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Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial

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Abstract

Background

Erythropoietin (EPO) and its receptor play a major role in embryonic brain, are weakly expressed in normal postnatal/adult brain and up-regulated upon metabolic stress. EPO protects neurons from hypoxic/ischemic injury. The objective of this trial is to study the safety and efficacy of recombinant human EPO (rhEPO) for treatment of ischemic stroke in man.

Materials and Methods

The trial consisted of a safety part and an efficacy part. In the safety study, 13 patients received rhEPO intravenously (3.3 × 104 IU/50 ml/30 min) once daily for the first 3 days after stroke. In the double-blind randomized proof-of-concept trial, 40 patients received either rhEPO or saline. Inclusion criteria were age <80 years, ischemic stroke within the middle cerebral artery territory confirmed by diffusion-weighted MRI, symptom onset <8 hr before drug administration, and deficits on stroke scales. The study endpoints were functional outcome at day 30 (Barthel Index, modified Rankin scale), NIH and Scandinavian stroke scales, evolution of infarct size (sequential MRI evaluation using diffusion-weighted [DWI] and fluid-attenuated inversion recovery sequences [FLAIR]) and the damage marker S100ß.

Results

No safety concerns were identified. Cerebrospinal fluid EPO increased to 60–100 times that of nontreated patients, proving that intravenously administered rhEPO reaches the brain. In the efficacy trial, patients received rhEPO within 5 hr of onset of symptoms (median, range 2:40–7:55). Admission neurologic scores and serum S100β concentrations were strong predictors ofoutcome. Analysis of covariance controlled for these two variables indicated that rhEPO treatment was associated with an improvement in follow-up and outcome scales. A strong trend for reduction in infarct size in rhEPO patients as compared to controls was observed by MRI.

Conclusion

Intravenous high-dose rhEPO is well tolerated in acute ischemic stroke and associated with an improvement in clinical outcome at 1 month. A larger scale clinical trial is warranted.

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Acknowledgments

This work has been supported in part by research grants from the Max-Planck Society and from Ortho Biotech Inc. to Dr Ehrenreich. We wish to thank Dr J. Donald Easton for valuable discussions.

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Authors and Affiliations

  1. Max-Planck-Institute for Experimental Medicine, Departments of Neurology and Psychiatry, Georg-August-University, Hermann-Rein-Str. 3, D-37075, Goettingen, Germany

    Hannelore Ehrenreich, Martin Hasselblatt, Christoph Dembowski, Lukas Cepek, Piotr Lewczuk, Sonja Jacob, Friederike Knerlich, Wolfgang Poser, Eckart Rüther, Hilmar Prange & Anna-Leena Sirén

  2. Departments of Radiology I and III, Georg-August-University, Goettingen, Germany

    Michael Stiefel, Hans-Heino Rustenbeck & Norbert Breiter

  3. Clinical Pharmacy, Georg-August-University, Goettingen, Germany

    Matthias Bohn

  4. Department of Family Medicine, Georg-August-University, Goettingen, Germany

    Michael Kochen

  5. Department of Medical Statistics, University of Erlangen, Erlangen, Germany

    Olaf Gefeller

  6. Department of Clinical Pharmacology, Eberhard-Karls-University, Tuebingen, Germany

    Christoph Gleiter

  7. Janssen Research Foundation, Titusville, NJ, USA

    Thomas C. Wessel

  8. Department of Neuropharmacology, Janssen Research Foundation, Beerse, Belgium

    Marc De Ryck

  9. Ortho Biotech Inc., Raritan, NJ, USA

    Loretta Itri

  10. The Kenneth S. Warren Institute, Kitchawan, New York, NY, USA

    Anthony Cerami & Michael Brines

Authors
  1. Hannelore Ehrenreich
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  2. Martin Hasselblatt
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  3. Christoph Dembowski
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  4. Lukas Cepek
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  5. Piotr Lewczuk
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  6. Michael Stiefel
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  7. Hans-Heino Rustenbeck
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  8. Norbert Breiter
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  9. Sonja Jacob
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  10. Friederike Knerlich
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  11. Matthias Bohn
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  12. Wolfgang Poser
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  13. Eckart Rüther
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  14. Michael Kochen
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  15. Olaf Gefeller
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  16. Christoph Gleiter
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  17. Thomas C. Wessel
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  18. Marc De Ryck
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  19. Loretta Itri
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  20. Hilmar Prange
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  21. Anthony Cerami
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  22. Michael Brines
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  23. Anna-Leena Sirén
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Corresponding author

Correspondence to Hannelore Ehrenreich.

Additional information

Contributed by A. Cerami.

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Ehrenreich, H., Hasselblatt, M., Dembowski, C. et al. Erythropoietin Therapy for Acute Stroke Is Both Safe and Beneficial. Mol Med 8, 495–505 (2002). https://doi.org/10.1007/BF03402029

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  • DOI: https://doi.org/10.1007/BF03402029

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