Participation of Women and Older Participants in Randomized Clinical Trials of Lipid-Lowering Therapies: A Systematic Review

Safi U Khan, Muhammad Zia Khan, Charumathi Raghu Subramanian, Haris Riaz, Muhammad U Khan, Ahmad Naeem Lone, Muhammad Shahzeb Khan, Eve-Marie Benson, Mohamad Alkhouli, Michael J Blaha, Roger S Blumenthal, Martha Gulati, Erin D Michos, Safi U Khan, Muhammad Zia Khan, Charumathi Raghu Subramanian, Haris Riaz, Muhammad U Khan, Ahmad Naeem Lone, Muhammad Shahzeb Khan, Eve-Marie Benson, Mohamad Alkhouli, Michael J Blaha, Roger S Blumenthal, Martha Gulati, Erin D Michos

Abstract

Importance: 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.

Objective: To determine the trends of representation of women and older patients (≥65 years) in RCTs of lipid-lowering therapies from 1990 to 2018.

Data sources: The electronic databases of MEDLINE and ClinicalTrials.gov were searched from January 1990 through December 2018.

Study selection: RCTs of lipid-lowering therapies with sample sizes of at least 1000 patients and follow-up periods of at least 1 year were included.

Data extraction and synthesis: Two independent investigators abstracted the data on a standard data collection form.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Blaha reported receiving grants from the National Institutes of Health, the US Food and Drug Administration, the American Hospital Association, and Aetna; receiving grants and personal fees from Amgen; and receiving personal fees for serving on the advisory boards of Sanofi, Regeneron, Novartis, Novo Nordisk, Bayer, and Akcea outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram of Selection Process
Figure 1.. Flow Diagram of Selection Process
Figure 2.. Patients Enrolled in Lipid-Lowering Therapy…
Figure 2.. Patients Enrolled in Lipid-Lowering Therapy Randomized Clinical Trials Over Time
Blue dotted lines indicate linear trend.
Figure 3.. Participation-to-Prevalence Ratio of Women in…
Figure 3.. Participation-to-Prevalence Ratio of Women in Lipid-Lowering Therapy Randomized Clinical Trials, Prevalence-Corrected Estimate
The ratio of the percentage of women among trial participants to the percentage of women among the disease population is the participation-to-prevalence ratio. A participation-to-prevalence ratio of 1.0 indicates that the sex composition of the randomized clinical trial was equal to that of the disease population. A participation-to-prevalence ratio between 0.8 and 1.2 indicates that proportion of women in the trial was similar to the proportion of women in the disease population.
Figure 4.. Number of Lipid-Lowering Therapy Randomized…
Figure 4.. Number of Lipid-Lowering Therapy Randomized Clinical Trials Reporting Clinical Outcomes Based on Subgroups of Women and Older Participants

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