Clinical trial sheds new light on potential risk associated with intravenous iron treatment

December 6, 2018 – A new clinical trial finds that many patients who were treated for iron deficiency anemia with ferric carboxymaltose showed persistent hypophosphatemia five weeks after receiving the treatment.

Results from a new clinical trial may shed new light on hypophosphatemia, a condition caused by a drop in phosphate levels in the blood that has emerged as a common side effect of a widely used intravenous iron treatment for iron deficiency anemia.

Although the first line of treatment for iron deficiency anemia is often oral iron, many patients who experience adverse effects require intravenous iron as an alternative treatment. A recent study led by Myles Wolf, MD, MMSc, of the DCRI (pictured) compared the risk of hypophosphatemia in two intravenous iron treatments – ferric carboxymaltose (Injectafer®), which is currently the most widely used on the market, and ferumoxytol (Feraheme®).

The study’s results were published today in the journal JCI Insight.

The FIRM trial was a randomized, double-blind trial that investigated 1,997 patients over a period of five weeks. Roughly half of the patients received a total of 1,500 mg of ferric carboxymaltose, while the other half received 1,020 mg of ferumoxytol. Each group received the first half of their treatment at baseline and the second half one week later. Hypophosphatemia is listed as a common side effect on the label for ferric carboxymaltose, but it has generally been considered a benign and transient condition, Wolf said. However, recent case reports and the results from the FIRM trial suggest otherwise.

“In the trial we saw that patients who were treated with ferric carboxymaltose were more likely than patients who received ferumoxytol to experience severe or extreme hypophosphatemia,” said William E. Strauss, MD, executive director of medical affairs at AMAG, the company that manufactures ferumoxytol. “These patients were also more likely to have severe hypophosphatemia that persisted at the end of the five week long study.”

The FIRM trial results were as follows, for ferric carboxymaltose and ferumoxytol recipients respectively:

  • 50.8 percent versus 0.9 percent had severe hypophosphatemia, defined as phosphate levels less than 2.0 mg/dL
  • 10.0 percent versus 0.0 percent had extreme hypophosphatemia, defined as phosphate levels below 1.3 mg/dL
  • 29.1 percent versus 0.0 percent had persistence of severe hypophosphatemia at the end of the five-week study period

Wolf said these results suggest hypophosphatemia is not always as transient as once thought. He added that recent case reports have shown instances of persistent hypophosphatemia that led to osteomalacia, bone fractures, and other musculoskeletal disorders. Other literature has found that some patients who take a single dose of ferric carboxymaltose have experienced fatigue and shortness of breath.

Researchers were also able to determine which patient populations were at higher risk because of the large study population. Results showed that both women with abnormal uterine bleeding and black patients were high-risk populations. Because kidney failure is associated with reduced ability to excrete phosphate, patients with healthy kidneys are more likely to develop intravenous iron-induced hypophosphatemia. This phenomenon, Wolf said, is a serious concern.

“This problem is slipping through the cracks in the health care system,” Wolf said. “Nephrologists often administer intravenous iron, and they focus on phosphate because they treat people with kidney failure who frequently develop hyperphosphatemia,” he said. “But they rarely see hypophosphatemia in response to iron because kidney diseases reduces the risk. In contrast, other practitioners who frequently administer intravenous iron to patients at high risk for hypophosphatemia do not think about phosphate levels, and phosphate levels are not measured in standard lab panels.

“Meanwhile patients feel poorly because of their lower phosphate levels, but it is easy to misattribute their symptoms to the original iron deficiency they are being treated for or the underlying disease that caused iron deficiency. If we don’t raise clinicians’ awareness of hypophosphatemia, it’s going to get missed, and grave consequences can ensue.”

DCRI researcher receives 2018 Carolinas Collaborative Grant

December 5, 2018 – Melissa Daubert, MD, will collaborate with researchers at UNC-Chapel Hill to study how to optimize cardiovascular care in women with hypertensive disorders of pregnancy.

The DCRI’s Melissa Daubert, MD, has received one of four 2018 Carolinas Collaborative Grant awards to examine the postpartum care received by pregnant women with hypertensive disorders.

“From retrospective studies, we know that hypertensive disorders during pregnancy put women at higher risk for cardiovascular events later in life,” Daubert said. “If we screen for these early markers for future disease and treat them appropriately, we have the potential to change the trajectory for these patients.”

