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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.

In this randomized trial involving patients with acute stroke, prehospital administration of magnesium sulfate by paramedics within 2 hours after the onset of stroke symptoms (within 1 hour for 74% of patients) did not improve neurologic outcomes. Stroke is the second leading cause of death and a leading cause of adult disability worldwide. Unfortunately, currently available therapies for acute ischemic stroke, which are all reperfusion-based, are only moderately effective. 1 , 2 Treatment with tissue plasminogen activator (t-PA), the only pharmacologic treatment approved by a regulatory agency for the treatment of acute ischemic stroke, results in early reperfusion in less than half of treated patients, can be started only after neuroimaging has ruled out intracerebral hemorrhage, and is used in only 2 to 7% of patients with acute ischemic stroke in the United States. 1 Mechanical thrombectomy devices improve patient . . .

In this trial, subjects in status epilepticus were given either intramuscular midazolam or intravenous lorazepam by paramedics before arrival in the ER. Seizures were controlled in more subjects with midazolam, and midazolam was at least as safe and effective as lorazepam. Early termination of prolonged epileptic seizures in response to intravenous administration of benzodiazepines by paramedics in the prehospital setting is associated with better patient outcomes. The randomized, controlled Prehospital Treatment of Status Epilepticus (PHTSE) trial (ClinicalTrials.gov number, NCT00004297) compared diazepam, lorazepam, and placebo given intravenously by paramedics to treat subjects with prolonged convulsive seizures. 1 The trial showed that both these benzodiazepines were an effective prehospital treatment for seizures, as compared with placebo. The proportion of subjects whose seizures were terminated at the time of arrival in the emergency department was 59.1% in the group receiving intravenous lorazepam, 42.6% in the . . .

In this trial in nondiabetic patients with insulin resistance and a recent ischemic stroke or transient ischemic attack, pioglitazone was associated with a lower risk of stroke and MI than was placebo but with a higher risk of weight gain, edema, and bone fracture. Ischemic stroke and transient ischemic attack (TIA) affect more than 14 million persons worldwide annually. 1 , 2 Affected patients are at increased risk for future cardiovascular events, 3 , 4 and prevention of these adverse outcomes is a major goal in their care. Treatment of insulin resistance represents a potential new preventive strategy that could be added to standard care after ischemic stroke or TIA. 5 Insulin resistance is nearly universal in patients with type 2 diabetes but is also present in more than 50% of patients without diabetes who have had an ischemic stroke or a TIA. 6 The presence of insulin resistance increases . . .

Background Many stroke recovery interventions are most beneficial when started 2-14d post-stroke, a time when patients become eligible for inpatient rehabilitation facilities (IRF) and neuroplasticity is often at its peak. Clinical trials focused on recovery need to expand the time from this plasticity to later outcome timepoints. Methods The disability course of patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) enrolled in Field Administration of Stroke Therapy Magnesium (FAST-MAG) Trial with moderate-severe disability (modified Rankin Scale [mRS] 3–5) on post-stroke day4 who were discharged to IRF 2-14d post-stroke were analyzed. Results Among 1422 patients, 446 (31.4%) were discharged to IRFs, including 23.6% within 2-14d and 7.8% beyond 14d. Patients with mRS 3–5 on day4 discharged to IRFs between 2-14d accounted for 21.7% (226/1041) of AIS patients and 28.9% (110/381) of ICH patients, ( p  < 0.001). Among these AIS patients, age was 69.8 (± 12.7), initial NIHSS median 8 (IQR 4–12), and day4 mRS = 3 in 16.4%, mRS = 4 in 50.0%, and mRS = 5 in 33.6%. Among these ICH patients, age was 62.4 (± 11.7), initial NIHSS median 9 (IQR 5–13), day 4 mRS = 3 in 9.4%, mRS = 4 in 45.3%, and mRS = 5 in 45.3% ( p  < 0.01 for AIS vs ICH). Between day4 to day90, mRS improved ≥ 1 levels in 72.6% of AIS patients vs 77.3% of ICH patients, p  = 0.3. For AIS, mRS improved from mean 4.17 (± 0.7) to 2.84 (± 1.5); for ICH, mRS improved from mean 4.35 (± 0.7) to 2.75 (± 1.3). Patients discharged to IRF beyond day14 had less improvement on day90 mRS compared with patients discharged between 2-14d. Conclusions In this acute stroke cohort, nearly 1 in 4 patients with moderate-severe disability on post-stroke day4 were transferred to IRF within 2-14d post-stroke. ICH patients had nominally greater mean improvement on mRS day90 than AIS patients. This course delineation provides a roadmap for future rehabilitation intervention studies.

