Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke: Meta-Analysis of 5 Randomized Trials.

Background and Purpose- TNK (tenecteplase), a newer fibrinolytic agent, has practical delivery advantages over ALT (alteplase) that would make it a useful agent if noninferior in acute ischemic stroke treatment outcome. Accordingly, the most recent US American Heart Association/American Stroke Association acute ischemic stroke guideline recognized TNK as an alternative to ALT, but only based on informal consideration, rather than formal meta-analysis, of completed randomized control trials. Methods- Systematic literature search and formal meta-analysis were conducted per PRISMA guidelines (Preferred Reporting Items for Systemic Reviews and Meta-Analyses), adapted to noninferiority analysis. The primary outcome of freedom from disability (modified Rankin Scale score, 0-1) outcome at 3 m, and additional efficacy and safety outcomes, were analyzed. Results- Systematic search identified 5 trials enrolling 1585 patients (828 TNK, 757 ALT). Across all trials, mean age was 70.8, 58.5% male, baseline National Institutes of Health Stroke Scale mean 7.0, and time from last known well to treatment start mean 148 minutes. All ALT patients received standard 0.9 mg/kg dosing, while TNK dosing was 0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%. For the primary end point, crude cumulative rates of disability-free (modified Rankin Scale score, 0-1) 3 m outcome were TNK 57.9% versus ALT 55.4%. Informal, random-effects meta-analysis, the risk difference was 4% (95% CI, -1% to 8%). The lower 95% CI bound fell well within the prespecified noninferiority margin. Similar results were seen for the additional efficacy end points: functional independence (modified Rankin Scale score, 0-2): crude TNK 71.9% versus ALT 70.5%, risk difference 2% (95% CI, -3% to 6%); and modified Rankin Scale shift analysis, common odds ratio 1.21 (95% CI, 0.93-1.57). For safety end points, lower event rates reduced power, but point estimates were also consistent with noninferiority Conclusions- Accumulated clinical trial data provides strong evidence that TNK is noninferior to ALT in the treatment of acute ischemic stroke. These findings provide formal support for the recent guideline recommendation to consider TNK an alternative to ALT.

Utilization of Emergent Neuroimaging for Thrombolysis-Eligible Stroke Patients.

BACKGROUND: Advances in diagnostic imaging of stroke include multimodal techniques such as noninvasive angiography and perfusion imaging. We aimed to characterize trends in neuroimaging utilization among acute stroke patients. Utilization of multimodal imaging for acute stroke in the community has remained largely uncharacterized despite its increased adoption at academic medical centers. METHODS: We quantified neuroimaging utilization in the emergency department (ED) for 1,700 hyperacute stroke patients presenting <2 hours after symptom onset who participated in the National Institutes of Health Field Administration of Stroke Therapy-Magnesium (FAST-MAG) study throughout Los Angeles and Orange Counties. FAST-MAG provided no recommendation as to imaging utilization. RESULTS: A total of 1,700 cases were imaged a median (interquartile range [IQR]) of 92 (74-120) minutes after last known well time and 28 (19-41) minutes after ED arrival. The initial scanner used in the ED was computed tomography (CT) in a preponderance of cases (N = 1,612, 95%), with magnetic resonance imaging (MRI) in 88 cases (5%). CT angiography (CTA) was obtained in 192 (11%) and perfusion CT (CTP) in 91 (5.4%) cases. MRI imaging was universally obtained using diffusion-weighted images, 60% with MR angiography and 33% included perfusion imaging. Rates of concomitant CTA or CTP use increased in the later years of the study from 4% in 2005-2006, 2% in 2007-2008, 8% in 2009-2010, and 26% in 2011-2012 (P for trend < .001). CONCLUSIONS: Among acute stroke patients, noncontrast CT was the most common initial imaging strategy in clinical practice in the 2005-2012 time period, though use of concomitant CTA grew to one-quarter of cases, suggestive of an upward trend.

Characteristics and Outcomes of Very Elderly Enrolled in a Prehospital Stroke Research Study.

BACKGROUND AND PURPOSE: Greater numbers of individuals aged ≥80 years enjoy a high quality of life, yet historically stroke trials have excluded this population. We aimed to describe a population of very elderly successfully enrolled into an acute stroke trial and compare their characteristics and outcomes with the younger cohort. METHODS: We analyzed consecutive patients enrolled <2 hours of symptom onset in a prehospital stroke treatment trial, the FAST-MAG clinical trial (Field Administration of Stroke Therapy-Magnesium). We gathered demographic, treatment, and outcome data for nonelderly (<80 years old), very elderly (≥80 years old), and extreme elderly (≥90 years old). We describe key differences in the population of elderly and the impact of their inclusion on the clinical trial. RESULTS: Of 1700 participants in FAST-MAG, there were 1210 nonelderly, 490 very elderly, and 60 extreme elderly subjects. Very elderly stroke patients successfully enrolled in a research study were more likely to be women, white, and have an ischemic mechanism rather than an intracerebral hemorrhage. Although the very elderly had generally poorer outcomes, 4 in 10 were functionally independent at 90 days. CONCLUSIONS: Inclusion of the very elderly population in acute stroke clinical trials would both significantly increase study participation and generalizability of future acute stroke clinical trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Deficiency in complement C1q improves histological and functional locomotor outcome after spinal cord injury.

Although studies have suggested a role for the complement system in the pathophysiology of spinal cord injury (SCI), that role remains poorly defined. Additionally, the relative contribution of individual complement pathways in SCI is unknown. Our initial studies revealed that systemic complement activation was strongly influenced by genetic background and gender. Thus, to investigate the role of the classical complement pathway in contusion-induced SCI, male C1q knock-out (KO) and wild-type (WT) mice on a complement sufficient background (BUB) received a mild-moderate T9 contusion injury with the Infinite Horizon impactor. BUB C1q KO mice exhibited greater locomotor recovery compared with BUB WT mice (p<0.05). Improved recovery observed in BUB C1q KO mice was also associated with decreased threshold for withdrawal from a mild stimulus using von Frey filament testing. Surprisingly, quantification of microglia/macrophages (F4/80) by FACS analysis showed that BUB C1q KO mice exhibited a significantly greater percentage of macrophages in the spinal cord compared with BUB WT mice 3 d post-injury (p<0.05). However, this increased macrophage response appeared to be transient as stereological assessment of spinal cord tissue obtained 28 d post-injury revealed no difference in F4/80-positive cells between groups. Stereological assessment of spinal cord tissue showed that BUB C1q KO mice had reduced lesion volume and an increase in tissue sparing compared with BUB WT mice (p<0.05). Together, these data suggest that initiation of the classical complement pathway via C1q is detrimental to recovery after SCI.