Recombinant human erythropoietin in the treatment of acute ischemic stroke.
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.
Ehrenreich
Hannelore
H
Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. ehrenreich@em.mpg.de
Weissenborn
Karin
K
Prange
Hilmar
H
Schneider
Dietmar
D
Weimar
Christian
C
Wartenberg
Katja
K
Schellinger
Peter D
PD
Bohn
Matthias
M
Becker
Harald
H
Wegrzyn
Martin
M
Jähnig
Peter
P
Herrmann
Manfred
M
Knauth
Michael
M
Bähr
Mathias
M
Heide
Wolfgang
W
Wagner
Armin
A
Schwab
Stefan
S
Reichmann
Heinz
H
Schwendemann
Günther
G
Dengler
Reinhard
R
Kastrup
Andreas
A
Bartels
Claudia
C
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
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D010959:Tissue Plasminogen Activator