The $50,000 grant, administered by the North Carolina Translational and Clinical Sciences Institute, calls for applicants to collaborate with researchers from other institutions to use resources from the Carolinas Collaborative. The Collaborative harmonizes electronic health record data across Duke, the University of North Carolina at Chapel Hill, the Medical University of South Carolina, and Wake Forest University.

Daubert, the principal investigator, will work with co-investigators in cardiology and obstetrics-gynecology at Duke (the DCRI’s Tracy Wang, MD, and Thomas Price, MD) and UNC-Chapel Hill (Rachel Urrutia, MD, MS, and Paula Miller, MD). The team will study women with hypertensive disorders of pregnancy who received treatment from Duke and UNC between January 2007 and June 2018. Preliminary results show that over 10,000 women have experienced a hypertensive disorder of pregnancy, which is about 14 percent of all pregnancies that received care at Duke and UNC-Chapel Hill during this time period.

“The national average for the proportion of pregnancies in which the mother has a hypertensive disorder is 10 percent, so these complications are particularly prevalent in our region,” Daubert said. “That makes this study especially important to figure out how best to care for this high-risk population of women and devise interventions to reduce their future cardiovascular risk.”

In North Carolina, many patients transition between Duke and the University of North Carolina Health Care Systems for their primary and specialty care needs. The collaborative nature of the study is also important, Daubert said, because if the research team looked at records from only one institution, there would be a high likelihood of missing follow-up care or treatment for women who saw providers at both Duke and UNC. Because the Carolinas Collaborative has coded electronic health records so that they can be viewed simultaneously across institutions, she said, it was the perfect opportunity to answer this research question.

Guidelines from the American Heart Association advise that women who have hypertensive disorders during pregnancy should be screened six to 12 months after giving birth. Daubert and her team will look at how consistently this screening is being carried out, as well as which types of providers are conducting the screening. They will also compare outcomes of women who received screenings and women who did not.

“While there is growing awareness that these hypertensive disorders increase risks down the road, this correlation is still often unrecognized by patients and providers,” Daubert said. “There is also a misconception that the cardiovascular events will occur decades later, but in reality, up to 45 percent of women who have hypertensive disorders during pregnancy will develop overt hypertension that needs treatment within five years of giving birth.”

Daubert said her team will also be considering how providers in different specialty areas can have the most impact, as well as how care for these patients should be distributed.

“Not only will this lay the groundwork for future studies, but it will also help us identify gaps in care and determine where therapeutics interventions could be implemented in clinical practice,” she said.

The project also recently received a $20,000 DCRI Innovation Award.

DCRI faculty make “highly cited” list again

November 28, 2018 – Ten DCRI faculty members are listed in a new ranking of the world’s most influential researchers.

Once again, several DCRI faculty members are included in the 2018 Highly Cited Researchers list compiled by Clarivate Analytics and Web of Science.

A high citation rate is an indication that a researcher’s work is influential in their field. In both 2016 and 2017, Duke was the fifth-highest cited U.S. institution.

The DCRI researchers listed on this year’s list are Robert Califf, Lesley Curtis, Pamela Douglas, Christopher Granger, Richard S.E. Keefe, L. Kristin Newby, E. Magnus Ohman, Manesh Patel, Michael Pencina, and Eric Peterson. Pencina, the school of medicine’s vice dean for data science and information technology, appears on the list in two separate categories. Several of this year’s researchers also appeared on previous year’s lists.

This year’s list of 6,078 names recognizes world-class researchers for their production of multiple highly cited papers that rank in the top one percent by citations for their field and over the past decade (2006 to 2016), based on Web of Science data. Clarivate’s website allows users to explore the data further.

“The Highly Cited Researchers 2018 list helps to identify the researchers who are having the greatest impact on the research community as measured by the rate at which their work is being cited by others and that contributes so greatly to extending the frontier and gaining knowledge and innovations for society,” said Annette Thomas, CEO of the Scientific and Academic Research group at Clarivate Analytics.

The DCRI’s Sheng Luo on the benefit of biostatistics

November 27, 2018 – DCRI biostatisticians play a key role in many of the organization’s projects.

When the Duke Department of Anesthesiology recently re-applied for a research grant from the National Institutes of Health (NIH), it invited DCRI’s Sheng Luo, PhD, to contribute his biostatistical expertise. The NIH grant would be for a study related to chronic pelvic pain affecting reproductive-aged women.

