Change of Heart

Over recent decades, cardiology as a field has made great strides in improving care and outcomes across the board. But for too many women, bypass surgery — the most common adult cardiac surgery globally — still remains a far riskier intervention than it is for men. A watershed study — published in JAMA Surgery in 2023 — starkly highlights the enduring sex disparity in this potentially lifesaving procedure.

Led by Dr. Mario Gaudino, the Stephen and Suzanne Weiss Professor in Cardiothoracic Surgery II, the study revealed that from 2011-2020, female bypass patients in the United States still had a nearly 50 percent higher risk of mortality compared to men in the first month post-procedure. Even after adjusting for age and health factors — women are more often referred for surgery at later ages with more severe disease — the disparity still stood at 30 percent.

“I was shocked to realize the difference by sex in clinical outcomes in coronary surgery has not improved,” says Dr. Gaudino, assistant dean for clinical trials at Weill Cornell Medicine and an attending cardiothoracic surgeon at NewYork-Presbyterian/Weill Cornell Medical Center. “We are not discussing a 2 percent difference; we are discussing a 30 percent difference, so very, very large.”

The study has been hailed as a call to action by the cardiology community to better understand and address sex disparities, as well as disparities across racial and ethnic demographics. To this end, Dr. Gaudino and his collaborators are now spearheading two first-of-their kind cardiac surgery clinical trials, known as ROMA:Women and RECHARGE, both sponsored by Weill Cornell Medicine.

In contrast to trials going back decades whose patient populations have overwhelmingly been white males, the new trials are enrolling only females, and for RECHARGE, specifically Black and Hispanic women. Researchers expect the groundbreaking trials to provide powerful new insights into best-practice treatments based on women’s distinct cardiovascular physiology and pathology, advancing clinical guidelines and standards of care.

“The differential outcomes in surgical and other cardiac interventions in women and underrepresented minorities is a critical issue and critical knowledge gap, and it’s an unacceptable barrier to care that the cardiology community needs to overcome,” says Dr. Jonathan Weinsaft, chief of the Greenberg Division of Cardiology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell, and a close collaborator of Dr. Gaudino.

“We need to have robust and rigorous evidence-based data so we can inform our decisions and provide shared decision-making with our patients,” says Dr. Weinsaft, who also is the Antonio M. Gotto Jr., M.D. Professor in Atherosclerosis and Lipid Research. “I’m absolutely confident that these trials are going to be doing that and will improve the lives of our patients.”

As the new female-centric clinical trials move forward, Dr. Gaudino and collaborators have also recently reported the identification of a key factor — anemia — behind women’s poorer outcomes overall. Against this backdrop of progress, Weill Cornell Medicine is continuing its major efforts to provide the best cardiac care through a dedicated Women’s Heart Program, focusing on unique risk factors women face and preventative, patient-tailored treatment.

Overlooked Differences

Worldwide, heart disease remains the leading cause of death for both men and women; in the United States specifically, coronary artery disease — a kind of heart disease — is the top killer. This condition occurs when heart muscles can’t get enough oxygen and nutrients because the arteries supplying them have become stiff and narrow due to the buildup of fatty plaque deposits.

Bypass surgery, the standard surgical procedure to treat coronary artery disease, is technically called coronary artery bypass grafting or CABG (pronounced “cabbage”). The surgery lasts three to six hours and involves replacing clogged coronary arteries with portions of healthy blood vessels — usually the saphenous vein in the leg, the internal thoracic artery in the chest or the radial artery in the arm — to boost blood supply to the heart.

Improving outcomes for this frequent surgery could have a tremendous impact on many patients’ lives. For the past several decades, Dr. Gaudino has studied the procedure and ways to enhance its safety and effectiveness. Recently, he served as the co-principal investigator on the ROMA (Randomized Comparison of the Clinical Outcome of Single vs Multiple Arterial Grafts) trial, which started in 2018. ROMA is rigorously assessing if grafting more than one artery onto the heart is more effective than grafting a single artery along with a vein.

Although multiple arterial grafting is seldom used, in only about 12 percent of bypass patients and 6 percent of women patients, there is reason to think the method could benefit women in particular.

