Sex Disparities in Enrollment in Recent Randomized Clinical Trials of Acute Stroke

Abstract

IMPORTANCEThe 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 MEASURESThe 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. RESULTSThe 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.

Effects of Antiplatelet Therapy After Stroke Caused by Intracerebral Hemorrhage

“…Most participants were male. Although we did not blind the assigned treatment to participants and physicians, the outcomes were objective and adjudicated blinded to treatment allocation, which minimizes bias. Adherence to the allocated treatment decreased over time but was greater than 80% even after 5 years of follow-up and did not seem to be affected by the publication of the main results.…”

Sex differences in Outcomes After Mechanical Thrombectomy for Acute Ischemic Stroke: Real-World Analysis and Literature Review

“…11 For instance, females are less likely than males to be enrolled in clinical trials of acute stroke across all regions and study types. 12,13 In a Japanese prospective registry study of 2,399 patients with AIS-LVO, females were less likely to receive endovascular therapy (47.9% versus 57.7%, p < 0.001). 6 In the current study, a similar phenomenon was observed, with a lower number of female patients than male patients receiving MT at our center over the 3year period studied (126 [36.3%] vs. 221 [63.7%]).…”

Sex disparities in enrollment and reporting of outcomes by sex in contemporary clinical trials of atrial fibrillation

“…To measure enrollment of females, we used a modified version of the enrollment disparity difference (EDD), a metric which accounts for sex prevalence inequalities in the general population, initially developed to characterize enrollment disparities in lung cancer treatment RCTs, 16 and also used in a recent study of sex enrollment disparities in RCTs of acute stroke therapies. 8 For each RCT, we calculated the proportion of females enrolled in the trial (PFT), and estimated the proportion of females with AF among the general population (PFG) using data from the Global Burden of Disease (GBD) database (https://gbd2017.healthdata.org/gbdsearch/). Each trial was matched to GBD prevalence data on the basis of the approximate median year of the trial recruitment period and geographic area.…”

“…Sex differences in disease pathophysiology, clinical patterns, and response to treatment should be considered in the design, analysis, and reporting of research studies 6,7 . Recent analyses have shown inadequate enrollment of women in randomized controlled trials (RCTs) of various cardiovascular diseases 8–10 . Given the well‐established importance of sex in the epidemiology of AF, 4 the underrepresentation of women in RCTs of therapies for patients with AF might undermine their generalizability and consequently the validity of the evidence guiding treatment of women.…”

“…Therefore, an upper age limit as a selection criterion in trials of AF should be considered only if medically indicated. If age is used as a surrogate of age-related health condition such as frailty, it would be desirable to exclude participants based on a formal assessment of the condition rather than age 8,21. We also observed that smaller trials enrolled fewer females.…”