The impact of cardiovascular disease prevalence on women's enrollment in landmark randomized cardiovascular trials: a systematic review.

Cardiovascular disease (CVD) is the most common cause of death in American women and accounts for a full one-third of all deaths.1 Although the common perception may be that CVD affects mainly men, there is equal prevalence of this disease between the genders by the age of 40, and by the age of 60 more women than men are affected. More women than men have died from CVD causes on a yearly basis since the mid 1980s, and whereas the CVD mortality has steadily declined in men over the past 30 years, it has remained steady in women until very recently when CVD mortality was noted to decrease for both genders.2 See accompanying article on page 277 The impact of cardiovascular disease (CVD) on the health status of American women is gaining more recognition and has become the focus of public education efforts such as the “Go Red for Women” campaign sponsored by the American Heart Association and the “Red Dress” project sponsored by the Department of Health and Human Services, the National Institutes of Health (NIH), and the National Heart Lung and Blood Institute (NHLBI). These programs are, in part, a response to the increasing awareness of cardiovascular disease as a major source of morbidity and mortality in U.S. women. The importance of CVD as a major source of mortality in women was recognized early on by federally funded institutes including the Public Health Service Task Force, which brought attention to concerns about the health information available to women and the historical lack of research focus on women’s health in its 1985 Report of the Public Health Service Task Force on Women’s Health Issues .3 In response to this report, the National Institutes of Health adopted a policy for the inclusion of women in clinical research …

Changing the Face of Cardiovascular Trial Participation: Moving Beyond Middle-Aged White Guys

Female Recruitment Into Cardiovascular Disease Trials

Bridging the Racial Disparity Gap in Lipid-Lowering Therapy.

Introduction Cardiovascular disease is the leading cause of death for women worldwide. Yet, women are often underrepresented in clinical trials of cardiovascular disease compared to population prevalence. Reasons for underrepresentation are multifactorial, and often attributed to trial criteria. Yet, women may also decide not to participate for more subconscious reasons, such as the perception of the trial acronym. Trial acronyms are used in patient communication and are often chosen to have a certain meaning, which can be perceived as gendered. We hypothesize that masculine trial names are associated with underrepresentation of women in clinical trials. Purpose To investigate if the perceived gender of the trial acronym, and other study characteristics affect the representation of women in cardiovascular clinical trials. Methods We performed a systematic search of ClinicalTrials.gov to collect information on randomized clinical trials testing drug interventions for cardiovascular disease. We extracted trial characteristics and acronyms from primary outcome publications. We conducted a survey among 148 cardiovascular patients (both women and men) recruited via an online patient forum and asked them whether they perceived trial acronyms names as more masculine, feminine or neutral. We defined female underrepresentation as those trials where the proportion of included women divided by the proportion of women in the disease population was below 0.8. We analyzed female underrepresentation and study setting, participant characteristics, and female first and last authorship. Results We identified 148 eligible clinical trials of which 29.9% of participants were women. Women were underrepresented in 61.5% of trials (Figure 1). Only 45.3% of publications reported sex-stratified results. The proportion of trials in which women were underrepresented increased between 1992 and 2022 from 48.3% to 70.5%. A total of 148 patients (67.6% women, mean age 61 y) evaluated the trial acronyms for their perceived gender. The majority (70.9%) of trial names was perceived as neutral, 17.6% as masculine and 11.5% as feminine. Female representation was not associated with the perceived gender of the trial name (OR 0.92, 95% CI 0.63 – 1.35) (Figure 2A). Trials had a higher odds of female underrepresentation if they recruited at an in-patient setting (OR 2.47, 95% CI 1.14 – 5.58), or if their participants were in the second-highest age group between 64.0 and 66.3 years (OR 3.93, 95% CI 1.25 – 14.18). Trials had lower odds of female underrepresentation if the last author was a woman (OR 0.10, 95% CI 0.01 – 0.49). Conclusion Female representation in cardiovascular clinical trials remains poor but is not depending on the perceived gender of the trial acronym. Female representation varies with recruitment type, participant age and last author gender, which are important starting points to improve participation rates of women.

