Duke hosts Precision Medicine World Conference

May 26, 2017 – The DCRI’s Robert Califf, MD, was among the speakers at the gathering of academics, entrepreneurs, and healthcare professionals.

Hundreds of people representing a broad spectrum of healthcare, research and technology converged on Duke University on May 24 and 25 for the Precision Medicine World Conference (PMWC). The gathering spotlighted the rapid growth of biomedical technologies spurring initiatives that enable the translation of precision medicine into direct improvements in healthcare.

The conference, co-hosted by Duke Health and Duke University, marked the first time the PMWC was held on the East Coast. This year’s theme was “Translating the Power of Precision Technologies into Better Health Care.” More than 30 sessions were held over the two days, featuring a total of more than 100 speakers from the healthcare and biotechnology sectors.

Geoffrey Ginsburg, MD, PhD (pictured), director of Duke Center for Applied Genomics and Precision Medicine and conference co-chair along with Chancellor Emeritus Ralph Snyderman, MD, said the meeting reflects a powerful convergence of important disciplines – ranging from genome sciences and data sciences to information technology, tissue and genetic engineering, behavioral science, and immune and cancer biology.

Francis Collins, MD, PhD, director of the National Institutes of Health (NIH), outlined NIH’s “All of Us” precision medicine initiative to study the impact of genes and environment. The study hopes to enroll 32,000 volunteers by the end of 2017 and 1 million by 2022. The data it collects will be accessible to researchers.

“This is a pretty exciting time to contemplate where we are in precision medicine and where we are going,” said Collins. Collins later received a PMWC Luminary Award, which recognizes recent contributions of leaders who have accelerated personalized medicine into the clinical marketplace.

The conference was co-hosted by Ginsburg and Snyderman.

Medical claims may not be enough to assess clinical outcomes in research trials

May 24, 2017 – According to DCRI researchers, while medical claims may be a reasonable resource to assess myocardial infarction (MI) and stroke outcomes, caution is still needed.

A recent study by DCRI researchers published May 24 in JAMA Cardiology found that one-year post-MI rates of recurrent MI, stroke and bleeding were lower when identified by medical claims than when adjudicated by physicians. The study also observed that the accuracy of medical claims in identifying events was, at best, modest for MI and stroke, using physician adjudication as gold standard, and lower for bleeding events.

“Pragmatic clinical trials have proposed use of readily-available data, such as patient medical claims, to assess clinical events, but the accuracy of billed diagnoses in identifying potential events is unclear,” said DCRI Fellow Patricia Guimaraes, MD, lead author of the study. According to Guimaraes, previous studies on the topic have all been limited to patients older than 65 years as they use data from Medicare.

“We wanted to take advantage of the TRANSLATE-ACS data–a study that included post-MI patients of all ages–and explore whether medical claims can accurately assess cardiovascular and bleeding events in an all-aged post-MI population,” Guimaraes said.

TRANSLATE-ACS, or Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome, was an observational, longitudinal study led by the DCRI and the American College of Cardiology Foundation. It examined post-discharge care patterns and treatment adherence of 12,365 patients enrolled at 233 U.S. hospitals, and evaluated the safety, effectiveness, and healthcare costs of antiplatelet therapy use among contemporary acute MI patient populations treated with percutaneous coronary intervention.

For the JAMA study, DCRI researchers obtained medical claims data for all rehospitalizations occurring within a year of the index acute MI in patients enrolled in the TRANSLATE-ACS study. They identified recurrent MI, stroke, and bleeding events based on diagnosis and procedure codes in the acquired medical bills. These clinical events were independently signed off by physicians based on medical record review.

“Our results suggest that we need to be cautious about using medical claims as the only method of event ascertainment, especially for bleeding events,” Guimaraes said. “Medical claims have limited accuracy in identifying bleeding events, which suggests the need for an alternative approach to ensure good safety surveillance in cardiovascular studies.”

According to Guimaraes, to improve the accuracy of events collected through existing billing claims, the coding algorithms used to find events can be further developed.

“We can ensure a broad search for events as done in the TRANSLATE-ACS study and ascertain events through different methods to avoid missing or over/under-classifying events,” she said.

