Valvular Heart Disease Interventional Trials From 2000 to 2024

Abstract

Background

Valvular heart disease (VHD) is a growing contributor to global cardiovascular morbidity, especially in aging populations. As transcatheter therapies expand, assessing enrollment trends and demographic representation is essential for equitable, generalizable evidence.

Objectives

The purpose of this study was to evaluate temporal trends in trial characteristics and demographic representation, particularly age and sex, in VHD interventional trials from 2000 to 2024.

Methods

We conducted a systematic review on VHD intervention trials indexed in PubMed between 2000 and 2024. Trials involving percutaneous or surgical interventions across aortic, mitral, tricuspid, and pulmonic valves were included. Descriptive and nonparametric statistics were used to assess trends in enrollment size, participant demographics, valve type, intervention modality, and trial scope.

Results

A total of 487 trials with 87,412 participants were included; 44.9% were women. Median trial size (z = 4.98; P < 0.01) and participant age (z = 10.08; P < 0.01) increased over time. Trials involving percutaneous (11% to 45%), bioprosthetic (22% to 53%), aortic valve (27% to 62%), and multinational (2% to 16%) interventions increased. Female enrollment did not improve significantly (z = −0.48; P = 0.63) but was higher in mitral (58.9%) and tricuspid (59%) trials, and more common in percutaneous (52%) than surgical (41.7%) studies. A positive correlation was observed between participant age and female representation (ρ = 0.196; P < 0.01).

Conclusions

VHD trials have expanded in scale and scope with increased trial-level mean age. However, persistent sex disparities and demographic variability highlight the need for more inclusive trial designs to guide equitable valve therapy.

Central Illustration

Valvular heart disease (VHD) continues to be a significant contributor to global cardiovascular (CV) morbidity and mortality^1,2, affecting over 75 million individuals worldwide as of 2019. The prevalence of calcific aortic valve (AV) disease and degenerative mitral valve disease is particularly notable in aging populations³, emphasizing the urgent need for effective therapeutic interventions and robust clinical research to guide clinical management.⁴ Over the past decades, advancements in both surgical and transcatheter interventions have transformed the management of VHD, shifting from predominantly surgical approaches to less invasive transcatheter interventions.⁵ Landmark trials such as the PARTNER (Placement of Aortic Transcatheter Valves) series⁶ have significantly broadened the indications for transcatheter aortic valve replacement (TAVR), leading to widespread adoption across patient risk profiles and rapidly increasing procedure volumes globally.⁷ Concurrently, mitral and tricuspid valve interventions have progressed more gradually due to anatomical complexities, with therapies like transcatheter edge-to-edge repair (TEER)⁸ and emerging tricuspid valve devices⁹ showing promising outcomes in high-risk patient populations. Despite these advancements, the generalizability and applicability of clinical trial findings remain limited by persistent demographic disparities in trial enrollment.¹⁰ Historically underrepresented groups—including women, older adults, and certain ethnic minorities—continue to be inadequately represented in CV trials, potentially undermining the external validity and effectiveness of treatments.11, 12, 13, 14, 15 Prior cardiology-wide reviews have documented persistent under-representation of women across drugs, devices, and interventional pathways.¹⁶ Building on this foundation, we provide a VHD-specific, valve- and modality-resolved, era-stratified synthesis of interventional trials, characterizing age distributions and temporal age trends and assessing trial-structure correlates (multinational status, sponsorship) that may shape representativeness. Accordingly, this systematic review aims to critically assess enrollment characteristics and trends in VHD interventional trials over the last 2 decades—across trial settings, geographical regions, and intervention types—to identify gaps in representation, provide insights into evolving recruitment practices, and inform strategies for more inclusive and equitable trial designs.

