Trials to assess CABG vs. PCI in women, people from underrepresented groups
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Key takeaways:
- Funding has been awarded for the first trials to examine CABG vs. PCI in women and in people from historically underrepresented races and ethnicities with CAD.
- Outcomes emphasize quality of life more than MACE.
The Patient-Centered Outcomes Research Institute has awarded nearly $30 million to fund a trial program comparing CABG vs. PCI in women and people from historically underrepresented races and ethnicities with coronary artery disease.
The RECHARGE program will include two randomized controlled trials — RECHARGE: Women, which will be the first trial to evaluate CABG vs. PCI in women with CAD, and RECHARGE: Minorities, which will be the first trial to evaluate CABG vs. PCI in patients from historically underrepresented races and ethnicities with CAD.
The program also differs from past trials in cardiac surgery and intervention because the trials’ primary outcome includes death and overall quality of life as assessed by the SF-12, instead of the traditional major adverse CV events (MACE). This “differs from all prior trials that have often been driven by processes of care that do not adequately reflect long-term symptom burden and quality of life,” according to a project summary on the Patient-Centered Outcomes Research Institute (PCORI) website.
The key secondary outcome is disease-specific quality of life as measured by the Seattle Angina Questionnaire overall summary score. Other outcomes include generic quality of life outcomes assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) instruments; MACE including death, stroke and MI; MACE plus all-cause readmission; and individual components of the composite outcomes, all at 3 years. The principal investigators are a cardiac surgeon, Mario Gaudino, MD, PhD, Stephen and Suzanne Weiss Professor in Cardiothoracic Surgery in the department of cardiothoracic surgery at NewYork Presbyterian | Weill Cornell Medicine, assistant dean for clinical trials at Weill Cornell Medicine and professor of clinical epidemiology and health services research at Weill Cornell Graduate School, and an interventional cardiologist, Gregg W. Stone, MD, director of academic affairs for the Mount Sinai Heart Health System and professor of medicine and population health sciences and policy at the Zena and Michael A. Wiener Cardiovascular Institute at the Icahn School of Medicine at Mount Sinai.
The development of the program included meetings between investigators and a patient and stakeholder advisory board to enable patients, caregivers, health systems leaders and policymakers to have input on trial design, recruitment and retention. The trial will have an 18-month pilot phase and will continue to completion if recruitment goals are met during the pilot phase.
Healio spoke to Gaudino about why there are little data on the best treatments for women and people from historically underrepresented races and ethnicities with CAD, how the trial program was organized, how the trials will work and what researchers are hoping to learn.
Healio: Why have women and people from historically underrepresented race and ethnicity groups been underrepresented in cardiology clinical trials?
Gaudino: The absolute percentage of women and nonwhite patients in cardiology trials in general and cardiac surgery trials in particular is very small. It is less than 20% for women and in the single digits for traditionally underrepresented races and ethnicities. If you look at the percentage of women that are referred for bypass surgery in large surgical registries, and the percentage of women included in PCI vs. CABG trials, they are both low: 30% to 35% in clinical practice vs. 20% in clinical trials.
There are two problems here. No. 1, the percentage of women in clinical trials does not represent the percentage of women referred for surgery or PCI. No. 2, there is a broader referral problem: Women with coronary artery disease are less likely to be referred for intervention than men with CAD. So there is an issue related to clinical trials, but there is also a more general referral bias that is a problem of the entire medical community. It probably has to do with the fact that all our diagnostic algorithms are essentially based on symptoms and clinical presentation in men. Women are underdiagnosed and often have a delayed diagnosis. The same applies to any other underrepresented group.
In terms of clinical trials, one issue is some of the classic inclusion criteria. We often exclude women with childbearing potential. That excludes 0% of men but a substantial proportion of women. Yet it has been used forever, in part because regulatory authorities are more comfortable with the exclusion criteria due to the idea that they are potentially protecting pregnant women and babies from participating in a clinical trial. But this backfires because then we do not know anything about that population, and we have fewer women in the trials.
The other problem is that we have not tried hard enough. For at least 20 years, everyone from the funding agencies to the professional societies have said that we need more information on women and underrepresented groups, but RECHARGE is the first PCI vs. CABG trial in women, and there have been more than 20 since 2000. No one has focused on women, and that is kind of embarrassing. ROMA-Women, which I am leading and which started enrollment in April, is the first CABG trial in women. So we trialists are guilty of not trying hard enough.
Healio: How did the proposal to do this study come together?
Gaudino: There were two major components. I have done a lot of work with women who need cardiac surgery in the last 5 or 6 years. Women are not small men, and we do not know enough about them. Dr. Stone suggested that if we are studying underrepresented populations, it should not only be by sex but also by race and ethnicity.
Developing RECHARGE has been an amazing process because of the collaborators such as Dr. Stone, but also because of how we worked with patients. We had focus groups and spent hours in person and on Zoom with patients. What we learned, particularly regarding underrepresented racial and ethnic minorities, is that you must work to reassure patients that what we are doing is in their best interest. There is a tradition of these populations not being respected, and sometimes even being abused, by the medical system. It was a painful episode in medical history. One patient representative, a reverend from the South, told me that the first thing Black patients will think is, “Why are you not including white patients? Are you experimenting on us, or doing something to us that you are not comfortable with doing to white patients?” This is a very interesting perspective that we did not think about. We have to build trust again and we need to reassure patients that this is not an experimentation. It has been humbling. We went into those meetings convinced that patients and patient representatives would look at us like heroes — the good doctors that are concerned about them, finally. But it was not a very warm welcome at the beginning. It was more like, “Why exactly are you here? Where is the trap?” We have learned a lot about the process.