In addition to Guimaraes, other authors included Arun Krishnamoorthy, Lisa A. Kaltenbach, Kevin J. Anstrom, Mark B. Effron, Daniel B. Mark, Patrick L. McCollam, Linda Davidson-Ray, Eric D. Peterson and Tracy Y. Wang.

Iron supplements do not improve exercise ability in heart failure patients

May 18, 2017 – High-dose oral iron supplements failed to improve peak exercise capacity and had little effect in replacing iron stores in chronic heart failure patients with anemia and reduced left ventricular ejection fraction, states a paper published in the Journal of the American Medical Association.

Iron deficiency – which occurs in around one-half of these patients – is an independent predictor of mortality. Two earlier trials had found that intravenous iron increased exercise capacity and quality of life in this population. The utility of inexpensive, readily available oral iron supplementation in heart failure was unknown.

Adrian Hernandez

The JAMA paper reports on the findings from a randomized, double-blind study known as the Oral Iron Repletion effects on Oxygen UpTake in Heart Failure (IRONOUT HF) trial. This investigated the effect of oral iron polysaccharide (150 mg twice daily) compared with matching placebo. Involving 225 patients at 23 U.S. sites between September 2014 and November 2015, IRONOUT HF was an NIH-sponsored multi-center trial.

The JAMA paper concluded that high-dose oral iron minimally repleted iron stores and did not improve exercise capacity in patients with heart failure with reduced left ventricular ejection fraction. The study findings do not support the use of oral iron supplementation to treat iron deficiency in these patients, say the authors.

“We are still trying to find the most straightforward approach to improving the health of patients with chronic heart failure,” said co-author Adrian F. Hernandez, MD, MHS, director of Health Services Outcomes Research at the DCRI. “Unfortunately in this study, we learned that oral iron therapy is not sufficient to improve anemia and ability to exercise in these patients. Intravenous iron supplementation may be more helpful, and is being investigated in a newly-launched large outcomes study called HEART-FID.”

Aimed at enrolling more than 3,000 adult patients across North America, HEART-FID will assess the efficacy and safety of iron therapy using intravenous ferric carboxymaltose, relative to placebo, in the treatment of patients with heart failure, iron deficiency and a reduced ejection fraction. Outcome measures will include the 12-month rate of death, hospitalization for worsening heart failure, and the six-month change in six-minute walk test for patients in heart failure with iron deficiency.

In addition to Hernandez, DCRI and Duke authors of the JAMA paper were Steven McNulty, MS; G. Michael Felker, MD; and Kevin J Anstrom, PhD.

Former FDA Commissioner Robert Califf will head initiatives at Duke, Verily

May 17, 2017 – DCRI founder Robert Califf, MD, will continue to serve as a senior advisor for the DCRI.

Robert Califf, MD, the former Commissioner of the U.S. Food and Drug Administration, an internationally renowned clinical trial expert, and a longtime Duke faculty leader will assume the position of Vice Chancellor for Health Data Science for Duke Health. Califf’s appointment was announced today by A. Eugene Washington, MD, Duke Chancellor for Health Affairs and President and CEO of the Duke University Health System.

“Dr. Califf is one of the most respected figures in academic medicine today and is widely regarded as a preeminent innovator in clinical evidence generation,” Washington said. “One of the primary themes that has defined his career has been his pursuit of translating clinical information into pragmatic approaches to improving healthcare and health. It is this lifelong quest that uniquely qualifies him to lead these vitally important health data science endeavors for Duke.”

Califf also becomes the director of a new cross-campus center at Duke University for integrated health data science. This center, which has not yet been formally named, will seek to advance and create inter-campus collaborations focused on health data science-driven research and innovation, amplify Duke’s role in building a nationally regarded network for clinical evidence generation, and develop a stronger presence and role for Duke in Silicon Valley and other areas known for data science innovation and excellence. Both of Califf’s appointments will be effective immediately.

In addition to these new roles at Duke, Califf will be joining the senior management team at Verily Life Sciences, an Alphabet company. He will split his time evenly between his responsibilities at Duke and at Verily.

