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A Gout Drug Used For Nearly A Decade Found To Increase Risk Of Death After The Trial’s Primary Endpoint

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Febuxostat, a gout drug that has been in use for nearly a decade, was found to significantly increase the risk of death, even though it did not raise the risk of the trial’s primary endpoint, a combined rate of fatal and nonfatal adverse cardiovascular events, according to research presented at the American College of Cardiology’s 67th Annual Scientific Session.

It is unusual for a clinical trial to reveal an increased risk of death without also showing a heightened risk of other cardiovascular outcomes such as nonfatal heart attack and stroke. The findings, which showed an uptick in deaths after patients had been taking Febuxostat for two years or longer, call into question the safety of long-term Febuxostat use in patients with cardiovascular disease, researchers said.

“This finding was entirely unexpected, and we’re at a loss at this time to explain why this finding was seen,” said William B. White, MD, professor of medicine at the Calhoun Cardiology Center of the University of Connecticut School of Medicine and the study’s lead author.

“The results were consistent across many subgroups; there was no evidence of a relationship with age, sex, race or ethnicity, history of cardiovascular disease, or duration or severity of the gout.”

Gout is a form of arthritis estimated to affect more than 8 million people in the U.S. It is caused by a buildup of urate levels in the body and leads to episodes of intense joint pain due to crystal formation and inflammation. Gout is more common in men and is associated with obesity; many people with gout also have or are at risk for heart disease. Although dietary and lifestyle changes can help manage the disease, many patients require medication called xanthine oxidase inhibitors to prevent flare-ups.

The drug allopurinol has served as the standard treatment for gout since the 1960s, but it can cause kidney problems and severe allergic reactions in some patients. Febuxostat was developed to offer a safer alternative, particularly for gout patients with chronic kidney disease.

Early clinical trials for Febuxostat showed the drug was effective for lowering serum urate but signaled a slightly elevated risk of adverse cardiovascular events. The U.S. Food and Drug Administration (FDA) approved Febuxostat for gout in 2009 under the condition that a robust trial is initiated to assess long-term cardiovascular outcomes.

The FDA-mandated trial, known as CARES, for which results are being reported now for the first time, was designed to assess whether Febuxostat was noninferior to allopurinol in terms of a composite primary endpoint that included death from cardiovascular causes, nonfatal heart attack, nonfatal stroke and unstable angina leading to urgent revascularization (a procedure to open blocked arteries). Researchers also examined rates of each of these outcomes separately, as well as other markers of cardiovascular and kidney health.

The trial enrolled more than 6,000 patients at 320 centers in North America. All study participants had gout as well as established cardiovascular disease, such as a previous heart attack, stroke, hospitalization for chest pain (unstable angina), peripheral arterial disease, or both diabetes and small vessel disease. Half of the patients were randomly assigned to receive febuxostat and half received allopurinol; neither the patients nor their doctors knew which drug they had received.

Participants continued taking their assigned medication while researchers tracked their health outcomes for more than 2.5 years on average and as long as 6.5 years in some patients.

By the end of the trial, 656 primary endpoints had occurred. Patients taking allopurinol and Febuxostat experienced the composite primary endpoint at nearly the same rate. These results met the study’s threshold for noninferiority, indicating that Febuxostat was not inferior to allopurinol. However, when the researchers examined each endpoint separately, they found those randomized to take Febuxostat had a 34 percent higher rate of death from cardiovascular causes and a 22 percent higher rate of death from any cause.

A high proportion of patients (45 percent) elected to stop taking their assigned drug before the study ended. In patients who stopped taking Febuxostat early, the elevated risk of death was diminished. Overall, however, more patients died after discontinuing their assigned medication than while taking the drug.

Researchers were unable to identify the reason for the surprising—and seemingly contradictory—findings. White said the results of previous tests in animal models and cell cultures do not point to any biological mechanisms that would explain how febuxostat might cause cardiovascular harm.

While the increased risk of death was consistent across subgroups of patients based on demographic factors and health conditions, there were two differences noted regarding medication use. Among patients receiving Febuxostat, those who did not regularly take aspirin and those who regularly took nonsteroidal anti-inflammatory drugs (NSAIDs) faced a higher risk of death compared with those taking aspirin or not taking NSAIDs. Researchers cautioned that the study was not designed to assess potential medication interactions, however.

“It is important to be careful when interpreting these findings; it doesn’t necessarily indicate there’s an interaction between these drugs and Febuxostat,” White said.

“It might have been that these patients had more active gout with more flares, for example.”

The researchers plan to continue to explore the data to determine whether the results may yield insights on the optimal treatment for gout in patients who have both cardiovascular disease and chronic kidney disease. In the approximately 50 percent of patients with a history of chronic kidney disease in the CARES trial, mortality was roughly equal among those taking Febuxostat and those taking allopurinol.