Methods

We performed a systematic search for all clinical trials on VHD published between January 1, 2000, and December 31, 2024, using PubMed with “valvular heart disease” as a MeSH search term. Using Boolean operators, we included “aortic valve,” “mitral valve,” “tricuspid valve,” “pulmonic valve,” including their respective valvular lesions such as “stenosis” and “regurgitation,” as well as “transcatheter edge-to-edge repair,” and “transcatheter valve implantation,” for a comprehensive search of the literature. Exclusion criteria included trials that enrolled pediatric patients only, but trials that involved both adult and pediatric patients were not excluded from analysis; publications reporting post hoc, interim, secondary, and subgroup analyses; trials that involved nonvalvular intervention; and trials that involved purely medical therapy for VHD. No limit was placed on minimum trial size. Four independent reviewers (P.P., N.T., G.T., and N.B.) screened 4388 VHD studies published between 2000 and 2024 and selected studies for inclusion. A fifth reviewer (F.R.) resolved any discordances. The data that support the findings of this study are available from the corresponding author upon reasonable request. Approval from the Institutional Review Board was not required for this study as publicly available data were utilized. This study was registered in the International Prospective Register of Systematic Reviews, with the identification number CRD420251042389.

Data abstraction

The following data were abstracted: year of publication, ClinicalTrials.gov NCT number (if applicable), trial start and end date, duration of enrollment, number of participating centers, total number of participating countries, number of participating countries by continent, source and type of funding, trial intervention (percutaneous or surgical), valve of interest, type of valvular lesion, total sample size, proportion of women, trial participant age mean and SD, and race and ethnicity, if reported. Any missing data from publications were extracted from the corresponding ClinicalTrials.gov, if available. We identified funding sources for trials as industry, government, university/organization, government and industry, and university and industry. Primary region of trial enrollment was divided into exclusively North America, exclusively Europe, exclusively Asia, multinational, and other.

Statistical analyses

Descriptive statistics were used to summarize clinical trial characteristics, including number of trials, trial size, participant demographics, and intervention types, stratified by 5-year intervals (2000-2024). Categorical variables were summarized as frequencies and percentages, while continuous variables were expressed as means (SD) or medians with IQRs, as appropriate. Tests for homogeneity across time periods were performed using the chi-square test for categorical variables and Kruskal-Wallis tests for continuous or ordinal variables. Temporal trends were further evaluated using nonparametric trend tests (eg, Jonckheere-Terpstra). Age was abstracted as the trial-level mean or median as reported; analyses treated age as a continuous variable, and no age cut points were prespecified. The relationship between mean age and proportion of female participants was examined using Spearman correlation. Statistical significance was set at P < 0.05, and all analyses were conducted using standard nonparametric procedures suitable for aggregate trial-level data because of the skewed data distribution especially in the proportion of females. All statistical analyses were performed using Stata/MP version 14 (StataCorp). Most figures were generated in Stata, while some summary figures were created in Microsoft Excel (Microsoft Corporation) for tabulation and visualization purposes.

Results

We were able to retrieve 487 trials from 2000 to 2024, including a total of 87,412 patients, where 39,207 (44.9%) were women (Supplemental Figure 1). Median participants per trial increased over time, reaching 180 in 2020-2024 (nptrend z = 4.98; P < 0.01). The median proportion of females per trial fluctuated slightly but showed no significant change in trend (chi-square⁴ = 6.23; P = 0.18; nptrend z = −0.48; P = 0.63). As seen in Figure 1, the proportion of women indexed by trial size did not demonstrate a significant temporal trend from 2000 to 2024 (z = −0.20; P = 0.842). Mean age of participants significantly increased over time, as seen in Figure 2 (chi-square⁴ = 109.9; P < 0.01; nptrend z = 10.08; P < 0.01). As illustrated in Figure 3, a weak, but significant positive correlation was found between mean age and proportion of women (Spearman ρ = 0.196; P < 0.01).

Figure 1.

Female Representation by Trial Size

Scatter plot showing the relationship between trial size and female enrollment. No significant correlation was found between trial size and female representation (z = −0.20; P = 0.842).

Figure 2.

Increase in Mean Age of Trial Participants

Line plot showing a significant rise in participant age in VHD trials over time (z = 10.08; P < 0.01). VHD = valvular heart disease.

