Response to Letter by Dame
In his letter, Christof Dame1 builds on and supports the points made in the discussion part of our recent erythropoietin (EPO) stroke article.2 Especially the exploratory analysis presented in this article, showing potential beneficial effects of EPO treatment in patients nonqualifying for recombinant tissue plasminogen activator (rtPA),2,3 should definitely stimulate further basic research to better understand and define potential contraindications to EPO treatment for future EPO stroke trials. For this purpose, we decided to share with your readers a new set of data obtained during our extensive post hoc evaluation of the study that might give additional insight into the risk profile of EPO treatment.
The Figure demonstrates the National Institute of Health Stroke Scale (NIHSS) outcomes of the intent-to-treat population over the whole study period, expressed as % individual score at entry, grouped by nonrtPA patients (A), patients receiving rtPA lege artis, that is, without rtPA contraindications (B), patients receiving rtPA with one (C), and patients receiving rtPA with 2 or more rtPA contraindications (D; mean±SEM presented). None of the subgroup differences are statistically significant (obviously due to the small sample sizes), but the tendency is clearly visible. Patients receiving EPO without rtPA may slightly profit from EPO treatment (in agreement with the findings of the previous Göttingen EPO Stroke Study3,4). Patients receiving EPO on top of lege artis rtPA do not show additional benefit but also no negative effects of EPO. Patients receiving EPO plus rtPA despite rtPA contraindications have worse outcomes on EPO as compared with placebo (C, D). Thus, negative effects of EPO in the presence of rtPA occur particularly in patients with delayed rtPA application (after >3 hours of symptom onset), prior anticoagulation, old age (>80 years), too large infarcts, or severe comorbidities.
Coming back to the letter by Christof Dame,1 one common denominator, explaining the increasing risk of EPO in situations of rtPA contraindications, may well be an EPO effect on “endothelium in distress” with its increased EPO receptor expression and thus augmented susceptibility to EPO, for example, see Sirén et al5 and Eid et al.6 Here, the release of compounds, influencing vasoactivity, cell adhesion, inflammation, or coagulation, may be heavily modulated. Some of these possibilities are presently under investigation in our laboratories. Hence, this is not the end of the EPO story in stroke treatment.
H. Ehrenreich holds a patent on the use of EPO for treatment of cerebral ischemia. H.C. Diener received honoraria for participation in clinical trials, and contribution to advisory boards or oral presentations from: Abbott, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, Knoll, MSD, Medtronic, MindFrame, Neurobiological Technologies, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pfizer, Sanofi-Aventis, Sankyo, Schering-Plough, Servier, Solvay, Thrombogenics, Wyeth, Yamaguchi. Financial support for research projects was provided by Astra/Zeneca, GSK, Boehringer Ingelheim, Lundbeck, Novartis, Janssen-Cilag, Sanofi-Aventis, Syngis, Talecris. The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, NIH, Bertelsmann Foundation and Heinz-Nixdorf Foundation. H.C. Diener has no ownership interest and does not own stocks of any pharmaceutical company. There are no other conflicts to report.
Dame C. Back to the ground [Letter]. Stroke. 2010; 41: e166.
Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jähnig P, Herrmann M, Knauth M, Bähr M, Heide W, Wagner A, Schwab S, Reichmann H, Schwendemann G, Dengler R, Kastrup A, Bartels C. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009; 40: e647–e656.
www.epo-study.de/index_eng.html. Last accessed on January 25, 2010.
Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck H-H, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Rüther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Sirén A-L. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002; 8: 495–505.