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Abstract
Background White matter hyperintensities (WMHs) are a highly prevalent MRI marker of cerebral small vessel disease (SVD), which predict stroke and dementia risk, and are being increasingly used as a surrogate marker in clinical trials. However, the influence of study population selection on WMH progression rate has not been studied and the effect of individual patient factors for WMH growth are not fully understood.
Methods We performed a systematic review and meta-analysis of the literature on progression of WMHs in longitudinal studies to determine rates of WMH growth, and how these varied according to population characteristics and cardiovascular risk factors. We used these data to calculate necessary sample sizes for clinical trials using WMH as an endpoint.
Results WMH growth rate was highest in SVD (2.50cc/year), intermediate in unselected stroke patients (1.29cc/year) and lower in patients with non-stroke cardiovascular disease, and with cognitive impairment. Age was significantly associated with progression (correlation coefficient 0.15cc/year, 95% CI 0.02 to 0.28cc/year) as was baseline lesion volume (0.6cc/year, 95% CI 0.13 to 1.06 cc/year). Both hypertension (OR 1.72, 95% CI 1.19 to 2.46) and current smoking (OR 1.48, 95% CI 1.02 to 2.16) were associated with WMH growth. Sample sizes for a clinical trial varied greatly with patient population selection and baseline lesion volume; estimates are provided.
Conclusions WMH progression varies markedly according to the characteristics of the population being studied and this will have a major impact on sample sizes required in a clinical trial. Our sample size estimates provide data for planning clinical trials using WMH as an outcome measure.
PROSPERO registration number CRD42020191781.
Data availability statement
Data are available on reasonable request. All data relevant to the study are available from published articles referenced in the text. Extracted data used for analysis are uploaded as online supplemental information or available at reasonable request.
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Data availability statement
Data are available on reasonable request. All data relevant to the study are available from published articles referenced in the text. Extracted data used for analysis are uploaded as online supplemental information or available at reasonable request.
Footnotes
Twitter @rbb_29, @_audreylow, @Camstroke
Contributors RB designed the study, performed the literature search, extracted the data, critically reviewed references, analysed the data and wrote the first draft of the manuscript. AL extracted the data, critically reviewed references and critically reviewed the manuscript. HSM designed the study, critically reviewed references and critically reviewed the manuscript.
Funding RB is supported by an Association of British Neurologists Clinical Research Training Fellowship funded by the Guarantors of Brain. AL is funded by the Fitzwilliam Lee Kuan Yew PhD Scholarship. HSM is supported by an NIHR Senior Investigator award. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).
Competing interests The authors declare that the research was conducted in the absence of any personal, professional or financial relationships that would constitute a potential conflict of interest.
Provenance and peer review Not commissioned; externally peer reviewed.
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