Figure 3.

Correlation Between Mean Age and Female Enrollment

Scatter plot indicating a weak but statistically significant positive correlation between mean age and female representation across trials (Spearman ρ = 0.196; P < 0.01).

Clinical trial characteristics

Among VHD clinical trials conducted from 2000 to 2024, notable shifts were observed in clinical trial characteristics (Table 1). Earlier trials used to be university-sponsored, from 86% in 2000-2004 to 27% in 2020-2024, whereas industry-sponsored trials, from 3% to 47% became more common for most of the more recent trials. Trials continue to be conducted mainly in western countries like those in Europe. However, more recent trials are becoming multinational (2% to 16%). The increase in multinational trials was also reflected by the increasing proportion of large-scale trials (≥399 participants), increasing from 7% to 27%.

Table 1.

Summary of Valvular Heart Disease Trial Characteristics and Female Representation (2000-2024)

	2000–2004	2005–2009	2010–2014	2015–2019	2020–2024	Total	P Value
Number of trials	91	118	121	102	55	487	<0.01a
Total participants, N	10,866	16,179	15,375	27,919	17,073	87,412	<0.01a
Participants per trial, median (IQR)	62 (30-108)	60 (30-136)	78 (162-279)	100 (50-300)	180 (48-455)	78 (35-189)	<0.01b
Total female participants, n	4,907	6,885	6,879	12,669	7,867	39,207	<0.01a
Female proportion per trial, %, median (IQR)	50 (35-62)	44 (32-58)	51 (34-62)	49 (38-61)	43 (37-53)	47 (36-60)	0.63b
Funding sources, n (%)							<0.01a
University	78 (86%)	78 (66%)	87 (72%)	36 (35%)	15 (27%)	294 (60%)
Industry	3 (3%)	28 (24%)	26 (21%)	48 (47%)	26 (47%)	131 (27%)
Government	4 (4%)	6 (5%)	4 (3%)	9 (9%)	9 (16%)	32 (7%)
Self-funded	3 (3%)	2 (2%)	1 (1%)	4 (4%)	0 (0%)	10 (2%)
Multiple	2 (2%)	2 (2%)	3 (2%)	5 (5%)	5 (9%)	17 (3%)
Region, n (%)							<0.01a
North America including USA	15 (16%)	10 (8%)	16 (13%)	20 (20%)	8 (15%)	69 (14%)
Multiregional	2 (2%)	4 (3%)	15 (12%)	18 (18%)	9 (16%)	48 (10%)
Europe	38 (42%)	69 (58%)	58 (48%)	51 (50%)	28 (51%)	244 (50%)
South America	5 (5%)	8 (7%)	3 (2%)	0 (0%)	1 (2%)	17 (3%)
Asia and Australia	24 (26%)	16 (14%)	28 (23%)	12 (12%)	7 (13%)	87 (18%)
Africa	1 (1%)	3 (3%)	1 (1%)	1 (1%)	1 (2%)	7 (1%)
Intervention type, n (%)							<0.01a
Surgical	79 (87%)	93 (79%)	70 (58%)	44 (43%)	13 (24%)	299 (61%)
Percutaneous	10 (11%)	23 (19%)	42 (35%)	48 (47%)	25 (45%)	148 (30%)
Multiple	2 (2%)	2 (2%)	9 (7%)	10 (10%)	17 (31%)	40 (8%)
Valve lesion, n (%)							<0.01a
Aortic	25 (27%)	62 (53%)	68 (56%)	73 (72%)	34 (62%)	262 (54%)
Mitral	44 (48%)	42 (36%)	34 (28%)	19 (19%)	10 (18%)	149 (31%)
Tricuspid	1 (1%)	5 (4%)	5 (4%)	4 (4%)	6 (11%)	21 (4%)
Pulmonic	4 (4%)	1 (1%)	3 (2%)	1 (1%)	2 (4%)	11 (2%)
Multiple	17 (19%)	8 (7%)	11 (9%)	5 (5%)	3 (5%)	44 (9%)
Valve type, n (%)							<0.01a
Mechanical	13 (14%)	11 (9%)	6 (5%)	2 (2%)	1 (2%)	33 (7%)
Bioprosthetic	20 (22%)	48 (41%)	63 (52%)	65 (64%)	29 (53%)	225 (46%)
Both	16 (18%)	9 (8%)	6 (5%)	1 (1%)	1 (2%)	33 (7%)
Trial size participants, n (%)							<0.01a
≤47	37 (41%)	46 (39%)	40 (33%)	25 (25%)	13 (24%)	161 (33%)
−48-124	35 (38%)	39 (33%)	39 (32%)	34 (33%)	9 (16%)	156 (32%)
−125-398	13 (14%)	24 (20%)	35 (29%)	24 (24%)	18 (33%)	114 (23%)
≥399	6 (7%)	9 (8%)	7 (6%)	19 (19%)	15 (27%)	56 (11%)

