DCRI Contributes to AHA Statement on HIV and Cardiovascular Disease

June 12, 2019 – The statement suggests that when treating people living with HIV who exhibit certain characteristics, clinicians should multiply conventional risk calculator scores by 1.5 to 2.

Gerald Bloomfield

The DCRI’s Gerald Bloomfield, MD (pictured), contributed to a statement from the American Heart Association recently published in Circulation that provides a thorough review of current knowledge on HIV-associated cardiovascular disease, as well as a gap analysis that details where more data are needed.

This statement was needed because currently no guidelines exist on how to address cardiovascular disease in people living with HIV, Bloomfield said. Because HIV used to be fatal, little is known about how people living with the virus experience cardiovascular disease. However, a number of observational studies have shown that as treatment for HIV has improved, people living with HIV are living longer and experiencing more age-related comorbidities, including cardiovascular disease.

“This population deserves special attention when assessing and treating for cardiovascular disease,” Bloomfield said. “We know that chronic exposure to HIV increases heart disease risk, so in treating people with HIV, we need to be aware that the underlying contributors to the disease may extend beyond traditional factors.”

For example, he explained, HIV affects heart muscle contraction in unique ways, increasing risk of heart failure. More data are needed to further understand the long-term impacts of these increased risks, as well as to address treatment and prevention. In addition to heart failure, the statement also addresses increased risk for heart attack and stroke which may be driven by the body’s chronic inflammatory response to the HIV virus.

Another important component of the paper, which distinguishes it from many statements made by the AHA, is that it examines how suggested guidelines could be applied outside the U.S.

“Because 70 percent people living with HIV live in Africa, our writing group thought it was important to discuss unique characteristics of HIV and cardiovascular disease in sub-Saharan Africa,” Bloomfield said. “If we had not addressed this, I think we would have been remiss.”

The paper also suggests that conventional risk calculators may under-predict risk for patients in this population and, for HIV+ patients with certain characteristics, recommends that clinicians multiply risk scores by 1.5 to 2.

“This is novel because there is no solid clinical trial data that supports this suggestion,” Bloomfield said. “However, because there are a large number of people living with HIV who are aging and clinicians are wondering what to do and how to treat them, we felt it was important to offer guidance now based on the best available evidence.”

Bloomfield added that studies are currently underway that will shed more light on this topic in a few years, such as the REPRIEVE trial, which the DCRI’s Pamela Douglas, MD, is working on.

DCRI study honored as practice-changing by New England Journal of Medicine

May 29, 2019 – The ARISTOTLE study found that apixaban was superior to warfarin in preventing stroke and decreasing risk of bleeding for patients with atrial fibrillation.

A DCRI-led study published in 2011 was recently honored by the New England Journal of Medicine’s editor-in-chief as one of 12 studies that has most changed clinical practice since 2000.

The ARISTOTLE study found that apixaban was superior to warfarin in treating patients with atrial fibrillation who have an increased risk of stroke. Apixaban was not only more effective than warfarin in preventing stroke, but also caused less bleeding. The trial included more than 18,000 patients from 39 countries.

Prior to his upcoming retirement, Jeffrey Drazen, the editor-in-chief of the New England Journal of Medicine, looked back at the science the journal published over the 19 years he spent in the role. From more than 80,000 submissions and nearly 4,000 published studies, he selected 12 to highlight as “Drazen’s Dozen” of “practice-changing and lifesaving papers.”

“This is really quite an honor, as there are plenty of trials that are equally important,” said the DCRI’s Christopher Granger, MD (pictured), who served as a primary investigator and co-chair on ARISTOTLE. “This is a tribute to a great collaboration—both among so many people at the DCRI and worldwide, especially my co-chair Lars Wallentin from Uppsala University in Sweden.”

The DCRI team also credits its industry partners, Bristol-Myers Squibb and Pfizer, with contributing to the success of ARISTOTLE. The DCRI’s John Alexander, MD, MHS, who worked on ARISTOTLE, started studying apixaban with colleagues from Bristol-Myers Squibb in 2005, but the drug had an unfavorable risk-benefit profile in patients with acute coronary syndrome. By contrast, ARISTOTLE, according to Alexander, was “a home run.”

“It has been a rare privilege to be so intimately involved in the development of a drug that has made, and is making, such a difference in patients’ lives,” Alexander said. “I’ve been involved with a lot of trials, but none have had as great an impact on patient care as ARISTOTLE.”

Apixaban is now the most commonly initiated drug for stroke prevention for patients with atrial fibrillation, Granger said. It is easier to use than warfarin because warfarin is associated with several food and drug interactions and requires monitoring.

“It is gratifying to be able to generate evidence that can be used to help improve patients’ lives,” Granger said. “This honor aligns nicely with the DCRI’s mission to share knowledge that improves patient care around the world—we have been able to publish and share knowledge gained from ARISTOTLE that we now use every day in our practice.”

