Journal of Clinical Outcomes Management

Premature births from cesarean (C-section) and induced deliveries dropped abruptly by 6.5% from the projected number in the first month of the COVID-19 pandemic and stayed at the lower rate consistently throughout the year, researchers have found.

Results of the study, led by Daniel Dench, PhD, assistant professor at the Georgia Institute of Technology School of Economics in Atlanta, were published online in Pediatrics.

The authors say their findings help answer the question of whether numbers of preterm (less than 37 weeks gestation) C-sections and induced deliveries would change if women didn’t see their physicians during pregnancy as often, especially in person, and raise the question of whether some birth interventions by physicians may not be necessary. The pandemic gave researchers a natural, ethical way to study the question.

The researchers found that in March 2020 – the start of business closures and stay-at-home orders around the country – preterm births from C-sections or induced deliveries immediately fell from the forecast number for the month by 0.4 percentage points. For the rest of 2020, the number remained on average 0.35 percentage points below the numbers predicted.

That means 350 fewer preterm C-sections and induced deliveries per 100,000 live births, or 10,000 fewer overall, the authors said.

Dr. Dench told this publication the numbers for those births had been steady from January 2010 to February 2020, but the pattern “diverges from this trend very clearly beginning exactly in March 2020 and does not return to trend by December 2020.”

Meanwhile, during the study period, the number of full-term cesarean and induced deliveries stayed steady and started to increase slightly in 2020. Researchers also adjusted for seasonality as, for example, preterm births are higher on average in February than in March.

So far, Dr. Dench said in a press release, it’s not clear whether the lower numbers mean physicians didn’t deliver babies that ended up surviving in the womb anyway or if they missed some that would die in the womb without intervention.

To better understand those implications, Dr. Dench says he is turning to fetal death records for March-December 2020 and he said he expects to have those results analyzed by the end of the year.

If there was no change in fetal deaths at the same time as the drop in preterm births, Dr. Dench said, that could point to physician interventions that may not have been necessary.

Mya R. Zapata, MD, an obstetrician-gynecologist with UCLA Health, who was not involved with the study, told this publication that checking the fetal deaths is a good start and an objective outcome in answering the question, but she points out there are other outcomes that will take a deeper analysis, such as whether there are differences later in developmental outcomes after fewer physician visits.

“It’s always a good question for health care,” she said, “are we doing more than we need to?”

Dr. Zapata is the obstetrics service chief for UCLA’s labor and delivery unit and was an integral part of decision-making as to what services were essential and for which patients. She said the fewer visits and fewer ultrasounds the researchers describe fit with what ob.gyns. at UCLA experienced as the pandemic hit.

“We really tried to hone in on people who were at highest risk for an adverse outcome,” she said. “I still have the question of whether there were things we missed in low-risk people. It will take time to get the entire answer. But it does make us reflect that perhaps less intervention could be better for patients and easier. It’s our job in medicine to keep asking the question of what is essential and safe and not just continue with current practice because that’s what we’ve always done.”

The amount of data gave the researchers an unusual view. They studied 38,891,271 singleton births in the United States from 2010 to 2020 with data from the National Center for Health Statistics.

“If you look at 1,000 births in a single hospital, or even at 30,000 births across a hospital system, you wouldn’t be able to see the drop as clearly,” Dr. Dench said. “The drop we detected is a huge change, but you might miss it in a small sample.”

The researchers acknowledge a limitation of the study is that half of all preterm C-sections and induced deliveries happen because of a ruptured membrane, a spontaneous cause. Those instances can’t be distinguished from the ones caused by doctors’ interventions in this study.

“Still, these findings are significant because the causes for preterm births are not always known,” the authors wrote in the press release.

The study authors and Dr. Zapata reported no relevant financial relationships.

Premature births from cesarean (C-section) and induced deliveries dropped abruptly by 6.5% from the projected number in the first month of the COVID-19 pandemic and stayed at the lower rate consistently throughout the year, researchers have found.

Results of the study, led by Daniel Dench, PhD, assistant professor at the Georgia Institute of Technology School of Economics in Atlanta, were published online in Pediatrics.

The authors say their findings help answer the question of whether numbers of preterm (less than 37 weeks gestation) C-sections and induced deliveries would change if women didn’t see their physicians during pregnancy as often, especially in person, and raise the question of whether some birth interventions by physicians may not be necessary. The pandemic gave researchers a natural, ethical way to study the question.

The researchers found that in March 2020 – the start of business closures and stay-at-home orders around the country – preterm births from C-sections or induced deliveries immediately fell from the forecast number for the month by 0.4 percentage points. For the rest of 2020, the number remained on average 0.35 percentage points below the numbers predicted.

That means 350 fewer preterm C-sections and induced deliveries per 100,000 live births, or 10,000 fewer overall, the authors said.

Dr. Dench told this publication the numbers for those births had been steady from January 2010 to February 2020, but the pattern “diverges from this trend very clearly beginning exactly in March 2020 and does not return to trend by December 2020.”

Meanwhile, during the study period, the number of full-term cesarean and induced deliveries stayed steady and started to increase slightly in 2020. Researchers also adjusted for seasonality as, for example, preterm births are higher on average in February than in March.

So far, Dr. Dench said in a press release, it’s not clear whether the lower numbers mean physicians didn’t deliver babies that ended up surviving in the womb anyway or if they missed some that would die in the womb without intervention.

To better understand those implications, Dr. Dench says he is turning to fetal death records for March-December 2020 and he said he expects to have those results analyzed by the end of the year.

If there was no change in fetal deaths at the same time as the drop in preterm births, Dr. Dench said, that could point to physician interventions that may not have been necessary.

Mya R. Zapata, MD, an obstetrician-gynecologist with UCLA Health, who was not involved with the study, told this publication that checking the fetal deaths is a good start and an objective outcome in answering the question, but she points out there are other outcomes that will take a deeper analysis, such as whether there are differences later in developmental outcomes after fewer physician visits.

“It’s always a good question for health care,” she said, “are we doing more than we need to?”

Dr. Zapata is the obstetrics service chief for UCLA’s labor and delivery unit and was an integral part of decision-making as to what services were essential and for which patients. She said the fewer visits and fewer ultrasounds the researchers describe fit with what ob.gyns. at UCLA experienced as the pandemic hit.

“We really tried to hone in on people who were at highest risk for an adverse outcome,” she said. “I still have the question of whether there were things we missed in low-risk people. It will take time to get the entire answer. But it does make us reflect that perhaps less intervention could be better for patients and easier. It’s our job in medicine to keep asking the question of what is essential and safe and not just continue with current practice because that’s what we’ve always done.”

The amount of data gave the researchers an unusual view. They studied 38,891,271 singleton births in the United States from 2010 to 2020 with data from the National Center for Health Statistics.

“If you look at 1,000 births in a single hospital, or even at 30,000 births across a hospital system, you wouldn’t be able to see the drop as clearly,” Dr. Dench said. “The drop we detected is a huge change, but you might miss it in a small sample.”

The researchers acknowledge a limitation of the study is that half of all preterm C-sections and induced deliveries happen because of a ruptured membrane, a spontaneous cause. Those instances can’t be distinguished from the ones caused by doctors’ interventions in this study.

“Still, these findings are significant because the causes for preterm births are not always known,” the authors wrote in the press release.

The study authors and Dr. Zapata reported no relevant financial relationships.

Premature births from cesarean (C-section) and induced deliveries dropped abruptly by 6.5% from the projected number in the first month of the COVID-19 pandemic and stayed at the lower rate consistently throughout the year, researchers have found.

Results of the study, led by Daniel Dench, PhD, assistant professor at the Georgia Institute of Technology School of Economics in Atlanta, were published online in Pediatrics.

The authors say their findings help answer the question of whether numbers of preterm (less than 37 weeks gestation) C-sections and induced deliveries would change if women didn’t see their physicians during pregnancy as often, especially in person, and raise the question of whether some birth interventions by physicians may not be necessary. The pandemic gave researchers a natural, ethical way to study the question.

The researchers found that in March 2020 – the start of business closures and stay-at-home orders around the country – preterm births from C-sections or induced deliveries immediately fell from the forecast number for the month by 0.4 percentage points. For the rest of 2020, the number remained on average 0.35 percentage points below the numbers predicted.

That means 350 fewer preterm C-sections and induced deliveries per 100,000 live births, or 10,000 fewer overall, the authors said.

Dr. Dench told this publication the numbers for those births had been steady from January 2010 to February 2020, but the pattern “diverges from this trend very clearly beginning exactly in March 2020 and does not return to trend by December 2020.”

Meanwhile, during the study period, the number of full-term cesarean and induced deliveries stayed steady and started to increase slightly in 2020. Researchers also adjusted for seasonality as, for example, preterm births are higher on average in February than in March.

So far, Dr. Dench said in a press release, it’s not clear whether the lower numbers mean physicians didn’t deliver babies that ended up surviving in the womb anyway or if they missed some that would die in the womb without intervention.

To better understand those implications, Dr. Dench says he is turning to fetal death records for March-December 2020 and he said he expects to have those results analyzed by the end of the year.

If there was no change in fetal deaths at the same time as the drop in preterm births, Dr. Dench said, that could point to physician interventions that may not have been necessary.

Mya R. Zapata, MD, an obstetrician-gynecologist with UCLA Health, who was not involved with the study, told this publication that checking the fetal deaths is a good start and an objective outcome in answering the question, but she points out there are other outcomes that will take a deeper analysis, such as whether there are differences later in developmental outcomes after fewer physician visits.

“It’s always a good question for health care,” she said, “are we doing more than we need to?”

Dr. Zapata is the obstetrics service chief for UCLA’s labor and delivery unit and was an integral part of decision-making as to what services were essential and for which patients. She said the fewer visits and fewer ultrasounds the researchers describe fit with what ob.gyns. at UCLA experienced as the pandemic hit.

“We really tried to hone in on people who were at highest risk for an adverse outcome,” she said. “I still have the question of whether there were things we missed in low-risk people. It will take time to get the entire answer. But it does make us reflect that perhaps less intervention could be better for patients and easier. It’s our job in medicine to keep asking the question of what is essential and safe and not just continue with current practice because that’s what we’ve always done.”

The amount of data gave the researchers an unusual view. They studied 38,891,271 singleton births in the United States from 2010 to 2020 with data from the National Center for Health Statistics.

“If you look at 1,000 births in a single hospital, or even at 30,000 births across a hospital system, you wouldn’t be able to see the drop as clearly,” Dr. Dench said. “The drop we detected is a huge change, but you might miss it in a small sample.”

The researchers acknowledge a limitation of the study is that half of all preterm C-sections and induced deliveries happen because of a ruptured membrane, a spontaneous cause. Those instances can’t be distinguished from the ones caused by doctors’ interventions in this study.

“Still, these findings are significant because the causes for preterm births are not always known,” the authors wrote in the press release.

The study authors and Dr. Zapata reported no relevant financial relationships.

Patients who leave a hospital against medical advice may be called “difficult” or “uncooperative.” But a new study suggests that in many cases, that label is unfair.

The analysis found that in about 1 in 5 cases, shortcomings in the quality of care and other factors beyond patients’ control explain why they leave the hospital before completing recommended treatment.

Clinicians may be quick to blame patients for so-called discharges against medical advice (AMA), which comprise up to 2% of hospital admissions and are associated with an increased risk of mortality and readmission. But “we as providers are very much involved in the reasons why these patients left,” Kushinga Bvute, MD, MPH, a second-year internal medicine resident at Florida Atlantic University, Boca Raton, who led the new study, told this news organization. Dr. Bvute and her colleagues presented their findings April 6 at the Society of General Internal Medicine (SGIM) 2022 Annual Meeting, Orlando, Florida.

Dr. Bvute and her colleagues reviewed the records of 548 AMA discharges – out of a total of 354,767 discharges – from Boca Raton Regional Hospital from January 2020 to January 2021. In 44% of cases, patients cited their own reasons for leaving. But in nearly 20% of AMA discharges, the researchers identified factors linked to treatment.

Hospital-related reasons patients cited for leaving AMA were general wait times (3.5%), provider wait times (2.6%), provider care (2.9%), the hospital environment (2.7%), wanting a private room (2%), and seeking medical care elsewhere (6.2%).

Patient-related factors were refusing treatment (27%), feeling better (3.5%), addiction problems (2.9%), financial complications (2.9%), and dependent care (2.4%). Ten (1.8%) eloped, according to the researchers.

Nearly 60% of patients who were discharged AMA were men, with a mean age of 56 years (standard deviation, 19.13). The average stay was 1.64 days.

In roughly one-third of cases, there was no documented reason for the departure – underscoring the need for better reporting, according to the researchers.

To address AMA discharges, hospitals “need to focus on factors they influence, such as high-quality patient care, the hospital environment, and provider-patient relationships,” the researchers report.
 

New procedures needed

The hospital is working on procedures to ensure that reasons for AMA discharges are documented. The administration also is implementing preventive steps, such as communicating with patients about the risks of leaving and providing discharge plans to reduce the likelihood that a patient will return, Dr. Bvute told this news organization.

Dr. Bvute said the findings should encourage individual clinicians to “remove any stereotypes that sometimes come attached to having those three letters on your charts.”

Data were collected during the COVID-19 pandemic, but Dr. Bvute does not believe that fear of coronavirus exposure drove many patients to leave the hospital prematurely.

The study is notable for approaching AMA discharges from a quality improvement perspective, David Alfandre, MD, MPH, a health care ethicist at the VA National Center for Ethics in Health Care, Washington, D.C., said in an interview.

