A new analysis of 11 phase 3/4 cardiovascular clinical trials conducted by the Thrombolysis in Myocardial Infarction (TIMI) group shows that women are more likely than men to discontinue study medications, and to withdraw from trials. The differences could not be explained by different frequencies of reporting adverse events, or by baseline differences.
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The findings are significant, since cardiovascular drugs are routinely prescribed to women based on clinical trials that are populated largely by men, according to lead study author Emily Lau, MD, who is an advanced cardiology fellow at Massachusetts General Hospital, Boston. “It highlights an important disparity in clinical research in cardiology, because if women are already not represented well in clinical trials, and if once in clinical trials they don’t complete the study, it’s very hard to extrapolate the clinical trial findings to our female population in an accurate way,” Dr. Lau said in an interview. She also noted that sex-specific and reproductive factors are increasingly recognized as being important in the development and progression of cardiovascular disease.
Dr. Emily Lau
The study was published in the journal Circulation.
The study refutes previously advanced explanations for higher withdrawal among women, including sex difference and comorbidities, according to an accompanying editorial by Sofia Sederholm Lawesson, MD, PhD, Eva Swahn, MD, PhD, and Joakim Alfredsson, MD, PhD, of Linköping University, Sweden. They also pointed out that the study found a larger between-sex difference in failure to adhere to study drug in North America (odds ratio, 1.35; 95% confidence interval, 1.30-1.41), but a more moderate difference among participants in Europe/Middle East/Africa (OR, 1.13; 95% CI, 1.09-1.17) and Asia/Pacific (OR, 1.13; 95% CI, 1.03-1.23) regions. And there were no sex differences at all among South/Central American populations.
They noted that high rates of nonadherence increase the chances of a false negative finding and overestimation of drug safety. “We know the associations between nonadherence and clinical outcomes. The next step should be to better understand the underlying reasons for, as well as consistent reporting of, nonadherence, and discontinuation in RCTs,” the editorial authors wrote.
Dr. Lau suggested a simple method to better understand reasons for withdrawal: Addition of questions to the case report form that asks about reasons for drug discontinuation or study withdrawal. “Was it an adverse event? Was it because I’m a mother of three and I can’t get to the clinical trial site after work and also pick up my kids? Are there societal barriers for women, or was it the experience of the clinical trial that was maybe less favorable for women compared to men? Or maybe there are medical reasons we simply don’t know. Something as simple as asking those questions can help us better understand the barriers to female retention,” said Dr. Lau.
The analysis included data from 135,879 men (72%) and 51,812 women (28%) enrolled in the trials. After adjustment for baseline differences, women were more likely than were men to permanently discontinue study drug (adjusted odds ratio [aOR], 1.22: P < .001), which did not vary by study duration. The finding was consistent regardless of the type of drug studied, as well as across placebo and active study arms.
Women also were more likely to prematurely discontinue study drug (trial-adjusted OR, 1.18; P < .001). The rate of drug discontinuation due to adverse event was identical in both men and women, at 36%.
Women were more likely to withdraw consent than were men in a meta-analysis and when individual patient-level results were pooled (aOR, 1.26; P < .001 for both).
Dr. Lau received funding from the National Institutes of Health and has no relevant financial disclosures. The editorial authors had various disclosures, including lecture fees from Bayer, Pfizer, and Boehringer Ingelheim, and they served on advisory boards for AstraZeneca and MSD.