Published Online
on March 27, 2008

A more recent version of this article appeared on June 1, 2008

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Submitted on September 5, 2007
Revised on October 15, 2007
Accepted on October 19, 2007

NXY-059 for the Treatment of Acute Stroke. Pooled Analysis of the SAINT I and II Trials

Hans-Christoph Diener MD^*; Kennedy R. Lees MD; Patrick Lyden MD; Jim Grotta MD; Antoni Davalos MD; Stephen M. Davis MD, PhD; Ashfaq Shuaib MD; Tim Ashwood PhD; Warren Wasiewski MD; Vivian Alderfer PhD; Hans-Goran Hårdemark MD; Larry Rodichok MD; for the SAINT I and II Investigators

From the Department of Neurology (H.C.D.), University of Duisburg-Essen, Essen, Germany; Acute Stroke Unit and Cerebrovascular Clinic (K.L.), University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland; University of California, San Diego, and VA Stroke Center (P.L.), San Diego, Calif; Department of Neurology (J.G.), University of Texas-Houston Medical School, Houston Tex; Department of Neurosciences (A.D.), Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain; Department of Neurology (S.D.), Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia; Division of Neurology, Department of Medicine (A.S.), University of Alberta, Edmonton, Canada; AstraZeneca R&D (T.A., H.-G.H.) Södertälje, Medical Neuroscience, Södertälje, Sweden; and AstraZeneca LP (W.W., V.A., L.R.), Wilmington, Del.

^* To whom correspondence should be addressed. E-mail: hans.diener{at}uni-duisburg-essen.de.

Background and Purpose—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.

Methods—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.

Results—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.

Conclusions—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.

Key words: ischemic stroke • neuroprotective therapy • pooled analysis • thrombolysis • predictors of outcome

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Is It Time to Definitely Abandon Neuroprotection in Acute Ischemic Stroke?

Maria Luisa Sacchetti
Stroke 2008 39: 1659-1660. [Extract] [Full Text] [PDF]

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