Historically, women and children have been an afterthought regarding continuous flow, durable device design, human factors testing, and clinical trial enrollment. In the USA, children have not had access to an FDA-approved, continuous flow ventricular assist device (VAD) until December 2020, with the expanded pediatric labeling for the HeartMate 3 (Abbott). Although this was a positive step, it has been decades without options, requiring many children with heart failure to live their lives inside a hospital. Despite being an afterthought, over the last decade, many lives have been saved through creative ingenuity to make the currently available durable devices “work” for women and children. We have had no choice but to follow clinical protocols based on limited trial data (often including <1/3 women and zero children to date) and use age/sex-biased educational materials that do not fully represent these populations. In some cases, the device requires off-label, aftermarket modifications to fit the small body habitus of women and children and we have even had to adjust the device settings to “trick” the manufacturer alarms. These issues extend to using nonmanufacturer-approved carrying bags or clothing purchased from third-party retailers, often Amazon, and further altering them with a home sewing machine. After all the effort put forth to best suit the device to the patient, we are required to clarify: “this is against the manufacturer’s recommendations.”
The time to start searching for the “perfect” VAD for women and children is now. It is not after FDA approval, that there may be little motivation to make changes. For example, there is currently only one durable continuous flow device available for these populations. There is no financial incentive to make a large device modification and start a new clinical trial. Alternatively, we could use real-world data, and learn to make the current VAD potentially safer through minor gender/size modifications. Using real-world data would allow us to “make do” with what we have while we start to work on what we want for the future. If we want to break away from the “let’s do what we’ve always done” motto; and make care better for future generations, we must make three significant changes at the least.
The first opportunity for change begins with device development. The bodies and minds of women and children often differ significantly from adult males and consequently have differing requirements for the “perfect” VAD. The “perfect” VAD may not yet be feasible. We hope to see it in the future. To begin to approach that goal, we would need to consider body habitus, gender, and age-specific comorbidities, psychosocial, and cognitive maturity and stressors, etc. These factors should be considered from the time of mechanical concept and design and not as an afterthought. There is no better way to achieve this goal than to ensure women’s health and pediatric providers have a seat at the table for each step of the design process. They are suited to ask such advocacy questions as, “Will it work for her anatomy/physiology without modification?,” “Can it be shorter, lighter or smaller?,” “What is the best way to educate this population—video game, small group, video, etc.” These advocates are essential for the pump design and all that is associated; this includes alarm programs, carry bags, educational materials, and clinical protocols/recommendations. The barrier to achieving this feedback and collaboration may be competition and concerns for intellectual property. Many scientists and engineers try to keep the device to themselves until it is too far along for change, which squashes collaboration. By the time the end users are consulted, “it will just have to work.” As a community, we have learned through practical experience that adapting the device to the smaller patient is not always feasible or safe. Feedback from real-life use is an example of how collaboration may lead to a better device and add efficiency to the process. For example, in children, the pediatric providers would be able to tell you early on what child safety devices might be needed or if a 2-year-old will be able to disconnect the battery from the controller. Just ask!
After development, women and children must be included in study designs for FDA approval. Regulatory agencies, providers, and the public must strongly request that all device trials represent a diverse group of patients, even if the trial numbers need to be larger to accommodate the various demographics.
Regarding children’s involvement in trials and access to devices: age is arbitrary! The best example of this arbitrariness is the fact that UNOS defines adults as >18 years of age while the FDA defines an adult as >22 years of age but the latest adult device trials include patients >18 years of age. As such, an 18-year-old qualifies for organ transplantation by the adult allocation system, but the FDA would consider devices for this age group as pediatric. In addition, this patient could be enrolled in the most recent device trial if he was cared for at an adult trial center but not at a pediatric center (not a trial site)! There is no clear, scientific reason for an age cutoff for the inclusion criteria of trials. The argument should be that device trials should be held to similar criteria as that of NIH funding which now in accordance with the 21st Century Cures Act requires people of all ages, including children under 18 years and older adults, to be included in clinical research studies. A body surface area (BSA) that is incompatible with device implant should be the only exclusion to trial enrollment. In the Momentum 3 Trial, the inclusion criteria was a BSA of 1.2 m2 or greater; however, while the average BSA for a 12-year-old boy is 1.5 m2, they were excluded. If the safety concern is size related, why would they be excluded?