Dr. Alfandre, who was not involved in the study, said it reflects growing recognition that hospitals can take steps to reduce adverse outcomes associated with AMA discharges. “It’s starting to shift the conversation to saying, this isn’t just the patient’s problem, but this is the health care provider’s problem,” he said.

Dr. Alfandre co-authored a 2021 analysis showing that hospital characteristics account for 7.3% of variation in the probability of a patient being discharged AMA. However, research is needed to identify effective interventions besides the established use of buprenorphine and naloxone for patients with opioid use disorder. “I think everybody recognizes the quality of communication is poor, but that doesn’t really help us operationalize that to know what to do,” he said.

Emily Holmes, MD, MPH, medical director of the Changing Health Outcomes Through Integrated Care Excellence Program at IU Health, Indianapolis, cautioned that data may be biased because defining AMA discharge can be subjective.

Reasons are not consistently documented and can be difficult to capture because they are often multifactorial, Dr. Holmes said. “For example, long wait times are more problematic when a patient is worried about finances and care for a child,” she said.

But Dr. Holmes, who was not involved in the study, said it does encourage clinicians “to think about what we can do systematically to reduce AMA discharges.”

Dr. Bvute, Dr. Alfandre, and Dr. Holmes reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who leave a hospital against medical advice may be called “difficult” or “uncooperative.” But a new study suggests that in many cases, that label is unfair.

The analysis found that in about 1 in 5 cases, shortcomings in the quality of care and other factors beyond patients’ control explain why they leave the hospital before completing recommended treatment.

Clinicians may be quick to blame patients for so-called discharges against medical advice (AMA), which comprise up to 2% of hospital admissions and are associated with an increased risk of mortality and readmission. But “we as providers are very much involved in the reasons why these patients left,” Kushinga Bvute, MD, MPH, a second-year internal medicine resident at Florida Atlantic University, Boca Raton, who led the new study, told this news organization. Dr. Bvute and her colleagues presented their findings April 6 at the Society of General Internal Medicine (SGIM) 2022 Annual Meeting, Orlando, Florida.

Dr. Bvute and her colleagues reviewed the records of 548 AMA discharges – out of a total of 354,767 discharges – from Boca Raton Regional Hospital from January 2020 to January 2021. In 44% of cases, patients cited their own reasons for leaving. But in nearly 20% of AMA discharges, the researchers identified factors linked to treatment.

Hospital-related reasons patients cited for leaving AMA were general wait times (3.5%), provider wait times (2.6%), provider care (2.9%), the hospital environment (2.7%), wanting a private room (2%), and seeking medical care elsewhere (6.2%).

Patient-related factors were refusing treatment (27%), feeling better (3.5%), addiction problems (2.9%), financial complications (2.9%), and dependent care (2.4%). Ten (1.8%) eloped, according to the researchers.

Nearly 60% of patients who were discharged AMA were men, with a mean age of 56 years (standard deviation, 19.13). The average stay was 1.64 days.

In roughly one-third of cases, there was no documented reason for the departure – underscoring the need for better reporting, according to the researchers.

To address AMA discharges, hospitals “need to focus on factors they influence, such as high-quality patient care, the hospital environment, and provider-patient relationships,” the researchers report.
 

New procedures needed

The hospital is working on procedures to ensure that reasons for AMA discharges are documented. The administration also is implementing preventive steps, such as communicating with patients about the risks of leaving and providing discharge plans to reduce the likelihood that a patient will return, Dr. Bvute told this news organization.

Dr. Bvute said the findings should encourage individual clinicians to “remove any stereotypes that sometimes come attached to having those three letters on your charts.”

Data were collected during the COVID-19 pandemic, but Dr. Bvute does not believe that fear of coronavirus exposure drove many patients to leave the hospital prematurely.

The study is notable for approaching AMA discharges from a quality improvement perspective, David Alfandre, MD, MPH, a health care ethicist at the VA National Center for Ethics in Health Care, Washington, D.C., said in an interview.

Dr. Alfandre, who was not involved in the study, said it reflects growing recognition that hospitals can take steps to reduce adverse outcomes associated with AMA discharges. “It’s starting to shift the conversation to saying, this isn’t just the patient’s problem, but this is the health care provider’s problem,” he said.

Dr. Alfandre co-authored a 2021 analysis showing that hospital characteristics account for 7.3% of variation in the probability of a patient being discharged AMA. However, research is needed to identify effective interventions besides the established use of buprenorphine and naloxone for patients with opioid use disorder. “I think everybody recognizes the quality of communication is poor, but that doesn’t really help us operationalize that to know what to do,” he said.

Emily Holmes, MD, MPH, medical director of the Changing Health Outcomes Through Integrated Care Excellence Program at IU Health, Indianapolis, cautioned that data may be biased because defining AMA discharge can be subjective.

Reasons are not consistently documented and can be difficult to capture because they are often multifactorial, Dr. Holmes said. “For example, long wait times are more problematic when a patient is worried about finances and care for a child,” she said.

But Dr. Holmes, who was not involved in the study, said it does encourage clinicians “to think about what we can do systematically to reduce AMA discharges.”

Dr. Bvute, Dr. Alfandre, and Dr. Holmes reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who leave a hospital against medical advice may be called “difficult” or “uncooperative.” But a new study suggests that in many cases, that label is unfair.

The analysis found that in about 1 in 5 cases, shortcomings in the quality of care and other factors beyond patients’ control explain why they leave the hospital before completing recommended treatment.

Clinicians may be quick to blame patients for so-called discharges against medical advice (AMA), which comprise up to 2% of hospital admissions and are associated with an increased risk of mortality and readmission. But “we as providers are very much involved in the reasons why these patients left,” Kushinga Bvute, MD, MPH, a second-year internal medicine resident at Florida Atlantic University, Boca Raton, who led the new study, told this news organization. Dr. Bvute and her colleagues presented their findings April 6 at the Society of General Internal Medicine (SGIM) 2022 Annual Meeting, Orlando, Florida.

Dr. Bvute and her colleagues reviewed the records of 548 AMA discharges – out of a total of 354,767 discharges – from Boca Raton Regional Hospital from January 2020 to January 2021. In 44% of cases, patients cited their own reasons for leaving. But in nearly 20% of AMA discharges, the researchers identified factors linked to treatment.

Hospital-related reasons patients cited for leaving AMA were general wait times (3.5%), provider wait times (2.6%), provider care (2.9%), the hospital environment (2.7%), wanting a private room (2%), and seeking medical care elsewhere (6.2%).

Patient-related factors were refusing treatment (27%), feeling better (3.5%), addiction problems (2.9%), financial complications (2.9%), and dependent care (2.4%). Ten (1.8%) eloped, according to the researchers.

Nearly 60% of patients who were discharged AMA were men, with a mean age of 56 years (standard deviation, 19.13). The average stay was 1.64 days.

In roughly one-third of cases, there was no documented reason for the departure – underscoring the need for better reporting, according to the researchers.

To address AMA discharges, hospitals “need to focus on factors they influence, such as high-quality patient care, the hospital environment, and provider-patient relationships,” the researchers report.
 

New procedures needed

The hospital is working on procedures to ensure that reasons for AMA discharges are documented. The administration also is implementing preventive steps, such as communicating with patients about the risks of leaving and providing discharge plans to reduce the likelihood that a patient will return, Dr. Bvute told this news organization.

Dr. Bvute said the findings should encourage individual clinicians to “remove any stereotypes that sometimes come attached to having those three letters on your charts.”

Data were collected during the COVID-19 pandemic, but Dr. Bvute does not believe that fear of coronavirus exposure drove many patients to leave the hospital prematurely.

The study is notable for approaching AMA discharges from a quality improvement perspective, David Alfandre, MD, MPH, a health care ethicist at the VA National Center for Ethics in Health Care, Washington, D.C., said in an interview.

Dr. Alfandre, who was not involved in the study, said it reflects growing recognition that hospitals can take steps to reduce adverse outcomes associated with AMA discharges. “It’s starting to shift the conversation to saying, this isn’t just the patient’s problem, but this is the health care provider’s problem,” he said.

Dr. Alfandre co-authored a 2021 analysis showing that hospital characteristics account for 7.3% of variation in the probability of a patient being discharged AMA. However, research is needed to identify effective interventions besides the established use of buprenorphine and naloxone for patients with opioid use disorder. “I think everybody recognizes the quality of communication is poor, but that doesn’t really help us operationalize that to know what to do,” he said.

Emily Holmes, MD, MPH, medical director of the Changing Health Outcomes Through Integrated Care Excellence Program at IU Health, Indianapolis, cautioned that data may be biased because defining AMA discharge can be subjective.

Reasons are not consistently documented and can be difficult to capture because they are often multifactorial, Dr. Holmes said. “For example, long wait times are more problematic when a patient is worried about finances and care for a child,” she said.

But Dr. Holmes, who was not involved in the study, said it does encourage clinicians “to think about what we can do systematically to reduce AMA discharges.”

Dr. Bvute, Dr. Alfandre, and Dr. Holmes reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Oral tebipenem pivoxil hydrobromide (TBP-PI-HBr) offers a safe and effective strategy for treating patients with complicated urinary tract infections, according to a new study.

“No new oral antibiotic alternative has emerged to treat these conditions in more than 25 years,” corresponding author Angela K. Talley, MD, said in an interview. The new research was published in the New England Journal of Medicine.

Courtesy Spero Therapeutics

Patients with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP), are often hospitalized and treated with intravenous therapy because of the lack of oral options, especially in cases of antibiotic-resistant pathogens, explained Dr. Talley, of Spero Therapeutics.

In their new phase 3, double-blind randomized trial, the researchers evaluated the safety and effectiveness of oral TBP-PI-HBr, compared with intravenous ertapenem in hospitalized patients with cUTIs or AP. Oral tebipenem is an investigational carbapenem with demonstrated activity against uropathogenic Enterobacterales, and it has shown effectiveness in animal models, the researchers noted in their paper.
 

Methods and results

The researchers randomized 1,372 adult patients. The microbiologic intent-to-treat population included 449 patients who received TBP-PI-HBr (600 mg every 8 hours) and 419 who received ertapenem (1 g every 24 hours) for 7-10 days or up to 14 days for patients with bacteremia.

The primary endpoint was a composite of clinical cure and favorable microbiologic response, assessed at a test-of-cure visit on day 19. Clinical cure was defined as “complete resolution or clinically significant alleviation of baseline signs and symptoms of complicated urinary tract infection or acute pyelonephritis and no new symptoms, such that no further antimicrobial therapy was warranted,” the researchers wrote. Microbiologic response was defined as a reduction to less than 103 CFU per milliliter in uropathogen levels from baseline at day 19.

Overall, the clinical response occurred in 58.8% of patients who received TBP-PI-HBr and 61.6% of those who received ertapenem at the test-of-cure visit.

Clinical cure rates were similar in the TBP-PI-HBr and ertapenem groups (93.1% vs. 93.6%) at the test-of-cure visit.

Both treatment groups showed similar responses to Enterobacterales pathogens at the test-of-cure visit (62.7% for TBP-PI-HBr and 65.2% for ertapenem).

Among patients with bacteremia at baseline, overall response rates were 72.3% and 66.0% for TBP-PI-HBr and ertapenem, respectively, at the test-of-cure visit, and 93.6% and 96.2%, respectively, at the end-of-treatment visit on or around day 25.

The overall incidence of adverse events was approximately 26% in both treatment groups. Most adverse events were mild or moderate in severity and did not limit treatment, the researchers wrote.

The mean age of the patients was 58.1 years; 46.1% were aged 65 and older, and 11.5% had bacteremia at baseline.

The study findings were limited by several factors, including the mandated 7- to 10-day course of antibiotics, which may not reflect the standard of care in other settings in the United States. The study’s trial sites were located in the United States, South Africa, and Europe. The study population was primarily White and from Central and Eastern Europe. Other limitations included the randomization of patients before confirming the baseline pathogen, although this was done to limit potential confounding from previous antibiotics, the researchers noted.
 

Safety and efficacy support application for approval

“To our knowledge, this is the first head-to-head evaluation of an IV vs. an oral drug for the treatment of cUTI and acute pyelonephritis,” Dr. Talley said in an interview.  

“The findings demonstrate that almost all patients in the study achieved complete resolution of the signs and symptoms of their infection,” she said.

TBP-PI-HBr has not been approved by the Food and Drug Administration, but a new drug application that included data from the current study was submitted to the FDA and is currently under review, Dr. Talley noted.

As for additional research, the current study was conducted in hospitalized patients, and the use of TBP-PI-HBr in the outpatient setting has not yet been evaluated, she said.
 

Approval and use of oral carbapenem will change practice

The current study is very important because it provides a viable and effective alternative form of antibiotic delivery for the patients with complicated UTI, Noel N. Deep, MD, emphasized in an interview.

“Currently these patients have to be treated with IV carbapenem antibiotics either in a hospital or through a home health nurse,” Dr. Deep, a general internist in group practice in Antigo, Wisc., explained.

Current IV strategies also carry the inherent risk associated with the insertion of an IV catheter that is left in place for several days or replaced periodically. “The oral antibiotic eliminates these risks and higher health care costs and provides a safer and equally efficacious option,” Dr. Deep said.

In the current study, “I was definitely surprised at the effectiveness of the oral carbapenem,” Dr. Deep said. “I am absolutely delighted with this new treatment option that physicians can now add to their armamentarium [assuming FDA approval] as we provide care to our patients,” he said.