In addition, White said ongoing studies being conducted in Europe may help shed light on the potential risks and benefits of febuxostat in patients who have cardiovascular risk factors but who do not have established cardiovascular disease.

The trial was funded by Takeda Pharmaceuticals U.S.A. Inc., maker of febuxostat.

This study was simultaneously published online in the New England Journal of Medicine at the time of presentation.

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Children Carry Evidence Of Toxins From Home Flooring And Furniture

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Children living in homes with all vinyl flooring or flame-retardant chemicals in the sofa have significantly higher concentrations of potentially harmful semi-volatile organic compounds (SVOCs) in their blood or urine than children from homes where these materials are not present, according to a new Duke University-led study.

The researchers presented their findings Sunday, Feb. 17 at the annual meeting of the American Association for the Advancement of Science in Washington, D.C.

They found that children living in homes where the sofa in the main living area contained flame-retardant polybrominated diphenyl ethers (PBDEs) in its foam had a six-fold higher concentration of PBDEs in their blood serum.

Exposure to PBDEs has been linked in laboratory tests to neurodevelopmental delays, obesity, endocrine and thyroid disruption, cancer and other diseases.

Children from homes that had vinyl flooring in all areas were found to have concentrations of benzyl butyl phthalate metabolite in their urine that were 15 times higher than those in children living with no vinyl flooring.

Benzyl butyl phthalate has been linked to respiratory disorders, skin irritations, multiple myeolma and reproductive disorders.

“SVOCs are widely used in electronics, furniture and building materials and can be detected in nearly all indoor environments,” said Heather Stapleton, an environmental chemist at Duke’s Nicholas School of the Environment, who led the research.

“Human exposure to them is widespread, particularly for young children who spend most of their time indoors and have greater exposure to chemicals found in household dust.”

“Nonetheless, there has been little research on the relative contribution of specific products and materials to children’s overall exposure to SVOCs,” she noted.

To address that gap, in 2014 Stapleton and colleagues from Duke, the Centers for Disease Control & Prevention, and Boston University began a three-year study of in-home exposures to SVOCs among 203 children from 190 families.

“Our primary goal was to investigate links between specific products and children’s exposures, and to determine how the exposure happened — was it through breathing, skin contact or inadvertent dust inhalation,” Stapleton said.

To that end, the team analyzed samples of indoor air, indoor dust and foam collected from furniture in each of the children’s homes, along with a handwipe sample, urine and blood from each child.

“We quantified 44 biomarkers of exposure to phthalates, organophosphate esters, brominated flame retardants, parabens, phenols, antibacterial agents and perfluoroalkyl and polyfluoroalkyl substances (PFAS),” Stapleton said.

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Your Home Is A Hidden Source Of Air Pollution

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Cooking, cleaning and other routine household activities generate significant levels of volatile and particulate chemicals inside the average home, leading to indoor air quality levels on par with a polluted major city, University of Colorado Boulder researchers have found.

What’s more, airborne chemicals that originate inside a house don’t stay there: Volatile organic compounds (VOCs) from products such as shampoo, perfume and cleaning solutions eventually escape outside and contribute to ozone and fine particle formation, making up an even greater source of global atmospheric air pollution than cars and trucks do.

The previously underexplored relationship between households and air quality drew focus today at the 2019 AAAS Annual Meeting in Washington, D.C., where researchers from CU Boulder’s Cooperative Institute for Research in Environmental Sciences (CIRES) and the university’s Department of Mechanical Engineering presented their recent findings during a panel discussion.

“Homes have never been considered an important source of outdoor air pollution and the moment is right to start exploring that,” said Marina Vance, an assistant professor of mechanical engineering at CU Boulder.

“We wanted to know: How do basic activities like cooking and cleaning change the chemistry of a house?”

In 2018, Vance co-led the collaborative HOMEChem field campaign, which used advanced sensors and cameras to monitor the indoor air quality of a 1,200-square-foot manufactured home on the University of Texas Austin campus. Over the course of a month, Vance and her colleagues conducted a variety of daily household activities, including cooking a full Thanksgiving dinner in the middle of the Texas summer.

While the HOMEChem experiment’s results are still pending, Vance said that it’s apparent that homes need to be well ventilated while cooking and cleaning, because even basic tasks like boiling water over a stovetop flame can contribute to high levels of gaseous air pollutants and suspended particulates, with negative health impacts.

To her team’s surprise, the measured indoor concentrations were high enough that that their sensitive instruments needed to be recalibrated almost immediately.

“Even the simple act of making toast raised particle levels far higher than expected,” Vance said.

“We had to go adjust many of the instruments.”

Indoor and outdoor experts are collaborating to paint a more complete picture of air quality, said Joost de Gouw, a CIRES Visiting Professor. Last year, de Gouw and his colleagues published results in the journal Science showing that regulations on automobiles had pushed transportation-derived emissions down in recent decades while the relative importance of household chemical pollutants had only gone up.