The devices will be used in the pediatric population, albeit with the aforementioned off-label indication and nonmanufacturer-approved modifications as soon as the pediatric cardiologist has access to them; why not study them in this population to ensure and develop effective and safe indications and proven patient-specific modifications? Furthermore, the device trials should be specifically designed to test and study device modifications to establish efficacy and safety and allow for guideline development in these populations. Additional benefits of having children in trials may include broadening knowledge for the care of adult congenital heart disease, other rare cardiac diseases that are increasingly transitioning to adult care, and patient populations that are at the extremes of the population size distribution. The narrative that the pediatric population does not need mechanical support trials because they have been able to adapt and use the existing devices (even off-label, so long as it fits) is dangerous. Off-label use in pediatrics leads to unsafe device modifications, lack of required industry support, difficulties with insurance approval, and FDA-required training being nonapplicable and taught by non-pediatric specialists.
Extending clinical device trials to children may seem prohibitive because of the cost of adding pediatric trial sites. However, the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) is working to address this issue in partnership with stakeholders including the FDA, industry sponsors, and providers. Partnering with trial sponsors, ACTION will be able to use registry data and a simple modification to pre-existing contracting/regulatory documents for prospective trials to include pediatric participants. ACTION is currently working with Berlin Heart EXCOR to bring the ACTIVE driver to the bedside. In addition, ACTION and Abbott have shown that by using real-world data, they could expand the label for the HeartMate 3 to include children and smaller-sized patients. These collaborative mechanisms are expected to keep costs down and allow children to be enrolled in a pediatric arm of future trials.
The pediatric population is not the only group historically ignored in VAD trials. In the ENDURANCE trial,1 for the HVAD (Medtronic), only 24% were women; in the Momentum trial2 for the HeartMate 3 (Abbott) only 20% of enrollees were women. Real-life data continues to emulate these low percentages, with the number of women receiving VADs being similarly low (~21%) over the last couple of decades despite HeartMate 3 being smaller, with significantly lower rates of hemocompatibility-related events compared with prior devices.3 Interestingly, there seems to be no difference in referral patterns for advanced HF therapies between men and women, despite the ongoing difference in implementation of therapy,4 supporting ongoing bias as to what we think we know the benefit of therapy for women will be. Clinical trial participation remains proportionally low when adjusted for disease prevalence, even when efforts are made to include women in trials.5 Reasons for difficulty in enrolling women in clinical device trials may be many: scientific concern that women may respond differently to treatment and confound the data, patient concerns about participating due to competing life responsibilities like caring for children and elderly, and a lack of prespecified study methodology to adjust for sex and gender differences in both inclusion criteria and outcome measures; just to name a few. However, these factors can be addressed. We can provide expanded, flexible timeframes for screening or onsite daycare. We can modify the study design to account for sex and gender-related pathophysiological differences. Lastly, we can learn what we do not yet know from increased participation. It is also of paramount importance that the clinical trial regulatory bodies mandate increased enrollment of women in device trials. It may be that if the device is better suited for women and more women providers are involved in the study, part of the problem will be solved. The benefits of including women in trials seem obvious and will lead to positive modifications of the devices and clinical protocols for all populations.
Questions remain: “Must we wait for the next trial to improve care? What can be done now?” In addition to addressing enrollment disparities for ongoing and future trials, there are other ways to contribute to the knowledge concerning advanced heart failure care of women. Like the ACTION endeavor, we can work on a women-centric registry to improve device care in women by gathering real-life data on quality of life with a VAD in women and modifications that lead to improvements.
Finally, the third intervention relates to bringing all stakeholders together to address these issues. This includes having adult and pediatric heart failure providers sharing their solutions for underserved populations. We must also include other vital stakeholders such as patients and advocacy groups, industry representatives, biomedical engineers, regulatory agency representatives, handbag/clothing designers, etc. Only with all parties at the table can we seek to achieve evidence-based practices to improve outcomes and quality of life of these underserved heart failure populations. We currently have access to some of the best devices with the greatest outcomes that we have seen in the field, yet their potential is limited for women and children. It is time to adapt to their needs and put women and children first.
1. Rogers JG, Pagani FD, Tatooles AJ, et al.: Intrapericardial left ventricular assist device for advanced heart failure. N Engl J Med. 376: 451–460, 2017.
2. Mehra MR, Uriel N, Naka Y, et al.; MOMENTUM 3 Investigators: A fully magnetically levitated left ventricular assist device—Final report. N Engl J Med. 380: 1618–1627, 2019.
3. Molina EJ, Shah P, Kiernan MS, et al.: The Society of Thoracic Surgeons Intermacs 2020 annual report. Ann Thorac Surg. 111: 778–792, 2021.
4. Herr JJ, Sheikh FH, Patel PJ, et al.: Disparities in practice patterns by sex, race, and ethnicity in patients referred for advanced heart failure therapies [Online ahead of print]. Am J Cardiol, 2022. doi:10.1016/j.amjcard.2022.09.015.
5. Pilote L, Raparelli V: Participation of women in clinical trials: Not yet time to rest on our laurels. J Am Coll Cardiol. 71: 1970–1972, 2018.