Sex Disparities in ACC Late-Breaking Cardiovascular Trials

Graphical abstract

What is the clinical question being addressed?

Among ACC late-breaking cardiovascular trials presented from 2016 through 2024, how did women's enrollment vary across clinical domains and compare with sex distributions in national registries?

What is the main finding?

Women comprised 32.2% of 366,953 participants. Registry-benchmarked representation was lowest in heart failure, acute coronary syndrome, and interventional trials, with 95% CIs excluding 1.0; the exploratory structural CI included 1.0.

Women remain underrepresented in cardiovascular trials despite longstanding inclusion policies. Prior studies by Holtzman et al¹ and Rivera et al² documented low participation of women in late-breaking and broader cardiovascular trials. We extend this work by evaluating 113 American College of Cardiology (ACC) late-breaking clinical trials (LBCTs) presented from 2016 through 2024, assessing variation across clinical domains, and comparing enrollment with sex distributions in national registries.

We identified ACC LBCTs presented from 2016 through 2024 using ACC meeting materials, trial publications, and ClinicalTrials.gov. Trials were eligible if they enrolled a cardiovascular clinical trial population and reported the number or percentage of women; extension studies, pooled analyses, subgroup reports, and post hoc analyses were excluded. Each trial was assigned to 1 of 7 clinical domains. Weighted enrollment was calculated as total women divided by total participants within each domain. For domains with a national U.S. registry population sufficiently aligned for benchmarking, we calculated a representation ratio (RR), defined as observed weighted enrollment divided by the registry percentage of women. Benchmarks were 31.3% from CathPCI for interventional trials, 34.4% from ACTION-Get With The Guidelines for acute coronary syndrome, 47.4% from Get With The Guidelines-Heart Failure, and 45.8% from the Society of Thoracic Surgeons/ACC Transcatheter Valve Therapy Registry for the structural/device/cardiothoracic surgery domain.3, 4, 5 We estimated 95% CIs for each RR by nonparametric bootstrap resampling of trials within each domain (100,000 replicates), recalculating the participant-weighted enrollment proportion in each resample and treating the registry comparator percentage as fixed. The structural/device/cardiothoracic surgery comparison was exploratory because that domain included heterogeneous procedures. We did not calculate RRs for electrophysiology or prevention domains because no single registry population adequately represented those mixed trial populations. Prespecified and reported subgroup analyses in women were verified using ClinicalTrials.gov and trial reports. Because this study used only publicly available trial-level data and no identifiable patient information, it was not human subjects research, and institutional review board approval was not required.

Among 113 ACC LBCTs, including 366,953 participants, 118,181 were women (weighted enrollment, 32.2%). Across trials, the median percentage of women was 29.0% (IQR: 24.0%-44.0%; range: 11.0% -88.0%). Enrollment differed across domains (Kruskal-Wallis P < 0.001): interventional, 24.9%; acute coronary syndrome, 25.2%; electrophysiology, 28.6%; heart failure, 29.9%; secondary/high atherosclerotic cardiovascular disease-risk prevention, 31.2%; structural/device/cardiothoracic surgery, 38.5%; and primary/cardiometabolic prevention, 46.3% (Figure 1).

Figure 1.

Women’s Enrollment and Registry Representation in American College of Cardiology Trials

(A) Trial and participant counts, observed enrollment, national registry comparator percentages, and representation ratios with 95% CIs. National registry comparators were CathPCI for interventional trials, ACTION-Get With The Guidelines for acute coronary syndrome, Get With The Guidelines-Heart Failure for heart failure, and the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry for structural/device/cardiothoracic surgery. (B) Representation ratios for registry-comparable domains with trial-cluster bootstrap 95% CIs; the vertical line marks 1.0. The structural/device/cardiothoracic surgery comparison was exploratory because the trial domain included heterogeneous procedures. Representation ratios were not calculated for electrophysiology or prevention domains because no single national registry comparator adequately represented those mixed populations. ACS = acute coronary syndrome; RR = representation ratio.

