Why Are Women Still Missing from Cardiovascular Clinical Trials?

For decades, women were systematically underrepresented in cardiovascular clinical trials, largely as a result of the misconception that heart disease predominantly affects men. This skewed focus on men’s health resulted in the development of treatments and guidelines without a full understanding of the differences in how heart disease affects the sexes. The issue was exacerbated in 1977 when the FDA issued guidelines that discouraged the participation of women of childbearing age in clinical trials based on concerns about potential harm a developing fetus.¹ As a result, sex-specific differences in cardiovascular disease went largely unstudied.

It wasn’t until the 1990s that significant steps were taken to address this disparity. The National Institutes of Health (NIH) began requiring the inclusion of women in federally funded research, and more emphasis was placed on analyzing clinical trial data by sex. This policy became federal law when it was written in by Congress to a section of the NIH Revitalization Act of 1993.²

How Big Is the Gap?

A review of 706 studies published between January 2010 and December 2020 revealed significant underrepresentation of women in trials studying heart failure with reduced ejection fraction (HFrEF).³ Women accounted for only 26% of the participants across these studies, with no significant differences observed in representation across various interventions, such as pharmacologic or device therapy.³

Although women’s participation gradually increased toward the end of the decade, the median percentage of women in HFrEF trials remained less than 50%. This under-enrollment challenges the generalizability of trial findings, given the known sex-based differences in heart failure characteristics and treatment responses. While efforts by government and industry stakeholders have led to some progress, further actions are necessary to identify and address barriers to recruitment of women in order to ensure trials are sufficiently powered to detect sex-specific interactions.³

In a separate review of women’s participation across 740 cardiovascular trials between 2010 and 2017, researchers found that of more than 860,000 enrolled adults, 38.2% were women.⁴ Representation was higher in trials of hypertension and pulmonary hypertension, but lower in trials for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure.

The review also found that representation of women in government-funded trials, studies with women aged 61 to 65 years, and procedural trials was much lower than in multisponsor–funded trials, studies with women aged 55 years and younger, and lifestyle intervention trials.⁴ While the review authors found notable increases in participation by women in stroke and heart failure trials from 2013 to 2017, men still predominated in cardiovascular trials overall, highlighting the need for continued efforts to achieve gender equity in clinical research.

“The lower participation rate of women in cardiovascular clinical trials logically begs the question, ‘Why don’t women participate in trials at rates similar to men?’” the review authors said. “Hypothetically, multiple opportunities exist for a patient to fall out of the enrollment pathway, and several of these opportunities can likely be influenced by both patient-related and trial site–related factors.”⁴

Why Are Women Still Being Left Out?

The factors underlying women's underrepresentation in cardiovascular trials are varied. As noted in the review of studies from 2010 to 2017,⁴ consumer awareness of trial opportunities is crucial, whether that is accomplished through patient identification via consumer channels or through proactive engagement by study sites. Access to trial centers is another hurdle, requiring appropriate referrals and logistical support for transportation and childcare.⁴

Kathryn Lindley, MD, associate professor of medicine and associate professor of obstetrics and gynecology at Vanderbilt University Medical Center, echoed this point during an exclusive interview with The American Journal of Managed Care® (AJMC®).⁵ She noted that women are often less likely to have health care insurance or access to transportation or childcare, as well as to face other barriers that may be less apparent.

“It's more difficult for women to participate in clinical trials because…you're busy working your job and taking care of your kids and taking care of your parents,” Lindley said. “It's physically more challenging to set aside time to participate in research studies, so a lot of our studies have really focused on men's health and not thought about the ways that it might be different for women.”⁵

It’s also important for potential trial participants to both understand and be comfortable with the clinical trial process and the process of informed consent.⁴ Additionally, cultural backgrounds, biases, investigator communication approaches, and written trial materials all influence women's comfort with enrollment. Studies have found, too, that women are generally less willing to participate in cardiovascular prevention trials compared with men, often related to their greater perceived risk of harm associated with trial participation.⁴

“Women had also been shown to take fewer risks than men under stress, and large health-based decisions could certainly be a source of stress,” the review authors said. “Randomized clinical trials present an added element of risk and uncertainty, and women have been shown to be more reluctant than men to consider participation.”⁴

Men and women also make decisions differently, with women often requiring more time and external input, such as from friends, family, or health care providers.4 Women are also more likely to be influenced by altruistic or selfless motivations, such as participating for “the greater good” rather than for a financial incentive.⁶

To address these enrollment gaps, Lindley called for a multipronged, comprehensive approach that includes⁵:

• Ensuring women have opportunities to participate in research
• Studying how sex and gender interact with cardiovascular health
• Educating clinicians on the differences in how heart disease affects women
• Empowering women to advocate for themselves and seek care when they sense something is wrong

“As clinicians, it's important that we're listening to our patients and are well educated on the ways that heart disease might affect women differently,” Lindley added. “Oftentimes women don't realize that they're at higher risk for certain heart conditions, so I think that's where it's really important that women just are able to access that knowledge and then advocate for themselves when they feel like something's not quite right.”⁵

References

1. McCarthy CR. Historical background of clinical trials involving women and minorities. Acad Med. 1994;69(9):695-698. doi:10.1097/00001888-199409000-00002

2. NIH inclusion outreach toolkit: how to engage, recruit, and retain women in clinical research. NIH. Accessed October 14, 2024. https://orwh.od.nih.gov/toolkit/recruitment/history

3. Gulab A, Essa H, Lo KB, Sankaranarayanan R, Rangaswami J. Gender distribution in randomized controlled trials among patients with heart failure with reduced ejection fraction: a systematic review. Glob Heart. 2022;17(1):8. doi:10.5334/gh.1093

4. Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL. Women's participation in cardiovascular clinical trials from 2010 to 2017. Circulation. 2020;141(7):540-548. doi:10.1161/CIRCULATIONAHA.119.043594

5. Klein HE. Dr Kathryn Lindley addresses barriers to women’s heart disease diagnosis. AJMC. June 15, 2024. Accessed October 14, 2024. https://www.ajmc.com/view/dr-kathryn-lindley-addresses-barriers-to-women-s-heart-disease-diagnosis

6. Lobato L, Bethony JM, Pereira FB, Grahek SL, Diemert D, Gazzinelli MF. Impact of gender on the decision to participate in a clinical trial: a cross-sectional study. BMC Public Health. 2014;14:1156. doi:10.1186/1471-2458-14-1156