title: Recombinant human erythropoietin in the treatment of acute ischemic stroke.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. ehrenreich@em.mpg.de
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.forename: Karin
authors.initials: K
authors.lastname: Weissenborn
authors.forename: Hilmar
authors.initials: H
authors.lastname: Prange
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schneider
authors.forename: Christian
authors.initials: C
authors.lastname: Weimar
authors.forename: Katja
authors.initials: K
authors.lastname: Wartenberg
authors.forename: Peter D
authors.initials: PD
authors.lastname: Schellinger
authors.forename: Matthias
authors.initials: M
authors.lastname: Bohn
authors.forename: Harald
authors.initials: H
authors.lastname: Becker
authors.forename: Martin
authors.initials: M
authors.lastname: Wegrzyn
authors.forename: Peter
authors.initials: P
authors.lastname: Jähnig
authors.forename: Manfred
authors.initials: M
authors.lastname: Herrmann
authors.forename: Michael
authors.initials: M
authors.lastname: Knauth
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Heide
authors.forename: Armin
authors.initials: A
authors.lastname: Wagner
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwab
authors.forename: Heinz
authors.initials: H
authors.lastname: Reichmann
authors.forename: Günther
authors.initials: G
authors.lastname: Schwendemann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dengler
authors.forename: Andreas
authors.initials: A
authors.lastname: Kastrup
authors.forename: Claudia
authors.initials: C
authors.lastname: Bartels
mesh_terms: D000208:Acute Disease / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D064420:Drug-Related Side Effects and Adverse Reactions; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009026:Mortality; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D018579:Patient Selection; D015990:Placebo Effect; D011994:Recombinant Proteins / Q000008:administration & dosage; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D010959:Tissue Plasminogen Activator