Patient Enrollment Low in Cardiovascular Clinical Trials in the US

Muhammad Shahzeb Khan, MD, MSc

Credit: Baylor Scott & White Health

According to a new analysis, clinical outcome trials in cardiology require an expanded number of sites to match enrollment targets, with approximately one-third of trials relying on more than 500 sites.¹

The database search included trials in major medical journals from 2019 to April 2024, identifying 51 relevant trials. Patient-per-site ratios were low, with the United States reporting the most sites but enrolling significantly fewer patients than other countries.

“Trial evidence must reflect diverse populations to ensure treatments are relevant to all. Solutions to accurate enrollment must also address these disparities,” wrote the investigative team, led by Muhammad Shahzeb Khan, MD, MSc, and Javed Butler, MD, MPH, Baylor Scott and White Research Institute. “Decentralized trials, offering remote and in-person participation, could broaden access and accelerate enrollment.”

Research has shown that, despite a high disease prevalence in the specialty, conducting cardiovascular trials in the US continues to exhibit challenges. These trials often require domestic and international sites to meet enrollment goals, and lacking enrollment can lead to depleted resources and delays for patients and clinicians.

In this analysis, Khan and colleagues searched PubMed, Cochrane, Embase, and Google Scholar for cardiology trials in JAMA, the New England Journal of Medicine (NEJM), and The Lancet. Trials were identified using search terms including ‘randomized controlled trials,’ ‘cardiovascular’, and ‘cardiology.’ These trials enrolled ≥500 patients, assessed a primary cardiovascular outcome, and involved US and international sites.

For analysis, the team calculated patient-per-site ratios by dividing total enrollment by sites. Enrollment rates assumed continuous recruitment without adjusting for site-specific activation times, given data limitations cited by Khan and colleagues.

The 51 trials enrolled 292,985 patients across 70 countries—these trials had a median of 320 sites, 4786 participants, and enrollment across 32 months. Patient-per-site metrics ranged from 3.8 to 131.9, with approximately half of trials involving 100 to 500 sites. Notably, nearly one-third exceeded 500 sites with a median of 12 patients per site.

Overall, the analysis showed patient enrollment was strongly associated with site count (P <.001). Among 10 trials (19.6%) with site-specific data in 4388 sites, the total enrollment was 89,172 patients, with a median enrollment of 12 and a rate of 0.3 per site per month. Nearly half of these trials recruited fewer than 10 patients.

North America reported the most trial sites (n = 1377; 31.4%), but the fewest patients per site (17.3 patients per site; P <.001). Despite reporting the fewest sites (n = 329; 7.5%), South America had the highest patient-per-site ratio (24.8 patients per site). Eastern European trials had the highest median per-site ratio (16.0 patients per site), while North America had the lowest (8.0 patients per site).

Khan and colleagues found that, although the US had the most sites (n = 1133; 25.8%), they only enrolled 19.9% of participants (n = 17,705), with the lowest per-site ratio (15.6 patients per site; P <.001). Further analysis showed the monthly enrollment rate (0.2 patients per site; P <.001) was the lowest in these trials.

The team noted the limitations of these findings including the inadequate reporting of site-specific enrollment, potential reporting bias, and focus on leading publications, which could overlook lower enrollment studies.

“These trends suggest underlying legal, regulatory, and cost-related barriers, highlighting the need for improved clinical trial infrastructure,” Khan and colleagues added.

References

1. _{Khan MS, Jamil A, Shakoor M, et al. Patient Enrollment for Cardiovascular Clinical Trials in the United States. JAMA Cardiol. Published online February 12, 2025. doi:10.1001/jamacardio.2024.5537}
2. _{Khan MS, Shahid I, Siddiqi TJ, et al. Ten-Year Trends in Enrollment of Women and Minorities in Pivotal Trials Supporting Recent US Food and Drug Administration Approval of Novel Cardiometabolic Drugs. J Am Heart Assoc. 2020;9(11):e015594. doi:10.1161/JAHA.119.015594}
3. _{Martin SS, Ou FS, Newby LK, et al. Patient- and trial-specific barriers to participation in cardiovascular randomized clinical trials. J Am Coll Cardiol. 2013;61(7):762-769. doi:10.1016/j.jacc.2012.10.046}