The disparate impact of COVID-19 along with widely publicized incidents of violence against members of certain minority groups have drawn attention to longstanding, deep and persistent health inequities faced by many people in the U.S.

While efforts to improve health equity are the focus for organizations like the ACC, patient advocacy groups and even some lawmakers, payers and industry groups, real and long-term change won't happen overnight. In the meantime, diversity in clinical trials is not optimal, outcomes for women and minorities continue to lag, and diversity in the existing workforce is lacking, despite some incremental progress.

What is needed to truly solve for health equity? One answer lies in the need for reliable and trusted research and data.

Cardiology spoke with leaders in the field to explore some of the challenges to conducting high-quality research and opportunities to overcome these barriers to derive actionable solutions that optimize care and outcomes for all patients.

Mandate Clinical Trial Diversity, Don't Suggest It

The foundation for today's standard of care treatment of cardiovascular disease is based on findings from clinical trials that fail to fully represent elderly patients, minority populations and women.¹ "This is something that keeps people like myself up at night," says Quinn Capers IV, MD, FACC, chair of ACC's Diversity and Inclusion Committee. As an example, Black people make up about 13% of the US population but make up less than 5% of the racial demographics in most cardiovascular research trials. Follow this through to clinical practice guidelines and the impact of this is clearly seen.

The current heart failure guideline from ACC/American Heart Association/Heart Failure Society of America published in 2013, with focused updates in 2016 and 2017, has just two examples where race/ethnicity is the focus of a specific treatment difference: one relates to the use of hydralazine-isosorbide dinitrate in NYHA class III-IV heart failure with reduced ejection fraction and the second to the relative frequency of aTTR cardiac amyloidosis in Black patients.²

The U.S. Food and Drug Administration (FDA) has attempted several times to improve the representation of women and minorities in clinical trials, with the most recent guidance issued in November 2020 specifically addressing eligibility criteria, enrollment practices and trial designs.

 

This is something that keeps people like myself up at night.  

 

Quinn Capers IV, MD, FACC

"The guidance provides the agency's current thinking on steps sponsors can take to broaden eligibility criteria in clinical trials through inclusive trial practices, trial designs and methodological approaches," says the FDA's Rear Admiral Richardae Araojo, PharmD, associate commissioner for Minority Health, Office of Minority Health and Health Equity.

"The guidance also provides recommendations for how sponsors can increase enrollment of underrepresented populations in their clinical trials and improve recruitment so trial participants will better reflect the population most likely to use the drug, if the drug is approved, while maintaining safety and effectiveness standards," she adds.

However, some think the problem with the FDA's guidance is that it stops short of mandating diversity.

"I think in the end, there will need to be a regulatory solution, both a carrot and a stick," says Paul L. Douglass, MD, MACC, chair of ACC's Health Equity Task Force. He suggests, for example, that research teams that meet their recruitment goals be rewarded in some fashion, while those that don't are penalized. "We need to be incremental in our approach, but clearly it's not going to just happen because we say it should happen," Douglass says.

Moving Clinical Research to Communities

Another opportunity to improve health equity research is to move studies away from academic centers and into the community.

"I think the potential for reducing disparities exists, but in order to do it, we need to have everyone contributing," says Douglass.

Araojo agrees, noting that the FDA remains committed and continues to work to increase the participation of racial and ethnic minorities and other diverse populations in clinical trials. The development and long-term sustainability of an infrastructure that brings clinical research into the community will help reap equity rewards to diverse populations.

"A multisector approach, partnerships, engaging patients and providers, and sharing of best practices are all opportunities to continue to advance racial and ethnic minority inclusion in clinical trials," she says.

Early collaborative efforts have shown that academic-community partnerships are possible and do work. For example, the Johns Hopkins Clinical Research Network (JHCRN) – founded in 2010 – has spearheaded the drive towards integrating clinical research with community-based health care delivery systems by creating collaborations that link its academic center with a diverse network of regional health systems, giving researchers access to more than 5 million potential research participants. Johns Hopkins manages much of the heavy lifting, like contract negotiations, budgets, internal review board approvals and regulatory reporting, while affiliate sites can decide which trials they want to participate in and even get help developing ideas for new studies.