Underrepresentation of women in cardiac imaging trials: A review

There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.

Barriers and Motivations for Women to Participate in Cardiovascular Trials

This editorial refers to ‘Women and men with stable coronary artery disease have similar clinical outcomes: insights from the international prospective CLARIFY registry’, by P.G. Steg et al. , doi:10.1093/eurheartj/ehs289 In 2010 a dedicated group of researchers interested in women's hearts, gathered in Brussels for a workshop discussing gender differences in cardiovascular disease (CVD).1 The workshop was undertaken as a result of an earlier report the same year from the European Heart Health Strategy (Euro-Heart) project showing that women are still under-represented in many cardiovascular clinical trials.2 Fewer women than men have been included in cardiovascular trials and, consequently, the evidence base is less firm for women regarding several treatments. The mean percentage of women enrolled in cardiovascular clinical trials since 2006 was 30%, while only 50% of trials reported results by gender analysis. Fewer evidence-based preventive, diagnostic, and therapeutic options for women with CVD may lead to undertreatment and a lower quality of care in comparison with men. Prospective studies to elucidate whether there are true differences in the effects of different treatment strategies according to gender and outcome are greatly needed to identify the most appropriate treatment for men and women, respectively ( Table …

With the recognition that certain aspects of cardiovascular disease are specific to sex, the government has sought to ensure that federally funded clinical research yields adequate high-quality information about heart disease in women. We tabulated the numbers of men and women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute (NHLBI) between 1965 and 1998, recording both total numbers and the numbers for each type of cardiovascular disease. We analyzed the data according to the sex-specific prevalence of disease and assessed changes in enrollment over time. We performed a similar analysis after excluding all single-sex trials. A total of 398,801 subjects (215,796 women and 183,005 men) were enrolled in NHLBI-funded studies of cardiovascular disease. The overall enrollment rate for women (54 percent) exceeded the prevalence of cardiovascular disease in women in the general population (49 percent) and increased over time (P=0.002). With single-sex trials excluded, the enrollment rate for women was 38 percent, which did not change significantly over time. In studies of coronary artery disease and hypertension the rates of enrollment of women were similar to or exceeded the prevalence of these disorders in women. The enrollment rate increased significantly over time in studies of coronary artery disease (P<0.001) but not in studies of hypertension or arrhythmia. Women were under-enrolled in studies of heart failure, and the rate of enrollment did not change significantly over time. When single-sex trials were excluded from the analysis of enrollment rates according to the prevalence of disease, the results were similar. There was no change in enrollment rates overtime for any category of disease. Federal efforts to increase the representation of women in clinical trials have been moderately successful primarily because of the institution of a small number of large, single-sex trials involving coronary artery disease. There has been no change in the sex composition of cohorts in the majority of studies of cardiovascular disease.

Women's enrolment in randomised clinical trials (RCTs) raises the attention of medical personnel and evidence-based medicine researchers to achieve the highest possible quality and transparency of conducted studies. This study aims to demonstrate various patterns and relationships of women's enrolment in cardiovascular RCTs conducted in Arab countries. Three databases (PubMed, Web of Science and Scopus) were accessed and searched for randomised clinical trials investigating cardiovascular diseases in Arab countries. Studies were screened, data were extracted and risk of bias of included studies was assessed independently by two sets of authors. The female to male ratio and the participation prevalence ratio (PPR) were calculated for each trial and the association of them with different variables were analysed. Of the 9071 patients enrolled in the 71 included RCTs, 38.02% were women. Various factors such as age of participants, publication year, therapeutic class, clinical indication, prevention type, and location of trial showed a significant association with the level of women enrolment in cardiovascular randomised clinical trials in Arab countries (P-value <.05). The median female to male ratio of all the trials was 0.55. The median female: male ratio varied by clinical indications (2.33 for valvular heart diseases vs 0.5 for stroke), intervention type (0.46 for surgical procedures vs 0.52 for drugs), prevention type (0.79 for secondary prevention, 0.74 for primary prevention and 0.52 for tertiary prevention), sample size (0.48 for Q1 vs 0.85 for Q2) and by age groups (0.98 for ages ≤50years old vs 0.47 for 56-60years old). Women were overrepresented in valvular heart disease trials (PPR = 1.37), and underrepresented in coronary artery disease, stroke and atrial fibrillation trials (PPR = 0.6, 0.63, and 0.71, respectively). As a result of the huge importance of RCTs in the medical field, and to reduce biases arising from inaccurate representation of different study populations, women's enrolment in Arab cardiovascular trials should be pre-planned and based on the percentage of women among the studied disease population.