“We’re honored that Dr. Califf has chosen this innovative career option from among the many significant and high level opportunities that were available to him following his exceptional service as FDA Commissioner,” said Mary Klotman, MD, chair of the Department of Medicine and dean-elect of Duke University School of Medicine. “Better understanding the most effective, pragmatic application of the mountains of data that continue to grow is one of the great opportunities in clinical medicine in the coming years.”

Califf has enjoyed an exceptional career that was highlighted in February 2015 with his appointment as Deputy Commissioner for Medical Products and Tobacco at the U.S. Food and Drug Administration. This appointment led to his being named FDA Commissioner in February 2016. Califf left the FDA in January 2017.

During his career at Duke, Califf has held many significant roles including serving vice chancellor of clinical and translational research, and the director of the Duke Translational Medicine Institute. Califf might be best known as a founding director of the DCRI, now the largest and one of the most respected academic clinical research organizations globally. Califf will continue to serve as a senior advisor at the DCRI.

Outside of Duke, Califf has led many landmark clinical studies, and is a nationally and internationally recognized expert in cardiovascular medicine, health outcomes research, health care quality, and clinical research. Califf also played a pivotal role in the development and leadership of the national Patient-Centered Outcomes Research Network, which is designed to enhance the quality and relevance of clinical evidence that is used to guide health decisions.

Califf was a member of the Institute of Medicine (IOM) committees that recommended Medicare coverage of clinical trials and the removal of the dietary supplement ephedra from the market, and of the IOM’s Committee on Identifying and Preventing Medication Errors.

Califf is one of the top 10 most-cited medical authors with more than 1,200 peer reviewed publications.

Califf earned both his undergraduate and M.D. degrees from Duke in 1973 and 1978 respectively, and left North Carolina only briefly when he completed an internal medicine residency at the University of San Francisco. Except for his two years at FDA, he has spent his entire career at Duke.

“We are most fortunate that Rob will invest his considerable expertise and energy to build a university-wide center that coalesces data science expertise and health data resources from across the campus for the improvement of human health,” said Sally Kornbluth, PhD, Duke University Provost. “I believe his commitment to this vision has the potential to create a unique engine for better understanding human health and disease.”

In his new role with Verily Life Sciences, Califf will serve to provide guidance for translation of Verily’s growing volume of health-related data into practical health applications.

“We were all very proud of Rob during his service to the country at the FDA,” said Washington. “But we are even more proud today that he is coming home to Duke to help us continue to create the future of healthcare and health.”

Combination therapy may reduce cardiovascular risk in chronic kidney disease patients

May 16, 2017 – A combination of simvastatin, a lipid lowering agent, and ezetimibe, an inhibitor of intestinal cholesterol, may benefit patients with moderately reduced kidney function, states a paper published today in the Journal of the American Society of Nephrology.

Chronic kidney disease (CKD) is a major public health problem that affects more than 20 million Americans, carrying an increased risk for death from cardiovascular disease, due to several factors such as malnutrition, chronic inflammation, increased oxidative stress, and vascular and endothelial dysfunction. Kidney function, as measured by estimated glomerular filtration rate, is an independent and strong predictor of this risk. However, CKD patients have historically been excluded from clinical trials, resulting in a limited understanding of the safety and efficacy of lipid modifying therapies in this population.

This post-hoc analysis examined data from 18,000 patients involved in the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). This was a multi-country, double-blind, randomized controlled study evaluating the effect of ezetimibe combined with simvastatin, compared with simvastatin alone, in individuals with known cardiovascular disease and baseline LDL (‘bad’) cholesterol values below 125 mg/dL.

“In our analysis, combination therapy with ezetimibe plus simvastatin appeared to be more effective than simvastatin monotherapy in reducing death from cardiovascular disease, major coronary events, or nonfatal stroke at moderately reduced levels of kidney function,” said lead author John W. Stanifer, MD, MSc. Stanifer is co-chief fellow at the DCRI and a fellow in the Division of Nephrology, Department of Medicine, Duke University. “These effects, seen over the seven years of the IMPROVE-IT study, could impact our ability to treat this high-risk population. However, further studies of combination lipid-lowering therapy in individuals with CKD are needed, particularly in those with more severely reduced kidney function.”

