R3i Editorials
R3i editorials, created by members of the R3i board, focus on addressing the persistent challenges of residual cardiovascular risk. These editorials serve to educate healthcare professionals about emerging insights and therapeutic strategies related to lipid-related risk factors, such as triglyceride-rich lipoproteins and lipoprotein(a).
Latest Editorial
September 2025
Clinical trials need to represent the wider population
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco
Inclusivity in clinical trials matters. This is because randomized clinical trials represent the primary evidence base that shapes guidelines and clinical practice. Yet cardiovascular outcomes studies tend to be conducted in predominantly white male patients, ignoring the obvious facts that about half the population are female and that racial diversity may modulate outcomes.
Diversity in cardiovascular outcomes studies is crucial because different populations may vary in their response to treatments. Ensuring representation from diverse racial, ethnic, and gender backgrounds is essential for understanding treatment efficacy and safety across all populations. Underrepresenting certain groups limits the generalizability of findings and potentially may lead to disparities in cardiovascular care and outcomes.
Although exploratory, the recent post hoc analysis of the STRENGTH trial, discussed in this month’s Landmark trial illustrates this point (1). STRENGTH investigated the effect of an omega-3 carboxylic acid formulation (a combination of eicosapentaenoic acid and docosahexaenoic acid) on cardiovascular outcomes in a patient population characterized by atherogenic dyslipidemia and high cardiovascular risk. As previously reported (2), the trial was terminated early following independent data monitoring review concluding a low probability of demonstrating clinical benefit with the study treatment over the corn oil placebo. However, teasing out treatment effects in patient subgroups may offer novel insights. In this analysis, treatment with the omega-3 carboxylic acid formulation was associated with lower rates for major adverse cardiovascular events in Asian patients compared with corn oil (14.8% versus 20.4%, Hazard ratio 0.72, 95% confidence interval 0.54–0.96, p =0.026), but not in non-Asian patients (15.6% and 15.9%, respectively) (1). The authors acknowledge that the analysis does not offer any insights into mechanisms that may underlie this difference in treatment response and conclude that their findings are hypothesis-generating for further research.
It is also important to bear in mind that the Asian cohort represented only about 10% of the STRENGTH trial population, consistent with that observed in other clinical trials in patients at high cardiovascular risk. Notably, in a review of trials of acute coronary syndrome patients, only 15% were non-White, of whom 10% were of Asian ethnicity (3). Even among more recent trials evaluating the proprotein convertase subtilisin/kexin type 9 inhibitors, only 10-13% of participants were of Asian ethnicity (4).
Poor representation of different ethnic groups limits the generalizability of the results, and potentially, may hinder access to this new treatment, exacerbating health disparities. The lack of guidance on which ethnicity categories are appropriate for use in trials compounds this problem. In a review of trial documentation for 407 randomized controlled trials published in the UK National Institute of Health Research library from 2016 to 2021, only 9.3% of trial reports accurately detailed the methods used for recording and reporting patient ethnicity (5). The issue of poor representation of different ethnic groups has also been highlighted in the context of the UK Biobank (6).
It is also well known that women are under-represented in cardiovascular clinical trials. In part this may relate to under-recognition of the importance of heart disease in women, even after adjusting for the population prevalence of the specific cardiovascular disease (4,7,8). Redress of this imbalance is urgently needed, given improved understanding of sex-specific factors that associate with greater cardiovascular risk. Women are also disproportionately impacted by diabetes, chronic kidney disease, and auto-immune inflammatory disease which exacerbate cardiovascular risk (9). This priority has been recently highlighted by expert groups including the European Atherosclerosis Society (10).
In conclusion, it is evident that we need to do more to address the lack of diversity in cardiovascular clinical trials. This is not only a moral and ethical issue, but also a scientific concern, imperative to ensuring health equity for all.
References
- 1. Wang TKM, Nicholls SJ, St John J, et al. Differential cardiovascular impact of ω-3 fatty acid in patients at high cardiovascular risk in Asians versus non-Asians: Sub-analysis of the STRENGTH randomized clinical trial. Atherosclerosis 2025; https://doi.org/10.1016/j.atherosclerosis.2025.120228.
2. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH Randomized Clinical Trial. JAMA 2020;324:2268-80.
3. Tahhan AS, Vaduganathan M, Greene SJ. Enrollment of older patients, women, and racial/ethnic minority groups in contemporary acute coronary syndrome clinical trials: a systematic review. JAMA Cardiol 2020;5:714–22.
4. Michos ED, Reddy TK, Gulati M, et al. Improving the enrollment of women and racially/ethnically diverse populations in cardiovascular clinical trials: An ASPC practice statement. Am J Prev Cardiol 2021;8:100250.
5. Wallace N, O’Keeffe S, Gardner H, Shiely F. Underrecording and underreporting of participant ethnicity in clinical trials is persistent and is a threat to inclusivity and generalizability. J Clin Epidemiol 2023;162:81e89.