Sheng LuoThe trial was a multi-site, randomized, double-blinded trial to compare the efficacy of individualized treatments in alleviating pain and improving outcomes for patients suffering from vestibulodynia (VBD). Investigators hoped the study’s findings would help patients, their partners, and their clinicians make more informed decisions about pain management related to VBD. The study design was longitudinal, with patients followed over a period of time and returning for follow-up visits.

“Because data will be collected at each visit,” Luo said, “it was especially important to add a statistical section in the proposal on how we analyze that kind of longitudinal data and what model the study will use. We want to plan for many variables and outcomes of interest.”

A major challenge in all clinical studies is patient enrollment and retention, and especially the probability of patient dropout, according to Luo.

“We want to be ready to handle that with the right statistical analysis plan,” he said. “A study could see as much as a 10 to 20 percent dropout rate, greatly reducing the chances of statistically and clinically significant results. So we use a whole set of criteria to assess how to increase sample size from the beginning to compensate for dropout.”

In general, he said, when preparing a grant application, “it’s ideal to have a statistician join the conversation as early as possible to tackle a wide range of challenges and issues. When properly designed, the study’s data should have sufficient power to show that therapies do or do not work. This is what we looked at with the VBD study.”

DCRI biostatisticians also help predict whether investigators can meet study targets on time, according to Luo, and if patients will be randomized and blinded properly. “The NIH is very concerned about these issues, which can create huge red flags. When studies are properly designed with enough patients and power to produce usable results, time and money will have been well-spent.”

Working with data related to living organisms, DCRI biostatisticians both crunch numbers and help design studies where enough data and the right kind of information are collected. Along the way, they analyze, evaluate, and interpret results while accounting for biases, and missing data, and other relevant issues.

Luo said that including biostatisticians as part of a study team during the grant application process can help boost the chances for a winning proposal. Thanks in part to Luo’s contributions, this fall the Department of Anesthesiology received the five-year NIH grant for its VBD study. Luo also credited Kevin Anstrom, the DCRI’s Director of Biostatistics, for his assistance in applying for the grant.

“Whether a clinical trial is for government or industry,” Luo said, “biostatistics should always play a major role. We’re glad to be brought into the process as early as possible to provide investigators with feedback on the protocol. The sooner the better, really.”

AHA 2018: Plasma proteins may be biomarkers for cardiovascular disease risk in persons living with HIV

November 12, 2018 – A DCRI substudy identified proteins that may differentiate diastolic dysfunction in HIV patients from non-HIV individuals.

As antiretroviral therapy has transformed HIV from a potentially fatal disease to a chronic one, persons living with HIV (PLHIV) may develop more cardiovascular risk factors and CV-related morbidity and mortality, even with viral suppression, than those not infected by HIV.

“Antiretrovirals have shifted the epidemiology of heart failure in HIV from systolic to diastolic dysfunction (DD), putting PLHIV at a higher risk for cardiovascular disease,” said the DCRI’s Svati Shah, MD, MHS. “The question has been what are the mechanisms?”

On Monday at the American Heart Association’s Scientific Sessions 2018 in Chicago, Shah presented her research on proteomics that identify inflammatory, lipid, and cell proliferative pathways in diastolic dysfunction in HIV. Her presentation was a substudy of the CHART (Characterizing Heart Function on Antiretroviral Therapy) clinical trial that recently enrolled 195 healthy PLHIV through the National Heart, Lung, and Blood Institute’s Heart Failure Network.

“With a goal of looking deeply at these patients, we used proteomic profiling technologies to test CHART blood samples and locate the novel biomarkers and potential mechanisms underlying DD in PLHIV,” Shah said. “Both cardiac fibrosis and inflammation have been proposed as key mechanisms in PLHIV underlying cardiovascular disease and heart failure with preserved ejection fraction (HFpEF), but those mechanisms had not been well understood.”

After assaying 977 unique protein biomarkers, Shah and her colleagues determined that cardiac fibrotic pathways (as represented by extracellular matrix proteins) rather than inflammatory pathways were the strong differentiators of DD in PLHIV. “We believe these biomarkers can help identify those PLHIV who have DD and are at risk of developing HFpEF or diastolic heart failure.”

