Cardiac Device Clinical Trials: Where Are the Women and What Are Their Outcomes?

In 1991, Dr. Bernadine Healy in an editorial for the New England Journal of Medicine coined the term “Yentl Syndrome” to describe coronary artery disease (CAD) in women and called for action to make women's cardiovascular health a priority. ¹ At the time of her editorial, most clinical trials at this point excluded women, yet the results of the studies were applied equally to both men and women. She highlighted the need for increased awareness, recognition, treatment of CAD in women, and the need for more research to understand gender-specific differences. Dr. Healy concluded her editorial with the hope that with these measures the Yentl syndrome “will slip back into history as a curiosity of times gone by.” ¹

Now nearly 30 years later, are we doing any better for women's cardiovascular health and its research? Cardiovascular disease (CVD) still remains the leading cause of death of women in the United States, accounting for 418,665 deaths in 2017 (49%), with a high CVD prevalence of 45% of women between 2013 and 2016 (Ref. ² ). Furthermore, myocardial infarction (MI) rates have been increasing among middle-aged women, ³ and women are also more likely to have higher mortality after an ST segment elevation MI. ⁴ A greater number of women presenting with ischemic heart disease have nonobstructive CAD. ⁵ These findings have suggested that there may be underlying gender differences, such as a propensity toward greater endothelial and coronary microvascular dysfunction in women, as well as unique risk factors such as adverse pregnancy outcomes that may result in varying disease processes in women compared with men. ⁶ In addition, studies have also reported that women are less likely to undergo revascularization, less likely to be prescribed and be maintained on antiplatelet and statin therapy for CVD, and have worse risk factor management for secondary prevention. ^{4,7 –9} Similarly, gender differences have also been noted in heart failure (HF). Women are more predisposed to HF with preserved ejection fraction and have differences in therapeutic responses to treatment compared with men. ¹⁰

Differences in clinical outcomes of CVD between men and women may be related to true gender-specific differences in pathophysiology, lack of access to care determined by a multitude of socioeconomic factors, differences in management, or perhaps due to insufficiency of robust gender-specific data from clinical trials. Randomized clinical trials provide the largest evidence base shaping clinical guidelines. The U.S. Food and Drug Administration has implemented policies encouraging diverse enrollment into clinical trials and greater participation of women. ¹¹ Despite this, women remain underrepresented in cardiovascular clinical trials of drug therapy, when compared with their relative disease burden in the population. ¹²

In this issue of the Journal of Women's Health, Ghare et al. conduct a narrative review of the landscape of female enrollment in clinical trials specifically for cardiac devices. ¹³ They found that for transcatheter aortic valve replacement (TAVR) interventions, there was encouraging progress for gender equity in trial enrollment, with women representing nearly 50% of trial participants. In contrast, they found that female enrollment was poor in studies of percutaneous coronary intervention (PCI) and HF-device interventions, where women only represented ∼25% of trial participants on average. ¹³

In regard to CAD after PCI, the review by Ghare et al. found that female patients experienced higher risk for vascular complications, bleeding, major adverse cardiovascular outcomes, stroke, and in-hospital mortality, compared with men. ¹³ These findings may in part be due to lack of gender-specific data. For example, women comprised <25% of enrollees among 26 randomized drug-eluting stent trials and have been excluded from some randomized trials after acute MI due to age.

In regard to structural interventions, the review by Ghare et al. found that similar to PCI trials, women experience more periprocedural vascular complications than men after TAVR. ¹³ In contrast, women had better overall survival after TAVR compared with men.

In regard to HF, the review by Ghare et al. found that most randomized controlled trials evaluating implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death have underrepresented women, with only 16%–30% enrollment of women. ¹³ Furthermore, ICD for primary prevention were used disproportionately more in male versus female patients. In several ICD trials, ICD therapy compared with placebo did not show survival benefit for women but did for men. However, these trials were not appropriately powered to show gender differences. In contrast, data from large registries such as “Get With The Guidelines for Heart Failure” and Medicare and Medicaid Services, primary prevention ICD conferred survival benefit in both women and men. Similarly, cardiac resynchronization therapy-defibrillator (CRT-D) trials have also enrolled fewer women (20%) but CRT-D has also proven survival benefit in women and men. Unfortunately, fewer women have received CRT-D therapy, with women being three-times less likely than men to have CRT-D implanted. ¹³

As for durable mechanical circulatory support, the review by Ghare et al. found that ventricular assist device (VAD) trials and registries have also underrepresented women (approximately <25% of participants). ¹³ Women after VAD implantation experience more complications than men, including stroke, major bleeding, arrhythmias, and right ventricular failure.

Although these cardiac device trials collected information about sociodemographics and traditional risk factors, generally these trials did not include questions about female-specific risk factors such as pregnancy or menopause history, which might offer additional insights into gender-specific differences. There is, though, a large all-female TAVR registry (Women's International Transcatheter Aortic Valve Implantation) that collects female-specific parameters such as pregnancy history.

Clinical trials represent the evidence base that shapes clinical guidelines. Even if trials report gender-specific outcomes in subgroup analysis, without adequate enrollment of women, the studies will be underpowered to determine efficacy and safety of these interventions for women to guide clinical practice. The absence of evidence is not evidence of an absence of gender-specific differences. Therefore, to ensure that findings from trials address the needs of populations seen in routine clinical practice, further efforts are needed to enhance representation of women in trials to generate more complete information about gender-specific benefit and risks of these therapies.

Ghare et al. reviewed various barriers to enrollment of women into trials. ¹³ Predictors of nonparticipation include patient-specific factors such as older age, transportation issues, and health-related factors, as well as trial-related factors such as lack of compensation, longer trial participant, and intensive testing. Many women have caregiver responsibilities and find it challenging to find time; they also may have safety concerns. Future studies are encouraged to identify gaps in gender participation in trials and to develop strategies that improve participant inclusion and representation.

In summary, the authors of this review conclude that there are likely multiple patient- and trial-specific factors that limit participation of women. The final recommendation by the authors is development of a comprehensive strategy with discrete steps to facilitate equal enrollment among genders. The authors raise valid concerns regarding insufficient and disparate enrollment of women in cardiac device trials. As most medication trials in recent years have aimed for equal representation of genders, similar efforts should be made for cardiac device trials. Until more gender balance in trials is achieved and research addressing gender-specific differences in CVD prioritized, the Yentl syndrome will continue to live on.