Two New Studies Highlight Lack of Diversity in Cardiovascular RCTs

Two new studies are highlighting the different ways that randomized, controlled trials have failed to include a diverse patient population when it comes to interventions aimed at lowering LDL cholesterol or treating patients with cardiovascular disease, diabetes, or obesity.  

The concern, say experts, is that these clinical trials, which are used to inform guideline recommendations, may not adequately represent large segments of the population, particularly people with lower socioeconomic status and those outside Europe and United States. 

Erin Weeda, PharmD (University of South Carolina School of Medicine, Greenville, SC), senior author for one of the two papers, published in the American Heart Journal, said they found that only 16% of US counties had clinical trial sites for studies that were ultimately used to guide cholesterol management. “This may mean that people from the remaining 84% of US counties may not be as well represented in the research,” she told TCTMD in an email.

Improving diversity, said Weeda, would ensure that the cholesterol guidelines apply to a wider range of patients.

In the second study, this one published in JACC: Asia, researchers led by Robert Azzopardi, MD (Monash University, Melbourne, Australia), showed that less than 10% of patients enrolled in major CVD, diabetes, or obesity trials were from the Asia-Pacific region.  

“Much has been written about the need for clinical trials to adequately represent population diversity from a gender and age perspective, but also with respect to race and ethnicity,” write the researchers. “Inability to achieve this diversity may compromise a study’s external validity, leaving extrapolation of results to be based on untested assumptions.”

Harriette Van Spall, MD, MPH (McMaster University/Population Health Research Institute, Hamilton, ON), who recently led a European Society of Cardiology (ESC) workshop on diversity and inclusion in cardiovascular research studies, said that recruiting a broader swath of patients requires an investment in areas outside the traditional regions where academic hospitals with clinical trial coordinating (CTC) centers are located.  

“There’s a disproportionality of who’s represented in these trials and who we apply the results to,” she told TCTMD. “This means we need to invest resources both in developing research capacity but also the infrastructure required. A lot of effort should be made in building trust, engaging community leaders, and bridging the divide that we see between [the research community] and people that we have marginalized historically through research in clinical care and who have lost trust in our research enterprise.”

Black, indigenous, and people of color, as well as women, older adults, people with complex comorbidities or disabilities, and those living outside North America and Europe, are all underrepresented in cardiovascular randomized trials, she said.  

Trials That Impact Clinical Guidelines

In recent years, numerous studies, including those led by Van Spall, have focused on inadequate representation of gender, race, age, and region in clinical trials, but changes have been slow to come. In 2020, the US Food and Drug Administration issued voluntary guidance to industry as a way develop clinical trials that better reflect the population most likely to use the drug or device if approved. The European Medicines Agency (EMA) also recently updated its Clinical Trial Regulations to promote greater diversity in research.

To TCTMD, Weeda said the goal with their study was to quantify and highlight where clinical trials informing the cholesterol guidelines were conducted, given that people from rural areas are often not part of these studies and tend to have less favorable health outcomes.

The researchers screened all citations in the 2018 American College of Cardiology/American Heart Association guidelines on the management of cholesterol and the 2022 expert consensus statement on the use of nonstatin therapies. They identified 37 randomized clinical trials of pharmacologic interventions performed at sites in 505 of the 3,142 US counties.

Overall, 58% of US counties were located more than 50 km (> 30 miles) from a clinical trial site. Moreover, the social determinants of health (SDOH) were less favorable in the 2,637 counties without a participating clinical trial site. Compared with US counties with a clinical trial site, those without a higher percentage of people living below the federal poverty line (10.0% vs 8.9%), without a high-school diploma (12.2% vs 10.1%), and without insurance (8.9% vs 7.7%). Additionally, US counties without a trial site had a higher percentage of vacant housing units (17.8% vs 10.0%).

“There are many studies that document the large impact that SDOH have on health outcomes and a treatment’s effect may differ based on SDOH,” said Weeda. “Thus, clinical trials of new treatments that we ultimately expect to change treatment guidelines would ideally include people that differ in terms of SDOH and collect data on SDOH, so that any differences in treatment effect due to SDOH could be explored.”

I plan the trials knowing there’ll be more losses to follow-up but it’s more inclusive. Harriette Van Spall

To TCTMD, Van Spall emphasized that social determinants remain the most powerful predictors of health outcomes. Across race, ethnicity, sex, and age, people with less favorable SDOH have less access to care, face disparities in the care they do receive, and ultimately live shorter lives. Socioeconomic deprivation, she said, can be a barrier to enrollment because there are often onerous requirements to participate in these studies. Such patients are not “ideal” candidates for randomized trials because they may have unstable living conditions that can result in loss to follow-up.

Nonetheless, if researchers want to run socially-just clinical trials, they need to account for this in their study sample size estimations.  

“Is it more of a challenge to deal with people who have pain and instability in their life? Absolutely. Do we have to pour more resources in? Absolutely. Would be easier to walk away? Yes. But these are the people I serve in my community and in my hospital,” said Van Spall. “I need to find a way to reach them also. So, I plan the trials knowing there’ll be more losses to follow-up but it’s more inclusive. It’s important that we all start shifting to that health-equity lens within our clinical trials, because then they can generate generalizable evidence.”

Investment Beyond a Single Trial

In the second study, Azzopardi and colleagues reviewed all cardiovascular, diabetes, and obesity-related randomized, controlled trials published in the New England Journal of Medicine, Lancet, and Journal of the American Medical Association between 2011 and 2020. They found that 8.3% of more than 2.6 million study participants identified as Asian and only 7.7% of total trial enrollment occurred in the Asia-Pacific region. There was an uptick in the percentage of Asian patients included in the trials over time, but the increase was only marginal, say investigators.     

In terms of trial leadership, 42.1% of the 651 lead authors listed on the studies were from the US and 37.1% were from Europe. For the 51 studies with Asia-Pacific lead authors, half were from Australia. There was an “encouraging trend” toward increasing trial leadership and collaboration from the Asia-Pacific region, but the absolute numbers remain low and mostly limited to higher-income regions such as East Asia and Oceania, according to investigators.

Van Spall said that when study investigators recruit trial sites, they tend to go those that have historically done a good job in the past. This creates a “self-fulfilling prophecy” because investigators are reluctant to sink time and resources into getting new sites up and running.  

“If you [already] have an academic center with existing research units, research coordinators, assistants, and nurses, who can be deployed as part of a larger role to recruit for one of many studies, it’s more efficient,” she said. “We’re faced with this as well, but we have to go beyond that and think about our ethical responsibilities and what we need to do to invest in communities so that we can give them a fair start to build the capacity and processes required to have more trials coming through.”

While the investment is initially research-specific, it ultimately will translate into better care for patients, she said. “I think it’s more of a long-term investment, not just for my trial’s recruitment but for other trials, for students in the region, for physicians or clinicians, for budding researchers, and also for the patients who then have access to our resources,” said Van Spall.