These findings are in line with those of the Study of Heart and Renal Protection (SHARP) study, which concluded that around a quarter of heart attacks, strokes, and operations to open blocked arteries could be avoided in people with chronic kidney disease by using the combination of simvastatin and ezetimibe to lower blood cholesterol levels. The SHARP study involved nearly 9,500 volunteers aged 40 or over with chronic kidney disease recruited from 380 hospitals in 18 countries.

Other Duke and DCRI authors on the paper were Jennifer White, MS; Yuliya Lokhnygina, PhD; Matthew T. Roe, MD, MHS; and Michael A. Blazing, MD.

A breakthrough in device evaluation

May 15, 2017 – Researchers from the DCRI and Mercy Health make vital contributions toward the adoption and use of Unique Device Identifiers (UDIs), to transform and streamline medical device evaluation and surveillance.

A study recently published in the Journal of the American Medical Informatics Association by the DCRI’s James Tcheng, MD, (pictured) and Mercy Health’s Joseph P. Drozda, MD, highlights the informatics aspects of the U.S. Food and Drug Administration (FDA)-funded Mercy Demonstration Project. The project was primarily conducted in the Mercy Health System in St. Louis, where prototype UDIs were incorporated into the enterprise’s electronic information systems.

Safety surveillance of medical devices has been a top priority of the FDA but there has been no universal mechanism of identifying these devices across healthcare. This lack of standardization has been a barrier to efficient business processes and device safety surveillance in the past. Therefore, the FDA, along with the European Commission and other regulators devised the UDI system as a framework for identifying medical devices using an alpha-numerical barcode system that can be applied globally. The demonstration project goes a step further by testing the implementation of UDIs in electronic health data, which according to Tcheng, is a key priority for the FDA.

“The FDA has been working tirelessly for a number of years to modernize the approaches they are taking to device surveillance to evaluate and improve both unapproved devices under development and those already on the market,” Tcheng said. “Via the Demonstration Project, we set out to build and implement prototype UDIs for coronary stents across all electronic health information systems, using Mercy Health’s information systems as the test bed,” he added.

The demonstration project involved multiple stakeholders including the FDA, the American College of Cardiology’s National Cardiovascular Data Registry, various departments across Mercy Health, manufacturers, health system partners, professional societies and information system vendors.

During the course of the project, the researchers created both a UDI reference database containing device characteristics and a UDI Research and Surveillance Database containing the connected clinical and device data, facilitating longitudinal assessment of device performance. The UDI prototype database has since evolved into a product that is now available from the FDA – the Global Unique Device Identifier Database (GUDID), which will serve as a reference catalog for every device with a UDI.

“[This work] not only represents a major milestone in developing a device evaluation system, serving as the framework for what’s going to be put in place nationally for device surveillance,” Tcheng said. “UDI implementation will improve patient safety, modernize device post-market surveillance, and facilitate medical device innovation.”

The findings are generalizable for everything from pacemakers and pacemaker leads, to intraocular lens implants, to hip prostheses or any other implantable medical device. It also provides the framework for the DCRI’s Medical Device Epidemiology Network’s Registry Assessment of Peripheral Interventional Devices project that seeks to improve quality and efficiency of peripheral interventional device evaluation.

The information and knowledge that the researchers gained through the demonstration project is now being applied to the GUDID through the Learning UDI Community (LUC). Both Tcheng and Drozda serve as chairs of several subgroups within the LUC to assist the FDA in improving the GUDID system.

“Ultimately, what we hope to do is have the American College of Cardiology’s National Cardiovascular Data Registry serve as a data aggregation point that enables improvement of devices across the total product lifecycle of devices,” said Tcheng.

In addition to Tcheng and Drozda, other researchers included James Roach, Thomas Forsyth, Paul Helmering and Benjamin Dummitt.

