Stroke. 2007;38:1997-1998
Published online before print April 19, 2007,
doi: 10.1161/STROKEAHA.107.482877
(Stroke. 2007;38:1997.)
© 2007 American Heart Association, Inc.
Colony Stimulating Factors (Blood Growth Factors) Are Promising but Unproven for Treating Stroke
Nikola Sprigg, MRCP
Philip M.W. Bath, MD
From the Division of Stroke Medicine, University of Nottingham, Nottingham, UK.
Correspondence to Philip M.W. Bath, Division of Stroke Medicine, University of Nottingham, Nottingham City campus, Nottingham, United Kingdom NG5 1PB. E-mail philip.bath{at}nottingham.ac.uk
Graeme J. Hankey MD, FRCP Section Editor
Key Words: colony-stimunlating factors • recovery • stem cells • stroke
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Introduction
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Colony stimulating factors (CSFs), also called hematopoietic
growth factors, regulate bone marrow production of circulating
blood cells. They have been shown to be neuroprotective in experimental
stroke. Some CSFs also mobilize the release of bone marrow stem
cells into the circulation; these could help brain repair processes
after stroke. We systematically assessed the effects of CSFs
on functional outcome and hematology measures in patients with
recent stroke.
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Search Strategy
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We searched the Cochrane Stroke Group Trials Register, the Cochrane
Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE
and Science Citation Index. Principal investigators of trials
were also contacted. Unconfounded randomized controlled trials
recruiting patients with acute or subacute ischemic or hemorrhagic
stroke were included. CSFs included stem cell factor, erythropoietin
(EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage
colony–stimulating factor (GM-CSF), macrophage colony–stimulating
factor (M-CSF, CSF-1), and thrombopoietin, or analogues of these.
The primary outcome was functional outcome (assessed as combined
death or disability and dependency using scales such as the
modified Rankin Scale or Barthel Index) at the end of the trial.
Secondary outcomes included safety at the end of treatment (death,
impairment, deterioration, extension or recurrence), death at
the end of follow-up, and hematology measures. Data on measures
by intention to treat were collected and analyzed using random-effects
models.
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Main Results
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No large trials were identified. EPO therapy was associated
with a nonsignificant reduction in death or dependency in 1
small trial (n=40 participants, odds ratio 0.66; 95% CI, 0.19
to 2.31;
Figure) but had no significant effect on hematological
measures.
1 G-CSF was associated with a nonsignificant reduction
in death and dependency in 2 small trials (n=46, odds ratio
0.21; 95% CI, 0 to 57.52)
2,3 (
Figure) and significantly elevated
white cell count in 3 trials (n=91, weighted mean difference
27.56; 95% CI, 17.56 to 37.56).
2–4
Further randomized controlled trials of CSFs are underway or recently completed; these include 1 with EPO5 and 2 with G-CSF.6,7 No trials of stem cell factor, GM-CSF, M-CSF, thrombopoietin, were identified.
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Discussion
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It is apparent that at least 2 paradigms are being studied with
CSF in the treatment of stroke. First, CSFs such as EPO and
G-CSF are neuroprotective in animal models of acute stroke,
and this potential mechanism is under investigation in patients
with acute stroke.
1,5,6 Second, stem cell mobilizing CSFs (as
with stem cell factor, G-CSF, and GM-CSF) could contribute to
brain repair through neurogenic-related mechanisms, again as
has been seen in experimental models of stroke; 3 trials have
investigated this approach, with a further trial ongoing.
7
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Implications for Future Research
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Further studies need to address mechanisms by which CSFs might
work; for example, preclinical studies suggest that CSF could
be neuroprotective whereas those factors which mobilize endogenous
stem cells could enhance neurogenesis. Understanding potential
mechanisms of action will help investigators decide when to
administer treatment for testing in phase III trials: for example,
during the hyperacute or subacute phases of stroke. Whether
CSFs aid recovery in chronic stroke also needs to be addressed.
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Conclusion
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No large trials of EPO, G-CSF or other CSFs have been performed,
and it is too early to know whether CSFs improve functional
outcome.
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Acknowledgments
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Disclosures
The authors are running an independent phase II trial of G-CSF funded by a UK charity, The Stroke Association. P.B. has acted as a consultant to Axaron (who are developing G-CSF) and Lundbeck (who are developing an EPO analogue); no monies received in consultancy fees from Axaron or Lundbeck were used in any way whatsoever for the development of the protocol, and neither company had any influence over the initiation, planning or production of the protocol.
Received January 18, 2007;
accepted February 2, 2007.
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References
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- Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL. Erythropoietin therapy for acute stroke is both safe and beneficial. Molecular Medicine. 2002; 8: 495–505.[Medline]
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- Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated cells. Circulation. 2004; 110: 1847–1854.[Abstract/Free Full Text]
- Sprigg N, Bath P, Zhao L, Willmot M, Gray LJ, Walker M, Dennis MS, Russel N. Granulocyte-colony stimulating factor mobilizes bone marrow stem cells in patients with sub-acute ischaemic stroke: The Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized controlled trial. Stroke. 2006; 37: 2979–2983.[Abstract/Free Full Text]
- Zhang J, Deng M, Zhang Y, Sui W, Wang L, Sun A, Song H, Lu M, Fan D. A short-term assessment of recombinant human granulocyte-stimulating factor (rhg-csf) in treatment of acute cerebral infarction. Cerebrovascular Diseases. 2006; 21 (suppl 4): 143. Abstract.
- Ehrenreich H. The Multicenter-Erythropoietin-Stroke trial. Available at: http://www.epo-study.de/index_eng.html. Accessed August 2006.
- Axaron Bioscience A. Treatment with ax200 for acute ischemic stroke. Available at: http://clinicaltrialsgov. Accessed August 2006.
- Bath PMW. Stem cell Trial of recovery EnhanceMent after Stroke 2 (STEMS2): pilot randomised placebo-controlled trial of granulocyte-colony stimulating factor in mobilising bone marrow stem cells in sub-acute stroke. Available at:http://www.controlled-trials.com/ISRCTN63336619. Accessed November 2006.
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Introduction
Search Strategy