If approved, TBP-PI-HBr will definitely change the treatment spectrum for the multidrug-resistant bacterial UTIs, said Dr. Deep. “Carbapenems have continued to be effective and low antibiotic resistance to carbapenems has been recorded.”

As for additional research, “I would like to see studies done in other ethnicities and different countries to ascertain the effectiveness of this antibiotic in those populations and against other bacterial strains with potentially different resistance mechanisms,” Dr. Deep said.

The study was supported by Spero Therapeutics and the Department of Health and Human Services. Lead author Paul B. Eckburg, MD, of Stanford (Calif.) University, and Dr. Talley are employees of Spero Therapeutics. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News.

Oral tebipenem pivoxil hydrobromide (TBP-PI-HBr) offers a safe and effective strategy for treating patients with complicated urinary tract infections, according to a new study.

“No new oral antibiotic alternative has emerged to treat these conditions in more than 25 years,” corresponding author Angela K. Talley, MD, said in an interview. The new research was published in the New England Journal of Medicine.

Courtesy Spero Therapeutics

Patients with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP), are often hospitalized and treated with intravenous therapy because of the lack of oral options, especially in cases of antibiotic-resistant pathogens, explained Dr. Talley, of Spero Therapeutics.

In their new phase 3, double-blind randomized trial, the researchers evaluated the safety and effectiveness of oral TBP-PI-HBr, compared with intravenous ertapenem in hospitalized patients with cUTIs or AP. Oral tebipenem is an investigational carbapenem with demonstrated activity against uropathogenic Enterobacterales, and it has shown effectiveness in animal models, the researchers noted in their paper.
 

Methods and results

The researchers randomized 1,372 adult patients. The microbiologic intent-to-treat population included 449 patients who received TBP-PI-HBr (600 mg every 8 hours) and 419 who received ertapenem (1 g every 24 hours) for 7-10 days or up to 14 days for patients with bacteremia.

The primary endpoint was a composite of clinical cure and favorable microbiologic response, assessed at a test-of-cure visit on day 19. Clinical cure was defined as “complete resolution or clinically significant alleviation of baseline signs and symptoms of complicated urinary tract infection or acute pyelonephritis and no new symptoms, such that no further antimicrobial therapy was warranted,” the researchers wrote. Microbiologic response was defined as a reduction to less than 103 CFU per milliliter in uropathogen levels from baseline at day 19.

Overall, the clinical response occurred in 58.8% of patients who received TBP-PI-HBr and 61.6% of those who received ertapenem at the test-of-cure visit.

Clinical cure rates were similar in the TBP-PI-HBr and ertapenem groups (93.1% vs. 93.6%) at the test-of-cure visit.

Both treatment groups showed similar responses to Enterobacterales pathogens at the test-of-cure visit (62.7% for TBP-PI-HBr and 65.2% for ertapenem).

Among patients with bacteremia at baseline, overall response rates were 72.3% and 66.0% for TBP-PI-HBr and ertapenem, respectively, at the test-of-cure visit, and 93.6% and 96.2%, respectively, at the end-of-treatment visit on or around day 25.

The overall incidence of adverse events was approximately 26% in both treatment groups. Most adverse events were mild or moderate in severity and did not limit treatment, the researchers wrote.

The mean age of the patients was 58.1 years; 46.1% were aged 65 and older, and 11.5% had bacteremia at baseline.

The study findings were limited by several factors, including the mandated 7- to 10-day course of antibiotics, which may not reflect the standard of care in other settings in the United States. The study’s trial sites were located in the United States, South Africa, and Europe. The study population was primarily White and from Central and Eastern Europe. Other limitations included the randomization of patients before confirming the baseline pathogen, although this was done to limit potential confounding from previous antibiotics, the researchers noted.
 

Safety and efficacy support application for approval

“To our knowledge, this is the first head-to-head evaluation of an IV vs. an oral drug for the treatment of cUTI and acute pyelonephritis,” Dr. Talley said in an interview.  

“The findings demonstrate that almost all patients in the study achieved complete resolution of the signs and symptoms of their infection,” she said.

TBP-PI-HBr has not been approved by the Food and Drug Administration, but a new drug application that included data from the current study was submitted to the FDA and is currently under review, Dr. Talley noted.

As for additional research, the current study was conducted in hospitalized patients, and the use of TBP-PI-HBr in the outpatient setting has not yet been evaluated, she said.
 

Approval and use of oral carbapenem will change practice

The current study is very important because it provides a viable and effective alternative form of antibiotic delivery for the patients with complicated UTI, Noel N. Deep, MD, emphasized in an interview.

“Currently these patients have to be treated with IV carbapenem antibiotics either in a hospital or through a home health nurse,” Dr. Deep, a general internist in group practice in Antigo, Wisc., explained.

Current IV strategies also carry the inherent risk associated with the insertion of an IV catheter that is left in place for several days or replaced periodically. “The oral antibiotic eliminates these risks and higher health care costs and provides a safer and equally efficacious option,” Dr. Deep said.

In the current study, “I was definitely surprised at the effectiveness of the oral carbapenem,” Dr. Deep said. “I am absolutely delighted with this new treatment option that physicians can now add to their armamentarium [assuming FDA approval] as we provide care to our patients,” he said.

If approved, TBP-PI-HBr will definitely change the treatment spectrum for the multidrug-resistant bacterial UTIs, said Dr. Deep. “Carbapenems have continued to be effective and low antibiotic resistance to carbapenems has been recorded.”

As for additional research, “I would like to see studies done in other ethnicities and different countries to ascertain the effectiveness of this antibiotic in those populations and against other bacterial strains with potentially different resistance mechanisms,” Dr. Deep said.

The study was supported by Spero Therapeutics and the Department of Health and Human Services. Lead author Paul B. Eckburg, MD, of Stanford (Calif.) University, and Dr. Talley are employees of Spero Therapeutics. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News.

Oral tebipenem pivoxil hydrobromide (TBP-PI-HBr) offers a safe and effective strategy for treating patients with complicated urinary tract infections, according to a new study.

“No new oral antibiotic alternative has emerged to treat these conditions in more than 25 years,” corresponding author Angela K. Talley, MD, said in an interview. The new research was published in the New England Journal of Medicine.

Courtesy Spero Therapeutics

Patients with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP), are often hospitalized and treated with intravenous therapy because of the lack of oral options, especially in cases of antibiotic-resistant pathogens, explained Dr. Talley, of Spero Therapeutics.

In their new phase 3, double-blind randomized trial, the researchers evaluated the safety and effectiveness of oral TBP-PI-HBr, compared with intravenous ertapenem in hospitalized patients with cUTIs or AP. Oral tebipenem is an investigational carbapenem with demonstrated activity against uropathogenic Enterobacterales, and it has shown effectiveness in animal models, the researchers noted in their paper.
 

Methods and results

The researchers randomized 1,372 adult patients. The microbiologic intent-to-treat population included 449 patients who received TBP-PI-HBr (600 mg every 8 hours) and 419 who received ertapenem (1 g every 24 hours) for 7-10 days or up to 14 days for patients with bacteremia.

The primary endpoint was a composite of clinical cure and favorable microbiologic response, assessed at a test-of-cure visit on day 19. Clinical cure was defined as “complete resolution or clinically significant alleviation of baseline signs and symptoms of complicated urinary tract infection or acute pyelonephritis and no new symptoms, such that no further antimicrobial therapy was warranted,” the researchers wrote. Microbiologic response was defined as a reduction to less than 103 CFU per milliliter in uropathogen levels from baseline at day 19.

Overall, the clinical response occurred in 58.8% of patients who received TBP-PI-HBr and 61.6% of those who received ertapenem at the test-of-cure visit.

Clinical cure rates were similar in the TBP-PI-HBr and ertapenem groups (93.1% vs. 93.6%) at the test-of-cure visit.

Both treatment groups showed similar responses to Enterobacterales pathogens at the test-of-cure visit (62.7% for TBP-PI-HBr and 65.2% for ertapenem).

Among patients with bacteremia at baseline, overall response rates were 72.3% and 66.0% for TBP-PI-HBr and ertapenem, respectively, at the test-of-cure visit, and 93.6% and 96.2%, respectively, at the end-of-treatment visit on or around day 25.

The overall incidence of adverse events was approximately 26% in both treatment groups. Most adverse events were mild or moderate in severity and did not limit treatment, the researchers wrote.

The mean age of the patients was 58.1 years; 46.1% were aged 65 and older, and 11.5% had bacteremia at baseline.

The study findings were limited by several factors, including the mandated 7- to 10-day course of antibiotics, which may not reflect the standard of care in other settings in the United States. The study’s trial sites were located in the United States, South Africa, and Europe. The study population was primarily White and from Central and Eastern Europe. Other limitations included the randomization of patients before confirming the baseline pathogen, although this was done to limit potential confounding from previous antibiotics, the researchers noted.
 

Safety and efficacy support application for approval

“To our knowledge, this is the first head-to-head evaluation of an IV vs. an oral drug for the treatment of cUTI and acute pyelonephritis,” Dr. Talley said in an interview.  

“The findings demonstrate that almost all patients in the study achieved complete resolution of the signs and symptoms of their infection,” she said.

TBP-PI-HBr has not been approved by the Food and Drug Administration, but a new drug application that included data from the current study was submitted to the FDA and is currently under review, Dr. Talley noted.

As for additional research, the current study was conducted in hospitalized patients, and the use of TBP-PI-HBr in the outpatient setting has not yet been evaluated, she said.
 

Approval and use of oral carbapenem will change practice

The current study is very important because it provides a viable and effective alternative form of antibiotic delivery for the patients with complicated UTI, Noel N. Deep, MD, emphasized in an interview.

“Currently these patients have to be treated with IV carbapenem antibiotics either in a hospital or through a home health nurse,” Dr. Deep, a general internist in group practice in Antigo, Wisc., explained.

Current IV strategies also carry the inherent risk associated with the insertion of an IV catheter that is left in place for several days or replaced periodically. “The oral antibiotic eliminates these risks and higher health care costs and provides a safer and equally efficacious option,” Dr. Deep said.

In the current study, “I was definitely surprised at the effectiveness of the oral carbapenem,” Dr. Deep said. “I am absolutely delighted with this new treatment option that physicians can now add to their armamentarium [assuming FDA approval] as we provide care to our patients,” he said.

If approved, TBP-PI-HBr will definitely change the treatment spectrum for the multidrug-resistant bacterial UTIs, said Dr. Deep. “Carbapenems have continued to be effective and low antibiotic resistance to carbapenems has been recorded.”

As for additional research, “I would like to see studies done in other ethnicities and different countries to ascertain the effectiveness of this antibiotic in those populations and against other bacterial strains with potentially different resistance mechanisms,” Dr. Deep said.

The study was supported by Spero Therapeutics and the Department of Health and Human Services. Lead author Paul B. Eckburg, MD, of Stanford (Calif.) University, and Dr. Talley are employees of Spero Therapeutics. Dr. Deep had no financial conflicts to disclose, but serves on the editorial advisory board of Internal Medicine News.

SEATTLE – A novel treatment for amyotrophic lateral sclerosis (ALS) that targets brain cell energy production to promote remyelination showed signs of efficacy in a phase 2 trial, though it did not meet its primary endpoint, which was the change in the summated motor unit index (MUNIX) from baseline to week 36.

The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.

Jim Kling/MDedge News

Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.

CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.

The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
 

Good safety signal

The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.

A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.

Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
 

Ongoing research

In September 2021, Clene announced a second expanded access program for people with ALS.

The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).

At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).

Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).

The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.

SEATTLE – A novel treatment for amyotrophic lateral sclerosis (ALS) that targets brain cell energy production to promote remyelination showed signs of efficacy in a phase 2 trial, though it did not meet its primary endpoint, which was the change in the summated motor unit index (MUNIX) from baseline to week 36.

The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.

Jim Kling/MDedge News

Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.

CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.

The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
 

Good safety signal

The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.

A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.

Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
 

Ongoing research

In September 2021, Clene announced a second expanded access program for people with ALS.

The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).

At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).

Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).

The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.

SEATTLE – A novel treatment for amyotrophic lateral sclerosis (ALS) that targets brain cell energy production to promote remyelination showed signs of efficacy in a phase 2 trial, though it did not meet its primary endpoint, which was the change in the summated motor unit index (MUNIX) from baseline to week 36.

The drug, CNM-Au8, is being developed by Clene, and would represent a novel mechanism of action. “This is a brand-new approach. We used it complementary with riluzole and it was well tolerated, so I see this as an add-on therapy. I think if we can show some more positivity and longer-term results, it’s going to be a game changer for ALS,” Matthew Kiernan, MBBS, PhD, said in an interview. Dr. Kiernan presented the results at the 2022 annual meeting of the American Academy of Neurology.

Jim Kling/MDedge News

Riluzole (Rilutek), which received Food and Drug Administration approval in 1995, inhibits glutamate release to counter excitotoxicity, which is believed to play a role in ALS, Huntington’s disease, ischemia, and other acute and chronic neurodegenerative diseases. The other FDA-approved agent for ALS is the neuroprotective agent and free-radical scavenger edaravone (Radicava), approved in 2017.

CNM-Au8 is made up of catalytically active gold nanocrystals that cross the blood-brain barrier, but lacks the toxicity associated with other synthetic gold compounds, according to the company. The formulation is also being investigated for the treatment of Parkinson’s disease and multiple sclerosis. Basic research has shown that it stabilizes mitochondria and reduces accumulation of the TDP-43 protein, which is linked to spread of ALS through the brain, Dr. Kiernan said during his presentation.