RENAL-AF trial enrolling first patients

May 12, 2017 – The Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation (RENAL-AF) trial is the first randomized clinical trial of any anticoagulant in patients on hemodialysis with atrial fibrillation (AF).

RENAL-AF is an interventional, prospective, open-label, blinded end-point evaluation trial that has recently enrolled its first patients with AF and end-stage renal disease (ESRD) receiving hemodialysis. Led by the DCRI’s Christopher Granger, MD, (pictured left) and Stanford University’s Glenn M. Chertow, MD, the study will assess the safety and efficacy of the oral anticoagulant apixaban by randomizing patients to apixaban versus warfarin, with clinically relevant, non-major bleeding event as the primary outcome.

“Roughly 20 per cent of patients that are on hemodialysis have a high burden of AF, yet there have been no studies or randomized trials addressing the use of oral anticoagulants in this population for AF and stroke prevention,” said Granger, principal investigator of the trial. Compared to the general population, AF is far more common and associated with a much higher risk of stroke in the dialysis population, leaving a major unmet clinical need in this high-risk population.

Warfarin has long been the anticoagulant of choice for preventing stroke in patients with AF. However, warfarin requires regular blood tests and can be affected by other medications and foods. These concerns are particularly important for patients on hemodialysis since they often have irregular diets and multiple medication changes. Newer blood thinners such as apixaban have been proven to be safer than warfarin in the general population but they have never been tested in patients on hemodialysis.

“All novel oral anticoagulants are cleared by the kidneys, however, apixaban has less renal clearance than the others, making it an ideal medication to study in this population,” said the DCRI’s Sean Pokorney, MD (pictured right).

The primary outcome assessed in the RENAL-AF trial is the time from randomization to the first major or clinically relevant non-major bleeding event, a common safety concern for any anticoagulant. Adherence to treatment with apixaban or warfarin will be assessed through medication adherence questionnaires, as well as pill counts for patients randomized to apixaban and time spent in therapeutic range for warfarin (which is assessed by routine blood checks). The study is expected to enroll over 750 adult patients across the United States. The full study will conclude by mid-2020.

The researchers are also conducting a pharmacokinetic and pharmacodynamic study within the RENAL-AF trial of patients randomized to apixaban. Biomarker samples are also being collected at baseline for research related to bleeding and stroke events.

“The first 50 patients will have extensive testing to understand how apixaban is absorbed and metabolized in patients with ESRD and AF,” Pokorney said. “These will be the first data to come out of the RENAL-AF trial, which means we will have some very important results as early as the end of this year.”

“Since this is the very first randomized clinical trial of any anticoagulant in patients on hemodialysis with AF, whatever the results show us, it will be important,” Granger said. “It will be an advance for clinical medicine if apixaban turns out to be safe and effective for this important population.”

Stem cell therapy holds promise for treating most severe cases of angina

May 11, 2017 – Meta-analysis shows CD34+ stem cells reduce mortality for class III and IV refractory angina patients.

An analysis of data from the entire development program consisting of three trials assessing the feasibility of using a stem cell therapy (CD34+ cells) to treat patients with the most severe cases of angina, refractory angina (RA), showed a statistically significant improvement in exercise time as well as a reduction in mortality.

Results from “CD34+ Stem Cell Therapy Improves Exercise Time and Mortality in Refractory Angina: A Patient Level Meta-Analysis” were presented today as a late-breaking clinical trial at the Society for Cardiovascular Angiography and Interventions (SCAI) 2017 Scientific Sessions in New Orleans.

One of the warning signs of coronary artery disease is angina, or chest pain, which occurs when the heart muscle does not receive enough blood. Unlike angina pectoris or “stable angina,” which can often be treated with medication, RA can be incapacitating, impacting quality of life. In the most severe cases, those with class III or IV angina, treatment options are exhausted, and patients remain severely debilitated. Unfortunately, one of the untoward consequences of the improved survival of patients with chronic ischemic heart disease is more patients with refractory angina.

A meta-analysis of three trials that each showed promising results looked at injecting RA patients with autologous CD34+ cells — which have been shown to increase blood flow — and the therapy’s effect on mortality and total exercise time (TET), an important predictor of long-term mortality. Data from 304 patients was extracted and analyzed from phase 1 (24 patients), ACT-34 and ACT-34 extension studies (168 patients), and RENEW (112 patients), which was prematurely terminated by the sponsor due to financial considerations.

