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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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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
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Comparison of Treatment Effects between Animal Experiments and Clinical Trials: Systematic Review
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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.
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Self-citationHow can we improve the pre-clinical development of drugs for stroke?
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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
Self-citationBenedek, A., Móricz, K., Jurányi, Z., Gigler, G., Lévay, G. I., Hársing, L. G., Mátyus, P., Szénási, G., & Albert, M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.07.123 · Cited by 192
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Türeyen, K., Vemuganti, R., Sailor, K. A., & Dempsey, R. J. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.04.029 · Cited by 180
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Sydserff, S. G., Borelli, A., Green, A. R., & Cross, A. J. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704449 · Cited by 154
Systematic review and meta‐analysis of the efficacy of melatonin in experimental stroke
Macleod, M. R., O'Collins, T., Horky, L. L., Howells, D., & Donnan, G. A. (2005) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2004.00172.x · Cited by 137
Self-citationSavitz, S. T. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.03.003 · Cited by 134
Marshall, J. W. B., Cummings, R. M., Bowes, L. J., Ridley, R. M., & Green, A. R. (2003) · Stroke · doi:10.1161/01.str.0000087790.79851.a8 · Cited by 132
Feuerstein, G., Zaleska, M. M., Krams, M., Wang, X., Day, M., Rutkowski, J., Finklestein, S. P., Pangalos, M. N., Poole, M., Stiles, G. L., et al. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600516 · Cited by 121
Lapchak, P. A., Araujo, D. M., Song, D., Wei, J., & Zivin, J. A. (2002) · Stroke · doi:10.1161/01.str.0000015346.00054.8b · Cited by 111
Zhao, Z., Cheng, M., Maples, K. R., Jing, Y., & Buchan, A. M. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02618-x · Cited by 103
Systematic Review and Meta-Analysis of the Efficacy of Tirilazad in Experimental Stroke
Sena, E. S., Wheble, P. C. R., Sandercock, P. A., & Macleod, M. R. (2007) · Stroke · doi:10.1161/01.str.0000254462.75851.22 · Cited by 95
Self-citationLapchak, P. A., Araujo, D. M., Song, D., Wei, J., Purdy, R. H., & Zivin, J. A. (2002) · Stroke · doi:10.1161/01.str.0000017145.22806.aa · Cited by 86
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Nitrone derivatives of trolox as neuroprotective agents
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NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia
Yoshimoto, T., Kanakaraj, P., Jing, Y., Cheng, M., Kerr, I., Malaiyandi, L. M., Watson, J. A., Siesjö, B. K., & Maples, K. R. (2002) · Brain Research · doi:10.1016/s0006-8993(02)02922-0 · Cited by 34
SAINT-I Worked, But the Neuroprotectant Is Not NXY-059
Proctor, P. H., & Tamborello, L. P. (2007) · Stroke · doi:10.1161/strokeaha.107.489161 · Cited by 19
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Power failure: why small sample size undermines the reliability of neuroscience
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Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0
Percie du Sert, N., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000411 · Cited by 2,677
Self-citationCan Animal Models of Disease Reliably Inform Human Studies?
van der Worp, H. B., Howells, D. W., Sena, E. S., Porritt, M. J., Rewell, S., O'Collins, V., & Macleod, M. R. (2010) · PLoS Medicine · doi:10.1371/journal.pmed.1000245 · Cited by 1,354
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Fisher, M., Feuerstein, G., Howells, D. W., Hurn, P. D., Kent, T. A., Savitz, S. I., & Lo, E. H. (2009) · Stroke · doi:10.1161/strokeaha.108.541128 · Cited by 1,352
Self-citationA call for transparent reporting to optimize the predictive value of preclinical research
Landis, S. C., Amara, S. G., Asadullah, K., Austin, C. P., Blumenstein, R., Bradley, E. W., Crystal, R. G., Darnell, R. B., Ferrante, R. J., Fillit, H., et al. (2012) · Nature · doi:10.1038/nature11556 · Cited by 1,196
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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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