Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. They should not exceed 750 words (excluding references) and may be subject to editing or abridgment. Please submit letters in duplicate, typed double-spaced. Include a fax number for the corresponding author and a completed copyright transfer agreement form (published in every issue). Effectively Bridging the Preclinical/Clinical Gap: The Results of the ASTIN Trial To the Editor: Recently, the results of

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... the Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN) were published. 1 In this trial, 966 patients presenting within 6 hours of acute stroke received varying doses of either placebo or UK-279,276, a CD11b/CD18 inhibitor. Additionally, a subgroup of 204 patients was coadministered tissue plasminogen activator (tPA) when clinically appropriate. The trial was stopped early when interim analysis demonstrated futility in achieving the primary end point of increased functional improvement from the patient's baseline as measured by the Scandinavian Stroke Scale (SSS) at 90 days. Post hoc analysis found that patients co-administered tPA and UK-279,276 exhibited a mean improvement of 1.6 points on the SSS, but this study was neither designed nor powered to achieve statistical significance in this group. While the study utilized a novel approach to clinical trial design and management, there are limitations in the design of this study that, while stated by the authors, merit additional attention. The first of these is the study's diminished emphasis on UK-279,276 as an adjuvant for tPA, with the drug administered as monotherapy to the majority of patients. Furthermore, evidence of spontaneous reperfusion (transcranial Doppler, perfusionweighted CT) was not used as an inclusion criterion. Because neuroprotective strategies targeting inflammatory events such as neutrophil influx primarily aim to attenuate reperfusion injury, agents such as UK-279,276 would be expected to demonstrate less efficacy in nonreperfused stroke. 2,3 Our own work with CD11b/CD18 established this: CD18 (-/-) knockout mice were protected in reperfused but not permanent models of middle cerebral artery occlusion. 4 In the current case, preclinical work with UK-279,276 supported this claim. Early work with the agent using a reperfused intraluminal suture model with 2 hours of occlusion demonstrated benefit in the form of decreased infarct volumes and improved neurological outcomes, but failed to demonstrate benefit for UK-279,276 when used in a nonreperfused models. 5,6 More recently, administration of UK-279,276 was shown to demonstrate no significant efficacy in a rat model of embolic stroke when the drug was administered alone, but led to significantly reduced infarct volumes and improved functional outcomes when co-administered with tPA, even when administered beyond the traditional tPA therapeutic window. 7 These data further strengthened the claim that UK-279,276 predominantly acts by attenuating cerebral reperfusion injury and as such would be less likely to improve the neurologic functioning of patients with lesser degrees of reperfusion. While future clinical efforts using UK-279,276 and similar drugs will likely refocus efforts toward subsets of patients who undergo either spontaneous, pharmacologic, or mechanical reperfusion, we feel this example further emphasizes the importance of effectively utilizing strong preclinical data to guide the design, nature, and aim of clinical stroke trials. 8,9 We hope that closer collaborations formed between basic scientists and clinical researchers will continue to strengthen the link between preclinical observations and clinical applications in the development of neuroprotective drugs.