Heart disease is a leading cause of death in women, yet it is often thought of as a predominantly male disease. In fact, heart disease affects women just as much as men, and in some cases, even more so. Historically, clinical trials for heart disease have overwhelmingly enrolled men, and the results have been applied to women without considering the differences in biology and risk factors between the two genders. As a result, women are often misdiagnosed or not diagnosed at all, and their symptoms are often dismissed as anxiety or stress. This can lead to delayed treatment and poor outcomes.
In 1977, the FDA recommended excluding women of childbearing potential from early phase (1 and 2) drug clinical trials, even if women used contraception or whose husbands were vasectomized. This approach resulted from the tragedy that occurred from the use of thalidomide in Europe and Canada. This led to an absence of data on how drugs affect women. Many people believe that individual women could decide for themselves whether they should participate in research or not and in the late 80s, the NIH encourage the inclusion of women and minorities in clinical research. In 1991, Dr. Bernadine Healy became the first female NIH director and launched the Women’s Health Initiative that enrolled >150,000 post-menopausal women over a period of 15 yrs.
Despite this, there is still low participation of women in cardiovascular trials particularly in studies that include devices and procedures. In studies of acute coronary syndromes, women constitute only 27% of the patient population. In ICD trials, women’s participation ranged from 15-31%. In studies of heart failure, women constitute only 28.6% of participants. Enrollment of women in clinical research is essential since women metabolize certain medications differently compared to men. In the treatment of heart failure, women obtain maximal benefit from 50% of the goal dose of ace inhibitors, ARB, and beta-blockers. Women were also more likely to have side effects even at the same dose compared to men.
When cardiac catheterization is performed for patients with chest pain or ACS, more women have nonobstructive coronary artery disease, yet they have equal or more severe ischemia and mortality. In the PROSPECT study of coronary atherosclerosis, compared to men, women had less extensive CAD, less calcium buildup, more plaque erosions, and smaller coronary arteries. This is primarily due to gaps in knowledge about microvascular disease or INOCA (ischemia with non-obstructive coronary disease) and spontaneous coronary artery dissection (SCAD) where 90% of cases are women. INOCA is diagnosed usually with invasive coronary artery testing of the vasomotor tone by using acetylcholine and nitroglycerin. It can also be evaluated non-invasively using PET cardiac imaging. The WISE clinical trial showed that ace inhibitors improved coronary blood flow reserve and symptoms of angina in women with microvascular disease. The WARRIOR study is ongoing and evaluating the effect of ace inhibitors and statin in >4,000 women with INOCA.
When women have ischemic heart disease, their mortality is worst than men. Within a year of the first MI, 23% of women and 18% of men will die. Within 5 yrs, 47% of women and 36% of men will die. This difference is greatest in younger women (<55 yrs). Not only mortality is high but morbidity is as well. Women with ischemic heart disease have more symptoms, declining health status with more frequent hospitalizations, and more procedure-related complications.
HOW CAN WE INCREASE THE PARTICIPATION OF WOMEN AND IMPROVE CLINICAL RESEARCH?
Less aggressive care for women has led to fewer women eligible for clinical trials of acute coronary syndrome and treatment of coronary artery disease. Similarly, fewer women are referred for afib. ablation and ICD devices. So, possibly clinical trials should be more inclusive to primary care providers and the community and expand access to trial enrollment. Certainly, the internet and social media could help disseminate the news and awareness about clinical studies but it is uncertain whether they can help with the recruitment of patients.
Age is a major factor in inclusion/exclusion criteria and in general, older adults, and women are underrepresented if the age cut-off is 80 yrs. When enrolment includes adults >80 years like in the original PARTNER 1 and PARTNER 2 treatment of aortic stenosis comparing TAVR and surgical AVR, a 50% enrolment of women was noted. In PARTNER 3, where lower-risk and younger patients are enrolled, only 32% of women were included. Women of childbearing age are frequently excluded from research due to the concern of potential harm to pregnant women and their unborn children. However, most women take prescription medications during their pregnancy, most of which have never been tested. How about pregnant women who need better treatment for their hypertension, diabetes, or their cholesterol, particularly if they have familial hypercholesterolemia and severely elevated LDL?
Lack of awareness of heart disease in women and lack of trust in the research process are additional factors. Limiting the number of visits and increasing remote monitoring could help with the concerns of women already burdened by caregiving responsibilities.
To encourage more women to participate in clinical trials, we need to address these barriers. Healthcare providers and researchers need to increase awareness and education about the importance of clinical trials and the benefits of participation. Additionally, building trust between researchers and potential participants is crucial. This can be achieved by involving women in the development of research protocols and ensuring that their voices and perspectives are heard. Finally, clinical trials need to be more diverse and inclusive, particularly in terms of race and ethnicity. Research has shown that black patients are less likely to trust medical research and are less likely to participate in clinical trials. We need to address this mistrust by involving more black researchers and ensuring that clinical trials are conducted in ways that are culturally sensitive and respectful.
This article was written in collaboration with Dr. Nicole Lohr, Director of the Division of Cardiovascular Disease and Co-Director of the UAB Medicine Cardiovascular Institute.