The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Evidence for the Efficacy of NXY-059 in Experimental Focal Cerebral Ischaemia Is Confounded by Study Quality
Open accessAbstract
Background and Purpose— The neutral results of the SAINT II trial have again highlighted difficulties translating neuroprotective efficacy from bench to bedside. Animal studies are susceptible to study quality biases, which may lead to overstatement of efficacy. We report the impact of study quality on published estimates of the efficacy of NXY-059 in animal models of stroke. Methods— We conducted a systematic review and stratified meta-analysis of published studies describing the efficacy of NXY-059 in experimental focal cerebral ischemia. Results— Overall, NXY-059 improved infarct volume by 43.3% (95% CI, 34.7 to 52.8). Only 2 of 9 publications reported randomization, concealment of treatment allocation, and blinded outcome assessment. Studies not reporting these quality items gave substantially higher estimates of efficacy than did higher-quality studies. Conclusions— The reported efficacy of NXY-059 in animal models of stroke is confounded by low study quality. The failure of SAINT II highlights the need for substantial improvements in the design, conduct, and reporting of animal studies; journals can play an important role in this by adopting standards for animal studies similar to those agreed over 10 years ago for clinical trials.
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“study quality is inversely related to effect size [79][80][81][82]”
From Power failure: why small sample size undermines the reliability of neuroscience (2013) · cites this paper as [81]
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“There are, however, compelling data from systematic reviews showing that nonblinded outcome assessment leads to the treatment effects being overestimated, and the lack of bias-reducing measures such as randomisation and blinding can contribute to as much as 30%–45% inflation of effect sizes [67,68,85].”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [85]
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“There are, however, compelling data from systematic reviews showing that nonblinded outcome assessment leads to the treatment effects being overestimated, and the lack of bias-reducing measures such as randomisation and blinding can contribute to as much as 30%–45% inflation of effect sizes [67,68,85].”
From Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0 (2020) · cites this paper as [85]
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Cites
Recommendations for Standards Regarding Preclinical Neuroprotective and Restorative Drug Development
Roundtable, S. T. A. I. (1999) · Stroke · doi:10.1161/01.str.30.12.2752 · Cited by 1,256
Comparison of Treatment Effects between Animal Experiments and Clinical Trials: Systematic Review
Perel, P., Roberts, I., Sena, E., Wheble, P., Briscoe, C., Sandercock, P., Macleod, M., Mignini, L. E., Jayaram, P., & Khan, K. S. (2007) · BMJ · doi:10.1136/bmj.39048.407928.be · Cited by 827
Self-citationPooling of Animal Experimental Data Reveals Influence of Study Design and Publication Bias
Macleod, M. R., O’Collins, T., Howells, D. W., & Donnan, G. A. (2004) · Stroke · doi:10.1161/01.str.0000125719.25853.20 · Cited by 734
Self-citationNXY-059 for the Treatment of Acute Ischemic Stroke
Shuaib, A. M., Lees, K. R., Lyden, P. D., Grotta, J. C., Dávalos, A., Davis, S. M., Diener, H., Ashwood, T. J., Wasiewski, W. W., & Emeribe, U. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa070240 · Cited by 733
NXY-059 for Acute Ischemic Stroke
Lees, K. R., Zivin, J. A., Ashwood, T., Davalos, A., Davis, S. M., Diener, H.-C., Grotta, J., Lyden, P., Shuaib, A., Hårdemark, H.-G., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa052980 · Cited by 660
Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis.
van der Worp, H. B., Sena, E., Donnan, G., Howells, D., & Macleod, M. (2007) · Brain : a journal of neurology · doi:10.1093/brain/awm083 · Cited by 520
Self-citationHow can we improve the pre-clinical development of drugs for stroke?
