Colony-Stimulating Factors for the Treatment of Stroke
Colony-stimulating factors (CSFs) regulate bone marrow production of red cells, white cells, and platelets. CSFs have been shown to be neuroprotective in experimental stroke, and some CSFs also mobilize bone marrow stem cells into the circulation. We systematically reviewed the safety and efficacy of CSFs in people with acute or subacute stroke and their effect on circulating blood counts.1
We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, EMBASE, Science Citation Index (up to September 2012), and reference lists of relevant articles and reviews. The manufacturers and principal investigators of trials were also contacted. Randomized controlled trials recruiting people with acute or subacute ischemic or hemorrhagic stroke were included. CSFs comprised stem cell factor, erythropoietin (EPO), granulocyte CSF (G-CSF), granulocyte-macrophage CSF, macrophage CSF (CSF-1), thrombopoietin, or analogs of these. The primary outcome was functional outcome at the end of the trial (poor outcome defined as modified Rankin score >2 or Barthel index <60). Secondary outcomes included safety, mortality, infarct volume, and hematology measures. Analyses were performed using random effects models.
We included a total of 11 studies involving 1275 participants. In 3 trials (n=782), EPO therapy was associated with a significant increase in death by the end of the trial (odds ratio, 1.98; 95% confidence interval, 1.19–3.3; P=0.009) and a nonsignificant increase in serious adverse events. EPO significantly increased the red cell count with no effect on platelet or white cell count, or infarct volume. Two small trials of carbamylated EPO have been completed but are yet to be reported. We included 8 small trials (n=548) of G-CSF. G-CSF was associated with a nonsignificant reduction in early impairment (mean difference, −0.4; 95% confidence interval, −1.82 to 1.01; P=0.58) but had no significant effect on functional outcome at the end of the trial (Figure). G-CSF significantly elevated white cell count and CD34+ cell count, but had no effect on infarct volume. Further trials of G-CSF are ongoing.
Although there are several types of bone marrow–modulating CSFs, only EPO and G-CSF have been studied in completed trials in people with acute or subacute stroke. Most studies were small, studying safety, except for a phase III trial of EPO and a phase II/III trial of G-CSF. EPO was associated with a significant increase in death, with no effect on functional outcome. G-CSF did not significantly alter functional outcome or death, was well tolerated, and seemed to be safe.
Implications for Research
The completed trials provide evidence for the practicality and feasibility of administering CSFs. However, further clinical studies using EPO in stroke should be avoided at least until safety aspects are explored further experimentally. Whether this applies to nonhematopoietic derivatives of EPO (eg, carbamylated EPO) is unclear. Although CSFs could be neuroprotective, reductions in stroke lesion size were not seen. G-CSF may also be neuroreparative. Results observed in preclinical studies suggest that mobilized stem cells could enhance neurogenesis and angiogenesis. Whether CSFs aid recovery in chronic stroke also needs to be addressed (eg, Stem cell Trial of recovery EnhanceMent after Stroke-3 (STEMS-3) [ISRCTN16714730]).
There are significant safety concerns regarding EPO therapy for stroke. It is too early to know whether other CSFs (such as G-CSF) improve functional outcome.
Drs Bath, Sprigg, and England performed 2 phase II trials of G-CSF (STEMS-1/2) funded by the Stroke Association and UK Medical Research Council. Drs Sprigg and Bath are doing a trial of G-CSF in chronic stroke (STEMS-3). Dr Bath was a consultant to Axaron/Sygnis (who were developing EPO) and a member of the Steering Committee for Lundbeck’s trials of carbamylated EPO; no consultancy fees from Axaron or Lundbeck were used in any way for the development of this review, and neither company had any influence over the initiation, planning, or production of the review, or interpretation of data.
This article is based on a Cochrane Review published in The Cochrane Library 2012, Issue 9 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review.
- Received August 6, 2013.
- Accepted August 12, 2013.
- © 2013 American Heart Association, Inc.