 

I think in the end, there will need to be a regulatory solution, both a carrot and a stick. We need to be incremental in our approach, but clearly it's not going to just happen because we say it should happen.  

 

Paul L. Douglass, MD, MACC

To be clear, diversifying the research participant population is less about revealing unknown biological differences in response to treatment, and more about ensuring generalizability. One other benefit, says Robert O. Roswell, MD, FACC, associate dean for Diversity, Equity and Inclusion at Zucker School of Medicine at Hofstra/Northwell in New York, is that clinical trial participation often cancels out certain negative social determinants of health, such as health care access, which can be very revealing in understanding disparate patient outcomes.

"We know that clinical trials don't really mirror real life. But in the case of social determinants of health, this could be a good thing and helps us better understand what's standing in the way of progress," he says. In addition to broadening the patient base, expanding research into the community can increase the diversity among those coordinating the trials and those doing the research studies.

"More minority principal investigators, and more community clinicians participating in clinical research will lead to enrolling more individuals from their communities," says Capers. "We've seen that when we have greater diversity among researchers, they are more successful at recruiting more diverse patients into the study and do a better job with retention of these individuals."

Diversity in trial coordinators is often overlooked, but also essential says Capers. "The research coordinators are where the rubber meets the road – they're the ones who sit down with the patients, explain the study, get informed consent, keep up with the patients. We need that group of people to be more diverse, be more culturally competent and culturally aware," he suggests.

A team at Vanderbilt University Medical Center has offered a creative solution to this.² They developed an eight-hour massive open online course to help study personnel gain knowledge and skills to enhance the recruitment of minorities. Preliminary evidence is promising, with post-test respondents (n=14) indicating the course improved their professional knowledge and the likelihood they would make changes to their recruitment and retention practices.

Strategizing and the Power of Neighborhoods

Roswell would like to see more population-based research in cardiology, similar to a study he recently published that looked at the out-of-hospital sudden death (OHSD) during the first COVID-19 wave in New York City (NYC), looking not at individuals but at zip codes.³

The amount of variation seen between different zip codes was hardly inconsequential. Overall, there was a 4.97-fold increase in the incidence of OHSD in the early part of the pandemic surge compared with the same time period in 2019, but this increase ranged across NYC zip codes from a 0.25-fold increase to a 19.5-fold increase.

"When we focused on neighborhoods and zip codes, rather than just counting individuals of different races and ethnic groups, and included socioeconomic and sociodemographic variables, two factors at the zip code level were the mostly likely driver of the increase in OHSD: less than a high school education and Black race," reports Roswell.

"I think we've gotten better at talking about structural racism and the impact that has on health equity. Now we need to move further and look at strategy to see how we can impact some of these modifiable factors that impact individuals and communities," Roswell adds.

The Groundwater Approach, described in a white paper from the Racial Equity Institute, tries to help practitioners at all levels internalize the impact of a racially structured society on inequity. Such an approach moves away from attributing disparate outcomes to individual factors or local systems of care, and recognizing deeper causes.

The metaphor is based on the idea that if one fish in the pond dies, the cause might be the fish. Even if two fish die, those fish might be to blame, or perhaps it's the pond. But if half the fish in all the ponds across the region die, it's time to consider the groundwater and recognize that "the underlying structure from which the fish seek life has failed."

"So, if we look at the community as the groundwater, then we can start to think about groundwater solutions," says Roswell.

Science Can Change the Groundwater

"Scientists and scientific journals have the opportunity to facilitate best practices and ultimately impact racial and ethnic disparities," write Khadijah Breathett, MD, MS, FACC, in a recent editorial on this topic.⁴ In other words, deliberate action to methodically examine structural factors when studying racial and ethnic disparities can improve the groundwater and improve equity.

