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, S. D.J., Doubal, F. N., Quinn, T. J. , Bath, P. M.W., Dennis, M. S. and Wardlaw, J. M. (2018) 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), pp. 66-73. (doi: 10.1177/2396987317728854)

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.

• Item Type: Articles
• Additional Information: The study was funded by the Wellcome Trust (grant 088134/Z/09/A), the Scottish Funding Council and the Chief Scientist Office, Scotland, through the Scottish Imaging Network: A Platform for Scientific Excellence (‘SINAPSE’) and the European Union Horizon 2020 research and innovation programme SVDs@Target under grant agreement 666881. FD and TQ are funded by the Stroke Association/ Garfield Weston Foundation and Stroke Association/Chief Scientist Office Senior Lectureships respectively. PMB is Stroke Association Professor of Stroke Medicine and is a NIHR Senior Investigator. The work was supported by the Fondation Leducq Transatlantic Network of Excellence in Small Vessel Disease ref no. 16 CVD 05, and the Horizon 2020 Programme PHC-03-15, project No 666881, ‘SVDs @Target.’
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Makin, Dr Stephen and Quinn, Professor Terry
• Authors: Makin, S. D.J., Doubal, F. N., Quinn, T. J., Bath, P. M.W., Dennis, M. S., and Wardlaw, J. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: European Stroke Journal
• Publisher: SAGE Publications
• ISSN: 2396-9873
• ISSN (Online): 2396-9881
• Published Online: 05 September 2017
• Copyright Holders: Copyright © 2017 European Stroke Organisation
• First Published: First published in European Stroke Journal 3(1): 66-73
• Publisher Policy: Reproduced under a Creative Commons License