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Original Investigation
April 26, 2021

Sex Disparities in Enrollment in Recent Randomized Clinical Trials of Acute Stroke: A Meta-analysis

Author Affiliations
  • 1Department of Epidemiology and Biostatistics, College of Human Medicine, Michigan State University, East Lansing
  • 2Stroke and Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia
  • 3Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham
  • 4George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
JAMA Neurol. Published online April 26, 2021. doi:10.1001/jamaneurol.2021.0873
Key Points

Question  Relative to their representation in underlying stroke populations, are women underenrolled in contemporary randomized clinical trials of acute stroke therapies?

Findings  In this meta-analysis of 115 acute stroke trials published in the last decade, relative to their representation in underlying stroke populations, women were underenrolled by 5.3 percentage points across all studies. The use of an upper age limit of 80 years as an exclusion criterion was associated with significantly less enrollment of women after multivariable adjustment.

Meaning  Per these findings, further efforts including changes to eligibility criteria are needed to ensure increased participation of women in acute stroke trials.

Abstract

Importance  The underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments.

Objective  To determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations.

Data Sources  MEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020.

Study Selection  Eligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset.

Data Extraction  Data extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database.

Main Outcomes and Measures  The primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates.

Results  The search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was −0.053 (95% CI, −0.065 to −0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was −0.067 (95% CI, −0.078 to −0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6–percentage point decrease in the enrollment of women.

Conclusions and Relevance  Further research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.

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