First-Ever Cardiac Surgery Trial in Women Poised to Launch: ROMA-Women

Hopes are high that the ROMA trial may finally answer the question of whether multiarterial grafts are better than a single arterial graft in patients undergoing primary isolated nonemergent CABG. But the trial is on track to enroll just 15% women, a group already less likely to be referred for CABG in the first place, more likely to have worse outcomes if they do, and less likely to receive guideline-directed surgical care.

Enter ROMA-Women: the first-ever cardiac surgery trial in women. With a unique, nested trial design that will leverage the infrastructure and recruiting sites of the primary ROMA trial—even repurposing the data from female patients randomized in ROMA—the trial is powered to get a decisive answer in women.

“ROMA, the parent trial, will stop enrollment on April 14th, and then on April 15th, the sites that are doing ROMA will transition to ROMA-Women,” Mario Gaudino, MD, PhD (Weill Cornell Medicine, New York, NY), one of the principal investigators, explained to TCTMD. Gaudino is also the lead author of a perspective describing the design and rationale of ROMA-Women published this week in Circulation.

“Also, we are opening many more sites because we will need more enrollers,” he added, noting that women make up just one-third of the overall population being referred for bypass surgery, “which is also intrinsically wrong,” he said.

The chronic under-enrollment of women in clinical trials—as well as the lack of representation of minority groups, and, most notably, minority women—is a long-standing problem in medicine, formally recognized in the National Institutes of Health (NIH) Revitalization Act in 1993. Explanations, excuses, and justifications abound, but 30 years later, women still make up less than one-third of the participants in cardiovascular clinical trials, despite accounting for roughly half of the annual CVD deaths in the US.

An Innovative Approach

For the specific question of multiarterial versus single arterial grafts, there are good reasons to think the ROMA results might differ in men and women, Gaudino and colleagues note in their paper. Women have different operative risk profiles at baseline, their operations are often more technically complex, and their procedural risks are higher. Physiologically, women have smaller coronary arteries and conduits that are more prone to spasm, a higher prevalence of microvascular dysfunction, and more varicose or diseased saphenous veins that make for lower-quality venous grafts.

There is really an urgency in the cardiac surgery community to try to understand why women do not do as well as men. Mario Gaudino

While other groups have proposed just capping the enrollment of men in trials when sufficient numbers are reached and thereafter randomizing women only, ROMA-Women represents an alternative approach that is “very innovative and exciting,” said Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York, NY), a co-author of the Circulation perspective and a founder of Women as One, one of the groups that endorsed the study along with a wide range of professional societies and the patient-centered WomenHeart organization. “The Lancet Commission [on women] has also endorsed this and we’re just very, very excited to be a part of this going forward,” Mehran said.

ROMA-Women’s novelty lies in the fact that it will leverage the infrastructure already in place for ROMA, including clinical trial units, database, case report forms, randomization system, site-training resources, informed consent forms, regulatory approvals, centralized event review committee and processes, and enrolling sites—although these, as noted, will be expanded for ROMA-Women. Statistical contingencies are built into the analysis plan to reduce any cohort effects of combining data from the parent and offspring trials.

Equity in Research

In recent decades, national and international funding agencies have issued statements and proposed plans for reducing inequities in biomedical research.

“So why is it 2023 and we’re still talking about this?” asked C. Noel Bairey Merz, MD (Cedars-Sinai Heart Institute, Los Angeles, CA), a longtime advocate for addressing sex- and gender-based research inequalities and a co-author of the Circulation perspective.

In the US, Research for All legislation was passed in 2016, encouraging representative numbers of women and minorities in federally funded research, and an NIH policy amendment went into effect in 2017 stipulating that NIH-funded trials should include adequate representation of women and minority groups. But neither have teeth to require specific criteria to be filled on the basis of sex and gender, explained Bairey Merz.

This is the first time that, to my knowledge, we've tried to do something like this, so it could fail. That's why they call it research, right? C. Noel Bairey Merz

That’s in contrast to the approach of the Canadian Institutes of Health Research (CIHR), one of the original funders of ROMA—Stephen Fremes, MD (University of Toronto/Sunnybrook Health Sciences Centre, Canada), is the other principal investigator and a co-author of this week’s perspective. The CIHR is much “more progressive,” said Bairey Merz. The CIHR created an Institute of Gender and Health more than two decades ago and requires researchers submitting grant proposals, as well as the people reviewing them, to complete mandatory training modules for integrating sex- and gender-based research.

Moreover, the proposals themselves must contain compulsory sex- and gender-based analysis (SGBA) questions, with grading of the planned SGBA forming part of grant review. In the US, said Bairey Merz, inclusion of sex- and gender-based analysis plans are not mandatory. “They strongly encourage it, but they still do not have [them] as line items,” Bairey Merz explained to TCTMD.

Gaudino, to TCTMD, agreed that the “well-intended” US legislative and NIH statements have not solved the problem of inequitable representation in US trials, but they have led to a shift. “They have at least the very important merit of having highlighted this situation and having people like me thinking, ‘Well, that's a problem.’”

Shining a Bright Light

Whether this offspring trial is any better than other ideas for making clinical trials more representative remains to be seen—there are many other factors that influence whether or not patients are encouraged to enroll or have the support in place to participate.

“This is the first time that, to my knowledge, we've tried to do something like this, so it could fail,” said Bairey Merz. “That’s why they call it research, right? If it succeeds, and it looks very feasible, then it could be a model [for other trials], because we're all struggling with the expense of doing these studies.”

Whichever way you look at it, whether it's a potential benefit or harm, it just is very, very important to make sure that women are represented. Roxana Mehran

Gaudino agreed. “The reason why I'm excited about ROMA-Women is because if it works, then it can be a model that can be adapted to essentially every other trial where you think that there is a group of patients where the result may be different than what you see in the general population.”

That’s key, he continued: “There is really an urgency in the cardiac surgery community to try to understand why women do not do as well as men. If in other areas, if there is not the same sense of urgency, then probably this trial design will not get a lot of traction, even though if you don't look, you will never know. . . . In the case of coronary surgery in women, we know well that at least there are very strong reasons to believe that what we see in men is not what is happening in women. So why would you combine these two different populations in the same trial? In the end, the overall result that you get will just be the mean or the average between what happened in one population and what happened in the other population, so essentially it will be meaningless for both populations.”

Not only is it important to think “a priori” about trials in which a given intervention might yield unique benefits in women, but also it’s critical to study which might be harmful, Mehran pointed out. “Whichever way you look at it, whether it's a potential benefit or harm, it just is very, very important to make sure that women are represented.”

She cited two other efforts underway that might lead to more-equitable clinical trial representation. In the first, the Academic Research Consortium (ARC), which has previously collaborated on bleeding risk and valve intervention endpoint definitions, “is taking on the whole idea of diversity in clinical trials and how to implement diversity—really thinking outside of the box to come up with trial designs as well as definitions for ARC-Diversity,” she said.

“Then the second part is that the Lancet Commission this whole year, 2023, will be mobilizing several think tanks to discuss clinical trials in women for topics that are very much prevalent, where we have very little data in women. So, we will be doing some more all-female studies going forward.”

Bairey Merz agreed there’s more work to be done.

“To generate policy, [we need] advocacy—shining a bright light and just being persistent and not saying, ‘Oh well, that's the way it's just always going to be,’” she said. “It's that tipping effect. Sometimes it seems like the world is going backwards right now for women . . . but if we think back 20 years ago, 30 years, 40 years ago, things were worse.  Progress is sometimes tiny.”