Does hemispheric lateralization influence functional and cardiovascular outcomes after stroke?: an analysis of placebo-treated patients from prospective acute stroke trials

<p><b>Background and Purpose:</b> The influence of stroke lateralization on functional and cardiovascular outcome after stroke is not well established. We evaluated the influence of hemispheric lateralization among patients enrolled in prospective acute stroke trials.</p> <p><b>Methods:</b> We obtained data from the VISTA database for acute stroke trials which reported lateralization. Baseline data, cardiac adverse events, and 90-day outcomes were compared between right and left hemisphere stroke patients. A "hemisphere unbiased" subscore of the NIHSS which omitted items strongly associated with lateralized cognitive deficits was also compared for trials which reported individual NIHSS item scores. A multivariable analysis of outcome predictors was performed.</p> <p><b>Results:</b> Three acute stroke trials met the prespecified inclusion criteria. 1644 placebo-treated patients with documented hemispheric lateralization were included in the analysis. Baseline NIHSS was higher for left hemisphere patients (mean 16.2, versus 12.8 right, P < 0.001); there was no difference in the "hemisphere unbiased" NIHSS subscore (10.88 left, 11.08 right, n=687, P= 0.49). There was no difference between hemispheres in 90-day modified Rankin Score (3.43 left, 3.29 right, P=0.13), mortality (22.1% left, 19.5% right, P=0.20), or cardiac adverse events (P=0.71). Hemispheric lateralization was not an independent predictor of outcome in the multivariable analysis after controlling for the hemispheric bias intrinsic to the NIHSS.</p> <p><b>Conclusions:</b> There is no difference in functional outcome between patients with right or left hemisphere stroke. Use of the baseline NIHSS score to predict stroke outcome must take hemispheric lateralization into account. Stroke lateralization is not an important predictor of cardiac adverse events or 90-day mortality.</p&gt

NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials

<p><b>Background and Purpose:</b> In animal models of acute ischemic stroke (AIS), the free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I and II were randomized, placebo-controlled, double-blind trials to investigate the efficacy of NXY-059 in patients with AIS.</p> <p><b>Methods:</b> Patients with AIS received an infusion of intravenous NXY-059 or placebo within 6 hours from the onset of stroke symptoms. A pooled individual patient analysis was prespecified to assess the overall efficacy and to examine subgroups. The primary end point was the distribution of disability scores measured on the modified Rankin scale (mRS) at 90 days. Neurologic and activities of daily living scores were investigated as secondary end points. We also evaluated whether treatment with NXY-059 would reduce alteplase-related intracranial hemorrhages. Finally, we evaluated possible predictors of good or poor outcome.</p> <p><b>Results:</b> An intent-to-treat efficacy analysis was based on 5028 patients. Baseline parameters and prognostic factors were well balanced between treatment groups. The distribution of scores on the mRS was not different in the group treated with NXY-059 (n = 2438) compared with the placebo group (n = 2456): odds ratio for limiting disability = 1.02; 95% CI, 0.92 to 1.13 (P = 0.682, Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an absence of benefit. There was no evidence of efficacy in prespecified subgroups or from the secondary outcome analyses. Mortality was equal in the 2 groups (16.7% vs 16.5%), and adverse event rates were similar. Among patients treated with alteplase, there was no decrease in rates of symptomatic or asymptomatic hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses identified National Institutes of Health Stroke Scale score, age, markers of inflammation, blood glucose, and right-sided infarct as predictors of poor outcome.</p> <p><b>Conclusions:</b> NXY-059 is ineffective for treatment of AIS within 6 hours of symptom onset. This is also true for subgroups and the prevention of alteplase-associated hemorrhage.</p&gt

Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable

BACKGROUND: Previous Stroke Therapy Academic Industry Roundtable (STAIR) meetings focused on preclinical evidence of drug efficacy and enhancing acute stroke trial design and performance. A fourth (STAIR-IV) was held to discuss relevant issues related to acute stroke drug development and regulatory approval. SUMMARY OF REVIEW: The STAIR-IV meeting had 3 main focus areas. The first topic was novel approaches to statistical design of acute stroke trials and appropriate outcome measures. The second focus was the need for better cooperation among participants in stroke therapy development that may be addressed through a national consortium of stroke trial centers in the United States and elsewhere. Lastly, regulatory issues related to the approval of novel mono and multiple acute stroke therapies were discussed. CONCLUSIONS: The development of additional acute stroke therapies represents a large unmet need with many remaining challenges and also opportunities to incorporate novel approaches to clinical trial design that will lead to regulatory approval. The STAIR-IV meeting explored new concepts of trial methodology and data analysis, initiatives for implementing a US clinical trialist consortium, and pertinent regulatory issues to expedite approval of novel therapies

Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems

Rodent models of focal cerebral ischemia are essential tools in experimental stroke research. They have added tremendously to our understanding of injury mechanisms in stroke and have helped to identify potential therapeutic targets. A plethora of substances, however, in particular an overwhelming number of putative neuroprotective agents, have been shown to be effective in preclinical stroke research, but have failed in clinical trials. A lot of factors may have contributed to this failure of translation from bench to bedside. Often, deficits in the quality of experimental stroke research seem to be involved. In this article, we review the commonest rodent models of focal cerebral ischemia - middle cerebral artery occlusion, photothrombosis, and embolic stroke models - with their respective advantages and problems, and we address the issue of quality in preclinical stroke modeling as well as potential reasons for translational failure

Phase I and Phase II Therapies for Acute Ischemic Stroke: An Update on Currently Studied Drugs in Clinical Research.

Acute ischemic stroke is a devastating cause of death and disability, consequences of which depend on the time from ischemia onset to treatment, the affected brain region, and its size. The main targets of ischemic stroke therapy aim to restore tissue perfusion in the ischemic penumbra in order to decrease the total infarct area by maintaining blood flow. Advances in research of pathological process and pathways during acute ischemia have resulted in improvement of new treatment strategies apart from restoring perfusion. Additionally, limiting the injury severity by manipulating the molecular mechanisms during ischemia has become a promising approach, especially in animal research. The purpose of this article is to review completed and ongoing phases I and II trials for the treatment of acute ischemic stroke, reviewing studies on antithrombotic, thrombolytic, neuroprotective, and antineuroinflammatory drugs that may translate into more effective treatments

Treating the acute stroke patient as an emergency: current practices and future opportunities

Developments in acute stroke therapy have followed advances in the understanding of the evolving pathophysiology in both ischaemic stroke and intracerebral haemorrhage (ICH). In ischaemic stroke, rapid reperfusion of the ischaemic penumbra with thrombolysis within 3 h of symptom onset is of proven benefit, but few patients currently receive therapy, mainly due to the short-time window and lack of stroke expertise. In ICH, a recent study indicated that a haemostatic agent can limit ongoing bleeding and improve outcomes when administered within 4 h of stroke onset. These advances in acute stroke therapy underlie the concept that ‘time is brain’ and that urgent intervention can limit cerebral damage. Neuroprotective therapy could offer the prospect of a greater proportion of stroke patients receiving treatment, potentially before imaging and even in the ambulance setting. Virtually all stroke patients would benefit from receiving multidisciplinary care in acute stroke units

Successfully Climbing the “STAIRs”: Surmounting Failed Translation of Experimental Ischemic Stroke Treatments

The Stroke Therapy Academic Industry Roundtable (STAIR) provided initial (in 1999) and updated (in 2009) recommendations with the goal of improving preclinical stroke therapy assessment and to increase the translational potential of experimental stroke treatments. It is important for preclinical stroke researchers to frequently consider and revisit these concepts, especially since promising experimental stroke treatments continue to fail in human clinical trials. Therefore, this paper will focus on considerations for several key aspects of preclinical stroke studies including the selection and execution of the animal stroke model, drug/experimental treatment administration, and outcome measures to improve experimental validity and translation potential. Specific points of interest discussed include the incorporation of human comorbid conditions and drugs, the benefits of defining a proposed mechanism of action, replication of results using multiple methods, using clinically relevant routes of administration and treatment time windows, and performing and reporting good experimental methods to reduce bias such as, as suggested by the updated STAIR recommendations, sample size calculations, randomization, allocation concealment, blinding, and appropriate inclusion/exclusion criteria. It is our hope that reviewing and revisiting these considerations will benefit researchers in their investigations of stroke therapies and increase the likelihood of translational success in the battle against stroke