^aChi-squared test for homogeneity.

^bKruskal-Wallis test and nonparametric trend test.

Percutaneous intervention trials increased from 11% to 45%, surpassing surgical trials, which declined proportionately from 87% to 24% (Figure 4). AV trials increased in proportion over time (27% to 62%), while mitral valve trials proportionately decreased (48% to 18%) (Figure 5). Bioprosthetic valve studies became more common, rising from 22% to 53%, steadily replacing mechanical valves (from 14% to 2%) in VHD studies.

Figure 4.

Changes in Intervention Type in VHD Trials

Stacked bar plot showing a shift from surgical to percutaneous interventions across VHD trials. Percutaneous trials overtook surgical trials in frequency during 2015-2019 and continued to rise through 2020-2024. Abbreviation as in Figure 2.

Figure 5.

Trends in Valve Type in VHD Trials

Stacked bar plot showing changes in valve focus: aortic valve trials increased from 27% to 62%, while mitral valve trials declined from 48% to 18%. Abbreviation as in Figure 2.

Mean age by clinical trial characteristics

The mean age of participants varied significantly across trial characteristics, with highly significant P values (P < 0.01) (Supplemental Table 1). Industry-sponsored trials enrolled older participants (mean age: 75.9 years) compared to university (60.5 years), government (68.7 years), and self-funded trials (59.9 years). Multinational trials had the highest mean age (76.5 years), while trials conducted in Africa and South America had the youngest cohorts (33.1 and 41.5 years, respectively). Trials of percutaneous interventions enrolled older participants (71.2 years) than surgical trials (63.2 years). AV trials had the highest mean age (75.6 years), while mitral (53.9 years) and multiple-valve (29.1 years) trials enrolled younger populations. Bioprosthetic valve trials enrolled older patients (75.7 years) compared to mechanical valve trials (51.8 years). Trials with ≥399 participants had the highest average age (70.5 years), compared to those with fewer than 125 participants (63.5-64.7 years).

Proportion of women by clinical trial characteristics

The proportion of women enrolled differed across trial location (P = 0.01), type of intervention (P < 0.01), heart valve affected (P = 0.04), and type of valve used in the trial (P = 0.04) (Supplemental Table 1). Trials conducted in South America had the highest female representation (median: 83.2%), while trials from Africa had the lowest (48.3%). Among intervention types, trials on percutaneous intervention enrolled a higher proportion of women (median: 52%) than surgical (41.7%) or multiple intervention trials (43.6%). Clinical trials on mitral valve had the highest female participation (58.9%) compared to other valve types. Clinical trials on bioprosthetic valves enrolled more women (45.5%) than mechanical valve trials (41.2%). There was no significant difference observed in female representation by funding source (P = 0.96) or trial size (P = 0.16).