We found a great partner in PCORI. Their approach is focused on the patient, not the physician. And they are very innovative. I don’t know how many funding agencies would have been supportive of a trial that is such a game-changer methodologically. During the review process, we got excellent feedback from them that we have incorporated. We are very excited to work with PCORI for this project.
Healio: What is the protocol for the study?
Gaudino: The protocol is very simple. It is essentially two separate trials. One is for women of any race or ethnicity. The other is for minority patients of any sex or gender. There will be approximately 600 patients in each trial, but I say “approximately” because there will be some overlap. For example, Black women will be part of both trials. So we don’t know how much overlap there will be. The higher the overlap, the smaller the total sample size we will need. At minimum, we would like to have 20% minority women, but we will aim for more than that. The pilot phase will be very important in determining that.
These are randomized trials with broad inclusion criteria. Essentially the only criterion is that there is local equipoise between CABG and PCI. This is a change from the past. We believe equipoise is strongly associated with local resources and expertise. It is difficult to make a blanket definition of equipoise. Some centers may have a lot of experience with complex PCI, including for left main or triple-vessel disease, and in other centers that may not be the case. Patients will be randomly assigned 1:1 to PCI or CABG. Follow-up is pretty frequent: at 1 month, 3 months, 6 months and every 6 months after that. We will capture both clinical events and generic quality of life outcomes. The primary outcomes include death and generic, not disease-specific, quality of life, evaluated using the win ratio.
Healio: What are you hoping to learn from this study?
Gaudino: I am hoping to learn several things. No. 1, whether a trial like this is even possible, because it has never been done. The work that some of the trial leaders will do with local principal investigators and patients to develop a dedicated enrollment strategy will be critical not only for this trial but also for people who want to do trials in these populations in the future. No. 2, whether this very innovative trial design is accepted in the trial community and in practice. No. 3, I hope that we can build trust with underrepresented groups. If we do, this could be the first of many similar trials. For example, there is the exact same issue with transcatheter aortic valve replacement vs. surgical AVR — we don’t know anything about how they compare in women and underrepresented racial and ethnic groups.
Healio: Quality of life is a major part of the primary outcome and the key secondary outcome. This is different from MACE-focused trials. Why did the team decide to emphasize quality of life?
Gaudino: A key change from the past is that we are looking at death and quality of life. All nonfatal cardiovascular outcomes that have traditionally been part of the composite MACE outcome in PCI and CABG trials are relegated to secondary outcomes. The main reason we decided that is because we have all been struggling with the definition of nonfatal events. For example, there has been controversy over perioperative MI. Also, there has been debate over what is a clinically significant stroke. You can see a small lesion on MRI but the patient is totally asymptomatic, or you can have a devastating stroke.
We wanted to emphasize other outcomes that are usually not captured but are important for patient quality of life such as arrhythmias, surgical site complications, bleeding, vascular access complications, social function and recovery from the intervention. Dr. Stone and I wrote an essay published in the Journal of the American College of Cardiology in May about how MACE endpoints do not really capture what is important for the patient. (Stone GW, et al. J Am Coll Cardiol. 2023;doi:10.1016/j.jacc.2023.03.387).
This is the first trial in CABG and PCI that is designed for the patients, not for the trialists. When we presented the idea to the trialists, we had some critics saying that we were making the analysis and the trial design and the sample sizes really complicated. It’s so easy to use the MACE outcome and the time-to-first event analysis. That’s true, but being complicated is not a reason not to do the trial if this way is better.
Healio: When do you expect the study to be completed and for results to be reported?
Gaudino: According to plan, we will start trial activity in October. There will be an 18-month pilot phase. If we check all the boxes and meet all the milestones, we have 5 years to report the outcomes. We are targeting 7 years from now in 2030. I think it is worth the investment in time, in energy and in all the money PCORI has invested.
Healio: How might the study influence treatment of these patient populations going forward?
Gaudino: We hope the trial will help us to determine the best way to treat these populations. We also hope it may change the referral patterns I mentioned earlier. We are currently anticipating 45 sites, but we could get more than 60, so perhaps through this trial, even local physicians could overcome their potential unconscious bias in referral. We hope to build trust with patients so that they will seek access to medical care in the earlier stages of their disease. That could also potentially change practice.
This is a trial that was really needed at this stage of knowledge about CAD, and I am excited to work with this stellar group of collaborators, and am grateful to PCORI for the opportunity.
References:
- PCORI approves $208 million for research on heart disease, chronic disease, palliative care and a range of conditions impacting people of all ages. www.pcori.org/news-release/pcori-approves-208-million-research-heart-disease-chronic-disease-palliative-care-and-range-conditions-impacting-people-all-ages. Published July 18, 2023. Accessed July 21, 2023.
- PCORI. Revascularization Choices Among Underrepresented Groups Evaluation (The RECHARGE Program). www.pcori.org/research-results/2023/revascularization-choices-among-under-represented-groups-evaluation-recharge-program. Published July 18, 2023. Accessed July 21, 2023.
- Stone GW, et al. J Am Coll Cardiol. 2023;doi:10.1016/j.jacc.2023.03.387.
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