Cardiovascular disease is a prevalent and prognostically important comorbidity among patients with kidney disease, and individuals with kidney disease make up a sizeable proportion (30%-60%) of patients with cardiovascular disease. However, several systematic reviews of cardiovascular trials have observed that patients with kidney disease, particularly those with advanced kidney disease, are often excluded from trial participation. Thus, currently available trial data for cardiovascular interventions in patients with kidney disease may be insufficient to make recommendations on the optimal approach for many therapies. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, convened a multidisciplinary, international work group and hosted a stakeholder workshop intended to understand and develop strategies for overcoming the challenges with involving patients with kidney disease in cardiovascular clinical trials, with a particular focus on those with advanced disease. These efforts considered perspectives from stakeholders, including academia, industry, contract research organizations, regulatory agencies, patients, and care partners. This article outlines the key challenges and potential solutions discussed during the workshop centered on the following areas for improvement: building the business case, re-examining study design and implementation, and changing the clinical trial culture in nephrology. Regulatory and financial incentives could serve to mitigate financial concerns with involving patients with kidney disease in cardiovascular trials. Concerns that their inclusion could affect efficacy or safety results could be addressed through thoughtful approaches to study design and risk mitigation strategies. Finally, there is a need for closer collaboration between nephrologists and cardiologists and systemic change within the nephrology community such that participation of patients with kidney disease in clinical trials is prioritized. Ultimately, greater participation of patients with kidney disease in cardiovascular trials will help build the evidence base to guide optimal management of cardiovascular disease for this population.

Inclusion of Under-Represented Racial and Ethnic Groups in Cardiovascular Clinical Trials.

Prevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: Insights from the ClinicalTrials.gov registry

BackgroundUnderstanding sex/gender in the context of health and disease is critical to deliver the best care. However, sex/gender have not been consistently considered in cardiovascular clinical trials. Global initiatives, including the Sex and Gender Equity in Research (SAGER)-guidelines, aim to improve the quality of the reporting, but it remains unclear if they are used consistently.MethodsWe conducted a systematic analysis of cardiovascular clinical trials published in PubMed between 2018 and 2024. To investigate the representation of women/females, we first analyzed the participation-prevalence-ratio (PPR). Second, we measured sex/gender-sensitive reporting (SGR) applying modified SAGER-guidelines. In addition, we determined whether study author sex/gender impacts the other variables.FindingsWe identified 1593 clinical trials with a total of 716,569 woman/female participants (38.5%). The median PPR of all trials remained suboptimal at 0.77 (95%-CI: 0.74–0.79) throughout the years with a modest positive trend towards 2024 and significant underrepresentation in some disease entities (e.g., ischemic heart disease, heart failure). Analyzing an evenly distributed sample of 632 trials, we found suboptimal SGR, especially for endpoints and discussions. We found a positive correlation of increased participation of women/females and SGR with women/females as authors.InterpretationOur results suggest an ongoing imbalance for the participation of women/females and suboptimal SGR in cardiovascular clinical trials, especially for certain diseases, with a modest positive trend. More women/females in the authorship team correlate with an increased PPR and are associated with an increase in SGR.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s00392-025-02793-3.