<0.0001) and Symbol Digit Modality measures (Z = 5.221, p<0.0001).
Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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