“The goal of this meta-analysis was to combine patient level data from three very similar trials to try understand what it would tell us,” said lead investigator Tom Povsic, MD, FSCAI, associate professor at the DCRI and an interventional cardiologist at Duke University School of Medicine.

Results showed that patients treated with CD34+ cell therapy (n=187) improved TET by 80.5 ± 12.1, 101.8 ±13.7, and 90.5 ± 14.7 seconds at three months, six months, and 12 months compared with 28.1 ± 15.7, 48.8 ± 18.2, and 39.5 ± 20.3 seconds for the placebo group (n=89), resulting in treatment effects of 52.5 (p=0.002), 52.9 (p=0.009) and 50.9
(p=0.027) seconds.

The relative risk of angina was 0.90 (p=0.40), 0.81 (p=0.14), and 0.79 (p=0.17) at three months, six months, and 12 months in CD34+ treated patients. CD34+ treatment decreased mortality by 24 months (2.6 percent vs. 11.8 percent, p=0.003). In addition, major adverse cardiac events were less frequent (29.8 percent for CD34+ patients vs. 40.0 percent for the placebo group,
p=0.08).

“Therapies for these patients are direly needed,” said Povsic, “and results from our meta-analysis are very compelling. Most importantly, the number of patients in our meta-analysis approximates those who were targeted for enrollment in RENEW, the prematurely terminated phase III study. These results suggest that had RENEW been completed, a regenerative therapy for these patients might meet criteria for approval. I still think this therapy has a lot of promise.”

Timothy Henry, MD, chief of cardiology at Cedars-Sinai Medical Center in Los Angeles, agrees “CD34+ cell therapy appears to be an extremely safe and effective therapy for this growing and challenging patient population with limited options.”

DCRI’s Kevin Schulman helps relaunch HMPI

May 11, 2017 – Schulman serves as a member of the journal’s editorial team.

The journal Health Management, Policy and Innovation (HMPI), which includes the DCRI’s Kevin Schulman, MD, as a member of its editorial team, relaunched today. The newly designed journal can be found at http://hmpi.org.

HMPI is sponsored by the Business School Alliance for Health Management, an international consortium of MBA programs with a health sector focus.

“We will draw from the research and experience of scholars and practicing leaders to provide relevant insights for public and private organizations in the international health sector,” writes journal editor Will Mitchell of the University of Toronto. “In achieving the goal of providing relevant insights for practicing managers, HMPI is central to BAHM’s mission of harnessing our collective energy, intellect, and resources to solve today’s healthcare problems and address opportunities to advance health care that are emerging around the world.”

DCRI receives CRO Leadership Awards for second year

May 10, 2017 – For the second year, the DCRI has been recognized by Life Science Leader magazine.

The DCRI has again received several CRO Leadership Awards from Life Science Leader magazine. This year, the DCRI was recognized in the categories of capabilities, compatibility, expertise, quality, and reliability. It also received individual attribute awards for data quality, meeting project timelines, offering innovative solutions, operational excellence, responsiveness, and technology for access to data.

In 2016, the DCRI received CRO Leadership Awards in the categories of capabilities, expertise, and quality, and individual attribute awards for data quality, innovative solutions, and real-time access to data.

The awards are based on surveys conducted by Industry Standard Research. Seventy-two contract research organizations were included in the research and evaluated on 27 different performance metrics. The award candidates included biopharmaceutical companies of all sizes. Survey respondents evaluated only companies with which they worked on an outsourced study within the past 18 months.

The results appear in the May issue of Life Science Leader. A list of winners can be found at http://croleadershipawards.com/index.php/winners.

“It’s an honor to be recognized again for the work we are doing to make tomorrow better than today for patients around the world,” said DCRI Executive Director Eric Peterson, MD, MPH. “This award is evidence that our peers understand the value of the unique perspective the DCRI brings to the most vital healthcare questions of the day.”