The treatment is well tolerated. “Normally in an ALS trial, we see about a 25% dropout rate. There were no dropouts on the active compound in the clinical trial. There are less deaths, so improved survival,” said Dr. Kiernan, the Bushell chair of neurology at the University of Sydney and codirector of the Brain and Mind Center in Sydney.
 

Good safety signal

The fact that the trial missed its primary endpoint isn’t too concerning, according to Nicholas Johnson, MD, who comoderated the session where the study was presented. “ALS clinical trials are incredibly difficult to conduct, especially a phase 2 learning-phase clinical trial. At this phase, I’m much more buoyed by the fact that they have a good safety signal, and that they’re willing to move forward to that phase 3 clinical trial,” Dr. Johnson said in an interview. He is vice chair of research at Virginia Commonwealth University, Richmond.

A phase 3 clinical trial is in development in the United States and Europe. The drug also is included as part of the HEALEY ALS Platform Trial, which is testing multiple ALS therapies simultaneously. “The results from that should be available by the second half of this year and it will also inform us as to what the approach should be,” said Dr. Kiernan.

Dr. Johnson also was enthusiastic. “I’m excited to see the results in terms of the primary endpoints for that next phase 3 clinical trial,” he said.
 

Ongoing research

In September 2021, Clene announced a second expanded access program for people with ALS.

The study included a 36-week double-blind treatment period followed by long-term, open-label follow-up. Twenty-three patients received 30 mg CNM-Au8, and 22 received placebo. In the first 36 weeks, the treatment group was more likely to have no disease progression, defined as death, tracheostomy, noninvasive ventilation, or a gastronomy tube (P = .0125). The researchers compared the probability of experiencing a less than 6-point decline in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. At 12 weeks, it was about 85% in both groups. At 24 weeks, it was about 60% to 50% in favor of the CNM-Au8 group, and at 36 weeks it was about 50% to 20% (P = .0350).

At 36 weeks, quality of life as measured by the ALS Specific Quality of Life–Short Form was better in the treatment group at 36 weeks (mean change, 0.9; P = .0177).

Survival was better in the treatment group at 96 weeks than the mortality derived from a European Network for the Cure of ALS prediction model (hazard ratio [HR], 0.2974; P = .0068). This benefit also was experienced by patients who received drug throughout the study (HR, 0.36; 95% confidence interval [CI], 0.12-1.1) and those who started out on placebo and converted to active drug during the open-label period (HR, 0.24; 95% CI, 0.064-0.88).

The study was funded by Clene and FightMND. Dr. Kiernan and Dr. Johnson have no relevant financial disclosures.

The rates of infection involving cardiac implanted electronic devices (CIEDs), like pacemakers and cardioverter defibrillators (ICDs), are substantial, but only a minority of patients in the United States receive the guideline-directed recommendation of device removal, according to data from a Medicare population.

The study was conducted on the hypothesis that adherence to guidelines were low, “but we were surprised by how low the extraction rates turned out to be,” Sean D. Pokorney, MD, an electrophysiologist at the Duke Clinical Research Institute, Durham, N.C., reported at the annual scientific sessions of the American College of Cardiology.

The major U.S. and European guidelines are uniform in recommending complete extraction for a CIED infection. The American Heart Association and the Heart Rhythm Society and two out of the three other guidelines cited by Dr. Pokorney not only recommend extraction but specify prompt extraction.

Neither complete extraction nor prompt extraction are typical.

Of the 11,619 CIED infection cases identified in the Medicare database, 18.2% underwent extraction within 30 days of diagnosis. Only 13% were extracted within 6 days.
 

Lack of extraction may cause avoidable mortality

The result is likely to be avoidable mortality. Among those with extraction within 30 days, 80% were still alive 1 year later. Survival at 1 year fell to 67.6% in those without an extraction within this time frame.

This translated to a 22% lower rate of death at 1 year (hazard ratio, 0.78; P = .008) in those who underwent extraction within 30 days.

For those in whom the device was extracted within 7 days, the associated HR for death at 1 year was more than 40% lower (HR, 0.59; P < .001), reported Dr. Pokorney, who characterized these reductions as occurring in “a dose-response fashion.”

The very high risk of relapse despite antibiotics is the reason that “there is a class 1 indication for complete hardware removal,” Dr. Pokorney. He cited five studies that addressed this question. With partial device removal or medical therapy alone, relapse was consistently 50% or greater. In one study, it was 67%. In another it was 100%.

With complete removal, the rate of infection relapse was 1% or lower in four. In the fifth, the rate was 4.2%.

Infections can occur early or late after implantation, but cases accumulate over time. In the Medicare data sample, infection rates climbed from 0.3% at 1 year to 0.6% at 2 years and then to 1.1% at 3 years, Dr. Pokorney reported.

Other studies have also shown a steady increase in the proportion of implanted devices associated with infection over time. In a cohort study conducted in Olmstead County, Minnesota, the cumulative probability of a CIED infection reached 6.2% after 15 years and 11.7% after 25 years. While about half of these were infections localized to the device pocket, the others were potentially life-threatening systemic infections, according to Dr. Pokorney, who cited this study.

In his analysis of the Medicare data, all fee-for-service patients receiving a first CIED implant over a period of 14 years were included. The 14-year period ended just before the COVID-19 epidemic.

The more than 11,000 CIED infections were identified in 1,065,549 total CIED patients. Most (72%) had received a pacemaker. Of the others , more than half received an ICD and the others received a cardiac resynchronization device. The median age was 78 years.
 

Female and Black patients even less likely to undergo extraction

About half (49.1%) of the overall study population was female, but females represented only about 40% of those who developed an infection. Blacks represented just under 8% of the population but nearly 16% of the CIED infections. Both females and Blacks were significantly less likely than the overall study population to undergo extraction for their infection (P < .001 for both).

Perhaps predictably, patients with comorbidities were more likely to develop CIED infections. For example, 87% of those with infection, versus only 64.9% of the overall population, were in heart failure at the time of implantation. Diabetes (68.3% vs. 49.3%), ischemic heart disease (91.9% vs. 79.4%), renal disease (70.5% vs. 37.9%), and chronic obstructive pulmonary disease (70.6% vs. 55.0%) were also more common at baseline in those who went on to a CIED infection than in the overall population.

Based on the evidence that there is a large unmet need to improve adherence to the guidelines, Dr. Pokorney called for care pathways and other quality initiatives to address the problem.

The reasons that so many patients are not undergoing prompt device extraction at the time of infection is unclear, but Dr. Pokorney offered some hypotheses.

“There appears to be a false belief in the efficacy of antibiotics for treating CIED infections,” Dr. Pokorney said.
 

Comorbidities shouldn’t delay extraction

It is also possible that clinicians are concerned about performing extractions in patients with multiple comorbidities. If clinicians are delaying extractions for this reason, Dr. Pokorney suggested this behavior is misdirected given the fact that delays appear to increase mortality risk.

Several experts, including Rachel Lambert, MD, an electrophysiologist and professor of medicine at Yale University, New Haven, Conn., agreed that these data deserve a response.

“I was not surprised by the mortality data, but I was surprised at this low extraction rate,” said Dr. Lambert, who concurs with the guidelines. She indicated this study provides teeth to prompt action.

“It is great to have these data about the increased mortality risk to back up the guidelines,” she said.

More information is needed to understand exactly why CIED infection is not now leading to guideline-directed care. Dr. Pokorney said: “Where do we go from here is a key question.”

While several different types of initiatives might be needed, Dr. Pokorney called for regionalization of care to address the fact that not every center that places CIEDs has the capability to perform extractions.

“Extraction is not available at every center, and it probably should not be available at every center, so mechanisms are need to get patients with infection to the specialized centers that provide care,” he said.

Dr. Pokorney has financial relationships with Boston Scientific, Bristol-Myers Squibb, Gilead, Janssen, Medtronic, Pfizer, and Philips. Dr. Lambert reported financial relationships with Abbott, Amgen, and Medtronic.

The rates of infection involving cardiac implanted electronic devices (CIEDs), like pacemakers and cardioverter defibrillators (ICDs), are substantial, but only a minority of patients in the United States receive the guideline-directed recommendation of device removal, according to data from a Medicare population.

The study was conducted on the hypothesis that adherence to guidelines were low, “but we were surprised by how low the extraction rates turned out to be,” Sean D. Pokorney, MD, an electrophysiologist at the Duke Clinical Research Institute, Durham, N.C., reported at the annual scientific sessions of the American College of Cardiology.

The major U.S. and European guidelines are uniform in recommending complete extraction for a CIED infection. The American Heart Association and the Heart Rhythm Society and two out of the three other guidelines cited by Dr. Pokorney not only recommend extraction but specify prompt extraction.

Neither complete extraction nor prompt extraction are typical.

Of the 11,619 CIED infection cases identified in the Medicare database, 18.2% underwent extraction within 30 days of diagnosis. Only 13% were extracted within 6 days.
 

Lack of extraction may cause avoidable mortality

The result is likely to be avoidable mortality. Among those with extraction within 30 days, 80% were still alive 1 year later. Survival at 1 year fell to 67.6% in those without an extraction within this time frame.

This translated to a 22% lower rate of death at 1 year (hazard ratio, 0.78; P = .008) in those who underwent extraction within 30 days.

For those in whom the device was extracted within 7 days, the associated HR for death at 1 year was more than 40% lower (HR, 0.59; P < .001), reported Dr. Pokorney, who characterized these reductions as occurring in “a dose-response fashion.”

The very high risk of relapse despite antibiotics is the reason that “there is a class 1 indication for complete hardware removal,” Dr. Pokorney. He cited five studies that addressed this question. With partial device removal or medical therapy alone, relapse was consistently 50% or greater. In one study, it was 67%. In another it was 100%.

With complete removal, the rate of infection relapse was 1% or lower in four. In the fifth, the rate was 4.2%.

Infections can occur early or late after implantation, but cases accumulate over time. In the Medicare data sample, infection rates climbed from 0.3% at 1 year to 0.6% at 2 years and then to 1.1% at 3 years, Dr. Pokorney reported.

Other studies have also shown a steady increase in the proportion of implanted devices associated with infection over time. In a cohort study conducted in Olmstead County, Minnesota, the cumulative probability of a CIED infection reached 6.2% after 15 years and 11.7% after 25 years. While about half of these were infections localized to the device pocket, the others were potentially life-threatening systemic infections, according to Dr. Pokorney, who cited this study.

In his analysis of the Medicare data, all fee-for-service patients receiving a first CIED implant over a period of 14 years were included. The 14-year period ended just before the COVID-19 epidemic.

The more than 11,000 CIED infections were identified in 1,065,549 total CIED patients. Most (72%) had received a pacemaker. Of the others , more than half received an ICD and the others received a cardiac resynchronization device. The median age was 78 years.
 

Female and Black patients even less likely to undergo extraction

About half (49.1%) of the overall study population was female, but females represented only about 40% of those who developed an infection. Blacks represented just under 8% of the population but nearly 16% of the CIED infections. Both females and Blacks were significantly less likely than the overall study population to undergo extraction for their infection (P < .001 for both).

Perhaps predictably, patients with comorbidities were more likely to develop CIED infections. For example, 87% of those with infection, versus only 64.9% of the overall population, were in heart failure at the time of implantation. Diabetes (68.3% vs. 49.3%), ischemic heart disease (91.9% vs. 79.4%), renal disease (70.5% vs. 37.9%), and chronic obstructive pulmonary disease (70.6% vs. 55.0%) were also more common at baseline in those who went on to a CIED infection than in the overall population.

Based on the evidence that there is a large unmet need to improve adherence to the guidelines, Dr. Pokorney called for care pathways and other quality initiatives to address the problem.

The reasons that so many patients are not undergoing prompt device extraction at the time of infection is unclear, but Dr. Pokorney offered some hypotheses.

“There appears to be a false belief in the efficacy of antibiotics for treating CIED infections,” Dr. Pokorney said.
 

Comorbidities shouldn’t delay extraction

It is also possible that clinicians are concerned about performing extractions in patients with multiple comorbidities. If clinicians are delaying extractions for this reason, Dr. Pokorney suggested this behavior is misdirected given the fact that delays appear to increase mortality risk.

Several experts, including Rachel Lambert, MD, an electrophysiologist and professor of medicine at Yale University, New Haven, Conn., agreed that these data deserve a response.

“I was not surprised by the mortality data, but I was surprised at this low extraction rate,” said Dr. Lambert, who concurs with the guidelines. She indicated this study provides teeth to prompt action.

“It is great to have these data about the increased mortality risk to back up the guidelines,” she said.

More information is needed to understand exactly why CIED infection is not now leading to guideline-directed care. Dr. Pokorney said: “Where do we go from here is a key question.”

While several different types of initiatives might be needed, Dr. Pokorney called for regionalization of care to address the fact that not every center that places CIEDs has the capability to perform extractions.

“Extraction is not available at every center, and it probably should not be available at every center, so mechanisms are need to get patients with infection to the specialized centers that provide care,” he said.

Dr. Pokorney has financial relationships with Boston Scientific, Bristol-Myers Squibb, Gilead, Janssen, Medtronic, Pfizer, and Philips. Dr. Lambert reported financial relationships with Abbott, Amgen, and Medtronic.