“Many traditional sources like fossil fuel-burning vehicles have become much cleaner than they used to be,” said de Gouw.

“Ozone and fine particulates are monitored by the EPA, but data for airborne toxins like formaldehyde and benzene and compounds like alcohols and ketones that originate from the home are very sparse.”

While de Gouw says that it is too early on in the research to make recommendations on policy or consumer behavior, he said that it’s encouraging that the scientific community is now thinking about the “esosphere,” derived from the Greek word ‘eso,’ which translates to ‘inner.’

“There was originally skepticism about whether or not these products actually contributed to air pollution in a meaningful way, but no longer,” de Gouw said.

“Moving forward, we need to re-focus research efforts on these sources and give them the same attention we have given to fossil fuels. The picture that we have in our heads about the atmosphere should now include a house.”

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Diet Drinks May Be Associated With Strokes Among Post-Menopausal Women

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Among post-menopausal women, drinking multiple diet drinks daily was associated with an increase in the risk of having a stroke caused by a blocked artery, especially small arteries, according to research published in Stroke, a journal of the American Heart Association.

This is one of the first studies to look at the association between drinking artificially sweetened beverages and the risk of specific types of stroke in a large, racially diverse group of post-menopausal women. While this study identifies an association between diet drinks and stroke, it does not prove cause and effect because it was an observational study based on self-reported information about diet drink consumption.

Compared with women who consumed diet drinks less than once a week or not at all, women who consumed two or more artificially sweetened beverages per day were:

  • 23 percent more likely to have a stroke;
  • 31 percent more likely to have a clot-caused (ischemic) stroke;
  • 29 percent more likely to develop heart disease (fatal or non-fatal heart attack); and
  • 16 percent more likely to die from any cause.

Researchers found risks were higher for certain women. Heavy intake of diet drinks, defined as two or more times daily, more than doubled stroke risk in:

  • women without previous heart disease or diabetes, who were 2.44 times as likely to have a common type of stroke caused by blockage of one of the very small arteries within the brain;
  • obese women without previous heart disease or diabetes, who were 2.03 times as likely to have a clot-caused stroke; and
  • African-American women without previous heart disease or diabetes, who were 3.93 times as likely to have a clot-caused stroke.

“Many well-meaning people, especially those who are overweight or obese, drink low-calorie sweetened drinks to cut calories in their diet. Our research and other observational studies have shown that artificially sweetened beverages may not be harmless and high consumption is associated with a higher risk of stroke and heart disease,” said Yasmin Mossavar-Rahmani, Ph.D., lead author of the study and associate professor of clinical epidemiology and population health at the Albert Einstein College of Medicine in the Bronx, New York.

Researchers analyzed data on 81,714 postmenopausal women (age 50-79 years at the start) participating in the Women’s Health Initiative study that tracked health outcomes for an average of 11.9 years after they enrolled between 1993 and 1998. At their three-year evaluation, the women reported how often in the previous three months they had consumed diet drinks such as low calorie, artificially sweetened colas, sodas and fruit drinks. The data collected did not include information about the specific artificial sweetener the drinks contained.

The results were obtained after adjusting for various stroke risk factors such as age, high blood pressure, and smoking. These results in postmenopausal women may not be generalizable to men or younger women. The study is also limited by having only the women’s self-report of diet drink intake.

“We don’t know specifically what types of artificially sweetened beverages they were consuming, so we don’t know which artificial sweeteners may be harmful and which may be harmless,” Mossavar-Rahmani said.

The American Heart Association recently published a science advisory that found there was inadequate scientific research to conclude that low-calorie sweetened beverages do – or do not – alter risk factors for heart disease and stroke in young children, teens or adults. The Association recognizes diet drinks may help replace high calorie, sugary beverages, but recommends water (plain, carbonated and unsweetened flavored) as the best choice for a no calorie drink.

“Unfortunately, current research simply does not provide enough evidence to distinguish between the effects of different low-calorie sweeteners on heart and brain health. This study adds to the evidence that limiting use of diet beverages is the most prudent thing to do for your health,” said Rachel K. Johnson, Ph.D., R.D., professor of nutrition emeritus, University of Vermont and the chair of the writing group for the American Heart Association’s science advisory, Low-Calorie Sweetened Beverages and Cardiometabolic Health.

“The American Heart Association suggests water as the best choice for a no-calorie beverage. However, for some adults, diet drinks with low calorie sweeteners may be helpful as they transition to adopting water as their primary drink. Since long-term clinical trial data are not available on the effects of low-calorie sweetened drinks and cardiovascular health, given their lack of nutritional value, it may be prudent to limit their prolonged use” said Johnson.

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