Compared to men, the saphenous veins in women are often not as high-quality for grafting because the vessels are smaller and likelier to be varicose. In contrast, arteries generally are more unobstructed, making them better graft candidates. Because women’s coronary and other arteries are naturally smaller than men’s, using additional grafted arteries versus veins could better perfuse the heart and lead to improved outcomes, Dr. Gaudino notes.

Despite recruitment efforts for ROMA, women still ended up representing only about 15 percent of the study’s total population — not enough to tell statistically if single- or multiple-grafting really makes a difference. So Dr. Gaudino and colleagues began to pursue ROMA:Women — an offspring trial that is leveraging ROMA’s existing infrastructure, recruiting sites and collected data.

ROMA:Women launched in mid-April 2024, aims to recruit 2,000 women and will conclude in 2030. Surgeons eagerly anticipate its findings on how to improve CABG. Dr. Lamia Harik, a general surgery resident in research at Weill Cornell Medicine who collaborates with Dr. Gaudino, says: “ROMA:Women will give us a whole lot more data about how women are doing before, during and after CABG, and that will be super important to bolster our claims and give us the leverage to effect clinical change.”

Dr. Leonard Girardi, the O. Wayne Isom Professor and Chair of the Department of Cardiothoracic Surgery at Weill Cornell Medicine, offers a comparison to “precision medicine,” the push in medicine to tailor treatment to individuals’ unique characteristics. “What we’re really talking about is trying to get more precision surgery,” says Dr. Girardi, who is also chief of cardiothoracic surgery at NewYork-Presbyterian/Weill Cornell. “Cardiac is a shining example of that, where we’re trying to do the right operation for the right person for the right reason.”

“These trials,” Dr. Girardi continues, also referring to RECHARGE, the second of Dr. Gaudino’s women-dedicated trials, “will help answer some of those questions, so we know what we’re supposed to be doing for the individual that has this profile, based on their sex, based on their size, based on their underlying comorbid conditions, their age, you name it.”

Evidence for Informed Decisions

The origins of the RECHARGE trial trace back to ROMA:Women, Dr. Gaudino says. “Women are not small men, right? But that’s exactly what the medical establishment has been thinking for decades,” says Dr. Gaudino. “We have just seen what happened in men and then applied the result to women. That was a huge mistake.”

RECHARGE, which stands for Revascularization Choices Among Under-Represented Groups Evaluation, is expected to launch this fall, having been awarded a nearly $30 million funding grant in July 2023 from the Patient-Centered Outcomes Research Institute (PCORI), a Washington-based nonprofit. The trial will be split up into two clinical studies, each enrolling about 600 women, with one study population comprised solely of Black and Hispanic women. The trial will compare outcomes of survival and quality of life improvement for coronary artery disease patients receiving either bypass surgery or a stent.

Annually, more than 1 million people in the United States receive one of these two blood flow-restoring procedures. Yet the evidence for which procedure is best indicated has, like most other trial-derived insights in cardiology, come almost exclusively from studies involving white male patients.

Sorting out which procedure is most appropriate matters because they vary significantly in patient burden, complexity, risk and long-term outcomes. As open-heart surgery, a bypass involves general anesthesia, opening up of the chest and incisions in a leg or arm, a long hospital stay and recovery, plus greater risks of complications — though lower odds of future heart attacks or need for repeat interventions, compared to stenting.

Inserting a stent (technically called percutaneous coronary intervention, or PCI) is, in contrast, a minimally invasive, same-day procedure done under minimal anesthesia. PCI involves running a catheter to the affected coronary arteries through an incision in the groin or wrist. A balloon at the top of the catheter is inflated to widen the artery as a stent wrapped around the balloon expands to hold the artery open.

Thanks to RECHARGE, patients in almost entirely unstudied demographics and their physicians will soon have actual evidence upon which to base treatment decisions.

“Understanding how outcomes vary allows us to make informed decisions as to how best treat our patients,” Dr. Weinsaft says. “We need to have a better sense of data in terms of how people of different racial, ethnic or sex-based groups are going to do after a given intervention.”

Importantly, RECHARGE is designed to follow its patients for five–10 years after their procedures, a study parameter that Dr. Girardi applauds. “Not only is RECHARGE going to look at underrepresented populations,” he says, “but there is going to be longitudinal, patient-centered outcome follow-up, which is crucial. We’re doing it for the patients, not just to create data.”