The rates of infection involving cardiac implanted electronic devices (CIEDs), like pacemakers and cardioverter defibrillators (ICDs), are substantial, but only a minority of patients in the United States receive the guideline-directed recommendation of device removal, according to data from a Medicare population.

The study was conducted on the hypothesis that adherence to guidelines were low, “but we were surprised by how low the extraction rates turned out to be,” Sean D. Pokorney, MD, an electrophysiologist at the Duke Clinical Research Institute, Durham, N.C., reported at the annual scientific sessions of the American College of Cardiology.

The major U.S. and European guidelines are uniform in recommending complete extraction for a CIED infection. The American Heart Association and the Heart Rhythm Society and two out of the three other guidelines cited by Dr. Pokorney not only recommend extraction but specify prompt extraction.

Neither complete extraction nor prompt extraction are typical.

Of the 11,619 CIED infection cases identified in the Medicare database, 18.2% underwent extraction within 30 days of diagnosis. Only 13% were extracted within 6 days.
 

Lack of extraction may cause avoidable mortality

The result is likely to be avoidable mortality. Among those with extraction within 30 days, 80% were still alive 1 year later. Survival at 1 year fell to 67.6% in those without an extraction within this time frame.

This translated to a 22% lower rate of death at 1 year (hazard ratio, 0.78; P = .008) in those who underwent extraction within 30 days.

For those in whom the device was extracted within 7 days, the associated HR for death at 1 year was more than 40% lower (HR, 0.59; P < .001), reported Dr. Pokorney, who characterized these reductions as occurring in “a dose-response fashion.”

The very high risk of relapse despite antibiotics is the reason that “there is a class 1 indication for complete hardware removal,” Dr. Pokorney. He cited five studies that addressed this question. With partial device removal or medical therapy alone, relapse was consistently 50% or greater. In one study, it was 67%. In another it was 100%.

With complete removal, the rate of infection relapse was 1% or lower in four. In the fifth, the rate was 4.2%.

Infections can occur early or late after implantation, but cases accumulate over time. In the Medicare data sample, infection rates climbed from 0.3% at 1 year to 0.6% at 2 years and then to 1.1% at 3 years, Dr. Pokorney reported.

Other studies have also shown a steady increase in the proportion of implanted devices associated with infection over time. In a cohort study conducted in Olmstead County, Minnesota, the cumulative probability of a CIED infection reached 6.2% after 15 years and 11.7% after 25 years. While about half of these were infections localized to the device pocket, the others were potentially life-threatening systemic infections, according to Dr. Pokorney, who cited this study.

In his analysis of the Medicare data, all fee-for-service patients receiving a first CIED implant over a period of 14 years were included. The 14-year period ended just before the COVID-19 epidemic.

The more than 11,000 CIED infections were identified in 1,065,549 total CIED patients. Most (72%) had received a pacemaker. Of the others , more than half received an ICD and the others received a cardiac resynchronization device. The median age was 78 years.
 

Female and Black patients even less likely to undergo extraction

About half (49.1%) of the overall study population was female, but females represented only about 40% of those who developed an infection. Blacks represented just under 8% of the population but nearly 16% of the CIED infections. Both females and Blacks were significantly less likely than the overall study population to undergo extraction for their infection (P < .001 for both).

Perhaps predictably, patients with comorbidities were more likely to develop CIED infections. For example, 87% of those with infection, versus only 64.9% of the overall population, were in heart failure at the time of implantation. Diabetes (68.3% vs. 49.3%), ischemic heart disease (91.9% vs. 79.4%), renal disease (70.5% vs. 37.9%), and chronic obstructive pulmonary disease (70.6% vs. 55.0%) were also more common at baseline in those who went on to a CIED infection than in the overall population.

Based on the evidence that there is a large unmet need to improve adherence to the guidelines, Dr. Pokorney called for care pathways and other quality initiatives to address the problem.

The reasons that so many patients are not undergoing prompt device extraction at the time of infection is unclear, but Dr. Pokorney offered some hypotheses.

“There appears to be a false belief in the efficacy of antibiotics for treating CIED infections,” Dr. Pokorney said.
 

Comorbidities shouldn’t delay extraction

It is also possible that clinicians are concerned about performing extractions in patients with multiple comorbidities. If clinicians are delaying extractions for this reason, Dr. Pokorney suggested this behavior is misdirected given the fact that delays appear to increase mortality risk.

Several experts, including Rachel Lambert, MD, an electrophysiologist and professor of medicine at Yale University, New Haven, Conn., agreed that these data deserve a response.

“I was not surprised by the mortality data, but I was surprised at this low extraction rate,” said Dr. Lambert, who concurs with the guidelines. She indicated this study provides teeth to prompt action.

“It is great to have these data about the increased mortality risk to back up the guidelines,” she said.

More information is needed to understand exactly why CIED infection is not now leading to guideline-directed care. Dr. Pokorney said: “Where do we go from here is a key question.”

While several different types of initiatives might be needed, Dr. Pokorney called for regionalization of care to address the fact that not every center that places CIEDs has the capability to perform extractions.

“Extraction is not available at every center, and it probably should not be available at every center, so mechanisms are need to get patients with infection to the specialized centers that provide care,” he said.

Dr. Pokorney has financial relationships with Boston Scientific, Bristol-Myers Squibb, Gilead, Janssen, Medtronic, Pfizer, and Philips. Dr. Lambert reported financial relationships with Abbott, Amgen, and Medtronic.

A dose-response relationship exists between number of years playing hockey and risk and severity of chronic traumatic encephalopathy (CTE), new research suggests. Early results from a study that examined donor brains showed that each additional year of ice hockey play increased the risk for CTE by 23%.

This information should be on the “radar” of all clinicians, said coinvestigator Jesse Mez, MD, associate professor of neurology at Boston University. “When they’re talking to kids and families and parents about playing contact sports, they should discuss the benefits as well as the risks so all that information can be taken into consideration.”

Dr. Mez noted that clinicians should also consider the amount of hockey played when assessing patients for thinking and memory trouble later in life. “CTE could be in the differential diagnosis,” he said.

The study findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

Football data

CTE is a neurodegenerative disease associated with repetitive hits to the head. In previous research, the investigators showed that the more that athletes play American football, the more likely they are to develop CTE.

“Hockey, like football, involves repetitive head impacts as part of the game,” said Dr. Mez. “So we hypothesized that we would see a similar type of dose-response relationship in hockey.”

From two brain banks – the Veterans Affairs–Boston University–Concussion Legacy Foundation and the Framingham Heart Study – the researchers accessed 74 consecutive brains from donors who had played ice hockey. They collected information about hockey play during “pretty comprehensive” interviews with next of kin, Dr. Mez reported.

The study participants ranged in age from 13 to 91 years. The cause of death varied; most died with end-stage dementia and neurodegenerative disease, but some died of cardiovascular disease, and others from accidents.

For 9% of the individuals, the highest level of play was a youth league; 34% had reached the high school level, 30% reached the juniors/college level, and 26% played professionally. In addition, 46% played another contact sport – including 43% who played American football.

Primary outcomes included evidence of CTE from stage 0 (no CTE) to stage IV and severity of CTE, which was defined by the amount of neurofibrillary tangle (NFT) burden in 11 brain regions. For this burden, the score ranged from 0 (absent) to 3 (severe) in each region for a total range of 0-33.

Dr. Mez noted that, in CTE, tau protein accumulates abnormally. “It typically begins in the cortex in the frontal lobe and then spreads to other parts of the brain, including to the medial temporal structures, and is widespread by stage IV.”

The researchers estimated the association of duration of ice hockey play in years with each neuropathologic outcome and adjusted for age at death and duration of football play.
 

Consistent findings

Results showed that, of the 74 donors, 40 (54%) had CTE. Each additional year of hockey play corresponded to increased chances for having CTE (odds ratio, 1.23; 95% confidence interval, 11%-36%; P < .01). This increase in risk is similar to that which was found with football players, Dr. Mez noted. This was somewhat surprising, as hockey involves fewer “hits” than football.

“Hits are not as quintessential to the game of hockey as they are in football, where contacts occur with nearly every play,” he said. “In football, you have several hundred impacts over the course of a season.”

Researchers also found a 15% increase in odds for increasing one CTE stage (95% CI, 8%-22%; P < .01), and a .03 standard deviation increase in cumulative NFT burden (95% CI, 0.01-0.05; P < .01).

Dr. Mez noted that the fact that the results were consistent across different outcomes “improves the validity” of the findings.

In a sensitivity analysis that excluded participants who also played football, estimates “were pretty similar” to those in the full analysis, said Dr. Mez.

The investigators have not yet examined the effect of level of hockey play, such as professionally or at the college level, on CTE risk. However, in football players, they found that level of play is another “valuable predictor of CTE pathology,” Dr. Mez said, adding that level of play, position played, and years of play “are all probably contributing” to CTE risk.

Asking about years of play is useful in a clinical setting. “It’s very easy for a clinician to ask patients how many years of hockey they played,” said Dr. Mez.

Overall, the new results are important, as “millions of individuals” play contact sports, whether that is hockey, football, or European soccer, he added. “And for all sports, there seems to be this relationship between more play and risk of this disease.”
 

‘Skewed’ population?

Commenting on the findings, Frank Conidi, MD, director, Florida Center for Health and Sports Neurology, Port St. Lucie, said he was surprised the investigators found a 23% per year increase in risk for CTE among hockey players.

Dr. Conidi has played hockey himself and works with the Florida Panthers of the National Hockey League. In his practice, he treats retired professional football players who have neurodegenerative disorders. From his experience, the number of repetitive direct head impacts in football is significantly higher than in hockey. “Most of the forces seen in hockey are from hits to the body, where the force is transferred to the head,” said Dr. Conidi, who was not involved with the research.

He noted differences in the way hockey is played around the world. In European countries, for example, the ice surface is relatively large and the emphasis tends to be more on skill than hitting.

“It would have been interesting to have the study group analyze the data based on where the athlete grew up,” he said. Dr. Conidi would also like to know when the participants played hockey. “The game is vastly different now than it was in the 1970s, ‘80s, and early ‘90s, when there was more fighting, less protective gear, and more hitting in general.”

As is the case for most studies of CTE in athletes, the study population is “skewed” because the participants likely had neurocognitive and other problems that led to their decision to donate their brain, said Dr. Conidi.

He also doesn’t believe the study should be the sole factor in a decision to continue or stop playing hockey. “We are still in the infancy stages of understanding the effects of high-impact sports on athletes’ brains.”

The study received funding from the National Institute of Neurological Diseases and Stroke and the National Institute on Aging. Dr. Mez and Dr. Conidi have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A dose-response relationship exists between number of years playing hockey and risk and severity of chronic traumatic encephalopathy (CTE), new research suggests. Early results from a study that examined donor brains showed that each additional year of ice hockey play increased the risk for CTE by 23%.

This information should be on the “radar” of all clinicians, said coinvestigator Jesse Mez, MD, associate professor of neurology at Boston University. “When they’re talking to kids and families and parents about playing contact sports, they should discuss the benefits as well as the risks so all that information can be taken into consideration.”

Dr. Mez noted that clinicians should also consider the amount of hockey played when assessing patients for thinking and memory trouble later in life. “CTE could be in the differential diagnosis,” he said.

The study findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

Football data

CTE is a neurodegenerative disease associated with repetitive hits to the head. In previous research, the investigators showed that the more that athletes play American football, the more likely they are to develop CTE.

“Hockey, like football, involves repetitive head impacts as part of the game,” said Dr. Mez. “So we hypothesized that we would see a similar type of dose-response relationship in hockey.”

From two brain banks – the Veterans Affairs–Boston University–Concussion Legacy Foundation and the Framingham Heart Study – the researchers accessed 74 consecutive brains from donors who had played ice hockey. They collected information about hockey play during “pretty comprehensive” interviews with next of kin, Dr. Mez reported.

The study participants ranged in age from 13 to 91 years. The cause of death varied; most died with end-stage dementia and neurodegenerative disease, but some died of cardiovascular disease, and others from accidents.

For 9% of the individuals, the highest level of play was a youth league; 34% had reached the high school level, 30% reached the juniors/college level, and 26% played professionally. In addition, 46% played another contact sport – including 43% who played American football.

Primary outcomes included evidence of CTE from stage 0 (no CTE) to stage IV and severity of CTE, which was defined by the amount of neurofibrillary tangle (NFT) burden in 11 brain regions. For this burden, the score ranged from 0 (absent) to 3 (severe) in each region for a total range of 0-33.

Dr. Mez noted that, in CTE, tau protein accumulates abnormally. “It typically begins in the cortex in the frontal lobe and then spreads to other parts of the brain, including to the medial temporal structures, and is widespread by stage IV.”

The researchers estimated the association of duration of ice hockey play in years with each neuropathologic outcome and adjusted for age at death and duration of football play.
 

Consistent findings

Results showed that, of the 74 donors, 40 (54%) had CTE. Each additional year of hockey play corresponded to increased chances for having CTE (odds ratio, 1.23; 95% confidence interval, 11%-36%; P < .01). This increase in risk is similar to that which was found with football players, Dr. Mez noted. This was somewhat surprising, as hockey involves fewer “hits” than football.

“Hits are not as quintessential to the game of hockey as they are in football, where contacts occur with nearly every play,” he said. “In football, you have several hundred impacts over the course of a season.”

Researchers also found a 15% increase in odds for increasing one CTE stage (95% CI, 8%-22%; P < .01), and a .03 standard deviation increase in cumulative NFT burden (95% CI, 0.01-0.05; P < .01).