Among registry-comparable domains, RRs were 0.63 (95% CI: 0.50-0.90) for heart failure, 0.73 (95% CI: 0.66-0.81) for acute coronary syndrome, 0.80 (95% CI: 0.72-0.86) for interventional, and 0.84 (95% CI: 0.71-1.02) for structural/device/cardiothoracic surgery (exploratory). The 95% CI excluded 1.0 for heart failure, acute coronary syndrome, and interventional trials but included 1.0 for the exploratory structural comparison. Subgroup analyses in women were prespecified in 25 trials (22.1%) and reported in 42 (37.2%). Trials that met their primary endpoint enrolled a numerically higher proportion of women than those that did not (mean, 35.8% vs 30.7%; difference, 5.0 percentage points; Welch P = 0.071).

These findings confirm and extend prior reports by showing persistent sex disparities in a larger, contemporary ACC LBCT cohort and by identifying particularly large registry-benchmarked deficits in heart failure, acute coronary syndrome, and interventional trials. The 95% CIs for these 3 domains excluded 1.0, whereas the exploratory structural CI included 1.0. The results support domain-specific recruitment strategies rather than uniform targets. Acute and procedural trials may benefit from earlier referral pathways, streamlined consent, site-level accountability, and enrollment goals informed by populations treated in national registries. More consistent prespecification and reporting of sex-specific analyses are also needed.

This study is limited by trial-level data, reliance on public reporting, and imperfect correspondence between trial eligibility criteria and registry populations. Registry years differed from trial years, and the structural comparison was exploratory because the domain was heterogeneous. We therefore restricted RRs to domains with the closest national comparators and reported the remaining domains descriptively rather than applying nonrepresentative proxies. Because the cohort included only ACC LBCTs, findings may not generalize to other meetings or all cardiovascular trials. Nevertheless, in heart failure, acute coronary syndrome, and interventional domains, trials enrolled fewer women than aligned national care populations, with RR 95% CIs below 1.0; the exploratory structural interval included 1.0. Transparent registry-benchmarked enrollment metrics and routine sex-specific analyses should become standard expectations for cardiovascular LBCTs.

Declaration of generative AI and AI-assisted technologies in the writing process

During revision, the authors used OpenAI ChatGPT to assist with language editing, statistical calculations, figure preparation, and submission-format checks. The authors reviewed and edited all content and take full responsibility for the paper.

Funding support and author disclosures

Dr Shaw has funding from the Blavatnik Family Foundation, Helen Gurley Brown Foundation, NIH-NIA (AG082994), DOD (W81XWH-17-2-0030), and NIH-NHLBI (R01HL159433; U01HL088942). Dr Lin has funding from the Blavatnik Family Foundation and NIH-NHLBI (R01HL159433). Dr Bhatt has served on the Advisory Board of Angiowave, Antlia Bioscience, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Repair Biotechnologies, Stasys, SandboxAQ (stock options), Tourmaline Bio, Viatris; has served on the Board of Directors of the American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); has served as a consultant for Alnylam, Altimmune, Broadview Ventures, Corcept Therapeutics, Corsera, GlaxoSmithKline, Hims, Sanofi, SERB, SFJ, Summa Therapeutics, Worldwide Clinical Trials; has served on Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hopitaux de Paris, Baim Institute for Clinical Research, Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Duke Clinical Research Institute, Engage Health Media, HMP Global (Editor in Chief, Journal of Invasive Cardiology), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Philips (Becker's Webinar on AI), Population Health Research Institute, WebMD (CME steering committees), Wiley (steering committee); other: Clinical Cardiology (Deputy Editor, unpaid); Progress in Cardiovascular Diseases (Deputy Editor, unpaid); Added Health (Editorial Board; stock options); has patent for Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital, which assigned it to Lexicon; neither Dr Bhatt nor Brigham and Women's Hospital receives income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Alnylam, Amarin, Amgen, AstraZeneca, Atricure, Bayer, Boehringer Ingelheim, Boston Scientific, CellProthera, Cereno Scientific, Chiesi, Cleerly, CSL Behring, Faraday Pharmaceuticals, Fractyl, Idorsia, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, MiRUS, Moderna, Novartis, Novo Nordisk, Pfizer, PhaseBio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, and 89Bio; has received royalties from Elsevier (Editor, Braunwald's Heart Disease); and has served as a site co-investigator for Cleerly. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.