Bath, Philip M.W.

Sprigg, Nik

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ISSN: 1524-4628 Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0039-2499. OnlineStroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514DOI: 10.1161/STROKEAHA.107.482877  2007;38;1997-1998; originally published online Apr 19, 2007; StrokeNikola Sprigg and Philip M.W. Bath  Unproven for Treating StrokeColony Stimulating Factors (Blood Growth Factors) Are Promising but http://stroke.ahajournals.org/cgi/content/full/38/6/1997located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprintsReprints: Information about reprints can be found online at    journalpermissions@lww.com410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters   http://stroke.ahajournals.org/subscriptions/Subscriptions: Information about subscribing to Stroke is online at  at UNIV OF NOTTINGHAM on June 5, 2007 stroke.ahajournals.orgDownloaded from Section Editor: Graeme J. Hankey, MD, FRCPColony Stimulating Factors (Blood Growth Factors) ArePromising but Unproven for Treating StrokeNikola Sprigg, MRCP; Philip M.W. Bath, MDColony stimulating factors (CSFs), also called hematopoi-etic growth factors, regulate bone marrow production ofcirculating blood cells. They have been shown to be neuro-protective in experimental stroke. Some CSFs also mobilizethe release of bone marrow stem cells into the circulation;these could help brain repair processes after stroke. Wesystematically assessed the effects of CSFs on functionaloutcome and hematology measures in patients with recentstroke.Search StrategyWe searched the Cochrane Stroke Group Trials Register, theCochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, EMBASE and Science Citation Index. Principalinvestigators of trials were also contacted. Unconfoundedrandomized controlled trials recruiting patients with acute orsubacute ischemic or hemorrhagic stroke were included.CSFs included stem cell factor, erythropoietin (EPO), gran-ulocyte colony-stimulating factor (G-CSF), granulocyte-mac-rophage colony–stimulating factor (GM-CSF), macrophagecolony–stimulating factor (M-CSF, CSF-1), and thrombopoi-etin, or analogues of these. The primary outcome wasfunctional outcome (assessed as combined death or disabilityand dependency using scales such as the modified RankinScale or Barthel Index) at the end of the trial. Secondaryoutcomes included safety at the end of treatment (death,impairment, deterioration, extension or recurrence), death atthe end of follow-up, and hematology measures. Data onmeasures by intention to treat were collected and analyzedusing random-effects models.Main ResultsNo large trials were identified. EPO therapy was associatedwith a nonsignificant reduction in death or dependency in 1small trial (n40 participants, odds ratio 0.66; 95% CI, 0.19to 2.31; Figure) but had no significant effect on hematologicalmeasures.1 G-CSF was associated with a nonsignificantreduction in death and dependency in 2 small trials (n46,Forest-plot showing the effect of CSF on combined death or disability and dependency at end of trial.Received January 18, 2007; accepted February 2, 2007.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 KingdomNG5 1PB. E-mail philip.bath@nottingham.ac.uk(Stroke. 2007;38:1997-1998.)© 2007 American Heart Association, Inc.Stroke is available at http://www.strokeaha.org DOI: 10.1161/STROKEAHA.107.4828771997Cochrane Corner at UNIV OF NOTTINGHAM on June 5, 2007 stroke.ahajournals.orgDownloaded from odds ratio 0.21; 95% CI, 0 to 57.52)2,3 (Figure) and signifi-cantly elevated white cell count in 3 trials (n91, weightedmean difference 27.56; 95% CI, 17.56 to 37.56).2–4Further randomized controlled trials of CSFs are underwayor recently completed; these include 1 with EPO5 and 2 withG-CSF.6,7 No trials of stem cell factor, GM-CSF, M-CSF,thrombopoietin, were identified.DiscussionIt is apparent that at least 2 paradigms are being studied withCSF in the treatment of stroke. First, CSFs such as EPO andG-CSF are neuroprotective in animal models of acute stroke,and this potential mechanism is under investigation in pa-tients with acute stroke.1,5,6 Second, stem cell mobilizingCSFs (as with stem cell factor, G-CSF, and GM-CSF) couldcontribute to brain repair through neurogenic-related mecha-nisms, again as has been seen in experimental models ofstroke; 3 trials have investigated this approach, with a furthertrial ongoing.7Implications for Future ResearchFurther studies need to address mechanisms by which CSFsmight work; for example, preclinical studies suggest that CSFcould be neuroprotective whereas those factors which mobi-lize endogenous stem cells could enhance neurogenesis.Understanding potential mechanisms of action will helpinvestigators decide when to administer treatment for testingin phase III trials: for example, during the hyperacute orsubacute phases of stroke. Whether CSFs aid recovery inchronic stroke also needs to be addressed.ConclusionNo large trials of EPO, G-CSF or other CSFs have beenperformed, and it is too early to know whether CSFs improvefunctional outcome.DisclosuresThe authors are running an independent phase II trial of G-CSFfunded by a UK charity, The Stroke Association. P.B. has acted as aconsultant to Axaron (who are developing G-CSF) and Lundbeck(who are developing an EPO analogue); no monies received inconsultancy fees from Axaron or Lundbeck were used in any waywhatsoever for the development of the protocol, and neither com-pany had any influence over the initiation, planning or production ofthe protocol.References1. Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, StiefelM, 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, ItriL, Prange H, Cerami A, Brines M, Siren AL. Erythropoietin therapy foracute stroke is both safe and beneficial. Molecular Medicine. 2002;8:495–505.2. Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H. Func-tional recovery of stroke rats induced by granulocyte colony-stimulatingfactor- stimulated cells. Circulation. 2004;110:1847–1854.3. Sprigg N, Bath P, Zhao L, Willmot M, Gray LJ, Walker M, Dennis MS,Russel N. Granulocyte-colony stimulating factor mobilizes bone marrowstem cells in patients with sub-acute ischaemic stroke: The Stem cell Trialof recovery EnhanceMent after Stroke (STEMS) pilot randomized con-trolled trial. Stroke. 2006;37:2979–2983.4. Zhang J, Deng M, Zhang Y, Sui W, Wang L, Sun A, Song H, Lu M, FanD. A short-term assessment of recombinant human granulocyte-stimulatingfactor (rhg-csf) in treatment of acute cerebral infarction. CerebrovascularDiseases. 2006;21(suppl 4):143. Abstract.5. Ehrenreich H. The Multicenter-Erythropoietin-Stroke trial. Available at:http://www.epo-study.de/index_eng.html. Accessed August 2006.6. Axaron Bioscience A. Treatment with ax200 for acute ischemic stroke.Available at: http://clinicaltrialsgov. Accessed August 2006.7. 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 insub-acute stroke. Available at:http://www.controlled-trials.com/ISRCTN63336619. Accessed November 2006.KEY WORDS: colony-stimunlating factors  recovery  stem cells  stroke1998 Stroke June 2007 at UNIV OF NOTTINGHAM on June 5, 2007 stroke.ahajournals.orgDownloaded from 