Dr. Mez noted that the fact that the results were consistent across different outcomes “improves the validity” of the findings.

In a sensitivity analysis that excluded participants who also played football, estimates “were pretty similar” to those in the full analysis, said Dr. Mez.

The investigators have not yet examined the effect of level of hockey play, such as professionally or at the college level, on CTE risk. However, in football players, they found that level of play is another “valuable predictor of CTE pathology,” Dr. Mez said, adding that level of play, position played, and years of play “are all probably contributing” to CTE risk.

Asking about years of play is useful in a clinical setting. “It’s very easy for a clinician to ask patients how many years of hockey they played,” said Dr. Mez.

Overall, the new results are important, as “millions of individuals” play contact sports, whether that is hockey, football, or European soccer, he added. “And for all sports, there seems to be this relationship between more play and risk of this disease.”
 

‘Skewed’ population?

Commenting on the findings, Frank Conidi, MD, director, Florida Center for Health and Sports Neurology, Port St. Lucie, said he was surprised the investigators found a 23% per year increase in risk for CTE among hockey players.

Dr. Conidi has played hockey himself and works with the Florida Panthers of the National Hockey League. In his practice, he treats retired professional football players who have neurodegenerative disorders. From his experience, the number of repetitive direct head impacts in football is significantly higher than in hockey. “Most of the forces seen in hockey are from hits to the body, where the force is transferred to the head,” said Dr. Conidi, who was not involved with the research.

He noted differences in the way hockey is played around the world. In European countries, for example, the ice surface is relatively large and the emphasis tends to be more on skill than hitting.

“It would have been interesting to have the study group analyze the data based on where the athlete grew up,” he said. Dr. Conidi would also like to know when the participants played hockey. “The game is vastly different now than it was in the 1970s, ‘80s, and early ‘90s, when there was more fighting, less protective gear, and more hitting in general.”

As is the case for most studies of CTE in athletes, the study population is “skewed” because the participants likely had neurocognitive and other problems that led to their decision to donate their brain, said Dr. Conidi.

He also doesn’t believe the study should be the sole factor in a decision to continue or stop playing hockey. “We are still in the infancy stages of understanding the effects of high-impact sports on athletes’ brains.”

The study received funding from the National Institute of Neurological Diseases and Stroke and the National Institute on Aging. Dr. Mez and Dr. Conidi have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A dose-response relationship exists between number of years playing hockey and risk and severity of chronic traumatic encephalopathy (CTE), new research suggests. Early results from a study that examined donor brains showed that each additional year of ice hockey play increased the risk for CTE by 23%.

This information should be on the “radar” of all clinicians, said coinvestigator Jesse Mez, MD, associate professor of neurology at Boston University. “When they’re talking to kids and families and parents about playing contact sports, they should discuss the benefits as well as the risks so all that information can be taken into consideration.”

Dr. Mez noted that clinicians should also consider the amount of hockey played when assessing patients for thinking and memory trouble later in life. “CTE could be in the differential diagnosis,” he said.

The study findings were presented at the 2022 annual meeting of the American Academy of Neurology.
 

Football data

CTE is a neurodegenerative disease associated with repetitive hits to the head. In previous research, the investigators showed that the more that athletes play American football, the more likely they are to develop CTE.

“Hockey, like football, involves repetitive head impacts as part of the game,” said Dr. Mez. “So we hypothesized that we would see a similar type of dose-response relationship in hockey.”

From two brain banks – the Veterans Affairs–Boston University–Concussion Legacy Foundation and the Framingham Heart Study – the researchers accessed 74 consecutive brains from donors who had played ice hockey. They collected information about hockey play during “pretty comprehensive” interviews with next of kin, Dr. Mez reported.

The study participants ranged in age from 13 to 91 years. The cause of death varied; most died with end-stage dementia and neurodegenerative disease, but some died of cardiovascular disease, and others from accidents.

For 9% of the individuals, the highest level of play was a youth league; 34% had reached the high school level, 30% reached the juniors/college level, and 26% played professionally. In addition, 46% played another contact sport – including 43% who played American football.

Primary outcomes included evidence of CTE from stage 0 (no CTE) to stage IV and severity of CTE, which was defined by the amount of neurofibrillary tangle (NFT) burden in 11 brain regions. For this burden, the score ranged from 0 (absent) to 3 (severe) in each region for a total range of 0-33.

Dr. Mez noted that, in CTE, tau protein accumulates abnormally. “It typically begins in the cortex in the frontal lobe and then spreads to other parts of the brain, including to the medial temporal structures, and is widespread by stage IV.”

The researchers estimated the association of duration of ice hockey play in years with each neuropathologic outcome and adjusted for age at death and duration of football play.
 

Consistent findings

Results showed that, of the 74 donors, 40 (54%) had CTE. Each additional year of hockey play corresponded to increased chances for having CTE (odds ratio, 1.23; 95% confidence interval, 11%-36%; P < .01). This increase in risk is similar to that which was found with football players, Dr. Mez noted. This was somewhat surprising, as hockey involves fewer “hits” than football.

“Hits are not as quintessential to the game of hockey as they are in football, where contacts occur with nearly every play,” he said. “In football, you have several hundred impacts over the course of a season.”

Researchers also found a 15% increase in odds for increasing one CTE stage (95% CI, 8%-22%; P < .01), and a .03 standard deviation increase in cumulative NFT burden (95% CI, 0.01-0.05; P < .01).

Dr. Mez noted that the fact that the results were consistent across different outcomes “improves the validity” of the findings.

In a sensitivity analysis that excluded participants who also played football, estimates “were pretty similar” to those in the full analysis, said Dr. Mez.

The investigators have not yet examined the effect of level of hockey play, such as professionally or at the college level, on CTE risk. However, in football players, they found that level of play is another “valuable predictor of CTE pathology,” Dr. Mez said, adding that level of play, position played, and years of play “are all probably contributing” to CTE risk.

Asking about years of play is useful in a clinical setting. “It’s very easy for a clinician to ask patients how many years of hockey they played,” said Dr. Mez.

Overall, the new results are important, as “millions of individuals” play contact sports, whether that is hockey, football, or European soccer, he added. “And for all sports, there seems to be this relationship between more play and risk of this disease.”
 

‘Skewed’ population?

Commenting on the findings, Frank Conidi, MD, director, Florida Center for Health and Sports Neurology, Port St. Lucie, said he was surprised the investigators found a 23% per year increase in risk for CTE among hockey players.

Dr. Conidi has played hockey himself and works with the Florida Panthers of the National Hockey League. In his practice, he treats retired professional football players who have neurodegenerative disorders. From his experience, the number of repetitive direct head impacts in football is significantly higher than in hockey. “Most of the forces seen in hockey are from hits to the body, where the force is transferred to the head,” said Dr. Conidi, who was not involved with the research.

He noted differences in the way hockey is played around the world. In European countries, for example, the ice surface is relatively large and the emphasis tends to be more on skill than hitting.

“It would have been interesting to have the study group analyze the data based on where the athlete grew up,” he said. Dr. Conidi would also like to know when the participants played hockey. “The game is vastly different now than it was in the 1970s, ‘80s, and early ‘90s, when there was more fighting, less protective gear, and more hitting in general.”

As is the case for most studies of CTE in athletes, the study population is “skewed” because the participants likely had neurocognitive and other problems that led to their decision to donate their brain, said Dr. Conidi.

He also doesn’t believe the study should be the sole factor in a decision to continue or stop playing hockey. “We are still in the infancy stages of understanding the effects of high-impact sports on athletes’ brains.”

The study received funding from the National Institute of Neurological Diseases and Stroke and the National Institute on Aging. Dr. Mez and Dr. Conidi have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Ohio House of Representatives recently passed a bill that would enable patients to use drug manufacturer coupons and other co-pay assistance as payment toward their annual deductible.

According to the Kaiser Family Foundation, approximately 1 in 4 Americans have difficulty paying for their prescription drugs, while almost half of U.S. adults report difficulty paying out-of-pocket costs not covered by their health insurance.

Supporting the bill that restricts co-pay accumulators are groups such as the Ohio State Medical Association, the Crohn’s and Colitis Foundation, Susan C. Komen, the National Multiple Sclerosis Society, and the American Diabetes Association. The bill faced opposition from health insurers and pharmacy benefit managers, reported The Columbus Dispatch.

“The debate on the management of rising drug costs between manufacturers and insurers unfortunately leaves patients caught in the middle, and practices like co-pay accumulators can have a devastating impact,” Monica Hueckel, senior director of government relations for the Ohio State Medical Association, told this news organization.

“Patients often do not even know about these policies until the coupons are no longer usable. As you can imagine, for patients with expensive medications and/or high deductible health plans, the impact is disastrous,” she said.

Ohio State Representative Susan Manchester, who co-sponsored the bill, told The Columbus Dispatch that the legislation “is needed to assist our constituents who find themselves increasingly subjected to more out-of-pocket costs as part of their insurance coverage.”

Other states blocking health insurers’ co-pay policies

With the passage of the bill, Ohio joins 12 states and Puerto Rico in preventing the use of health insurers’ co-pays to increase patients’ out-of-pocket costs, reported The Columbus Dispatch; 15 states are also considering this type of legislation.

Eighty-three percent of patients are in plans that include a co-pay accumulator, according to consulting firm Avalere, which wrote that, beginning in 2023, the Center for Medicare & Medicaid Services requires patients with Medicaid to receive “the full value of co-pay assistance” on drugs.

According to the National Conference of State Legislatures, co-pay adjustment programs present challenges for patients, with plans that include high cost sharing or co-insurance whereby a patient pays a percentage of the cost instead of a flat amount.

For example, with a co-pay adjustment policy, a patient with a $2,000 deductible plan couldn’t use a $500 coupon toward meeting the deductible, writes the National Conference of State Legislatures. Conversely, a patient in a plan without a co-pay adjustment policy could use the coupon to satisfy their annual deductible.

Patients with complex conditions, such as cancer, rheumatoid arthritis, and diabetes, which often require expensive medications, may have little choice but to fork over the unexpected co-pays, according to the organization that represents state legislatures in the United States.

The bill now moves to the Ohio Senate, reported The Columbus Dispatch.

A version of this article first appeared on Medscape.com.

The Ohio House of Representatives recently passed a bill that would enable patients to use drug manufacturer coupons and other co-pay assistance as payment toward their annual deductible.

According to the Kaiser Family Foundation, approximately 1 in 4 Americans have difficulty paying for their prescription drugs, while almost half of U.S. adults report difficulty paying out-of-pocket costs not covered by their health insurance.

Supporting the bill that restricts co-pay accumulators are groups such as the Ohio State Medical Association, the Crohn’s and Colitis Foundation, Susan C. Komen, the National Multiple Sclerosis Society, and the American Diabetes Association. The bill faced opposition from health insurers and pharmacy benefit managers, reported The Columbus Dispatch.

“The debate on the management of rising drug costs between manufacturers and insurers unfortunately leaves patients caught in the middle, and practices like co-pay accumulators can have a devastating impact,” Monica Hueckel, senior director of government relations for the Ohio State Medical Association, told this news organization.

“Patients often do not even know about these policies until the coupons are no longer usable. As you can imagine, for patients with expensive medications and/or high deductible health plans, the impact is disastrous,” she said.

Ohio State Representative Susan Manchester, who co-sponsored the bill, told The Columbus Dispatch that the legislation “is needed to assist our constituents who find themselves increasingly subjected to more out-of-pocket costs as part of their insurance coverage.”

Other states blocking health insurers’ co-pay policies

With the passage of the bill, Ohio joins 12 states and Puerto Rico in preventing the use of health insurers’ co-pays to increase patients’ out-of-pocket costs, reported The Columbus Dispatch; 15 states are also considering this type of legislation.

Eighty-three percent of patients are in plans that include a co-pay accumulator, according to consulting firm Avalere, which wrote that, beginning in 2023, the Center for Medicare & Medicaid Services requires patients with Medicaid to receive “the full value of co-pay assistance” on drugs.

According to the National Conference of State Legislatures, co-pay adjustment programs present challenges for patients, with plans that include high cost sharing or co-insurance whereby a patient pays a percentage of the cost instead of a flat amount.

For example, with a co-pay adjustment policy, a patient with a $2,000 deductible plan couldn’t use a $500 coupon toward meeting the deductible, writes the National Conference of State Legislatures. Conversely, a patient in a plan without a co-pay adjustment policy could use the coupon to satisfy their annual deductible.

Patients with complex conditions, such as cancer, rheumatoid arthritis, and diabetes, which often require expensive medications, may have little choice but to fork over the unexpected co-pays, according to the organization that represents state legislatures in the United States.

The bill now moves to the Ohio Senate, reported The Columbus Dispatch.

A version of this article first appeared on Medscape.com.

The Ohio House of Representatives recently passed a bill that would enable patients to use drug manufacturer coupons and other co-pay assistance as payment toward their annual deductible.

According to the Kaiser Family Foundation, approximately 1 in 4 Americans have difficulty paying for their prescription drugs, while almost half of U.S. adults report difficulty paying out-of-pocket costs not covered by their health insurance.

Supporting the bill that restricts co-pay accumulators are groups such as the Ohio State Medical Association, the Crohn’s and Colitis Foundation, Susan C. Komen, the National Multiple Sclerosis Society, and the American Diabetes Association. The bill faced opposition from health insurers and pharmacy benefit managers, reported The Columbus Dispatch.