In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS. We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0·68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389. At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0·51). The hazard ratio of reaching the primary endpoint was 1·13 (95% CI 0·61–2·07). The study was stopped at the first interim analysis because criterion for futility was met (p=0·78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0·15 (95% CI −0·43 to 0·73, p=0·61). There were no major safety concerns. Falls (p=0·04) and back pain (p=0·05) were more common in the lithium group than in the placebo group. We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS. National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada.

Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack (TIA). The IRIS Trial is evaluating an approach to secondary prevention based on the established association between insulin resistance and increased risk for ischemic vascular events. Specifically, IRIS will test the effectiveness of pioglitazone, an insulin-sensitizing drug of the thiazolidinedione class, for reducing the risk for stroke and myocardial infarction (MI) among insulin resistant, nondiabetic patients with a recent ischemic stroke or TIA. Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment–Insulin Resistance >3.0 without meeting criteria for diabetes. Within 6 months of the index stroke or TIA, patients were randomly assigned to pioglitazone (titrated from 15 to 45 mg/d) or matching placebo and followed for up to 5 years. The primary outcome is time to stroke or MI. Secondary outcomes include time to stroke alone, acute coronary syndrome, diabetes, cognitive decline, and all-cause mortality. Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013. Participant follow-up will continue until July 2015. The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic, insulin-resistant patients with stroke or TIA. Results are expected in early 2016.

Background. Cardiac adverse events are common among patients presenting with acute stroke and contribute to overall morbidity and mortality. Prophylactic measures for the reduction of cardiac adverse events in hospitalized stroke patients have not been well understood. We sought to investigate the effect of early initiation of high-dose intravenous magnesium sulfate on cardiac adverse events in stroke patients. Methods. This is a secondary analysis of the prehospital Field Administration of Stroke Therapy-Magnesium (FAST-MAG) randomized phase-3 clinical trial, conducted from 2005-2013. Consecutive patients with suspected acute stroke and a serum magnesium level within 72 hours of enrollment were selected. Twenty grams of magnesium sulfate or placebo was administered in the ambulance starting with a 15-minute loading dose intravenous infusion followed by a 24-hour maintenance infusion in the hospital. Results. Among 1126 patients included in the analysis of this study, 809 (71.8%) patients had ischemic stroke, 277 (24.6%) had hemorrhagic stroke, and 39 (3.5%) with stroke mimics. The mean age was 69.5 (SD13.4) and 42% were female. 565 (50.2%) received magnesium treatment, and 561 (49.8%) received placebo. 254 (22.6%) patients achieved the target, and 872 (77.4%) did not achieve the target, regardless of their treatment group. Among 1126 patients, 159 (14.1%) had at least one CAE. Treatment with magnesium was not associated with fewer cardiac adverse events. A multivariate binary logistic regression for predictors of CAEs showed a positive association of older age and frequency of CAEs (R=1.04, 95% CI 1.03-1.06, p<0.0001). Measures of early and 90-day outcomes did not differ significantly between the magnesium and placebo groups among patients who had CAEs. Conclusion. Treatment of acute stroke patients with magnesium did not result in a reduction in the number or severity of cardiac serious adverse events.

Background and Purpose: Subject retention into clinical trials is vital, and prehospital enrollment may be associated with higher rates of subject withdrawal than more traditional methods of enrollment. We describe rates of subject retention in a prehospital trial of acute stroke therapy. Methods: All subjects were enrolled into the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) phase 3 clinical trial. Paramedics screened eligible subjects and contacted the physician-investigator using a dedicated in-ambulance cellular phone. Physician-investigators obtained explicit informed consent from the subject or on-scene legally authorized representative (LAR) who reviewed and signed a consent form. Exception from informed consent (EFIC) was utilized in later stages of the study. Results: There were 1,700 subjects enrolled; 1,017 provided consent (60%), 662 were enrolled via LAR (39%), and 21 were enrolled via EFIC (1%). Of the 1,700 patients, 1,413 (83%) completed the 90-day visit, 265 (16%) died prior to the 90-day visit, and 22 (1.3%) withdrew from the study before completion. There were no differences in rates of withdrawal by method of study enrolment, i.e., self-consent (n = 14), 1.4%; LAR (n = 8), 1.2%; EFIC (n = 0) 0%. Conclusion: There was a high rate of retention when subjects were enrolled into prehospital stroke research using a phone-based method to obtain explicit consent.