Discussion

Over the 24-year period, the number and scale of VHD trials have increased, as reflected by the rising median number of participants per trial (Central Illustration). This expansion aligns with global efforts to refine and broaden evidence-based treatment strategies, particularly in the context of a growing older population with valvular pathology.^1,17 Surgical valve replacement has been the mainstay treatment for severe stenosis since the 1960s. However, even in the contemporary era, surgical mortality remains notable, approximately 2% for aortic and 5% for mitral valve replacement. As patient populations age and comorbidity burden rises, surgical risk has become a growing concern, fueling demand for less invasive alternatives such as transcatheter therapies.¹⁸ The shift from predominantly university-sponsored studies to more industry-funded and multinational trials reflects increasing commercial interest and global collaboration, likely driven by the growing market for transcatheter valve technologies and the need for diverse, generalizable data that offer increased safety and efficacy.¹⁹

Central Illustration.

Trends in Enrollment and Demographics in VHD Interventional Trials, 2000 to 2024

Visual summary of 487 VHD trials highlighting increases in trial size and participant age over time. Female representation remained unchanged. Additional trends include a shift toward percutaneous and bioprosthetic valve use and variation in female enrollment by intervention type, valve focus, and geographic region Abbreviation as in Figure 2.

The rise of percutaneous interventions, particularly TAVR, and the corresponding decline in surgical trials represent a paradigm shift in VHD management. The peak in 2011 for percutaneous intervention enrollment and the dramatic rise in AV trials reflect TAVR’s rapid evolution from a niche therapy for inoperable patients to a mainstream intervention across all surgical risk categories.^7,20 TAVR was first approved for high-risk patients in 2012 following the pivotal PARTNER 1⁶ trials and newer technology with CoreValve²¹ self-expanding valve, which demonstrated either noninferiority or superiority over surgical aortic valve replacement. Since then, intermediate- and low-risk trials—including PARTNER 2,^22,23 PARTNER 3,²⁴ and Medtronic self-expanding valve²⁵ trials—have consistently shown favorable outcomes, leading to the U.S. Food and Drug Administration (FDA)’s expansion of TAVR indications to all symptomatic severe aortic stenosis patients by 2019. This trajectory has catalyzed an exponential increase in TAVR utilization, with TAVR’s volume surpassing surgical aortic valve replacement’s since 2017.²⁶

Unlike the AV, mitral and tricuspid valves present greater anatomical complexity, leading to a slower evolution of transcatheter therapies. Functional mitral regurgitation (MR), which accounts for up to 90% of MR cases in the United States, has historically lacked randomized data supporting surgical intervention in this population. TEER has emerged as a treatment option for high-risk patients, particularly after the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy) trial demonstrated its benefit in functional MR refractory to guideline-directed medical therapy,²⁷ resulting in FDA approval in 2019. Similarly, transcatheter tricuspid therapies—historically limited by surgical risk—are gaining momentum. The TriClip system (Abbott Structural Heart), adapted from the mitral TEER platform, has shown early success in reducing tricuspid regurgitation severity.²⁸ Similarly, the EVOQUE⁹ system (Edwards Lifesciences) recently completed its pivotal trial and received FDA approval. Meanwhile, other replacement devices such as the LuX-Valve (Jenscare Biotechnology) has demonstrated promising feasibility outcomes in early clinical studies.²⁹ Our review reflects this trajectory, with a decline in mitral trials and a modest rise in tricuspid studies, underscoring the emerging role of transcatheter therapies for atrioventricular valves in high-risk populations.