Shah’s team also used STRING bioinformatics tools to analyze which pathways may be “overrepresented” in the data. The extra cellular matrix, which is the core component of cardiac fibrosis, was overrepresented in the significant proteins, Shah said.

“This reinforces other findings that it is not just one protein but several proteins in that pathway that are significant in the development of DD in PLHIV,” she said. “The beauty of these relatively new technologies is the ability to measure so many proteins in very small amounts of blood. It’s like a liquid biopsy, and with such high specificity that we can be confident of what we are measuring.”

“Basically, we are measuring the stiffness of the heart, which is, at a simple level, what DD is,” Shah said. “These proteins essentially show us how cells talk to each other and how they become stiff and cause cardiovascular disease. Going forward, we plan to compare these results to a non-HIV infected group and to perform longitudinal assessments.”

Shah said this may be the first time anyone has been able to look at this many plasma proteins at one time.

“We may also be the first to use high throughput large-scale proteomic profiling to get this comprehensive and unbiased view of the diverse biological pathways underlying DD in PLHIV,” she said.

In addition to Shah, DCRI contributors included Lydia Coulter Kwee, Steven McNulty, and Adrian Hernandez.

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.”

AHA 2018: Female patients significantly less likely to receive statin therapy compared with male patients

November 11, 2018 – A DCRI analysis of patient data from the PALM Registry examines possible reasons for the treatment gap.

While the safety and efficacy of statin therapy for the prevention of atherosclerotic cardiovascular disease is well-established, female patients have historically received less aggressive lipid management than males, according to the DCRI’s Michael Nanna, MD. The reasons for those differences, he said, have been poorly understood.

To investigate this discrepancy, Nanna and his colleagues examined patient data from the PALM (Patient and Provider Assessment of Lipid Management) Registry. Their findings were presented Saturday at the American Heart Association annual meeting in Chicago.

“In looking at why statins are underutilized in eligible women,” Nanna said, “we concluded that they were more likely to never be offered a statin, to decline a statin, and to discontinue a statin than men, even when meeting a treatment indication. This was also after adjusting for patient beliefs, demographics, provider type, and other factors.”

The investigators identified nearly 6,000 adult patients (43 percent female) potentially eligible for primary or secondary prevention statins at 138 U.S. cardiology, primary care, and endocrinology practices in 2015 in the PALM Registry. PALM data and patient surveys showed that 36.7 percent of female patients were on statin treatment and guideline-recommended statin intensity compared to 45.2 percent of male patients, and that these results were consistent across levels of education and income as well as type of treating physician.

Nanna’s study used the 2013 American College of Cardiology and the American Heart Association guidelines on the treatment of blood cholesterol to identify patients eligible for guideline-recommended statin treatment.

“I was surprised to find that such differences persist in contemporary practice and the degree to which they do so,” Nanna said. “Another surprising insight was the difference in beliefs and perception between female and male patients — women were more worried about heart attacks and strokes, for example, but less likely to believe in the association between cholesterol and their heart attack risk.”

Nanna’s study also showed that about 50 percent of female and 43 percent of male patients currently on statins reported adverse effects associated with statin use and that nearly 7.8 percent of women versus 3.6 percent of men reported stopping their statin use as a result. In addition, female patients who were formerly on statins and those that were never on statins were both less willing to try a statin compared with males.

The study had several limitations, according to Nanna. The researchers were unable to specifically capture reasoning for statin prescribing and did not have access to longitudinal data on statin dosing.

“We feel that we can begin to close this treatment gap through better education and communication, especially from clinicians,” he said. “Statins are an important medication for cardiovascular risk reduction, especially for those with existing cardiovascular disease.”

In addition to Nanna, DCRI researchers contributing to the study included Tracy Wang, Qun Xiang, Eric Peterson, and Ann Marie Navar. The study was funded by a National Institutes of Health (NIH) training grant and by Sanofi and Regeneron Pharmaceuticals.

AHA 2018: Heart failure patients receiving sacubitril-valsartan therapy had greater reduction of key biomarker

November 11, 2018 – A new therapy could lead to improved outcomes for patients with acute decompensated heart failure.

New study results support the safety of in-hospital initiation of sacubitril-valsartan for heart failure with reduced ejection fraction (HFrEF) and may point to improved short-term clinical outcomes for patients who receive this treatment.