Breathett and colleagues outline several best practices for authors conducting and reporting their research. Their advice ranges from forming diverse and inclusive study teams to explicitly describing the rationale and methodology for including diverse patient populations, including a description of how race and ethnicity were analyzed in statistical models.

It's not something that can be left as an afterthought, notes Capers. "If halfway through enrollment you realize you only have five Hispanics in the whole study, it's too late. It's something that has to be built in from the beginning," he says.

 

I think we've gotten better at talking about structural racism and the impact that has on health equity. Now we need to move further and look at strategy to see how we can impact some of these modifiable factors that impact individuals and communities.  

 

Robert O. Roswell, MD, FACC

Authors should also contextualize their discussions of results by identifying contributing factors and strategies for eliminating barriers to more equitable outcomes. "To be most effective, we have realized that disparities research requires reframing all phases of the research protocol to ultimately achieve cardiovascular health equity," write Breathett, et al.

At the end of the day, problems can't be solved if they are not understood. Health equity cannot be achieved until all parts of the health ecosystem fully understand and accommodate for the differences between patients. Democratizing clinical research such that the evidence-base from which clinical practice is guided is inclusive of racial and ethnic differences is an important initial step.

Douglass notes, "We need more trials and better trials to get to a degree of precision medicine where we'll be able to understand how an individual responds to a particular pharmaceutical or device. Ultimately, I think we'll see that the influence of race on health outcomes is small. The factors that will be a greater determinant of how a person fares are whether or not there is transportation back and forth to the doctor, whether there is access to quality health care, whether an environment has been built that encourages health and provides an opportunity for leisure activities and exercise, and whether a person lives in a food desert. All of these things will be much more important than ethnicity or racial background."

 

We need more trials and better trials to get to a degree of precision medicine where we'll be able to understand how an individual responds to a particular pharmaceutical or device. Ultimately, I think we'll see that the influence of race on health outcomes is small.  

 

Paul L. Douglass, MD, MACC

References

1. Ortega RF, Yancy CW, Mehran R, Batchelor W. Overcoming lack of diversity in cardiovascular clinical trials. Circulation 2019; 140:1690-2.
2. Piña IL, Jimenez S, Lewis EF, et al. Race and ethnicity in heart failure: JACC focus seminar 8/9. J Am Coll Cardiol 2021;78:2589-98.
3. Kusnoor SV, Villalta-Gil V, Michaels M, et al. Design and implementation of a massive open online course on enhancing the recruitment of minorities in clinical trials – Faster Together. BMC Med Res Methodol 2021;21:44.
4. Mountantonakis SE, Epstein LM, Coleman K, et al. The association of structural inequities and race with out-of-hospital sudden death during the COVID-19 pandemic. Circ Arrhythm Electrophysiol 2021;14:e009646.
5. Breathett K, Spatz ES, Kramer DB, et al. The groundwater of racial and ethnic disparities research. Circulation Cardiovasc Qual Outcomes 2021; 14:e007868.
6. Graham SE, Clarke SL, Wu KHH, et al. The power of genetic diversity in genome-wide association studies of lipids. Nature 2021;Dec. 9:[Epub ahead of print].
7. Capers Q, Johnson A, Berlacher K, Douglas PS. The urgent and ongoing need for diversity, inclusion, and equity in the cardiology workforce in the United States. J Am Heart Assoc 2021;10(6):e018893.
8. Johnson AE, Talabi MB, Bonifacino E, et al. Racial diversity among American cardiologists: Implications for the past, present, and future. Circulation 2021;143:2395-2405.
9. Santhosh L, Babik JM. Trends in racial and ethnic diversity in internal medicine subspecialty fellowships from 2006 to 2018. JAMA Netw Open 2020;3(2):e1920482.
10. Woodcock J, Araojo R, Thompson T, Puckrein GA. Integrating research into community practice - toward increased diversity in clinical trials. N Engl J Med 2021;385:1351-53.