Building on DCRI’s strong history in building cardiovascular evidence, researchers at the Institute with a wide range of expertise are also considering how cardiovascular disease factors into other conditions.
Great strides have been made over the past few decades in the prevention of cardiovascular disease—but there is much work to be done to make similar advancements in other disease states such as kidney disease, in which cardiovascular disease is rampant and historically, has been understudied.
But kidney questions, for example, don’t have to be answered solely through kidney trials—they also can be addressed through studies that focus primarily on other problems, such as heart failure. Diseases often overlap across several specialty areas, necessitating collaboration among experts in these different specialties. The DCRI, which houses eight therapeutic areas under one roof, provides the optimal environment to pursue these collaborations via clinical research.
Reviewing the Research
One example of collaboration across therapeutic areas is a recent state-of-the-art review, in which a DCRI nephrologist and cardiologist worked with colleagues from other institutions to review the research surrounding vascular calcification, a hardening of the arteries due to deposition of minerals calcium and phosphate, which are the same minerals that given bone its strength. The review, which was published in Journal of the American College of Cardiology: Basic to Translational Science, outlined the mechanisms behind the phenomenon and therapeutic approaches to treating it.
The review included the expertise of nephrologists, who are accustomed to seeing vascular calcification because it is often dramatically amplified in patients with chronic kidney disease. It also used cardiologists’ perspectives to consider the management of vascular calcification in these patients with chronic kidney disease as a potential avenue to prevent cardiovascular disease.
“This is a particularly common phenomenon seen in patients with kidney disease because their calcium and phosphate levels are altered by their disease, which enables this calcification—almost bone-like in nature—to develop in the walls of the arteries,” said DCRI nephrologist Myles Wolf, MD, MMSc (pictured right). “Not only is vascular calcification far more common in kidney patients than in the general population, but their disease is usually far more severe.”
The paper’s authors surmise that best practices surrounding the treatment of vascular calcification may soon change due to recent findings that have emerged.
“Although cardiologists have been aware of the presence of vascular calcification for quite some time,there was no real evidence we could slow or reverse its progression,” said DCRI cardiology fellow Adam Nelson, MBBS, PhD (pictured right). “However, recent evidence, which we review in this paper, suggests that vascular calcification may actually be a tightly regulated process in which we could intervene.”
A Focus on Renal Endpoints
Sometimes, cardiovascular trials uncover insights into kidney disease that lead to further exploration.
That was the origin of EMPA-KIDNEY, a trial currently underway that is co-led by DCRI’s Jennifer Green, MD. EMPA-KIDNEY stems from a landmark cardiovascular trial called EMPA-REG OUTCOME, which confirmed that empagliflozin reduced cardiovascular events in patients with cardiovascular disease and Type 2 diabetes. A secondary exploratory endpoint investigated whether the drug also helped to slow progression or delay onset of kidney disease, which frequently impacts patients with cardiovascular disease. As the findings from EMPA-REG OUTCOME were promising, EMPA-KIDNEY was planned to examine this question further. The trial, which is studying patients with chronic kidney disease both with and without diabetes, will primarily determine the impact of empagliflozin therapy on clinically important measures of kidney disease progression or cardiovascular death, and will also explore the impact of therapy on rates of heart failure hospitalization.
“It’s important that we look at multiple endpoints together in the same study. Cardiovascular and kidney disease are common comorbidities, and we don’t focus on only one problem or the other when treating our patients. Our research should reflect real patient care as much as possible,” Green (pictured right) said. “The majority of deaths among people with chronic kidney disease are caused by cardiovascular complications, which may occur long before patients reach end-stage renal disease. It is critical that we search for ways to improve cardiovascular outcomes for this population.”
Like many at the DCRI, Wolf advocates for trials that are designed to answer questions about multiple systems in the body. He argues that every major cardiovascular trial should also consider kidney-related questions—so long as any extra data collection does not make the trial too cumbersome to effectively study the primary endpoints. In most cases, he said, this should not be a limitation.
“Historically, patients with chronic kidney disease have been excluded from randomized clinical trials, especially cardiovascular trials, because they are at higher risk,” Wolf said. “However, this is finally changing as cardiologists are realizing that patients with kidney disease are driving a large proportion of cardiovascular event rates. There is a need to make our clinical trials tell us more—while designing cardiovascular trials, we should include kidney endpoints and make the data collection robust enough to support sophisticated kidney-related analyses and subgroup analyses of patients with different degrees of kidney disease.”
Research Reflected in Patient Care
The need to conduct research that focuses on various systems in the body is underscored in the patients who DCRI faculty care for in the clinic. Cardiologist and heart failure specialist Adam DeVore, MD, MHS (pictured right), is part of the care team for a patient who recently received the U.S.’s first-ever simultaneous heart and kidney transplant from a Donor After Circulatory Death.
The transplant was led by the Duke Transplant Center’s Jacob Schroder, MD, and was conducted as part of the Donors After Circulatory Death Heart Trial, which is testing TransMedics’ OCS Heart device. The device enables the heart to continue beating while in transport, rather than the traditional method of keeping organs on ice. However, because the device had never been used on a patient requiring a dual organ transplant, the team had to seek compassionate use approval from the FDA.
“This operation highlights how Duke uses innovative methods to expand access to transplants to more patients,” DeVore said. “The patient is now doing well, and this dual organ transplant is particularly exciting because about a quarter of my patients have both cardiovascular and kidney disease.”
A Pulmonary Perspective
As research that combines questions about cardiovascular disease and kidney disease continues at the DCRI, experts who represent other DCRI therapeutic areas are also considering how cardiovascular disease factors into conditions they treat every day. DCRI respiratory medicine fellow Christopher Mosher, MD (pictured top right), recently collaborated with DCRI cardiologist Robert Mentz, MD (pictured bottom right), on a paper in American Heart Journal discussing the increased prevalence of cardiovascular disease among patients with idiopathic pulmonary fibrosis (IPF).
IPF, a progressive and fatal lung disease characterized by scarring of the lungs, shares a set of common risk factors with cardiovascular disease, but research reviewed in the paper shows that cardiovascular disease is even more prevalent in patients with IPF than these shared risk factors would suggest. The paper also provides a clinical review of IPF, for which diagnosis remains a challenge, so that cardiovascular clinicians are better equipped to recognize it.
The paper explores future areas for intersectional research. Much of this work can be done through registries, including the DCRI-led IPF-PRO Registry. As new therapeutic agents are developed to treat IPF and survival of IPF improves, it will be increasingly important to track cardiovascular outcomes in these patients. Some of these therapeutics, originally designed for IPF, may be able to safely and effectively treat cardiovascular conditions, as well; one of the clinical trials highlighted in the paper, PIROUETTE, is testing the antifibrotic medication pirfenidone in the treatment of heart failure.
“Future intersectional research between IPF and cardiovascular disease could advance both fields and has the potential of leading to novel therapeutics for patients with cardiopulmonary disease,” Mosher said.
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