Exposure to cannabis alters the genetic profile of sperm

December 19, 2018 – Whether genetic changes can be reversed or are passed on to children is still unknown.

As legal access to marijuana continues expanding across the U.S., more scientists are studying the effects of its active ingredient, tetrahydrocannabinol (THC), in teens, adults and pregnant women.

New research from DCRI and Duke investigators suggests men in their child-bearing years should also consider how THC could impact their sperm and possibly the children they conceive during periods when they’ve been using the drug.

Much like previous research that has shown tobacco smoke, pesticides, flame retardants and even obesity can alter sperm, the Duke research shows THC also affects epigenetics, triggering structural and regulatory changes in the DNA of users’ sperm.

Experiments in rats and a study with 24 men found that THC appears to target genes in two major cellular pathways and alters DNA methylation, a process essential to normal development.

The researchers do not yet know whether DNA changes triggered by THC are passed to users’ children and what effects that could have. Their findings were published online Dec. 19 in the journal Epigenetics.

“What we have found is that the effects of cannabis use on males and their reproductive health are not completely null, in that there’s something about cannabis use that affects the genetic profile in sperm,” said the DCRI’s Scott Kollins, PhD, senior author of the study.

“We don’t yet know what that means, but the fact that more and more young males of child-bearing age have legal access to cannabis is something we should be thinking about,” Kollins said.

National research has shown a steady decline in the perceived risk of regular marijuana use. This, combined with the demand and wide availability of marijuana bred specifically to yield higher THC content, make this research especially timely, Kollins said.

The study defined regular users as those who smoked marijuana at least weekly for the previous six months. Their sperm were compared to those who had not used marijuana in the past six months and not more than 10 times in their lifetimes.

The higher the concentration of THC in the men’s urine, the more pronounced the genetic changes to their sperm were, the authors found.

THC appeared to impact hundreds of different genes in rats and humans, but many of the genes did have something in common — they were associated with two of the same major cellular pathways, said lead author Susan K. Murphy, PhD, associate professor and chief of the Division of Reproductive Sciences in obstetrics and gynecology at Duke.

One of the pathways is involved in helping bodily organs reach their full size; the other pathway involves a large number of genes that regulate growth during development. Both pathways can become dysregulated in some cancers.

“In terms of what it means for the developing child, we just don’t know,” Murphy said. It’s unknown whether sperm affected by THC could be healthy enough to even fertilize an egg and continue its development into an embryo, she said.

The study was a starting point on the epigenetic effects of THC on sperm and is limited by the relatively small number of men involved in the trial, Murphy said. The findings in men also could be confounded by other factors affecting their health, such as their nutrition, sleep, alcohol use and other lifestyle habits.

The Duke team plans to continue its research with larger groups. They intend to study whether changes in sperm are reversed when men stop using marijuana. They also hope to test the umbilical cord blood of babies born to fathers with THC-altered sperm to determine what, if any epigenetic changes, are carried forward to the child.

“We know that there are effects of cannabis use on the regulatory mechanisms in sperm DNA, but we don’t know whether they can be transmitted to the next generation,” Murphy said.

“In the absence of a larger, definitive study, the best advice would be to assume these changes are going to be there,” Murphy said. “We don’t know whether they are going to be permanent. I would say as a precaution, stop using cannabis for at least six months before trying to conceive.”

In addition to Kollins and Murphy, study authors include Nilda Itchon-Ramos, Zachary Visco, Zhiqing Huang, Carole Grenier, Rose Schrott, Kelly Acharya, Marie-Helene Boudreau, Thomas M. Price, Douglas J. Raburn, David L. Corcoran, Joseph E. Lucas, John T. Mitchell, F. Joseph McClernon, Marty Cauley, Brandon J. Hall, and Edward D. Levin.

The research was supported by a grant from the John Templeton Foundation.

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 140 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 7.9 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.

For updated information on PIONEER-HF, check out ACC 2019: Compound improves heart failure biomarker even after hospitalization.

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 AF 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.

AHA 2018: Multifaceted interventions improve adherence to evidence-based measures in high-risk CV disease

November 10, 2018 – The DCRI’s Renato Lopes, MD, MHS, PhD, contributed to two late-breaking clinical trials from the BRIDGE initiative.

Cardiovascular diseases remain the leading cause of death globally–particularly in low and middle-income countries, where 80 percent of the burden resides–yet research has shown that patients with high cardiovascular risk often fail to receive evidence-based therapies in community practice.

