Abstract
Randomized clinical trials (RCTs) of lipid-lowering therapies form the evidence base for national and international guidelines. However, concerns exist that women and older patients are underrepresented in RCTs. To determine the trends of representation of women and older patients (≥65 years) in RCTs of lipid-lowering therapies from 1990 to 2018. The electronic databases of MEDLINE and ClinicalTrials.gov were searched from January 1990 through December 2018. RCTs of lipid-lowering therapies with sample sizes of at least 1000 patients and follow-up periods of at least 1 year were included. Two independent investigators abstracted the data on a standard data collection form. Patterns of representation of women and older adults were examined overall in lipid-lowering RCTs and according to RCT-level specific characteristics. The participation-to-prevalence ratio (PPR) metric was used to estimate the representation of women compared with their share of disease burden. A total of 60 RCTs with 485 409 participants were included. The median (interquartile range) number of participants per trial was 5264 (1062-27 564). Overall, representation of women was 28.5% (95% CI, 24.4%-32.4%). There was an increase in the enrollment of women from the period 1990 to 1994 (19.5%; 95% CI, 18.4%-20.5%) to the period 2015 to 2018 (33.6%; 95% CI, 33.4%-33.8%) (P for trend = .01). Among common limiting factors were inclusion of only postmenopausal women or surgically sterile women (28.3%; 95% CI, 18.5%-40.7%) or exclusion of pregnant (23.3%; 95% CI, 14.4%-35.4%) and lactating (16.6%; 95% CI, 9.3%-28.1%) women. Women were underrepresented compared with their disease burden in lipid RCTs of diabetes (PPR, 0.74), heart failure (PPR, 0.27), stable coronary heart disease (PPR, 0.48), and acute coronary syndrome (PPR, 0.51). Only 23 RCTs with 263 628 participants reported the proportion of older participants. Overall representation of older participants was 46.7% (95% CI, 46.5%-46.9%), which numerically increased from 31.6% (95% CI, 30.8%-32.3%) in the period 1995 to 1998 to 46.2% (95% CI, 46.0%-46.5%) in the period 2015 to 2018 (P for trend = .43). A total of 53.0% (95% CI, 41.8%-65.3%) and 36.6% (95% CI, 25.6% to 49.3%) trials reported outcomes according to sex and older participants, respectively, which did not improve over time. In this systematic review of RCTs of lipid-lowering therapies, the enrollment of women and older participants increased over time, but women and older participants remained consistently underrepresented. This limits the evidence base for efficacy and safety in these subgroups.
Highlights
Women and older patients carry significant burden of atherosclerotic cardiovascular disease.[1,2,3,4,5] concerns exist that despite the high prevalence of cardiovascular morbidity among these subgroups, they are underrepresented in clinical trials.[5,6] Randomized clinical trials (RCTs) are considered the criterion standard for evidence-based medicine; they shape guideline recommendations for patients and play a critical role in the prevention and treatment of cardiovascular disease
Among common limiting factors were inclusion of only postmenopausal women or surgically sterile women (28.3%; 95% CI, 18.5%-40.7%) or exclusion of pregnant (23.3%; 95% CI, 14.4%-35.4%) and lactating (16.6%; 95% CI, 9.3%-28.1%) women
Women were underrepresented compared with their disease burden in lipid RCTs of diabetes (PPR, 0.74), heart failure (PPR, 0.27), stable coronary heart disease (PPR, 0.48), and acute coronary syndrome (PPR, 0.51)
Summary
Women and older patients carry significant burden of atherosclerotic cardiovascular disease.[1,2,3,4,5] concerns exist that despite the high prevalence of cardiovascular morbidity among these subgroups, they are underrepresented in clinical trials.[5,6] Randomized clinical trials (RCTs) are considered the criterion standard for evidence-based medicine; they shape guideline recommendations for patients and play a critical role in the prevention and treatment of cardiovascular disease. Given that the efficacy and toxicity of a drug are potentially influenced by several factors, including sex hormones and age-related issues of absorption and metabolism, underrepresentation of women and older adults in RCTs can undermine the generalizability of the findings to these subsets of the population. In 1986, the National Institutes of Health advisory committee recommended inclusion of women to grant applicants.[7] Over the decades, US Food and Drug Administration (FDA) recommendations have evolved regarding reporting of sex and other demographic variables in RCTs. In recent years, there has been an ongoing effort in industry-funded trials to recruit women and older patients.[8,9]
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