Colony stimulating factors (blood growth factors) are promising but unproven for treating stroke

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Sprigg, Nik and Philip Michael Willian, Bath (2007) Colony stimulating factors (blood growth factors) are promising but unproven for treating stroke. Stroke, 38 . pp. 1997-1998. Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/517/1/colony_stimulating_factors_stroke_2007.pdfCopyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions.This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence.  For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdfA note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukISSN: 1524-4628 Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0039-2499. OnlineStroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514DOI: 10.1161/STROKEAHA.107.482877  2007;38;1997-1998; originally published online Apr 19, 2007; StrokeNikola Sprigg and Philip M.W. Bath  Unproven for Treating StrokeColony Stimulating Factors (Blood Growth Factors) Are Promising but http://stroke.ahajournals.org/cgi/content/full/38/6/1997located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprintsReprints: Information about reprints can be found online at    journalpermissions@lww.com410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters   http://stroke.ahajournals.org/subscriptions/Subscriptions: Information about subscribing to Stroke is online at  at UNIV OF NOTTINGHAM on June 5, 2007 stroke.ahajournals.orgDownloaded from Section Editor: Graeme J. Hankey, MD, FRCPColony Stimulating Factors (Blood Growth Factors) ArePromising but Unproven for Treating StrokeNikola Sprigg, MRCP; Philip M.W. Bath, MDColony stimulating factors (CSFs), also called hematopoi-etic growth factors, regulate bone marrow production ofcirculating blood cells. They have been shown to be neuro-protective in experimental stroke. Some CSFs also mobilizethe release of bone marrow stem cells into the circulation;these could help brain repair processes after stroke. Wesystematically assessed the effects of CSFs on functionaloutcome and hematology measures in patients with recentstroke.Search StrategyWe searched the Cochrane Stroke Group Trials Register, theCochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, EMBASE and Science Citation Index. Principalinvestigators of trials were also contacted. Unconfoundedrandomized controlled trials recruiting patients with acute orsubacute ischemic or hemorrhagic stroke were included.CSFs included stem cell factor, erythropoietin (EPO), gran-ulocyte colony-stimulating factor (G-CSF), granulocyte-mac-rophage colony–stimulating factor (GM-CSF), macrophagecolony–stimulating factor (M-CSF, CSF-1), and thrombopoi-etin, or analogues of these. The primary outcome wasfunctional outcome (assessed as combined death or disabilityand dependency using scales such as the modified RankinScale or Barthel Index) at the end of the trial. Secondaryoutcomes included safety at the end of treatment (death,impairment, deterioration, extension or recurrence), death atthe end of follow-up, and hematology measures. Data onmeasures by intention to treat were collected and analyzedusing random-effects models.Main ResultsNo large trials were identified. EPO therapy was associatedwith a nonsignificant reduction in death or dependency in 1small trial (n40 participants, odds ratio 0.66; 95% CI, 0.19to 2.31; Figure) but had no significant effect on hematologicalmeasures.1 G-CSF was associated with a nonsignificantreduction in death and dependency in 2 small trials (n46,Forest-plot showing the effect of CSF on combined death or disability and dependency at end of trial.Received January 18, 2007; accepted February 2, 2007.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 KingdomNG5 1PB. E-mail philip.bath@nottingham.ac.uk(Stroke. 2007;38:1997-1998.)