The DCRI’s Renato Lopes, MD, PhD, started working on the trial as a DCRI fellow, and later became part of the core leadership team of the study as a DCRI faculty member.

“When you work on a trial for so long and put in so much effort, it becomes part of your life,” Lopes said. “We are pleased that ARISTOTLE is still generating knowledge and helping patients all over the world, and it’s extremely rewarding and gratifying to be recognized for the work done by so many to make the trial successful.”

In addition to the primary manuscript published in 2011, there have been over 60 publications from ARISTOTLE with over half published in high-impact journals.

Other DCRI faculty who contributed to ARISTOTLE include Hussein Al-Khalidi, PhD, who was the statistician, and Sana Al-Khatib, MD, MHS, who ran clinical events classification for the trial. Many operational staff also contributed to ARISTOTLE’s success.

TRANSFORM-HF team pioneers new type of clinical trial

January 2, 2019 – One of the first DCRI studies of its kind could become a model for the future.

Heart failure patients have a tendency to accumulate excess fluid in the body, which can lead to debilitating symptoms such as shortness of breath and swelling. Loop diuretic medication, aims to prevent accumulation of this fluid and is the cornerstone treatment for heart failure signs and symptoms. With more than six million Americans affected by heart failure, and about one million hospitalized every year, a new DCRI study called TRANSFORM-HF will directly compare two well-known diuretics – furosemide and torsemide – to determine which is the most effective.

At the same time, the trial’s innovative design could change the way medical research is developed and managed for years to come. Investigators hope that TRANSFORM-HF, which began this summer, will live up to its name – that its innovative approach will transform the clinical trial experience for researchers, site staff, and patients.

“This is one of the first contemporary heart failure studies to significantly streamline the trial process in many important ways,” said Robert Mentz, MD, (pictured) co-principal investigator on the study. “It’s designed to have a lighter touch than most heart failure trials and reduce the burden on everyone involved. We’re striving to surpass traditional rates of site activation and patient enrollment.”

TRANSFORM-HF is being led by the DCRI team and Eric Velazquez at Yale University as well as the National Heart, Lung, and Blood Institute, which recently awarded both institutions grants for the Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC). The primary endpoint is all-cause mortality. Secondary endpoints include patient-reported quality of life and hospitalizations.

The trial was designed to improve the clinical research experience for site coordinators and patients at enrolling hospitals. The study has a projected enrollment of 6,000 patients at approximately 50 sites in the U.S. over the next three years. Enrollment criteria are very broad so that those with both low ejection fraction (weak hearts) and normal ejection fraction (stiff hearts) may enroll. Patients are randomized to either furosemide or torsemide as the study drug, but medication dose and frequency are determined by the patient’s usual medical team.

To date, no large, definitive clinical trial has determined which loop diuretic— furosemide or torsemide—is best, and neither American College of Cardiology nor American Heart Association HF guidelines provides a specific recommendation.

“With slow enrollment across many recent heart failure trials, we’ve been in a particularly challenging time for this kind of research,” Mentz said. “So a key aim was to make TRANSFORM-HF as streamlined as possible for site staff as well as patients, many of whom are elderly and might not otherwise enroll because of the burden of participating in a traditional trial.”

TRANSFORM-HF also aims to streamline data collection and enroll a broad representative population of heart failure patients.

During TRANSFORM-HF, heart failure patients admitted to the hospital are enrolled and randomized equally between the two diuretics before discharge, and then continued on that diuretic as part of their daily care after they return home. While most trials require patients to come to the clinic for extra visits, patients in TRANSFORM-HF follow up per usual care with their normal care teams—there are no extra visits.

Instead, study follow-up is coordinated by the DCRI call center, with patients receiving a 15-minute phone call 30 days into the study and then every six months for up to 36 months, asking scripted questions about medication use, quality of life, and hospitalizations. This “televisit” process saves patients the time, effort, and expense of the extra clinic visits usually required from conventional studies. Hospital records and the National Death Index also will be used to gather follow-up information.

“We knew that if questions were to be answered, TRANSFORM-HF needed to be a really large study in addition to being simple, decentralized, and patient-centered,” said Kevin Anstrom, PhD, co-principal investigator at the trial’s DCC. “There was no way we could do this study with the traditional model.”

“We worked closely with sites on the trial design and the processes to enroll patients and collect patient data,” said Eric Eisenstein, DBA, another co-principal investigator at the DCC. “And because the trial is essentially embedded in the patient’s usual care with their healthcare providers, nothing changes for them –we’re not impacting how they’re otherwise treated. Fewer moving parts lowers trial costs and makes it much easier for everyone in the study.”