Better Prevention and Awareness

Well ahead of the highly anticipated results from ROMA:Women and RECHARGE, Weill Cornell Medicine physicians have already taken an array of actions to address historical care disparities and improve cardiac outcomes for women. The overall approach is holistic, starting with preventative and diagnostic care long before patients ever need to see the operating room, and carrying through into the postsurgical period and beyond.

An important step was the founding of the Weill Cornell Department of Cardiology Women’s Heart Program in 2017. The seven physicians on the program’s staff bring together a broad base of clinical expertise in identifying risk factors and delivering early treatment for heart health-threatening conditions that are present only in women or occur more commonly in this group. Examples of the former include pregnancy-associated conditions, such as preeclampsia and gestational diabetes, as well as premature menopause and polycystic ovarian syndrome, and the latter includes certain autoimmune conditions such as rheumatoid arthritis or lupus.

“The purpose of a women’s heart program is really to have a collection of experts tailored to raise awareness, make timely diagnosis and initiate targeted treatment of a range of cardiovascular conditions that can affect women,” says Dr. Nupoor Narula (M.S. ’21), director of the Women’s Heart Program, an assistant professor of medicine and the Bruce B. Lerman, M.D., Clinical Scholar.

“Our Women’s Heart Program is an exceptionally well-developed, robust program, integrating the latest in terms of evidence-based medicine for both diagnosis and therapeutic management of women with an array of cardiovascular conditions,” adds Dr. Weinsaft.

A major emphasis is earlier detection of potential disease. Better awareness of the non-classic symptoms that women are more prone to experience than men — such as shortness of breath and nausea — is a starting point, along with access to advanced imaging through cardiac MRI and CT scans, made available throughout Weill Cornell Medicine’s care network in New York City.

“Like a lot of things, whether it’s coronary disease or cancer, the earlier you [detect] something, the better, and the more your options are, the better your outcome is likely going to be,” says Dr. Girardi. “We have a laser focus on that here at Weill Cornell Medicine.”

Questioning Orthodoxy

Greater awareness of women’s distinct physiology is also being extended into the operating room. For instance, a March 2024 study in the Journal of the American College of Cardiology led by Dr. Harik, with Drs. Gaudino and Girardi as coauthors, identified a dangerously low threshold for anemia during surgery as a plausible factor for women’s poorer outcomes after bypass procedures.

Women are inherently likelier to have insufficient red blood cell concentrations at baseline than men. In addition, women are usually smaller than men, so the fluids routinely administered during surgery can dilute women’s blood more. Yet as Dr. Harik points out, the same protocols are employed for all patients put on heart-lung machines, which pump and oxygenate blood during CABG surgery. The upshot: Women are likelier to experience severe intraoperative anemia than men, and the study found this condition to be associated with a third of women’s excess mortality.

“All of those previously proposed drivers for why women do worse are immutable — you can’t change the size of someone’s coronary arteries, and it’s really difficult to change referral patterns so that women see a cardiac surgeon sooner,” says Dr. Harik. “But is there a driver that we as surgeons have direct control over in the operating room? Interoperative anemia looks like one.”

“We have shown that over 30 percent of the excess risk that we see in women can probably be avoided even if we just correct for anemia,” adds Dr. Gaudino.

Toward that end, the doctors are looking into clinical trials that would use smaller bypass machines or change how bypass machines are primed so blood becomes less diluted.

Generational Change

A fundamental way to further dispel care disparities is confronting women’s underrepresentation in the medical field of cardiology. In the United States, only about 15 percent of practicing cardiologists are women, and in both cardiothoracic surgery and interventional cardiology, the skews are even more dramatic at under 10 percent. “That’s pretty disturbing,” says Dr. Harik.

Dr. Weinsaft agrees, calling the statistics “unacceptable.”

“It’s evidence of the fact that we need to do better in terms of training and developing the next generation of academic and clinical leaders,” he says. To this end, Dr. Weinsaft has prioritized recruiting more women for the Weill Cornell Medicine catheterization (“cath”) labs where interventional cardiologists work.

Dr. Gaudino is optimistic about how inclusion and more research through endeavors such as ROMA:Women and RECHARGE can bring about equity in cardiology.

“I think it’s finally the moment to do things differently,” says Dr. Gaudino. “In the next 10 years, probably we will develop a different approach so that the medical therapy is different between men and women, and even the decision to do or not do surgery will be based on different information for women. It really represents a sea change.”