on October 15, 2009
Published online before print October 15, 2009, doi: 10.1161/STROKEAHA.109.564872
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Submitted on August 6, 2009
From the Division of Clinical Neuroscience (H.E., M.W., C.B.), Max Planck Institute of Experimental Medicine, Göttingen, Germany; Center for Neurological Medicine (K.W., R.D.), Hannover Medical School, Hannover, Germany; the Department of Neurology (H.P., M.B., A.K.), University Medical Center Göttingen, Georg-August-University, Göttingen, Germany; the Department of Neurology (D.S., A.W.), University Hospital of Leipzig, Leipzig, Germany; the Department of Neurology (C.W.), University of Duisburg-Essen, Essen, Germany; the Department of Neurology (K.W., H.R.), Stroke Center, University of Technology Dresden, Dresden, Germany; the Department of Neurology (P.D.S., S.S.), University Hospital of Erlangen, Erlangen, Germany; Central Pharmacy (M.B.), University Medical Center Göttingen, Georg-August-University, Göttingen, Germany; Applied Science and Technology (H.B.), Zwingenberg, Germany; Data Management and Biostatistical Services (P.J.), PAREXEL International GmbH, Berlin, Germany; the Department of Neuropsychology and Behavioral Neurobiology (M.H.), University of Bremen, Bremen, Germany; the Department of Neuroradiology (M.K.), University Medical Center Göttingen, Georg-August-University, Göttingen, Germany; the Department of Neurology (W.H.), General Hospital Celle, Celle, Germany; and the Department of Neurology (G.S.), University Hospital Bremen-Mitte, Bremen, Germany. * To whom correspondence should be addressed. E-mail: ehrenreich{at}em.mpg.de.
Background and Purpose—Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods—This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Results—Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke. Conclusions—Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.
Revised on August 26, 2009
Accepted on September 4, 2009
Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke
Hannelore Ehrenreich MD, DVM*;
Key words: clinical trial • hematopoietic growth factor • neuroprotection • NIHSS • rtPA