According to Eisenstein, investigators also wanted to focus on minimizing the amount of data collected throughout the trial, by, for example, limiting the detail of case report forms. They wanted to optimize the process without sacrificing data quality or the study’s scientific validity, he said.

Because investigators are not “dealing with an investigative product where we don’t know the side effects, this kind of comparative study lends itself well to a streamlined model,” said Mary Creed, MSN, associate director of DCRI’s clinical operations.

“That said, we still have the challenge of keeping the study foremost in patients’ minds and helping to prevent dropout, particularly without the in-person site visits. But simple strategies such as wallet cards in English and Spanish and refrigerator magnets should be helpful.”

TRANSFORM-HF is an exception to traditional HF trials where so few patients qualify, according to DCRI Fellow Stephen Greene, MD.

“Most heart failure trials have many exclusion and inclusion criteria, so only a small percentage of patients seen in general practice qualify,” he said. “TRANSFORM-HF is different – the vast majority of patients seen in everyday practice are going to be eligible. This will help the enrollment rate, and importantly, will also generate trial results that will apply to the at-large heart failure community.”

“Loop diuretics are such an incredibly common heart failure therapy that we really need to know if there is a best one to use,” said Greene. “We owe it to the scientific community, and to our patients, to know the best loop diuretic for heart failure patients.”

Other DCRI contributors on TRANSFORM-HF include Ingrid Jones, Sharon Settles, Varsha Gajjar, Wendy Johnson, Joshua D. Lance, Vivian Thompson, Tina Harding, Amanda Harrington, Kristi Prather, Carol Pereira, Rochelle Suffern, and Shelby Morgan.

AHA 2018: DCRI founder Robert Califf honored with Braunwald Mentoring Award

November 11, 2018 - The award is given to physicians who demonstrate excellence in mentoring young academic clinicians.

The American Heart Association (AHA) has awarded DCRI founder and former FDA Commissioner Robert M. Califf, MD, the 2018 Eugene Braunwald Award for Academic Mentoring. The award, which is given to physicians who demonstrate a consistent track record of outstanding mentorship of young academic physicians, was presented to Califf Sunday at the AHA’s annual meeting in Chicago.

For Califf, who is currently the director of Duke Forge, vice chancellor for health data science, and Donald F. Fortin Professor of Cardiology at the Duke University School of Medicine, the award recognizes a commitment to teaching and mentoring that has been a recurring theme throughout a four-decade career as a cardiologist, researcher, teacher, and public servant.

With the exception of an internal medicine residency at the University of California – San Francisco and two years serving as Deputy Commissioner and then Commissioner of the FDA, almost all of Califf’s career, including his time as an undergraduate and medical student, has been spent at Duke University. But despite his long association with Duke, Califf remains keenly aware that learning and mentoring are to be found in many places.

“Mentoring is a two-way street,” said Califf, noting that some of the most profound lessons of his career have been imparted outside of academia.

Although perhaps best known as a leading figure in cardiovascular clinical trials and as the founding director of the DCRI, Califf also taught and mentored multiple generations of academic physicians at Duke, incorporating continuous learning and teaching into the fabric of the institution he helped create. In addition to mentoring individual learners, Califf also contributed to the creation of innovative training curricula, including the DCRI Research Fellowship Training Program and the University of North Carolina-Duke Collaborative Postdoctoral Training Program.

“Without question, he is the single most important influence in my professional development as both a cardiovascular clinician and a cardiovascular clinical researcher,” said Robert Harrington, MD, chair of the Department of Medicine at Stanford University and incoming AHA president. Harrington, who spent more than two decades at Duke as a cardiologist and clinical researcher, first met Califf in 1990 upon arriving at Duke to begin a cardiology fellowship.

“He has an amazing ability to push people into areas where they are not yet accomplished, to step back and let them run a bit on their own, but to always be available when things don’t work out,” Harrington continued, noting that Califf’s mentoring style helped trainees to grow into true colleagues.

His extensive contributions as mentor at Duke were honored in 2012 with the Duke Clinical Research Mentoring Award, and the DCRI's award given to faculty for outstanding mentorship of fellows is named in honor of Califf. Among the numerous clinicians and researchers, and academic leaders that Califf mentored are Harrington and the Chair of the 2018 Scientific Sessions, Eric Peterson, MD, MPH, – both of whom also followed Califf in the role of director of the DCRI.

During Califf’s remarks at the award presentation, he also issued a call to service. Noting that amid deep cultural and political division the United States is currently experiencing significant health challenges that threaten to erode hard-won gains in life expectancy and quality of life, he challenged his audience to continue to engage with the wider world outside of academic medicine.

“Keeping our heads down in our respective academic or clinical foxholes will not solve the daunting problems that we face both as health professionals and as members of society,” Califf said. “We must work together to re-envision and change the ways that we work to achieve better health outcomes.”