Sena, E. S., van der Worp, H. B., Howells, D. W., & Macleod, M. R. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.06.009 · Cited by 367
Self-citationBench to Bedside: The Quest for Quality in Experimental Stroke Research
Dirnagl, U. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600298 · Cited by 348
Self-citationKuroda, S., Tsuchidate, R., Smith, M., Maples, K. R., & Siesjö, B. K. (1999) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199907000-00008 · Cited by 247
Empirical Evidence of Bias in the Design of Experimental Stroke Studies
Crossley, N. A., Sena, E. S., Göhler, J., Horn, J., van der Worp, H. B., Bath, P. M., Macleod, M. R., & Dirnagl, U. (2008) · Stroke · doi:10.1161/strokeaha.107.498725 · Cited by 235
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Hoyte, L. C., Sutherland, B. A., & Buchan, A. M. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-809324-5.02030-7
Kiermer, V. (2022) · Editorial Office News · doi:10.18243/eon/2022.15.3.4
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Selection of animal models for drug efficacy
Veening-Griffioen, D. H. (2023) · Utrecht University Repository (Utrecht University) · doi:10.33540/1605
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Sharif, A., Jeffers, M. S., Fergusson, D. A., Bapuji, R., Nicholls, S. G., Humphrey, J., Johnston, W., Mitchell, E., Speirs, M.-A., Stronghill, L., et al. (2025) · eLife · doi:10.7554/elife.103245.2
Bone Marrow-Derived Mesenchymal Stromal Cells in the Treatment of Stroke
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Granados-Martinez, C., Alfageme-Lopez, N., Fernandez-Bustelo, A., Amarilla, M. A., Navarro-Oviedo, M., Sevillano, D., Alou, L., Hurtado, O., Moro, M. Á., Lizasoaín, I., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.13.688219
Kaartinen, J., Hynes, A., & Bennett, R. C. (2025) · Veterinary Anaesthesia and Analgesia · doi:10.1016/j.vaa.2025.101173
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Jeffers, M. S., Tangamornsuksan, W., Dorus, B., Bedford, P., Kimmelman, J., McIsaac, D. I., Fergusson, D. A., & Lalu, M. M. (2026) · EBioMedicine · doi:10.1016/j.ebiom.2026.106456
Vascular dysfunction and translational biomarker discovery in stroke prevention
Siakabanze, C., Bwalya, K., Mwape, L., Mweene, B. C., Siame, L., Luwaya, E., & Masenga, S. K. (2026) · Discover Medicine · doi:10.1007/s44337-026-00716-3
(2015) · PubMed Central · Cited by 20
Metadata
- Authors
- Macleod, M. R., van der Worp, H. B., Sena, E. S., Howells, D. W., Dirnagl, U., & Donnan, G. A.
- Affiliations
- University Medical Center Utrecht (NL)
- From Clinical Neurosciences (M.R.M., E.S.S.), University of Edinburgh, Scotland, UK; the Department of Neurology (H.B.v.d.W.), Rudolf Magnus Institute of Neuroscience, University Medical Centre, Utrecht, The Netherlands; the National Stroke Research Institute (E.S.S., D.W.H., G.A.D.), Melbourne, Australia; and the Department Neurology (U.D.), Charite Hospital, Berlin, Germany.
- Venue
- Stroke
- Published
- 2008-10
- Volume
- 39
- Issue
- 10
- Pages
- 2824-2829
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- OpenAlex
- W2168672683
- Cited by
- 319
- References
- 28
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 11 · 2023: 12 · 2022: 16 · 2021: 15 · 2020: 17 · 2019: 33 · 2018: 11 · 2017: 18 · 2016: 26 · 2015: 19 · 2014: 28 · 2013: 26 · 2012: 19
- FWCI
- 12.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- Keywords
- NXY-059, focal cerebral ischemia, animal models of stroke, study quality bias, infarct size, neuroprotection, translational research
- MeSH terms
- Animals, Benzenesulfonates, Cardiovascular Agents, Brain Ischemia, Clinical Trials as Topic, Research Design, Bias
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