Erythropoietin for stroke treatment: dead or alive?

Endothelial progenitor cell (EPC) mobilization from the bone marrow was considered to improve outcome after ischemic stroke. Erythropoietin (EPO) might be a potential candidate stroke drug that increases the number of circulating EPCs. In the previous issue of Critical Care, Yip and colleagues investigated the effect of EPO in stroke patients on both clinical outcome and EPC stimulation. Although beneficial effects of EPO were observed, several issues regarding EPO's suitability as a stroke drug remain.

Endothelial progenitor cells (EPCs) are hematopoietic cells derived from immature bone marrow that circulate in the peripheral blood [1]. EPCs have the capability to diff erentiate into mature endothelial cells and are assumed to replace dysfunctional endothelium. Consistent with this hypothesis, decreased levels of EPCs were shown to predict atherosclerotic disease progression and to be an independent risk factor for cardiovascular events [2]. After ischemic stroke, EPC levels decrease [3]. On the other hand, increasing EPC numbers during the acute phase of stroke are associated with smaller lesion growth and with improved neurological outcome [3,4]. Th erefore, pharmacological mobilization of EPCs from the bone marrow may enhance functional recovery poststroke. A potential candidate stroke drug that increases the number of circulating EPCs is erythropoietin (EPO) [5]. Several preclinical stroke studies demonstrated the effi cacy of EPO in reducing infarct volumes and in improving recovery of neurological function [6]. However, no human stroke study so far investigated the eff ects of EPO on both neurological outcome and EPC levels.
In the previous issue of Critical Care, Yip and colleagues [1] report on a prospective clinical trial in which 167 ischemic stroke patients were randomized to receive either 5,000 IU EPO or placebo subcutaneously at 48 and 72 hours after symptom onset. On day 21, EPC levels were signifi cantly higher in the EPO group. After 90 days, EPO treatment was associated with a signifi cantly lower proportion of patients with a National Institute of Health Stroke Scale (NIHSS) score ≥8 as well as with signifi cant reductions in recurrent strokes and in the composite endpoint of recurrent stroke, NIHSS ≥8 and death. Overall, two questions arise: is bone marrow stimulation to increase EPC levels in the peripheral blood a suitable therapy for stroke; and is EPO a candidate drug that can improve neurological outcome post-stroke by EPC stimulation?
Since increasing EPC levels post-stroke were shown to be associated with a favorable outcome, the primary question is whether EPCs are only a surrogate marker of neurological improvement or whether a causal relationship exists. Actually, both possibilities are reasonable. EPC numbers were shown to be lower in stroke patients with more severe neurological defi cits who, in turn, have a reduced potential for recovery compared to patients with less severe defi cits and higher EPC levels [7]. A pathophysiological explanation for the hypothesis that EPCs refl ect only the severity of stroke is the assumption that larger infarcts cause an excessive consumption of EPCs for endothelial repair, with subsequent lower peripheral EPC levels [8]. However, results of experimental stroke studies suggest a causal association between EPCs and improved functional recovery because EPC administration leads to reduced infarct volumes and improved functional recovery in diff erent animal stroke models [9][10][11]. Increased EPC-derived angiogenesis in the periinfarct region was identifi ed as an underlying mechanism.
So, is EPO a suitable drug for EPC stimulation in stroke patients? Besides other mechanisms in stroke, such as anti-apoptotic eff ects and increasing neurogenesis and angiogenesis, EPO was found to enhance EPC numbers [5,12]. However, in contrast to pathophysiological considera tions and results of experimental studies, the random ized phase II/III German Multicenter EPO Stroke Trial, which is the largest clinical EPO stroke study that has been published so far, was negative [13]. Th e primary endpoint of the German EPO Trial, change in Barthel Index on day 90, and all secondary outcomes, including the NIHSS and the modifi ed Rankin Scale, failed to show any benefi t of EPO. Moreover, in the German EPO trial increased mortality was observed after EPO treatment.

Abstract
Endothelial progenitor cell (EPC) mobilization from the bone marrow was considered to improve outcome after ischemic stroke. Erythropoietin (EPO) might be a potential candidate stroke drug that increases the number of circulating EPCs. In the previous issue of Critical Care, Yip and colleagues investigated the eff ect of EPO in stroke patients on both clinical outcome and EPC stimulation. Although benefi cial eff ects of EPO were observed, several issues regarding EPO's suitability as a stroke drug remain.
Th e discrepancy with the positive fi ndings in the study of Yip and colleagues might be explained by the chosen endpoints. Th e primary endpoint of the present study, which was reported at the Current Controlled Trial register [14], is the composite of recurrent stroke, NIHSS ≥8 and death. Th is endpoint primarily refl ects the frequency of recurrent stroke on day 90. When considering the components of the composite endpoint, the significantly higher number of patients with a NIHSS ≥8 after placebo treatment is also likely to be caused by the high rate of recurrent strokes and does not necessarily refl ect improved neurological function in the EPO group. Concordantly, the means of the NIHSS on day 90 did not diff er between the two groups. Th e 90-day mortality, which is the third component of the composite endpoint, was even higher in the EPO group. In contrast to the fi nding of increased mortality after EPO treatment in the larger German EPO trial, this diff erence was statistically not signifi cant.
Overall, the results of the study of Yip and colleagues suggest that EPO might be suitable for the secondary prevention of ischemic stroke. Th e effi cacy regarding improved neurological outcome, which is usually measured by the modifi ed Rankin Scale or the Barthel Index at day 90, was not investigated. Moreover, the results of the study of Yip and colleagues are weakened by the fact that the study was fi rst assigned to a trial register in January 2011, which was 10 months after the inclusion of the last patients in March 2010 [14]. Th us, the endpoints were not published before completion of the study. Furthermore, there are severe doubts regarding the potency of EPO as a drug for secondary stroke prevention, since long-term use of EPO was shown to even increase the risk for stroke [15].
In conclusion, the potential side eff ects and the failed effi cacy in a large clinical trial will presumably prevent the use of EPO as a therapy to increase EPCs after stroke. However, a direct systemic transplantation of EPCs or the mobilization of EPCs by other drugs -for example, granulocyte colony-stimulating factor -remain as promis ing options to improve outcome after stroke [16].