The cardiovascular research community can and must do better by women with cardiovascular disease (CVD), contends an American College of Cardiology (ACC) committee, and the group has issued eight specific recommendations to make that happen.
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The recommendations are the focus of a JACC Council Perspectives article published in the Journal of the American College of Cardiology by a writing team of the ACC’s Cardiovascular Disease in Women Committee Leadership Council led by Leslie Cho, MD, Director of the Women’s Cardiovascular Center at Cleveland Clinic.
“It has long been recognized that women are consistently underrepresented in cardiovascular trials even though cardiovascular disease is the top cause of death among women,” says Dr. Cho. “Despite modest gains in women’s participation in these trials in recent decades, progress has been slow and recent analyses consistently show that women — and particularly underrepresented minority women — remain substantially underenrolled in most clinical trials in cardiology.” She notes that the participation gaps are widest in trials involving coronary artery disease, heart failure with reduced ejection fraction and arrhythmias — particularly in studies of devices and procedures.
“Because a variety of differences between the sexes have been identified when it comes to the presentation and treatment of cardiovascular diseases, management recommendations based on studies with few female participants are likely to underserve and potentially harm female patients,” Dr. Cho continues. “Our committee sought to identify key barriers to enrollment and retention in cardiovascular trials among women, and to address those barriers with specific and novel strategy recommendations to overcome them.”
In addition to reviewing extensive recent literature evidence of lingering gaps in women’s representation in cardiovascular trials, the authors enumerate eight barriers to that representation and offer recommendations for each, as summarized below.
Some obstacles to trial recruitment and retention of women stem from systemic differences in how men and women with CVD are cared for, the authors write. These differences tend to manifest in lower rates of referral and less-aggressive care for CVD among women.
In response, the authors recommend expanding awareness of ongoing cardiovascular trials beyond specialty clinics (where women are less likely to be referred) and expanding the number and location of trial sites. Additionally, novel recruitment strategies — including various digital tools and platforms — should be assessed for increasing female participation, and lessons learned about beneficial strategies for enrolling women must be broadly disseminated after each trial.
Since CVD prevalence is substantially higher among women of older ages, the fact that older adults are often excluded from clinical trials tends to exacerbate the underrepresentation of women in cardiovascular trials. This can be remedied by expanding trials’ age criteria and limiting exclusion criteria that disproportionately impact older adults, the authors argue.
The authors cite evidence that women tend to be more reluctant than men to consider participating in clinical trials and have a lower awareness of their CVD risk. Among women from underrepresented racial and ethnic minorities, this reluctance and reduced awareness may be intensified by perceived lack of cultural sensitivity and ineffective communication on the part of researchers. Moreover, women’s ability to participate in trials is more likely to be hampered by time, resource and logistical constraints related to women’s greater caregiver requirements and economic challenges relative to men.
To combat logistical obstacles, the authors urge limiting the number of onsite visits for trial participation and promoting remote monitoring when workable. They also endorse expanding onsite visits beyond standard business hours and offering child/elder care and options for free transportation. To increase awareness of CVD risk among women, the authors call for stepped-up public education efforts that replicate and build on initiatives like the American Heart Association’s Go Red for Women campaign. They also argue for sex-specific tailoring of strategies for engaging female and underrepresented minority trial candidates, including instruction for clinical investigators and medical trainees on how to address women’s questions and concerns about clinical trials.
Most significant advances in women’s healthcare have stemmed from advances in women’s leadership in academic medicine, the authors note. They write: “Because of evidence that female representation in clinical trial leadership is associated with both greater female enrollment and higher rates of reporting sex-based outcomes, it is essential that women are included in trial leadership and design.” Nevertheless, they cite abundant evidence that women remain significantly underrepresented in cardiovascular clinical trial leadership despite modest recent progress.
In response, the authors call for increasing inclusion of women and underrepresented minorities at all levels of trial leadership, including in site investigator roles. They call on government entities and other trial funders and stakeholders to “engage all researchers and sponsors to solve this problem.”
The authors note that women from underrepresented racial and ethnic minorities are particularly underrepresented in both trial participation and trial leadership. But by citing examples like the A-HeFT (African American Heart Failure) trial, in which 40% of enrolled patients were Black women, the authors point out that robust participation of underrepresented women in both trial leadership and enrollment is possible.
To replicate such participation more often, the authors advocate a multipronged approach that tailors many of the above recommendations — such as those for addressing differential care and logistical barriers — specifically to underrepresented minority women. They particularly emphasize the importance of novel trial site locations, referencing the success of the Barber Shop trial and the FAITH study, and the utility of engaging stakeholder community groups and associations that are representative of potential trial enrollees.
Some of the historical underrepresentation of women in clinical trials stems from the frequent exclusion of pregnant and all women of childbearing potential from trials in the wake of the thalidomide tragedies of the 1950s and 1960s. Although those exclusions have been eased in recent decades, their legacy is a lingering cautiousness at the FDA and beyond about including pregnant women in clinical trials. Since CVD can substantially impact the health of a woman and her fetus during pregnancy, the ramifications of this cautiousness are especially pronounced when it comes to cardiovascular trials.
In response, the authors recommend encouragement of more drug studies on pregnant animals to allow data extrapolation to inform inclusion of pregnant women in clinical trials. They also argue for inclusion of pregnant and lactating women in trials with proper oversight of local IRBs, researchers and women themselves, and they urge inclusion of obstetric and maternal-fetal medicine consultants in the design of trials that could include women of childbearing age.
Some of the shortfall in women’s participation in cardiovascular trials likely relates to sex-related differences in disease and clinical presentation, the authors note. To remedy this, they call for more studies to be performed in cardiovascular conditions that are specific to or more prevalent among women, particularly coronary artery disease, heart failure with preserved ejection fraction, stress-induced cardiomyopathy and microvascular disease.
While recruitment of women for cardiovascular trials has drawn much attention, scant data are available on potential sex differences in study discontinuation and patient follow-up after successful enrollment. “If differential rates of premature study discontinuation between men and women exist, this could contribute toward apparent effect modification and provide the appearance that a therapy is less effective for patients of one sex,” the authors write. They call for clinical trial case reports to include reasons for study drug discontinuation and withdrawal of consent, as well as comprehensive reporting of such data by patient sex and race.
The comprehensiveness of these eight recommendations will be key to their potential success, observes Dr. Cho. “The challenge of overcoming barriers to recruitment and retention of women in cardiovascular clinical trials is not new, and there is no single solution,” she says. “What will be essential is a comprehensive and targeted effort that engages everyone who is a stakeholder, from female patients themselves to referring physicians, clinical investigators, research coordinators, health systems, the FDA, healthcare payers, study sponsors, professional societies and community organizations.”