METHODS: This randomised, double-blind, parallel-group trial was undertaken in 802 centres in 46 countries. Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were randomly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin. Patients and investigators were masked to treatment allocation. The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (excluding haemorrhagic death). We planned a sequential statistical analysis of non-inferiority (margin 1.05) followed by analysis of superiority. Analysis was by intention to treat. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee. This study is registered, number ISRCTN66157730.

FINDINGS: 9562 patients were assigned to terutroban (9556 analysed) and 9558 to aspirin (9544 analysed); mean follow-up was 28.3 months (SD 7.7). The primary endpoint occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1.02, 95% CI 0.94-1.12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1147 [12%] vs 1045 [11%]; HR 1.11, 95% CI 1.02-1.21), but no significant differences in other safety endpoints.

INTERPRETATION: The trial did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban. In a worldwide perspective, aspirin remains the gold standard antiplatelet drug for secondary stroke prevention in view of its efficacy, tolerance, and cost.

FUNDING: Servier, France.

METHODS: The Safety and Efficacy of NeuroFlo in Acute Ischemic Stroke trial is a randomized trial of the safety and efficacy of NeuroFlo treatment in improving neurological outcome versus standard medical management. The primary safety end point was the incidence of serious adverse events through 90 days. The primary efficacy end point on a modified intent-to-treat population was a global disability end point at 90 days. Secondary end points included mortality, intracranial hemorrhage, modified Rankin scale score outcome of 0 to 2, and modified Rankin scale shift analysis.

RESULTS: Between October 2005 and January 2010, 515 patients were enrolled at 68 centers in 9 countries. The primary efficacy end point did not reach statistical significance (OR, 1.17; CI, 0.81-1.67; P=0.407). The primary safety end point did not show a difference in serious adverse events (P=0.923). Ninety-day mortality was 11.3% (26/230) in treatment and 16.3% (42/257) in control (P=0.087). Post hoc analyses showed that patients presenting within 5 hours (OR, 3.33; CI, 1.31-8.48), with NIHSS score 8 to 14 (OR, 1.80; CI, 0.99-3.30), or older than age 70 years (OR, 2.02; CI, 1.02-4.03) had better modified Rankin scale score outcomes of 0 to 2; additionally, there were fewer stroke-related deaths in treatment compared to control groups (7.4% = 17/230; 14.4% = 37/257).

CONCLUSIONS: The trial met its primary safety end point but not its primary efficacy end point. Signals of treatment effect were suggested on all-cause mortality, in patients presenting early, older than age 70 years, or with moderate strokes, but these require confirmation.

CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00119717.

METHODS: Rats were subjected to permanent middle cerebral artery occlusion by the suture occlusion method and were treated 1 hour thereafter with a single 5-minute intravenous infusion of the postsynaptic density-95 protein inhibitor Tat-NR2B9c (7.5 mg/kg) or saline (n=8/group). Arterial spin-labeled perfusion-weighted MRI and diffusion weighted MRI were obtained with a 4.7-T Bruker system at 30, 45, 70, 90, 120, 150, and 180 minutes postmiddle cerebral artery occlusion to determine cerebral blood flow and apparent diffusion coefficient maps, respectively. At 24 hours, animals were neurologically scored (0 to 5), euthanized, and the brains stained with 2-3-5-triphenyl tetrazolium chloride to ascertain infarct volumes corrected for edema. Additionally, the effects of Tat-NR2B9c on adenosine 5'-triphosphate levels were measured in vitro in neurons subjected to oxygen-glucose deprivation.

RESULTS: Final infarct volume was decreased by 30.3% in the Tat-NR2B9c-treated animals compared with controls (P=0.028). There was a significant improvement in 24 hours neurological scores in the Tat-NR2B9c group compared with controls, 1.8+/-0.5 and 2.8+/-1.0, respectively (P=0.021). Relative to controls, Tat-NR2B9c significantly attenuated diffusion-weighted imaging lesion growth and preserved the diffusion-weighted imaging/perfusion-weighted imaging mismatch (ischemic penumbra) without affecting cerebral blood flow in the ischemic core or penumbra. Tat-NR2B9c treatment of primary neuronal cultures resulted in 26% increase in cell viability and 34% greater adenosine 5'-triphosphate levels after oxygen-glucose deprivation.

CONCLUSIONS: Preservation of adenosine 5'-triphosphate levels in vitro and neuroprotection in permanent middle cerebral artery occlusion in rats is achievable without cerebral blood flow augmentation using a postsynaptic density-95 protein inhibitor.

METHODS: In experiment 1 we used in vitro optimization of clot visualization using multiple MRI contrast agents in concentrations ranging from 5 to 50 muL in 250 muL blood. In experiment 2, we used in vivo characterization of the time course of clot lysis using the clot developed in the previous experiment. Diffusion, perfusion, angiography, and T1-weighted MRI for clot imaging were conducted before and during treatment with vehicle (n=6), tPA (n=8), or rA2 plus tPA (n=8) at multiple time points. Brains were removed for ex vivo clot localization.