“The debate on the management of rising drug costs between manufacturers and insurers unfortunately leaves patients caught in the middle, and practices like co-pay accumulators can have a devastating impact,” Monica Hueckel, senior director of government relations for the Ohio State Medical Association, told this news organization.

“Patients often do not even know about these policies until the coupons are no longer usable. As you can imagine, for patients with expensive medications and/or high deductible health plans, the impact is disastrous,” she said.

Ohio State Representative Susan Manchester, who co-sponsored the bill, told The Columbus Dispatch that the legislation “is needed to assist our constituents who find themselves increasingly subjected to more out-of-pocket costs as part of their insurance coverage.”

Other states blocking health insurers’ co-pay policies

With the passage of the bill, Ohio joins 12 states and Puerto Rico in preventing the use of health insurers’ co-pays to increase patients’ out-of-pocket costs, reported The Columbus Dispatch; 15 states are also considering this type of legislation.

Eighty-three percent of patients are in plans that include a co-pay accumulator, according to consulting firm Avalere, which wrote that, beginning in 2023, the Center for Medicare & Medicaid Services requires patients with Medicaid to receive “the full value of co-pay assistance” on drugs.

According to the National Conference of State Legislatures, co-pay adjustment programs present challenges for patients, with plans that include high cost sharing or co-insurance whereby a patient pays a percentage of the cost instead of a flat amount.

For example, with a co-pay adjustment policy, a patient with a $2,000 deductible plan couldn’t use a $500 coupon toward meeting the deductible, writes the National Conference of State Legislatures. Conversely, a patient in a plan without a co-pay adjustment policy could use the coupon to satisfy their annual deductible.

Patients with complex conditions, such as cancer, rheumatoid arthritis, and diabetes, which often require expensive medications, may have little choice but to fork over the unexpected co-pays, according to the organization that represents state legislatures in the United States.

The bill now moves to the Ohio Senate, reported The Columbus Dispatch.

A version of this article first appeared on Medscape.com.

DENVER – An investigational once-daily oral neuroactive steroid is linked to significant improvement in quality of life (QoL) and well-being in patients with major depressive disorder (MDD), new research shows.

In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.

In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.

“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

First oral formulation

Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.

As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).

In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.

The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.

Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.

In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.

Integrated data

In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.

By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).

Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.

Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.

Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.

“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.

The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.

“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.

Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.

The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.

Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
 

Clinically meaningful?

Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.

“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.

Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.

Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.

“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.

Courtesy Dr. Jonathan E. Alpert

Dr. Alpert was not involved in the research and has no relationship with the drug’s development.

He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.

“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.

However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.

“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.

The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

DENVER – An investigational once-daily oral neuroactive steroid is linked to significant improvement in quality of life (QoL) and well-being in patients with major depressive disorder (MDD), new research shows.

In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.

In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.

“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

First oral formulation

Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.

As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).

In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.

The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.

Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.

In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.

Integrated data

In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.

By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).

Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.

Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.

Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.

“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.

The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.

“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.

Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.

The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.

Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
 

Clinically meaningful?

Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.

“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.

Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.

Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.

“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.

Courtesy Dr. Jonathan E. Alpert

Dr. Alpert was not involved in the research and has no relationship with the drug’s development.

He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.

“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.

However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.

“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.

The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

DENVER – An investigational once-daily oral neuroactive steroid is linked to significant improvement in quality of life (QoL) and well-being in patients with major depressive disorder (MDD), new research shows.

In a phase 3 trial that included more than 500 adult patients with MDD, those who received zuranolone for 14 days showed greater improvement at day 15 across numerous QoL outcomes, compared with their counterparts in the placebo group.

In addition, combined analysis of four zuranolone clinical trials showed “mental well-being and functioning improved to near general population norm levels” for the active-treatment group, reported the researchers, led by Anita H. Clayton, MD, chair and professor of psychiatry, University of Virginia, Charlottesville.

“Based on these integrated analyses, the benefit of treatment with zuranolone may extend beyond reduction in depressive symptoms to include potential improvement in quality of life and overall health, as perceived by patients,” they add.

The findings were presented as part of the Anxiety and Depression Association of America Anxiety & Depression conference.
 

First oral formulation

Zuranolone represents the second entry in the new class of neuroactive steroid drugs, which modulate GABA-A receptor activity – but it would be the first to have an oral formulation. Brexanolone, which was approved by the Food and Drug Administration in 2019 for postpartum depression, is administered through continuous IV infusion over 60 hours.

As previously reported by this news organization, zuranolone improved depressive symptoms as early as day 3, achieving the primary endpoint of significantly greater reduction in scores on the 17-item Hamilton Rating Scale for Depression from baseline to day 15 versus placebo (P = .014).

In the new analysis, patient-reported measures of functional health and well-being were assessed in the WATERFALL trial. It included 266 patients with MDD who were treated with zuranolone 50 mg daily for 2 weeks and 268 patients with MDD who were treated with placebo.

The study used the Short Form–36 (SF-36v2), which covers a wide range of patient-reported measures, including physical function, bodily pain, general health, vitality, social function, and “role-emotional” symptoms.

Results showed that although the treatment and placebo groups had similar baseline SF-36v2 scores, those receiving zuranolone reported significantly greater improvements at day 15 in almost all of the assessment’s domains, including physical function (treatment difference, 0.8), general health (1.0), vitality (3.1), social functioning (1.1), and role-emotional symptoms (1.5; for all comparisons, P < .05). The only exceptions were in role-physical symptoms and bodily pain.

In measures that included physical function, bodily pain, and general health, the patients achieved improvements at day 15 that were consistent with normal levels, with the improvement in vitality considered clinically meaningful versus placebo.

Integrated data

In further analysis of integrated data from four zuranolone clinical trials in the NEST and LANDSCAPE programs for patients with MDD and postpartum depression, results showed similar improvements at day 15 for zuranolone in QoL and overall health across all of the SF-36v2 functioning and well-being domains (P <.05), with the exceptions of physical measure and bodily pain.

By day 42, all of the domains showed significantly greater improvement with zuranolone versus placebo (all, P <.05).

Among the strongest score improvements in the integrated trials were measures in social functioning, which improved from baseline scores of 29.66 to 42.82 on day 15 and to 43.59 on day 42.

Emotional domain scores improved from 24.43 at baseline to 39.13 on day 15 and to 39.82 on day 42. For mental health, the integrated scores for the zuranolone group improved from 27.13 at baseline to 42.40 on day 15 and 42.62 on day 42.

Of note, the baseline scores for mental health represented just 54.3% of those in the normal population; with the increase at day 15, the level was 84.8% of the normal population.

“Across four completed placebo-controlled NEST and LANDSCAPE clinical trials, patient reports of functional health and well-being as assessed by the SF-36v2 indicated substantial impairment at baseline compared to the population norm,” the researchers reported.

The improvements are especially important in light of the fact that in some patients with MDD, functional improvement is a top priority.

“Patients have often prioritized returning to their usual level of functioning over reduction in depressive symptoms, and functional recovery has been associated with better prognosis of depression,” the investigators wrote.

Zuranolone trials have shown that treatment-emergent adverse events (AEs) occur among about 60% of patients, versus about 44% with placebo. The most common AEs are somnolence, dizziness, headache, sedation, and diarrhea, with no increases in suicidal ideation or withdrawal.

The rates of severe AEs are low, and they are observed in about 3% of patients, versus 1.1% with placebo, the researchers noted.

Further, as opposed to serotonergic antidepressants such as SNRIs and SSRIs, zuranolone does not appear to have the undesirable side effects of decreased libido and sexual dysfunction, they added.
 

Clinically meaningful?

Andrew J. Cutler, MD, clinical associate professor of psychiatry at State University of New York, Syracuse, said the data are “very significant” for a number of reasons.

“We need more options to treat depression, especially ones with novel mechanisms of action and faster onset of efficacy, such as zuranolone,” said Dr. Cutler, who was not involved in the current study. He has coauthored other studies on zuranolone.

Regarding the study’s QoL outcomes, “while improvement in depressive symptoms is very important, what really matters to patients is improvement in function and quality of life,” Dr. Cutler noted.

Also commenting on the study, Jonathan E. Alpert, MD, PhD, chair of the department of psychiatry and behavioral sciences and professor of psychiatry, neuroscience, and pediatrics at Albert Einstein College of Medicine, New York, said the investigational drug could represent an important addition to the armamentarium for treating depression.

“Zuranolone has good oral bioavailability and would represent the first neuroactive steroid antidepressant available in oral form and, indeed, the first non–monoamine-based antidepressant available in oral form,” he said in an interview.

Courtesy Dr. Jonathan E. Alpert

Dr. Alpert was not involved in the research and has no relationship with the drug’s development.

He noted that although there are modest differences between the patients who received zuranolone and those who received placebo in the trials, “this may have been related to high placebo response rates, which often complicate antidepressant trials.

“Further research is needed to determine whether differences between zuranolone and placebo are clinically meaningful, though the separation between drug and placebo on the primary endpoint, as well as some other measures, such as quality of life measures, is promising,” Dr. Alpert said.

However, he added that comparisons with other active antidepressants in terms of efficacy and tolerability remain to be seen.

“Given the large number of individuals with major depressive disorder who have incomplete response to or do not tolerate monoaminergic antidepressants, the development of agents that leverage novel nonmonoaminergic mechanisms is important,” Dr. Alpert concluded.

The study was funded by Sage Therapeutics and Biogen. Dr. Cutler has been involved in research of zuranolone for Sage Therapeutics. Dr. Alpert has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Emma Moore felt cornered. At a community health clinic in Portland, Ore., the 29-year-old nurse practitioner said she felt overwhelmed and undertrained. Coronavirus patients flooded the clinic for 2 years, and Ms. Moore struggled to keep up.

Then the stakes became clear. On March 25, about 2,400 miles away in a Tennessee courtroom, former nurse RaDonda Vaught was convicted of two felonies and facing 8 years in prison for a fatal medication mistake.

Like many nurses, Ms. Moore wondered if that could be her. She’d made medication errors before, although none so grievous. But what about the next one? In the pressure cooker of pandemic-era health care, another mistake felt inevitable.

Four days after Ms. Vaught’s verdict, Ms. Moore quit. She said Ms. Vaught’s verdict contributed to her decision.

“It’s not worth the possibility or the likelihood that this will happen,” Ms. Moore said, “if I’m in a situation where I’m set up to fail.”

In the wake of Ms. Vaught’s trial – an extremely rare case of a health care worker being criminally prosecuted for a medical error – nurses and nursing organizations have condemned the verdict through tens of thousands of social media posts, shares, comments, and videos. They warn that the fallout will ripple through their profession, demoralizing and depleting the ranks of nurses already stretched thin by the pandemic. Ultimately, they say, it will worsen health care for all.

Statements from the American Nurses Association, the American Association of Critical-Care Nurses, and the National Medical Association said Ms. Vaught’s conviction set a “dangerous precedent.” Linda H. Aiken, PhD, RN, a nursing and sociology professor at the University of Pennsylvania, Philadelphia, said that although Ms. Vaught’s case is an “outlier,” it will make nurses less forthcoming about mistakes.

“One thing that everybody agrees on is it’s going to have a dampening effect on the reporting of errors or near misses, which then has a detrimental effect on safety,” Dr. Aiken said. “The only way you can really learn about errors in these complicated systems is to have people say, ‘Oh, I almost gave the wrong drug because …’

“Well, nobody is going to say that now.”

Fear and outrage about Ms. Vaught’s case have swirled among nurses on Facebook, Twitter, and Reddit. On TikTok, a video platform increasingly popular among medical professionals, videos with the “#RaDondaVaught” hashtag totaled more than 47 million views.

Ms. Vaught’s supporters catapulted a plea for her clemency to the top of Change.org, a petition website. And thousands also joined a Facebook group planning to gather in protest outside Ms. Vaught’s sentencing hearing in May.

Ashley Bartholomew, BSN, RN, a 36-year-old Tampa nurse who followed the trial through YouTube and Twitter, echoed the fear of many others. Nurses have long felt forced into “impossible situations” by mounting responsibilities and staffing shortages, she said, particularly in hospitals that operate with lean staffing models.

“The big response we are seeing is because all of us are acutely aware of how bad the pandemic has exacerbated the existing problems,” Ms. Bartholomew said. And “setting a precedent for criminally charging [for] an error is only going to make this exponentially worse.”

Ms. Vaught, who worked at Vanderbilt University Medical Center in Nashville, Tenn., was convicted in the death of Charlene Murphey, a 75-year-old patient who died from a drug mix-up in 2017. Ms. Murphey was prescribed a dose of a sedative, Versed, but Ms. Vaught accidentally withdrew a powerful paralyzer, vecuronium, from an automated medication-dispensing cabinet and administered it to the patient.

Prosecutors argued that Ms. Vaught overlooked many obvious signs she’d withdrawn the wrong drug and did not monitor Ms. Murphey after she was given a deadly dose. Ms. Vaught owned up to the error but said it was an honest mistake, not a crime.

Some of Ms. Vaught’s peers support the conviction.

Scott G. Shelp, BSN, RN, a California nurse with a small YouTube channel, posted a 26-minute self-described “unpopular opinion” that Ms. Vaught deserves to serve prison time. “We need to stick up for each other,” he said, “but we cannot defend the indefensible.”

Mr. Shelp said he would never make the same error as Ms. Vaught and “neither would any competent nurse.” Regarding concerns that the conviction would discourage nurses from disclosing errors, Mr. Shelp said “dishonest” nurses “should be weeded out” of the profession anyway.