Acute decompensated heart failure, a clinical syndrome involving new or worsening signs and symptoms of heart failure, leads to more than 1 million hospitalizations per year in the U.S. alone. Despite the availability of promising new therapies, the standard of care — comprising of decongestion with intravenous diuretics and hemodynamic support with vasodilators and inotropes — has been largely unchanged over the past 45 years.

Adam DeVoreThe PIONEER-HF trial, which sought to compare the in-hospital initiation of sacubitril-valsartan therapy with enalapril, showed no significant difference in rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema in heart failure patients with HFrEF.

These findings were presented Sunday at the 2018 American Heart Association Scientific Sessions in Chicago.

PIONEER-HF was a multicenter, randomized, double-blind study of the effect of sacubitril-valsartan versus enalapril on changes in NT-proBNP, as well as safety and tolerability of in-hospital initiation in HFrEF patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF). Of the 881 patients at 129 U.S. sites who were randomized, 440 were assigned to receive sacubitril-valsartan and 441 to enalapril.

In this patient population, sacubitril-valsartan therapy led to a greater and more rapid reduction in NT-proBNP than enalapril therapy. NT-proBNP is a biomarker associated with subsequent cardiovascular events. The beneficial effect of sacubitril-valsartan on NT-proBNP was accompanied by a reduction in the concentration of high-sensitivity cardiac troponin, a biomarker of myocardial injury that is associated with abnormalities in cardiac structure and function and with a worse prognosis among patients with heart failure.

An analysis of exploratory clinical outcomes showed that the in-hospital initiation of sacubitril-valsartan therapy was associated with a decrease in the rate of rehospitalization for heart failure at eight weeks.

“These study results address an important information gap in how to use sacubitril-valsartan in patients with HFrEF, showing that this is a safe strategy in these patients, and provides a marked improvement in a key biomarker,” said the DCRI’s Adam DeVore, MD, MHS, who contributed to the research.

“We also observed improved short-term clinical outcomes,” DeVore said. “Our results expand the population that could potentially benefit from sacubitril-valsartan, including patients who are hospitalized for acute decompensated heart failure, patients who have de novo heart failure, and patients not being treated with ACE inhibitors or ARBs at the time of hospitalization. Importantly, 36 percent of the U.S. patients in our trial identified as black, providing much-needed data on the use of this therapy in this population.”

The favorable effect of sacubitril–valsartan versus enalapril was evident from the in-hospital initiation of treatment and continued during the transition to home and the subsequent “vulnerable period,” when morbidity and mortality among patients with acute decompensated heart failure remain high.

“These results support a strategy of in-hospital initiation of sacubitril-valsartan for patients hospitalized with acute decompensated heart failure and have a reduced left ventricular ejection fraction,” DeVore said.

Former DCRI fellow Andrew Ambrosy, MD, also contributed to this research.

This study was funded by Novartis Pharmaceuticals.

AHA 2018: Heart failure patients with specific genetic variants could see extra benefit with beta blocker bucindolol

November 11, 2018 – A new study suggests an alternative treatment for patient groups who do not benefit from more widely used anti-arrhythmic agents.

Because many anti-arrhythmic agents for atrial fibrillation (AF) and atrial flutter (AFL) are ineffective or even unsafe for heart failure patients, researchers are investigating alternative therapies to reduce AF in this patient population.

The recently completed GENETIC-AF phase IIB clinical trial compared pharmacogenetically targeted bucindolol with metoprolol for the prevention of AF and AFL in a genotype-defined heart failure population with a high risk of AF/AFL recurrence. With 267 enrolled patients, the study showed trends for bucindolol superiority in population subgroups with the ADRB1 Arg389Arg genetic variant.

At the Scientific Sessions of the American Heart Association in Chicago Sunday, the DCRI’s Jonathan Piccini, MD, presented findings from that trial’s subgroup of 69 heart failure patients who had continuous rhythm monitoring via implanted loop recorders or other devices to evaluate AF burden (AFB). Heart failure patients with AFB of six or more hours per day, as measured by implanted cardiac devices, are more likely to be hospitalized for their heart failure, said Piccini. Therefore, AFB was defined in GENETIC-AF as 6 hours or more of AF during a 24-week follow-up period.

The substudy had two purposes: to examine AFB as an endpoint as well as its implications for clinical trial development and patient care, and to determine if pharmacogenetically guided bucindolol is superior to standard beta-blocker therapy.