RESULTS: Clots created with 25 muL Magnevist were the most stable and provided the highest contrast-to-noise ratio. In the vehicle group, clot length as assessed by T1-weighted imaging correlated with histology (r=0.93). Clot length and cerebral blood flow-derived ischemic lesion volume were significantly smaller than vehicle at 15 minutes after treatment initiation in the rA2 plus tPA group, whereas in the tPA group no significant reduction from vehicle was observed until 30 minutes after treatment initiation. The rA2 plus tPA group had a significantly shorter clot length than the tPA group at 60 and 90 minutes after treatment initiation and significantly smaller cerebral blood flow deficit than the tPA group at 90 minutes after treatment initiation.

CONCLUSIONS: We introduce a novel MRI-based clot imaging method for in vivo monitoring of clot lysis. Lytic efficacy of tPA was enhanced by rA2.

Methods and Results—This retrospective cohort study of 695 patients enrolled at a university hospital-based anticoagulation clinic includes patients who received anticoagulation with warfarin or warfarin and aspirin between June 1, 2007 and September 30, 2008. All patients were ≥45 years old, had AF as the indication for anticoagulation, and did not have mechanical heart valves. Hemorrhages were classified as major if they caused death, involved critical sites, or required hospitalization with transfusion of ≥2 units of blood. All other bleeds were classified as minor. Of the 695 patients 307(44.2%) received combination therapy. Hemorrhage rates in the warfarin and the combination cohorts were 5.2% and 7.0% per 100-people years (p=0.29), respectively. There were 17 (3.4%) patients with major hemorrhages in the warfarin only group and 9 (2.8%) in the combination group (p=0.62). On average, patients on combination therapy had lower international normalized ratio (INR) values circa presentation (4.27 vs 3.13 p=0.049). In either group, any history of hemorrhage was associated with a 3.8 (95% CI, 1.79-8.13) times higher risk of hemorrhaging compared to patients without such a history.

Conclusions—This study highlights the high incidence of combination therapy and suggests that patients on combination therapy may bleed at lower INR levels. However, hemorrhagic outcomes did not differ significantly.

METHODS: An Internet-based survey was sent to 400 US vascular neurologists affiliated with a university to assess whether there are consensus opinions on how they treat patients beyond 3 hours from symptom onset and which patients they are willing to enroll into clinical trials of fibrinolysis for acute ischemic stroke.

RESULTS: We received 161 responses; 81% were male. Ninety-three percent of respondents treat patients with intravenous tissue plasminogen activator beyond 3 hours. More than 80% were treated beyond 3 hours with intra-arterial therapy (IAT). When asked if IAT improves stroke outcome, >50% selected the choice of "yes for middle cerebral artery and basilar occlusions" and only 2% selected the choice that "IAT does not improve outcome." Over half believe that imaging could be used to approximate the penumbra but with improvements to better identify salvageable tissue. Eighty-seven percent were willing to enroll patients into a placebo-controlled intravenous thrombolysis beyond 3 hours. For IAT trials, >80% would randomize beyond 3 hours with or without prior intravenous treatment.

CONCLUSIONS: Vascular neurologists have been treating acute ischemic stroke beyond 3 hours with intravenous tissue plasminogen activator even before the American Heart Association guidelines supported extending the therapeutic window. There is a paradox among the respondents willing to enroll patients into trials involving IAT given that a majority is offering IAT as part of their practice. These results suggest that clinical practice may impair enrollment into trials testing reperfusion therapies for acute ischemic stroke.

METHODS: We reviewed the literature focusing on case-control studies of the 5 most commonly inherited disorders of coagulation: protein C deficiency, protein S deficiency, antithrombin deficiency, and the factor V Leiden and prothrombin gene mutations in patients with stroke. We also analyzed the available data on stroke patients with inherited thrombophilia and patent foramen ovale.

RESULTS: Multiple case-control studies have not convincingly shown an association of the inherited thrombophilias with ischemic stroke, even in young patients and patients with patent foramen ovale.

CONCLUSIONS: If there is an association between the inherited thrombophilias and arterial stroke, then it is a weak one, likely enhanced by other prothrombotic risk factors. The consequences of ordering these tests and attributing causality to an arterial event can result in significant costs to the health care system and pose a potential risk to patients, because this may lead to inappropriate use of long-term oral anticoagulants, exposing patients to harm without a clearly defined benefit.

METHODS: Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.

RESULTS: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures.

CONCLUSIONS: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.

METHODS: Four intravenous dose regimens (total cumulative doses of 30-180 mug/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch.

RESULTS: Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions > 14-17 cm(3).

CONCLUSIONS: We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points.