Evidence for the Efficacy of NXY-059 in Experimental Focal Cerebral Ischaemia Is Confounded by Study Quality
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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 in animal model studies.
“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]
The Results report that estimated efficacy was highest in lower-quality studies of NXY-059 in animal models of stroke. This supports the inverse relationship in the studies analyzed, but does not establish it across animal model studies generally. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCompelling data from systematic reviews show that nonblinded outcome assessment leads to treatment effects being overestimated.
“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]
The Discussion says efficacy may have been overstated by methodological flaws and identifies blinded outcome assessment as a measure that might reduce bias. But Potential Weaknesses says the impact of blinded outcome assessment is not yet clear, so the source does not establish the claim’s categorical causal conclusion. The Results report lower efficacy estimates with randomization and allocation concealment, but do not substantiate the cited sentence’s 30%–45% inflation figure. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLack of bias-reducing measures such as randomisation and blinding can contribute to as much as 30%-45% inflation of effect sizes.
“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]
The Results report higher estimated NXY-059 efficacy in animal studies that did not report randomization or allocation concealment, supporting the general concern about bias. They do not report 30%–45% inflation of effect sizes, and they found no significant effect of reported blinded outcome assessment. The Discussion describes methodological flaws as a possible reason efficacy was overstated. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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- 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 › Epidemiology › Acute Ischemic Stroke Management
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- 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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