The effect of different combinations of vascular, dependency and cognitive endpoints on the sample size required to detect a treatment effect in trials of treatments to improve outcome after lacunar and non-lacunar ischaemic stroke

Makin, Stephen D.J.; Doubal, Fergus; Quinn, Terence J.; Bath, Philip M.W.; Dennis, Martin S.; Wardlaw, Joanna M.

Abstract

Background

Endpoints that are commonly used in trials of moderate/severe stroke may be less frequent in patients with minor, non-disabling stroke thus inflating sample sizes. We tested whether trial efficiency might be improved with composite endpoints.

Methods

We prospectively recruited patients with lacunar and minor non-lacunar ischaemic stroke (NIHSS ≤ 7) and assessed recurrent vascular events (stroke, transient ischaemic attack (TIA), ischemic heart disease (IHD)), modified Rankin Score (mRS) and cognitive testing with the Addenbrooke’s Cognitive Examination (ACE-R) one year post-stroke. For a potential secondary prevention randomised controlled trial (RCT), we estimated sample sizes using individual or combined outcomes, at power 80% (and 90%), alpha 5%, required to detect a relative 10% risk reduction.

Results

Amongst 264 patients (118 lacunar, 146 non-lacunar), at one year, 30/264 (11%) patients had a recurrent vascular event, 5 (2%) had died, 3 (1%) had clinically-diagnosed dementia, 53/264 (20%) had mRS ≥ 3 and 29/158 (19%) had ACE-R ≤ 82 (57 could not attend for cognitive testing). For a potential trial, at 80% power, using mRS ≥ 3 alone would require n > 5000 participants, recurrent vascular events alone n = 9908 participants, and a composite of any recurrent vascular event, ACE-R ≤ 82, dementia or mRS ≥ 2 (present in 56% of patients) n = 2224 patients. However, including cognition increased missing data. Results were similar for lacunar and non-lacunar minor ischaemic stroke.

Conclusions

Composite outcomes including vascular events, dependency, and cognition reduce sample size and increase efficiency, feasibility, and relevance to patients of RCTs in minor ischaemic stroke. Efficiency might be improved further with more practical cognitive test strategies.

Citation

Makin, S. D., Doubal, F., Quinn, T. J., Bath, P. M., Dennis, M. S., & Wardlaw, J. M. (in press). The effect of different combinations of vascular, dependency and cognitive endpoints on the sample size required to detect a treatment effect in trials of treatments to improve outcome after lacunar and non-lacunar ischaemic stroke. European Stroke Journal, 3(1), https://doi.org/10.1177/2396987317728854

• Journal Article Type: Article
• Acceptance Date: Jul 24, 2017
• Online Publication Date: Sep 5, 2017
• Deposit Date: Oct 5, 2017
• Publicly Available Date: Oct 5, 2017
• Journal: European Stroke Journal
• Electronic ISSN: 2396-9873
• Publisher: SAGE Publications
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 1
• DOI: https://doi.org/10.1177/2396987317728854
• Keywords: Stroke, Randomised trial, Sample size, Power calculation, Lacunar, Cognition, Dependency, Outcome
• Public URL: https://nottingham-repository.worktribe.com/output/880858
• Publisher URL: http://journals.sagepub.com/doi/10.1177/2396987317728854
• Contract Date: Oct 5, 2017