The increased focus on AV disease and bioprosthetic valves aligns with an aging patient population, for whom less invasive procedures and reduced requirement of long-term anticoagulation are preferable.³⁰ Between 2020 and 2050, the U.S. population aged ≥85 years is projected to increase by nearly 200%³¹—the very group most affected by degenerative calcific aortic stenosis—highlighting the urgency for scalable, lower-risk treatment strategies. Our findings reflect this demographic shift: AV trials represented the largest proportion of VHD studies and enrolled the oldest participants (mean age 75.6 years), with percutaneous trials consistently enrolling older cohorts than surgical trials. The overall rise in trial-level mean age over time suggests greater inclusion of older adults in aggregate, predominantly within aortic transcatheter cohorts, while mitral surgical cohorts remained younger on average, underscoring heterogeneity by valve and modality. This pattern is consistent with prior reports that eligibility criteria related to frailty and comorbidity can limit participation of older adults in CV trials.³² This demographic is also more likely to present with risk factors that predispose them to TAVR-related complications; for example, pre-existing chronic kidney disease, heart failure, and peripheral artery disease are all significant independent predictors of postprocedural acute kidney injury.^33,34 Notably, industry-sponsored and multinational trials enrolled significantly older participants, potentially reflecting broader eligibility criteria and efforts to capture more representative, real-world populations.

However, the representation of women remains suboptimal. Despite modest fluctuations, there was no significant trend toward improved female enrollment over the study period. Women comprised only 44.9% of all participants, with substantial variability depending on intervention type, valve focus, and geographic region. This mirrors persistent patterns seen across other CV trials,^14,15 including those in heart failure and coronary artery disease, where women are consistently underrepresented despite constituting a significant portion of the disease burden.³⁵ Underlying drivers are likely multifactorial, reflecting biological, diagnostic, and sociocultural barriers. On the biological/anatomic side, women more often have smaller aortic annuli and iliofemoral diameters and may present with paradoxical low-flow, low-gradient aortic stenosis—features that can complicate device sizing and access and increase the risk of vascular injury or coronary obstruction during transcatheter procedures.³⁶ Sociocultural and system-level barriers—including caregiver responsibilities, transportation/logistical constraints, and clinician selection/referral practices—may further reduce women’s trial participation, particularly in acute pathways such as ST-segment -elevation myocardial infarction where undertreatment has been documented.³⁷ Trial-level features can also influence representation; observational work suggests that certain industry-sponsored or large multinational studies enroll fewer women than academic-led trials, and under-representation of women in trial leadership may affect eligibility criteria, site selection, and recruitment strategies.³⁷

Our observation that mitral valve trials demonstrated higher female participation aligns with epidemiologic data showing that both rheumatic and degenerative mitral valve disease are more prevalent in women.³⁸ Likewise, the slightly higher representation of women in bioprosthetic valve trials may reflect clinical preferences and specific contraindications to long-term anticoagulation, which are more commonly encountered in female patients. Women of childbearing age, in particular, are often steered toward bioprosthetic valves to avoid the teratogenic risks of vitamin K antagonists required with mechanical valves. Case-based evidence supports this practice, showing favorable maternal and valve-related outcomes even during multiple pregnancies.³⁹

However, while clinical decision-making often favors bioprosthetic valves for reproductive-age women, recent meta-analytic data suggest that long-term survival between bioprosthetic and mechanical AV recipients may be comparable, though differences in postoperative risks persist—with higher reoperation rates observed in the former and increased atrial fibrillation in the latter.⁴⁰ These findings underscore the importance of individualized, shared decision-making in prosthetic valve selection, especially among female patients, where considerations beyond valve durability such as reproductive goals, lifestyle preferences, anticoagulation tolerance, and overall quality of life must be carefully weighed.

Interestingly, the weak yet significant correlation between mean age and proportion of female participants may reflect demographic realities such as women's longer life expectancy and higher burden of CV disease in advanced age groups.⁴¹ Women comprise the majority of patients with CVD aged 80 years and above, which may partly explain their increased representation in older VHD trial cohorts. Additionally, women are more likely to be considered high surgical risk, potentially influencing their selection for transcatheter over surgical trials. Yet this demographic reality alone does not address underlying systemic issues such as selection bias, eligibility restrictions, and the lack of sex-specific recruitment targets.

