Author + information
- aDivision of Cardiovascular Medicine, Stanford University, Stanford, California
- bCardiovascular Research Institute, Stanford University, Stanford, California
- cDepartment of Medicine, Stanford University, Stanford, California
- ↵∗Address for correspondence:
Dr. Fatima Rodriguez, Division of Cardiovascular Medicine, Stanford University School of Medicine, 870 Quarry Road, Falk CVRC, Stanford, California 94305-5406.
Although cardiovascular disease (CVD) is the leading cause of death for women in the United States, the evidence base for treating women is inadequate (1). Academicians, federal agencies, and professional societies have all noted this glaring gap in evidence (2–4), but we need to move beyond describing this disparity to increasing female representation in CVD clinical trials so that the evidence for clinical decision-making matches the population with CVD.
A wide spectrum of CVD presentations and outcomes demonstrate sex differences. Women are often older and have more comorbidities than men at the time of a CVD event. This naturally affects their response to treatment and inclusion in clinical trials in which complex medical regimens or multiple comorbidities may be criteria for exclusion. Evidence from clinical trials can only be generalized to populations with similar characteristics to the participants who were actually enrolled in those trials.
In cardiovascular medicine, interactions between sex and treatment have often been documented. For example, there were early observations that potent platelet inhibition benefited women presenting with an acute coronary syndrome less than men. When larger studies were done among troponin-positive patients presenting with acute coronary syndromes, however, glycoprotein IIb/IIIa inhibitors were found to be equally efficacious in men and women (5). Without appropriate sample sizes of both men and women, and sex-specific analyses, we may end up with erroneous and even life-threatening interpretations of study results.
Although federally funded clinical trials have guidelines for including women and minority groups, most device-related clinical trials are sponsored by industry, and although the Food and Drug Administration encourages enrollment of diverse populations in all regulated trials, sponsors are not obliged to actually do so. Can under-representation of women in clinical trials lead to inappropriate underuse of evidence-based therapies? For medical devices, this is certainly a possibility. Even with recent campaigns to increase heart disease awareness among women and their providers, women are less likely to be referred to the cardiac catheterization laboratory, to receive timely treatment for ST-segment elevation myocardial infarctions, or to undergo appropriate implantation of defibrillators (6,7). Such disparities in the use of appropriate interventions and devices may in turn result in a lower likelihood of including women in clinical trials that recruit participants during these procedures, and thus create a vicious cycle of underenrollment and under-representation.
In this issue of JACC: Cardiovascular Interventions, Ghare et al. (8) offer a multistakeholders approach to recruiting and retaining women in CVD device trials. The stakeholders include clinicians, professional societies, clinical trialists, academic research organizations, funding agencies, regulators, and industry partners. The authors, including several high-profile interventional cardiologists and clinicians, identify some important and unique barriers to female participation in clinical trials. They note, for example, that women may be more risk averse to randomization, rely less on self-autonomy for decision-making, distrust clinical research, and be more susceptible to the burden of clinical trial enrollment and follow-up.
We commend the authors for moving beyond describing the problem of female under-representation in CVD trials to proposing a multiprong approach to recruit and retain women in device clinical trials. In order to promote greater research participation, the authors recommend reducing the burden of time and money required for study participation. Increasing the number of clinical trials that can be conducted remotely has the potential to greatly diversify study participant populations that may be limited by geographic or sociodemographic barriers to onsite trial engagement. In parallel, the authors recommend broad awareness and education campaigns that target potential female participants. Simplifying study language and the consent process would certainly help demystify the process of clinical trial participation and informed consent for all study participants. Partnering with community organizations and social media platforms might further increase the reach of clinical research beyond the health care setting.
The authors then describe the importance of educating clinicians and researchers about eliminating bias in clinical trial enrollment and ensuring that evidence generated from clinical trials can be applied to women. As the authors point out, stakeholder engagement is paramount in these efforts and requires prioritization of sex-based research in study design and result reporting. Clinical investigators and funding partners should align their goals to ensure that their study results are applicable to the diverse populations of patients with the diseases that these devices are intended to treat.
Although this position paper serves as an important first step in clearly delineating the barriers and some potential strategies to improve recruitment and retention of women into CVD device clinical trials, the authors have not fully addressed several important issues. First, educational campaigns and voluntary calls to action from stakeholders may offer a modest improvement in female participation but will not be the entire solution. Raising visibility and providing guidelines for enrollment have been suggested by regulatory bodies and government funding agencies, yet these efforts have been insufficient for increasing the participation of women in device clinical trials. More likely, mandates will be necessary to ensure that there are minimal standards across government- and industry-funded CVD trials such that female enrollment is proportional to the number of women affected by the disease of interest. Industry sponsors should encourage and support investigator-initiated proposals that include creative solutions to improve female participant enrollment. Similarly, there needs to be a plan for regular monitoring and assessment of the success of the proposed interventions across a variety of trial designs and devices. Finally, regular re-evaluation of strategic plans is necessary to ensure an iterative process that learns from program successes and failures.
An area not addressed by the authors but likely important in this discussion is the low percentage of women cardiologists compared with men (9). Clinical cardiovascular care of women and their engagement in the clinical research process might be greatly facilitated by greater numbers of women cardiologists and investigators to mirror the percentage of women training in internal medicine residency programs (10). This is a particular area of concern for interventional cardiology, which has <10% women in the field and undoubtedly contributes to the clinical trials’ enrollment disparities discussed by the authors. Efforts by the American College of Cardiology to increase the numbers of women cardiologists, including in interventional cardiology, should have a positive effect on women’s participation in clinical trials (11). Despite recognition of the problem for over 30 years, women continue to be under-represented in CVD clinical trials. Resolving this critical challenge will require creative multistakeholder solutions that should be continually developed, implemented, and evaluated.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Rodriguez has received research support from Verily Life Sciences; and has been a consultant to HealthPals and Novo Nordisk. Dr. Harrington has received institutional research grants from Apple, Sanofi, AstraZeneca, Portola, Janssen, Bristol-Myers Squibb, Novartis, CSL, and The Medicines Company; has been a consultant and served on advisory boards for Element Science, MyoKardia, and WebMD; and has served on the board of directors of Signal Path, American Heart Association (unpaid), and Stanford HealthCare (unpaid).
- 2019 American College of Cardiology Foundation
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