Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials

Woodhouse, Lisa J.; Montgomery, Alan A.; Mant, Jonathan; Davis, Barry R.; Algra, Ale; Mas, Jean-Louis; Staessen, Jan A.; Thijs, Lutgarde; Tonkin, Andrew; Kirby, Adrienne; Pocock, Stuart J.; Chalmers, John; Hankey, Graeme J.; Spence, J. David; Sandercock, Peter; Diener, Hans-Christoph; Uchiyama, Shinichiro; Sprigg, Nikola; Bath, Philip M.

Abstract

Background: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them.

Methods: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan’s multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test.

Results: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes.

Conclusions: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Citation

Woodhouse, L. J., Montgomery, A. A., Mant, J., Davis, B. R., Algra, A., Mas, J.-L., Staessen, J. A., Thijs, L., Tonkin, A., Kirby, A., Pocock, S. J., Chalmers, J., Hankey, G. J., Spence, J. D., Sandercock, P., Diener, H.-C., Uchiyama, S., Sprigg, N., & Bath, P. M. (2021). Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials. BMC Medical Research Methodology, 21, Article 218. https://doi.org/10.1186/s12874-021-01388-6

• Journal Article Type: Article
• Acceptance Date: Aug 17, 2021
• Online Publication Date: Oct 17, 2021
• Publication Date: 2021-12
• Deposit Date: Oct 20, 2021
• Publicly Available Date: Oct 21, 2021
• Journal: BMC Medical Research Methodology
• Electronic ISSN: 1471-2288
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Article Number: 218
• DOI: https://doi.org/10.1186/s12874-021-01388-6
• Keywords: Health Informatics; Epidemiology
• Public URL: https://nottingham-repository.worktribe.com/output/6504421
• Publisher URL: https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-021-01388-6
• Additional Information: This meta-analysis was undertaken using fully anonymised individual patient data shared from randomised clinical trials that each had their own research ethics committee approvals and consents for data sharing. The anonymised data from each trial were shared after a data sharing agreement was completed and signed by the data owner (or an appropriate representative) and the representative for the Collaboration (PMB). An ethics and consent waiver for this research was granted on 22nd July 2015 by the School of Medicine Research Ethics Committee, University of Nottingham (Reference: DB21072015 SoM CN).; : Not applicable.; : PMB is Stroke Association Professor of Stroke Medicine and is a NIHR Senior Investigator. PMB was Chief Investigator for the ENOS and TARDIS trials, which were shared with the study. LJW was funded in part by UK MRC ENOS (G0501797) and NIHR TARDIS (10/104/24). AAM, JM, BRD, AA, J-LM, JAS, LT AT, AK, SJP, JC, GJH, JDS, PS, HCS, SU & NS report no conflicts of interest.