Saurav Das, MD
@sauravmed
Despite a higher burden of intracerebral hemorrhage (ICH) in women, their enrollment in clinical trials is low. Given sex differences in pathophysiology and outcomes following ICH, disparities in enrollment limit the generalizability of trial results. In this study, Dr. Greige et al. examine the reasons for exclusion of women compared to men from the Intracerebral Hemorrhage Deferoxamine (iDEF) trial. The iDEF trial was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase 2 trial that evaluated the use of deferoxamine mesylate versus placebo (saline) infusions in patients with ICH at 40 hospitals in Canada and the United States. The trial results were published in Lancet Neurology in May 2019.1 The screening log for all ICH patients found ineligible to participate in this study was reviewed to identify the reason for exclusion (of the 29 pre-defined reasons). Chi-square test was used to evaluate whether women and men differed with regard to reason for exclusion; adjustments for multiple testing were made during analyses.
In this trial, 9609 patients were screened, 8776 patients failed screening, and 58 patients were excluded from analysis due to missing data regarding sex. 8718 patients were included in the analysis, of which 3982 (46%) were women. The trial enrolled 293 subjects, 38% of whom were women. The authors found that the enrollment rates were lower in women (2.7%) than in men (3.7%), p=0.01. Women were likely to be excluded than men because of age >80 years (22.4% vs 12.6%, adjusted p=0.0007). On the other hand, men were likely to be excluded because of mild ICH severity, coagulopathy, inability to comply with study protocol, Serum Creatinine > 2mg/dL, drug/ alcohol dependence and evidence of aspiration at presentation. There was no difference in ability to obtain consent, and patient or family refusal to participate in clinical trial.
The authors discussed that underrepresentation of women in ICH trials results from limiting the age of enrollment to patients ≤ 80 years. A few other interesting observations highlighted include that a numerically higher rate of exclusion of women was due to pre-existing Do Not Resuscitate/Do Not Intubate orders. Studies have suggested that women are more likely to express their wishes regarding end-of-life decisions than men and ask for less aggressive and heroic resuscitative measures than their male counterparts. Also, the severity of ICH was worse in women. The authors propose this may be due to loss of any protective effects of gonadal steroids in the post-menopausal period. The study only included patients from North America, and did not have data regarding race of the participants available for analysis. Nevertheless, it highlights a good point that substituting an upper limit of age as an entry criterion with a pre-morbid functional status and co-morbidity index may lead to higher participation of women in ICH trials.
References:
- Selim M, Foster LD, Moy CS, et al. Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol. 2019;18(5):428-438.