© 2007 American Heart Association, Inc.Stroke is available at http://www.strokeaha.org DOI: 10.1161/STROKEAHA.107.4828771997Cochrane Corner at UNIV OF NOTTINGHAM on June 5, 2007 stroke.ahajournals.orgDownloaded from odds ratio 0.21; 95% CI, 0 to 57.52)2,3 (Figure) and signifi-cantly elevated white cell count in 3 trials (n91, weightedmean difference 27.56; 95% CI, 17.56 to 37.56).2–4Further randomized controlled trials of CSFs are underwayor recently completed; these include 1 with EPO5 and 2 withG-CSF.6,7 No trials of stem cell factor, GM-CSF, M-CSF,thrombopoietin, were identified.DiscussionIt is apparent that at least 2 paradigms are being studied withCSF in the treatment of stroke. First, CSFs such as EPO andG-CSF are neuroprotective in animal models of acute stroke,and this potential mechanism is under investigation in pa-tients with acute stroke.1,5,6 Second, stem cell mobilizingCSFs (as with stem cell factor, G-CSF, and GM-CSF) couldcontribute to brain repair through neurogenic-related mecha-nisms, again as has been seen in experimental models ofstroke; 3 trials have investigated this approach, with a furthertrial ongoing.7Implications for Future ResearchFurther studies need to address mechanisms by which CSFsmight work; for example, preclinical studies suggest that CSFcould be neuroprotective whereas those factors which mobi-lize endogenous stem cells could enhance neurogenesis.Understanding potential mechanisms of action will helpinvestigators decide when to administer treatment for testingin phase III trials: for example, during the hyperacute orsubacute phases of stroke. Whether CSFs aid recovery inchronic stroke also needs to be addressed.ConclusionNo large trials of EPO, G-CSF or other CSFs have beenperformed, and it is too early to know whether CSFs improvefunctional outcome.DisclosuresThe authors are running an independent phase II trial of G-CSFfunded by a UK charity, The Stroke Association. P.B. has acted as aconsultant to Axaron (who are developing G-CSF) and Lundbeck(who are developing an EPO analogue); no monies received inconsultancy fees from Axaron or Lundbeck were used in any waywhatsoever for the development of the protocol, and neither com-pany had any influence over the initiation, planning or production ofthe protocol.References1. Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, StiefelM, 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, ItriL, Prange H, Cerami A, Brines M, Siren AL. Erythropoietin therapy foracute stroke is both safe and beneficial. Molecular Medicine. 2002;8:495–505.2. Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H. Func-tional recovery of stroke rats induced by granulocyte colony-stimulatingfactor- stimulated cells. Circulation. 2004;110:1847–1854.3. Sprigg N, Bath P, Zhao L, Willmot M, Gray LJ, Walker M, Dennis MS,Russel N. Granulocyte-colony stimulating factor mobilizes bone marrowstem cells in patients with sub-acute ischaemic stroke: The Stem cell Trialof recovery EnhanceMent after Stroke (STEMS) pilot randomized con-trolled trial. Stroke. 2006;37:2979–2983.4. Zhang J, Deng M, Zhang Y, Sui W, Wang L, Sun A, Song H, Lu M, FanD. A short-term assessment of recombinant human granulocyte-stimulatingfactor (rhg-csf) in treatment of acute cerebral infarction. CerebrovascularDiseases. 2006;21(suppl 4):143. Abstract.5. Ehrenreich H. The Multicenter-Erythropoietin-Stroke trial. Available at:http://www.epo-study.de/index_eng.html. Accessed August 2006.6. Axaron Bioscience A. Treatment with ax200 for acute ischemic stroke.Available at: http://clinicaltrialsgov. Accessed August 2006.7. 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 insub-acute stroke. Available at:http://www.controlled-trials.com/ISRCTN63336619. Accessed November 2006.KEY WORDS: colony-stimunlating factors  recovery  stem cells  stroke1998 Stroke June 2007 at UNIV OF NOTTINGHAM on June 5, 2007 stroke.ahajournals.orgDownloaded from 

Nottingham ePrints

English

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.

Erythropoietin therapy for acute stroke is both safe and beneficial.

Functional recovery of stroke rats induced by granulocyte colony-stimulating factor- stimulated cells.

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.

Stem cell Trial of recovery EnhanceMent after Stroke 2 (STEMS2): pilot randomised placebo-controlled trial of granulocytecolony stimulating factor in mobilising bone marrow stem cells in sub-acute stroke.

The Multicenter-Erythropoietin-Stroke trial. Available at: http://www.epo-study.de/index_eng.html. Accessed

Treatment with ax200 for acute ischemic stroke. Available at: http://clinicaltrialsgov. Accessed

http://eprints.nottingham.ac.uk/517/1/colony_stimulating_factors_stroke_2007.pdf

Colony stimulating factors (blood growth factors) are promising but unproven for treating stroke

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