Emerging evidence further underscores the importance of sex-conscious analyses in VHD trials, particularly in the context of bicuspid aortic valve (BAV), a congenital condition that is significantly more prevalent in men.⁴² In a recent national study of patients undergoing TAVR for bicuspid aortic stenosis, men accounted for the majority of procedures (61.1%) and had a higher comorbidity burden. Yet, despite these differences, in-hospital mortality and complication rates were similar between sexes, even after multivariable adjustment.⁴² Historically, early TAVR trials excluded patients with BAV due to concerns regarding valve ellipticity, asymmetric calcification, and the risk of coronary obstruction.⁴³ More recent real-world registry data, however, have demonstrated the feasibility and safety of TAVR in select BAV patients, leading to the removal of these anatomical exclusions by the FDA and the expansion of eligibility criteria.^44,45 As TAVR continues to gain traction in younger and lower-risk populations—including those with BAV—sex-specific differences in disease prevalence and anatomy are expected to play an increasingly important role in patient selection, procedural planning, and trial design. The rising number of TAVR cases, coupled with declining mortality in both sexes, further underscores the need for balanced demographic representation to ensure equitable access to emerging therapies and optimize outcomes across diverse patient populations.

Our analysis also reveals stark regional differences in enrollment characteristics. For instance, trials conducted in South America had a significantly higher female representation, while those in Africa enrolled notably younger participants. These disparities underscore the need for context-sensitive trial designs that account for regional demographics, health care infrastructure, and local disease patterns. Additionally, the growing number of multinational trials is a promising development, potentially enabling more inclusive data generation, provided that enrollment strategies ensure equitable representation across all participating sites.

Contemporary federal frameworks: the FDA’s Diversity Action Plans (FDORA [Food and Drug Omnibus Reform Act]) set study- and site-level strategies and monitoring for representative enrollment,⁴⁶ and National Institutes of Health’s Inclusion Across the Lifespan policy requires justification for age-based exclusions and encourages enrollment of older adults.⁴⁷ Harmonizing case-report forms and registry fields with the updated 2024 Office of Management and Budget race/ethnicity standards will enable standardized reporting and cross-trial benchmarking.⁴⁸ In VHD trials, these can be operationalized via enrollment targets and site-level screening logs, prespecified sex- and age-stratified analyses, and, where appropriate, decentralized follow-up.

To address these disparities, regulatory agencies, trial sponsors, and investigators must work collaboratively to mandate and implement more inclusive trial designs. One crucial step is adopting broader eligibility criteria that better reflect real-world populations; older adults and women are often excluded due to comorbidities, frailty, or reproductive considerations, but nuanced risk assessments and individualized informed consent can mitigate these barriers. Regulatory guidance should be more rigorously enforced and consistently applied to CV device trials.

Adaptive trial designs offer a promising solution by allowing flexible inclusion of underrepresented subgroups as trials progress, potentially enhancing both safety and efficiency without compromising scientific rigor.⁴⁹ Furthermore, community engagement and decentralized trial models, which bring research closer to participants, can reduce logistical barriers, particularly for older or rural populations.^50,51 Partnering with community health centers, using mobile health units, and leveraging telehealth platforms have been shown to improve recruitment and retention in CV trials.

Another critical strategy is the routine implementation of sex-stratified and age-stratified analyses, which allow for more granular insight into differential treatment effects.⁵² Such analyses should be prespecified in trial protocols and incorporated into regulatory submissions and guideline development to ensure subgroup-specific evidence informs clinical care. Moreover, requiring the public reporting of demographic enrollment data can enhance transparency and accountability.

Education and training programs targeting investigators and ethics committees should also emphasize the importance of diversity and equity in clinical research. Encouraging patient advocacy groups to participate in trial planning and oversight may also help ensure that the needs and perspectives of underrepresented populations are considered from the outset.

Taken together, the past 2 decades have marked a transformative shift in the management of VHD, with transcatheter therapies increasingly displacing surgical approaches and expanding access for high-risk, older, and medically complex patients. As these interventions extend into younger and lower-risk populations, future trials must maintain rigorous design, incorporate sex- and age-specific analyses, and ensure equitable demographic representation. Failure to address persistent disparities in trial enrollment may limit the generalizability of findings and hinder the delivery of truly personalized, population-relevant valve care. To sustain clinical impact and guide the next generation of therapeutic innovation, VHD research must embrace inclusivity, anatomical diversity,⁵³ and long-term follow-up across the full spectrum of patient populations.