It is well established that statins, antiplatelet therapy, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) lower the long-term risk of cardiovascular events in patients with atherothrombotic disease. However, registries have shown that utilization of these therapies in practice is suboptimal and that care gaps are even wider in low- and middle-income countries. Trials studying the effects of quality improvement interventions on the use of these therapies have rarely been conducted in lower-resource settings.

To help address this evidence gap, BRIDGE (Brazilian Intervention to Increase Evidence Usage in Practice), a quality improvement initiative, was launched 10 years ago. This initiative conducts randomized trials to examine the impact of multifaceted quality improvement interventions on use of evidence-based therapies and clinical outcomes. The DCRI’s Renato Lopes MD, MHS, PhD, was co-chair of the BRIDGE-Acute Coronary Syndrome (ACS) trial, which revealed in 2012 that this type of intervention can improve the use of evidence-based therapies and clinical outcomes in ACS patients.

Results from two additional studies, BRIDGE-Cardiovascular Prevention and BRIDGE-Stroke, were presented Saturday at the 2018 American Heart Association Scientific Sessions in Chicago. Lopes was an investigator on both of these studies, testing the same concept as BRIDGE-ACS — this time in patients with stroke and high cardiovascular risk.

“The two studies, led by Brazilian investigators, showed that in general, multifaceted quality improvement interventions resulted in significant improvement in the use of evidence-based therapies, although they were not powered to assess impacts on clinical outcomes,” Lopes said. “Our interventions are relatively simple and feasible, so they could form the basis of quality improvement programs to maximize use of evidence-based interventions to manage patients with stroke and high cardiovascular risk.”

BRIDGE-CV was a cluster-randomized clinical trial including 1,619 patients with established atherothrombotic disease from 40 outpatient clinics or primary care units. The intervention tested involved case management, audit and feedback reports, and distribution of educational materials to health care providers and patients. The primary endpoint was the adherence to combined evidence-based therapies. Institutions that received a multifaceted intervention adhered to 73.5 percent of evidence-based therapies while the control group that received routine care adhered to just 58.7 percent.

The BRIDGE-Stroke trial examined the impact of a multifaceted quality improvement intervention to increase the adherence to 10 evidence-based performance metrics therapies for acute ischemic stroke and transient ischemic attack patients. This two-arm, cluster-randomized trial included 1,624 patients from 36 hospitals in Brazil, Argentina, and Peru. The intervention group adhered to 85.3 percent of the evidence-based performance measures, and the control group adhered to 77.8 percent, a difference that was not statistically significant. Although the intervention did not result in an overall improvement in adherence to evidence-based performance measures relative to standard of care, individual care elements did improve, including a significant increase in the use of thrombolysis and smoking cessation.

Additional DCRI contributors to BRIDGE-Stroke included Ying Xian, Janet Prvu Bettger, and Eric Peterson.

BRIDGE-CV is funded by Amgen as an investigator-initiated trial. BRIDGE-Stroke is funded by the Brazilian Ministry of Health in partnership with Hospital do Coração (HCor) – Programa Hospitais de Excelência à Serviço do SUS (PROADI-SUS). This study also received educational support from Boehringer Ingelheim and Lepetit Pharma.

AHA 2018: Rivaroxaban, warfarin have similar risks of stroke and bleeding for obese AF patients

November 10, 2018 – Patients on rivaroxaban had significantly lower healthcare costs than patients who took warfarin.

New study results examining the comparative effectiveness, safety, and costs of rivaroxaban and warfarin among morbidly obese patients with non-valvular atrial fibrillation (NVAF) were presented Saturday at the 2018 American Heart Association (AHA) Scientific Sessions in Chicago.

Obesity and morbid obesity are associated with an increased risk of developing NVAF, which may be more severe and persistent this population. Anticoagulation is the standard of care for prevention of embolic events in patients with NVAF, with warfarin and direct-acting oral anticoagulants (DOACs) significantly reducing the risk of stroke in these patients. Because limited data exist regarding clinical outcomes of DOACs in patients with NVAF who are morbidly obese, care guidelines currently recommend against use of these therapies.

Although the study revealed that treatment with rivaroxaban and with warfarin resulted in similar risk, patients who took rivaroxaban, a DOAC, required significantly less total healthcare resource utilization and costs per patient per year, inclusive of medication costs, due to fewer inpatient and outpatient encounters than with patients on warfarin. Rivaroxaban has also been associated with reduced intracranial hemorrhage in NVAF patients when compared with warfarin.