“In any other circumstance, I can’t believe anyone – including nurses – would accept ‘I didn’t mean to’ as a serious defense,” Mr. Shelp said. “Punishment for a harmful act someone actually did is justice.”

Ms. Vaught was acquitted of reckless homicide but convicted of a lesser charge, criminally negligent homicide, and gross neglect of an impaired adult. As outrage spread across social media, the Nashville district attorney’s office defended the conviction, saying in a statement it was “not an indictment against the nursing profession or the medical community.”

“This case is, and always has been, about the one single individual who made 17 egregious actions, and inactions, that killed an elderly woman,” said the office’s spokesperson, Steve Hayslip. “The jury found that Vaught’s actions were so far below the protocols and standard level of care, that the jury (which included a longtime nurse and another health care professional) returned a guilty verdict in less than four hours.”

The office of Tennessee Gov. Bill Lee confirmed he is not considering clemency for Ms. Vaught despite the Change.org petition, which had amassed about 187,000 signatures as of April 4.

Casey Black, press secretary for Gov. Lee, said that outside of death penalty cases the governor relies on the Board of Parole to recommend defendants for clemency, which happens only after sentencing and a board investigation.

But the controversy around Ms. Vaught’s case is far from over. As of April 4, more than 8,200 people had joined a Facebook group planning a march in protest outside the courthouse during her sentencing May 13.

Among the event’s planners is Tina Visant, the host of “Good Nurse Bad Nurse,” a podcast that followed Ms. Vaught’s case and opposed her prosecution.

“I don’t know how Nashville is going to handle it,” Ms. Visant said of the protest during a recent episode about Ms. Vaught’s trial. “There are a lot of people coming from all over.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Emma Moore felt cornered. At a community health clinic in Portland, Ore., the 29-year-old nurse practitioner said she felt overwhelmed and undertrained. Coronavirus patients flooded the clinic for 2 years, and Ms. Moore struggled to keep up.

Then the stakes became clear. On March 25, about 2,400 miles away in a Tennessee courtroom, former nurse RaDonda Vaught was convicted of two felonies and facing 8 years in prison for a fatal medication mistake.

Like many nurses, Ms. Moore wondered if that could be her. She’d made medication errors before, although none so grievous. But what about the next one? In the pressure cooker of pandemic-era health care, another mistake felt inevitable.

Four days after Ms. Vaught’s verdict, Ms. Moore quit. She said Ms. Vaught’s verdict contributed to her decision.

“It’s not worth the possibility or the likelihood that this will happen,” Ms. Moore said, “if I’m in a situation where I’m set up to fail.”

In the wake of Ms. Vaught’s trial – an extremely rare case of a health care worker being criminally prosecuted for a medical error – nurses and nursing organizations have condemned the verdict through tens of thousands of social media posts, shares, comments, and videos. They warn that the fallout will ripple through their profession, demoralizing and depleting the ranks of nurses already stretched thin by the pandemic. Ultimately, they say, it will worsen health care for all.

Statements from the American Nurses Association, the American Association of Critical-Care Nurses, and the National Medical Association said Ms. Vaught’s conviction set a “dangerous precedent.” Linda H. Aiken, PhD, RN, a nursing and sociology professor at the University of Pennsylvania, Philadelphia, said that although Ms. Vaught’s case is an “outlier,” it will make nurses less forthcoming about mistakes.

“One thing that everybody agrees on is it’s going to have a dampening effect on the reporting of errors or near misses, which then has a detrimental effect on safety,” Dr. Aiken said. “The only way you can really learn about errors in these complicated systems is to have people say, ‘Oh, I almost gave the wrong drug because …’

“Well, nobody is going to say that now.”

Fear and outrage about Ms. Vaught’s case have swirled among nurses on Facebook, Twitter, and Reddit. On TikTok, a video platform increasingly popular among medical professionals, videos with the “#RaDondaVaught” hashtag totaled more than 47 million views.

Ms. Vaught’s supporters catapulted a plea for her clemency to the top of Change.org, a petition website. And thousands also joined a Facebook group planning to gather in protest outside Ms. Vaught’s sentencing hearing in May.

Ashley Bartholomew, BSN, RN, a 36-year-old Tampa nurse who followed the trial through YouTube and Twitter, echoed the fear of many others. Nurses have long felt forced into “impossible situations” by mounting responsibilities and staffing shortages, she said, particularly in hospitals that operate with lean staffing models.

“The big response we are seeing is because all of us are acutely aware of how bad the pandemic has exacerbated the existing problems,” Ms. Bartholomew said. And “setting a precedent for criminally charging [for] an error is only going to make this exponentially worse.”

Ms. Vaught, who worked at Vanderbilt University Medical Center in Nashville, Tenn., was convicted in the death of Charlene Murphey, a 75-year-old patient who died from a drug mix-up in 2017. Ms. Murphey was prescribed a dose of a sedative, Versed, but Ms. Vaught accidentally withdrew a powerful paralyzer, vecuronium, from an automated medication-dispensing cabinet and administered it to the patient.

Prosecutors argued that Ms. Vaught overlooked many obvious signs she’d withdrawn the wrong drug and did not monitor Ms. Murphey after she was given a deadly dose. Ms. Vaught owned up to the error but said it was an honest mistake, not a crime.

Some of Ms. Vaught’s peers support the conviction.

Scott G. Shelp, BSN, RN, a California nurse with a small YouTube channel, posted a 26-minute self-described “unpopular opinion” that Ms. Vaught deserves to serve prison time. “We need to stick up for each other,” he said, “but we cannot defend the indefensible.”

Mr. Shelp said he would never make the same error as Ms. Vaught and “neither would any competent nurse.” Regarding concerns that the conviction would discourage nurses from disclosing errors, Mr. Shelp said “dishonest” nurses “should be weeded out” of the profession anyway.

“In any other circumstance, I can’t believe anyone – including nurses – would accept ‘I didn’t mean to’ as a serious defense,” Mr. Shelp said. “Punishment for a harmful act someone actually did is justice.”

Ms. Vaught was acquitted of reckless homicide but convicted of a lesser charge, criminally negligent homicide, and gross neglect of an impaired adult. As outrage spread across social media, the Nashville district attorney’s office defended the conviction, saying in a statement it was “not an indictment against the nursing profession or the medical community.”

“This case is, and always has been, about the one single individual who made 17 egregious actions, and inactions, that killed an elderly woman,” said the office’s spokesperson, Steve Hayslip. “The jury found that Vaught’s actions were so far below the protocols and standard level of care, that the jury (which included a longtime nurse and another health care professional) returned a guilty verdict in less than four hours.”

The office of Tennessee Gov. Bill Lee confirmed he is not considering clemency for Ms. Vaught despite the Change.org petition, which had amassed about 187,000 signatures as of April 4.

Casey Black, press secretary for Gov. Lee, said that outside of death penalty cases the governor relies on the Board of Parole to recommend defendants for clemency, which happens only after sentencing and a board investigation.

But the controversy around Ms. Vaught’s case is far from over. As of April 4, more than 8,200 people had joined a Facebook group planning a march in protest outside the courthouse during her sentencing May 13.

Among the event’s planners is Tina Visant, the host of “Good Nurse Bad Nurse,” a podcast that followed Ms. Vaught’s case and opposed her prosecution.

“I don’t know how Nashville is going to handle it,” Ms. Visant said of the protest during a recent episode about Ms. Vaught’s trial. “There are a lot of people coming from all over.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Emma Moore felt cornered. At a community health clinic in Portland, Ore., the 29-year-old nurse practitioner said she felt overwhelmed and undertrained. Coronavirus patients flooded the clinic for 2 years, and Ms. Moore struggled to keep up.

Then the stakes became clear. On March 25, about 2,400 miles away in a Tennessee courtroom, former nurse RaDonda Vaught was convicted of two felonies and facing 8 years in prison for a fatal medication mistake.

Like many nurses, Ms. Moore wondered if that could be her. She’d made medication errors before, although none so grievous. But what about the next one? In the pressure cooker of pandemic-era health care, another mistake felt inevitable.

Four days after Ms. Vaught’s verdict, Ms. Moore quit. She said Ms. Vaught’s verdict contributed to her decision.

“It’s not worth the possibility or the likelihood that this will happen,” Ms. Moore said, “if I’m in a situation where I’m set up to fail.”

In the wake of Ms. Vaught’s trial – an extremely rare case of a health care worker being criminally prosecuted for a medical error – nurses and nursing organizations have condemned the verdict through tens of thousands of social media posts, shares, comments, and videos. They warn that the fallout will ripple through their profession, demoralizing and depleting the ranks of nurses already stretched thin by the pandemic. Ultimately, they say, it will worsen health care for all.

Statements from the American Nurses Association, the American Association of Critical-Care Nurses, and the National Medical Association said Ms. Vaught’s conviction set a “dangerous precedent.” Linda H. Aiken, PhD, RN, a nursing and sociology professor at the University of Pennsylvania, Philadelphia, said that although Ms. Vaught’s case is an “outlier,” it will make nurses less forthcoming about mistakes.

“One thing that everybody agrees on is it’s going to have a dampening effect on the reporting of errors or near misses, which then has a detrimental effect on safety,” Dr. Aiken said. “The only way you can really learn about errors in these complicated systems is to have people say, ‘Oh, I almost gave the wrong drug because …’

“Well, nobody is going to say that now.”

Fear and outrage about Ms. Vaught’s case have swirled among nurses on Facebook, Twitter, and Reddit. On TikTok, a video platform increasingly popular among medical professionals, videos with the “#RaDondaVaught” hashtag totaled more than 47 million views.

Ms. Vaught’s supporters catapulted a plea for her clemency to the top of Change.org, a petition website. And thousands also joined a Facebook group planning to gather in protest outside Ms. Vaught’s sentencing hearing in May.

Ashley Bartholomew, BSN, RN, a 36-year-old Tampa nurse who followed the trial through YouTube and Twitter, echoed the fear of many others. Nurses have long felt forced into “impossible situations” by mounting responsibilities and staffing shortages, she said, particularly in hospitals that operate with lean staffing models.

“The big response we are seeing is because all of us are acutely aware of how bad the pandemic has exacerbated the existing problems,” Ms. Bartholomew said. And “setting a precedent for criminally charging [for] an error is only going to make this exponentially worse.”

Ms. Vaught, who worked at Vanderbilt University Medical Center in Nashville, Tenn., was convicted in the death of Charlene Murphey, a 75-year-old patient who died from a drug mix-up in 2017. Ms. Murphey was prescribed a dose of a sedative, Versed, but Ms. Vaught accidentally withdrew a powerful paralyzer, vecuronium, from an automated medication-dispensing cabinet and administered it to the patient.

Prosecutors argued that Ms. Vaught overlooked many obvious signs she’d withdrawn the wrong drug and did not monitor Ms. Murphey after she was given a deadly dose. Ms. Vaught owned up to the error but said it was an honest mistake, not a crime.

Some of Ms. Vaught’s peers support the conviction.

Scott G. Shelp, BSN, RN, a California nurse with a small YouTube channel, posted a 26-minute self-described “unpopular opinion” that Ms. Vaught deserves to serve prison time. “We need to stick up for each other,” he said, “but we cannot defend the indefensible.”

Mr. Shelp said he would never make the same error as Ms. Vaught and “neither would any competent nurse.” Regarding concerns that the conviction would discourage nurses from disclosing errors, Mr. Shelp said “dishonest” nurses “should be weeded out” of the profession anyway.

“In any other circumstance, I can’t believe anyone – including nurses – would accept ‘I didn’t mean to’ as a serious defense,” Mr. Shelp said. “Punishment for a harmful act someone actually did is justice.”

Ms. Vaught was acquitted of reckless homicide but convicted of a lesser charge, criminally negligent homicide, and gross neglect of an impaired adult. As outrage spread across social media, the Nashville district attorney’s office defended the conviction, saying in a statement it was “not an indictment against the nursing profession or the medical community.”

“This case is, and always has been, about the one single individual who made 17 egregious actions, and inactions, that killed an elderly woman,” said the office’s spokesperson, Steve Hayslip. “The jury found that Vaught’s actions were so far below the protocols and standard level of care, that the jury (which included a longtime nurse and another health care professional) returned a guilty verdict in less than four hours.”

The office of Tennessee Gov. Bill Lee confirmed he is not considering clemency for Ms. Vaught despite the Change.org petition, which had amassed about 187,000 signatures as of April 4.

Casey Black, press secretary for Gov. Lee, said that outside of death penalty cases the governor relies on the Board of Parole to recommend defendants for clemency, which happens only after sentencing and a board investigation.

But the controversy around Ms. Vaught’s case is far from over. As of April 4, more than 8,200 people had joined a Facebook group planning a march in protest outside the courthouse during her sentencing May 13.

Among the event’s planners is Tina Visant, the host of “Good Nurse Bad Nurse,” a podcast that followed Ms. Vaught’s case and opposed her prosecution.

“I don’t know how Nashville is going to handle it,” Ms. Visant said of the protest during a recent episode about Ms. Vaught’s trial. “There are a lot of people coming from all over.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.

The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).

Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter

“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”

The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.

Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”

The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.

Peggy Peterson Photograph

Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.

However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.

Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.


 

A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.

The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).

Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter

“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”

The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.

Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”

The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.

Peggy Peterson Photograph

Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.

However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.

Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.


 

A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.

The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).

Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter

“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”

The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.

Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”

The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.

Peggy Peterson Photograph

Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.

However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.

Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.