“Atrial fibrillation burden is a hot topic because several studies have shown that it is linked to several cardiovascular outcomes,” Piccini said. “For example, AFB is associated with increased risks of stroke and hospitalization.”

“GENETIC-AF was an innovative study not only because it used AFB as an endpoint but also because it addressed the concept of pharmacogenetically guided therapy for AF in patients with heart failure. GENETIC-AF was designed to determine whether patients’ genetic background can be harnessed for added benefit from bucindolol — that is, reducing AF. This was the first pharmacogenetic trial for this indication- rhythm control of AF.”

Bucindolol was previously studied in the BEST phase III trial, with 2,708 congestive heart failure patients. The primary endpoint of BEST was all-cause mortality. A substudy of 1,040 patients showed genotype-dependent enhancements for several heart failure endpoints. Bucindolol has two unique pharmacologic properties that favorably interact with the Arg389Arg genotype, sympatholysis and inverse agonism, which bring clinical benefits in patients with heart failure.

“In patients with this beta-1 receptor variant, bucindolol appeared to have a stronger impact than metoprolol,” said Piccini.

Piccini’s substudy found that continuous monitoring with devices such as pacemakers tended to detect more AF/AFL events than ECG monitoring. Furthermore, the AFB events tracked with traditional measures of symptomatic AF detected by traditional electrocardiographic monitoring.

“Event rates were higher for device-based monitoring than intermittent monitoring,” said Piccini. “These results are important because with a proliferation of monitoring technologies, including the Apple Watch, we don’t have to ask patients to call in. Their symptoms and rhythm can be recorded on their phone and other handheld rhythm capture technologies.”

Piccini said that the trial asked a very fundamental question.

“In an age of personalized medicine, wouldn’t it be great to know that a particular patient with a particular genotype would do really well with, for example, bucindolol, because it can lower her AF burden?” he said. “The study also confirms that monitoring with implanted cardiac monitoring devices provides the most precise data. There is still much to learn, of course, but someday we could be looking at a new kind of concierge pharmacology for patients with AF and heart failure.”

AHA 2018: Study finds lower risk of bleeding in adults with Afib and vascular disease taking DOACs versus warfarin

November 11, 2017 – Despite evidence that DOACs can help with bleeding in patients with atrial fibrillation, the researchers cautioned that more research is needed.

Treatment patterns and outcomes for patients with vascular disease and atrial fibrillation (AF) are not well characterized, adding complexity to treatment decisions for this population. A DCRI study found that although direct-acting oral anticoagulants (DOACs) may reduce the risk of bleeding events in patients with new-onset AF and vascular disease, the use of antiplatelet therapy in this population may need further review.

Results from the study were presented Sunday at the 2018 American Heart Association (AHA) Scientific Sessions in Chicago, Illinois.

Taku InoharaAccording to the analysis, DOACs such as apixaban, dabigatran, edoxaban, and rivaroxaban have been increasingly used, along with concomitant use of antiplatelet therapy, to manage this patient population. But the study found that antiplatelet agents, and particularly dual antiplatelet therapy (DAPT), seem to increase bleeding risk with no apparent clinical benefit to the patients. 

The retrospective cohort study set out to analyze treatment and outcomes in 6,203 patients from 229 sites with new-onset AF from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II) registry. In total, the registry enrolled 13,394 patients with AF at 244 sites from February 2013 to July 2016. In the new-onset AF cohort, vascular disease was associated with increased risk of major adverse cardiovascular or neurological events, cardiovascular death, and heart attack, also called a myocardial infarction, but not thromboembolic (involving a blood clot) or bleeding events.

“Relative to new onset-AF patients with vascular disease on warfarin, the rate of bleeding events appeared to be lower in those treated with DOACs, with similar efficacy,” said lead author and presenter Taku Inohara, MD, PhD, of the DCRI. “For these patients, DOACs may be preferable to warfarin.”

“Concomitant use of antiplatelet agents, especially DAPT, needs to be reconsidered, due to the increased risk of bleeding, without evidence of improved cardiovascular outcome,” he said. “Further studies are needed to clarify optimal management for this specific high-risk patient population.”

In addition to Inohara, Duke contributors to the research included Peter Shrader, Karen Pieper, Rosalia Blanco, Eric Peterson, and Jonathan Piccini.