Strengths and limitations

This study represents the first comprehensive, longitudinal assessment of participant enrollment patterns across interventional trials in VHD over a 24-year period, encompassing both surgical and percutaneous approaches across all major valve types. By extracting detailed demographic and trial-level data, including age, sex, intervention type, and geographic scope, this review provides a granular view of how clinical research in VHD has evolved in parallel with technological advancements and population aging. The inclusion of multivariable trend analyses adds methodological rigor to observed shifts in enrollment practices and sponsor characteristics.

Several limitations warrant consideration. First, analyses were performed at the trial level; individual patient characteristics, risk profiles, or treatment outcomes were unavailable. We therefore cannot evaluate treatment effects or safety stratified by age, sex, race/ethnicity, or their intersections; subgroup patterns reported here should be interpreted strictly as enrollment trends, not as indicators of differential efficacy or harm. Because no pooled effect estimates were calculated, conventional meta-analytic heterogeneity statistics (eg, Cochran’s Q, I²) were not applicable; instead, we report dispersion using medians with IQRs and means, and assess trends nonparametrically across eras and strata. Second, age was analyzed as a continuous, trial-level measure, and we did not prespecify age cut points; proportional representation of the oldest adults cannot be established without harmonized age strata or individual-patient data. Third, while we included all valves to reflect the field-wide VHD portfolio, important clinical heterogeneity exists by valve (eg, degenerative aortic stenosis vs secondary MR/TR). Tricuspid, pulmonic, and multivalve trials comprised a small proportion of studies and often enrolled distinct populations, which may influence pooled summaries. Etiology (eg, degenerative vs functional MR; primary vs secondary TR) was inconsistently reported and could not be harmonized; therefore, valve-etiology–specific pooling was not performed. Readers should interpret portfolio-level findings as dominated by aortic and mitral trials, with more limited generalizability to tricuspid/pulmonic populations. Fourth, race and ethnicity were inadequately reported across source publications and registries, precluding robust assessment of racial/ethnic representation or intersectional patterns; improving standardized demographic reporting remains essential for equity-focused trial design. Finally, the review was limited to trials indexed in PubMed and/or those with adequate documentation in ClinicalTrials.gov; unpublished or ongoing studies were not included. Despite these limitations, the findings underscore actionable gaps in representativeness and offer concrete directions for more inclusive VHD trial designs.

Conclusions

Over the past 2 decades, VHD interventional trials expanded in scale and geographic reach with trial-level age increasing over time—most prominently in aortic transcatheter cohorts. Female participation remained below parity and varied by valve and modality, indicating persistent gaps in representativeness. Embedding equity-focused design features—sex-conscious eligibility, standardized demographic reporting, prespecified sex- and age-stratified analyses, and decentralized follow-up—will better align VHD trials with real-world populations and strengthen external validity.

Perspectives.

COMPETENCY IN MEDICAL KNOWLEDGE: This study highlights persistent gaps in the enrollment patterns of VHD trials, addressing domains of Medical Knowledge, Patient Care, and Systems-Based Practice. By illustrating demographic shifts—particularly the increasing age of participants and persistent underrepresentation of women—this work informs evidence appraisal, trial design, and equitable guideline development. Practicing clinicians should consider these disparities when applying trial findings to real-world patient populations, especially women, older adults, and those with nonaortic VHD.

TRANSLATIONAL OUTLOOK: As transcatheter valve therapies expand across risk profiles and age groups, inclusive trial design remains a major translational priority. Future studies should adopt broader eligibility criteria, embed sex- and age-stratified analyses, and leverage decentralized and community-based enrollment strategies. These steps are critical to ensure trial populations reflect real-world demographics—thereby enhancing the generalizability and equity of emerging evidence in valve therapy.

Funding support and author disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.