The study used two large, geographically diverse, U.S. healthcare claims databases to examine health outcomes, resource utilization and costs for morbidly obese NVAF patients treated with rivaroxaban or warfarin from December 1, 2010 to December 31, 2016. A total of 267,467 adult patients met entry criteria, and 3,563 matched pairs of patients treated with rivaroxaban or warfarin were identified. Rivaroxaban and warfarin patients were 1:1 propensity score matched, helping reduce selection biases from measured confounders, such as comorbidities, and improving the internal validity of the estimates.

Rivaroxaban and warfarin had similar effectiveness (stroke: 1.4 percent versus 1.6 percent) and safety (major bleeding: 2.2 percent versus 2.7 percent), yet rivaroxaban was associated with lower total healthcare costs per patient per year than warfarin (total costs: $48,552 versus $52,418). This was primarily driven by lower hospitalization rate (50.2 percent versus 54.1 percent), shorter length of stay (7.5 versus 9.1 days), and less utilization of outpatient services (86 versus 115 encounters per patient per year). Routine monitoring of the anticoagulant effect of rivaroxaban is not recommended, contributing to this reduced use of outpatient services.

“This type of study is where comparative effectiveness research really shines,” said lead author and presenter Eric D. Peterson, MD, MPH, of the DCRI.

“We were able to gain real-world insights into outcomes and costs in this relatively rare patient population,” Peterson said. “Our findings extend the results of the ROCKET AF trial and add to the pharmacokinetic and pharmacologic data supporting the use of rivaroxaban in overweight and obese patients with NVAF without the need for routine monitoring. This will reassure clinicians that current dosing strategies are adequate and efficient in these populations.”

Janssen Scientific Affairs, LLC, funded this study.

AHA 2018: High-dose spironolactone does not improve congestion among high-risk acute heart failure patients

November 10, 2018 – An analysis showed the addition of high-dose spironolactone offered no benefit in those with heightened risk for poor response to standard loop diuretics.

For clinicians treating patients with acute heart failure (AHF), managing fluid overload is a critical component of treatment in the hospital. Water retention leads to breathing problems and swelling, and standard hospital care involves removing excess fluid using diuretics.

However, many patients do not fully respond to standard diuretics and end up leaving the hospital with excess fluid. These patients are at increased risk of death or rehospitalization.Stephen Greene

ATHENA-HF, a trial conducted by the Heart Failure Network from 2014 to 2016, assessed whether congestion would improve in AHF patients if high-dose spironolactone was added to usual therapy. The primary endpoint was a proportional change in NT-proBNP, a blood test commonly used as a marker of heart failure severity.

The trial included patients with a wide degree of risk and showed no benefit in the overall population. However, the investigators proposed that patients at highest risk of not responding to standard therapy could benefit from high-dose spironolactone.

Testing that theory, a secondary analysis of the trial focused on patients with kidney disease and other risk factors for diuretic resistance. The results of that analysis were presented today at the annual Scientific Sessions of the American Health Association in Chicago.

“Our study aimed to examine those patients who have a difficult time losing excess fluid with usual in-hospital care,” said the DCRI’s Stephen Greene, MD, who led the study. “We wanted to see if high-dose spironolactone could offer any extra benefit in the subsets of patients who do not adequately respond to typical diuretic therapy.”

“Would giving high-dose spironolactone to these high-risk patients result in them losing extra fluid, feeling better, and further lowering of NT-proBNP? Based on our study, the short answer is no.”

The researchers looked at many characteristics that put patients at increased risk of poor response to standard in-hospital care, such as kidney disease, diabetes, lower blood pressure, and high loop diuretic dose. In all of these subgroups, high-dose spironolactone did not provide extra lowering of NT-proBNP or any signal of benefit, he said.

Greene cautioned, however, that the analysis has limitations.

“Because of the design of the ATHENA-HF trial , this analysis looked at patients at risk for poor diuretic response. We weren’t able to look at the treatment effect among patients with confirmed poor diuretic response,” he said. “This is a big difference. In fact, we ended up seeing that many patients at risk for poor response actually ended up responding fairly well to standard therapy. If we studied addition of high-dose spironolactone in a population with confirmed poor urine output despite days of standard therapy, we might have seen a different result.”

Diuretic resistance is a major problem in heart failure and developing effective treatment strategies must be research priority, Greene said.

“As a field, we still need to keep searching for effective therapies to tackle this problem,” he said

Other DCRI contributors to the study included G. Michael Felker, Anna Giczewska, Hrishikesh Chakraborty, Adam DeVore, Marat Fudim, Steven McNulty, Robert Mentz, and Adrian Hernandez.