A new poll of emergency physicians on the front lines of the COVID-19 pandemic shows many are fearful of seeking mental health care for fear of stigma and the potential career impact.

wutwhanfoto/Getty Images

The results of the nationally representative poll, conducted Oct. 7-13 by the American College of Emergency Physicians, showed almost half (45%) of 862 emergency physician respondents reported being uncomfortable seeking available psychiatric care. The poll had a margin of error of plus or minus 3 percentage points.

The findings provide new insight into both the challenges of serving in emergency medicine during the pandemic and the persistent barriers to mental health care in terms of stigma and concerns about potential career setbacks.

In the poll, 42% of respondents said they have been feeling much more stress since the start of COVID-19, with another 45% report they were feeling somewhat more stressed.

When asked about causes of stress related directly to COVID-19, 83% cited concerns about family and friends contracting COVID-19. Also factoring into emergency physicians’ stress and burnout were concerns about their own safety (80%) and lack of personal protective equipment or other needed resources (60%).

In the poll, 29% of respondents reported having excellent access to mental health treatment and 42% reported having good access. Despite this, 30% of respondents still reported feeling there was a lot of stigma in their workplace about seeking mental health treatment, with another 43% reporting they felt there was some stigma.

Poll results also showed that 24% of respondents were very concerned about what might happen with their employment if they were to seek mental health treatment, with another 33% saying they were somewhat concerned.

In recent years there have been efforts to break down cultural roadblocks in medicine that deter many physicians from seeking mental health treatment, but more needs to be done, said Mark Rosenberg, DO, MBA, who was elected president of ACEP at last weekend’s annual meeting, ACEP20.

“The pandemic emphatically underscores our need to change the status quo when it comes to physicians’ mental health,” Dr. Rosenberg said.

As previously reported by Medscape Medical News, current efforts to remove such barriers include initiatives to limit inquiries into clinicians’ past or present mental health treatment.

In May, the influential Joint Commission issued a statement urging organizations to refrain from asking about any history of mental health conditions or treatment. The Joint Commission said it supports recommendations already made by the Federation of State Medical Boards and the American Medical Association to limit inquiries on licensing applications to conditions that currently impair a clinician’s ability to perform their job.

Also supporting these efforts is the Dr. Lorna Breen Heroes’ Foundation, created in honor of an emergency physician who died by suicide in April amid the pandemic.

Lorna Breen, MD, had been working intensely in the response to the pandemic. During one shift, she covered two EDs in Manhattan at locations 5 miles apart, according to a backgrounder on the foundation’s web site.

At an ACEP press conference this week, Dr. Breen’s brother-in-law, J. Corey Feist, JD, MBA, cofounder of the foundation, noted that some states’ licensing applications for physicians include questions that fall outside of the boundaries of the Americans With Disabilities Act. He cited an analysis of state medical boards’ initial licensing questions published in 2018 in the Journal of the American Academy of Psychiatry and the Law.

In many cases, states have posed questions that extend beyond an assessment of a physician’s current ability to care for patients, creating a needless hurdle to seeking care, wrote the paper’s lead author, Carol North, MD, of the University of Texas Southwestern Medical Center, Dallas.

“Over the years, many medical licensure boards have asked applicants intrusive questions about whether they have any psychiatric history. This has created a major problem for applicants, and unfortunately this has discouraged many of those who need psychiatric treatment from seeking it because of fear of the questions,” Dr. North and colleagues noted. They cited Ohio as an example of a state that had overhauled its approach to questioning to bring it in compliance with the ADA.

Ohio previously required applicants to answer lengthy questions about their mental health, including:

• Within the last 10 years, have you been diagnosed with or have you been treated for bipolar disorder, schizophrenia, paranoia, or any other psychotic disorder?
• Have you, since attaining the age of eighteen or within the last 10 years, whichever period is shorter, been admitted to a hospital or other facility for the treatment of bipolar disorder, schizophrenia, paranoia, or any other psychotic disorder?
• Do you have, or have you been diagnosed as having, a medical condition which in any way impairs or limits your ability to practice medicine with reasonable skill and safety?

In the new version, the single question reads: “In the past 5 years, have you been diagnosed as having, or been hospitalized for, a medical condition which in any way impairs or limits your ability to practice medicine with reasonable skill and safety?”

Other states such as New York pose no mental health questions on applications for licensure.

Still, even when states have nondiscriminatory laws, physicians may not be aware of them, said Mr. Feist at an ACEP press conference. In addition to his work with the foundation, Mr. Feist is the CEO of the University of Virginia Physicians Group.

He said his sister-in-law Dr. Breen may have worried without cause about potential consequences of seeking psychiatric treatment during the pandemic. In addition, physicians in need of psychiatric care may worry about encountering hitches with medical organizations and insurers.

“This stigma and this fear of professional action on your license or your credentialing or privileging is pervasive throughout the industry,” he said.

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

A new poll of emergency physicians on the front lines of the COVID-19 pandemic shows many are fearful of seeking mental health care for fear of stigma and the potential career impact.

wutwhanfoto/Getty Images

The results of the nationally representative poll, conducted Oct. 7-13 by the American College of Emergency Physicians, showed almost half (45%) of 862 emergency physician respondents reported being uncomfortable seeking available psychiatric care. The poll had a margin of error of plus or minus 3 percentage points.

The findings provide new insight into both the challenges of serving in emergency medicine during the pandemic and the persistent barriers to mental health care in terms of stigma and concerns about potential career setbacks.

In the poll, 42% of respondents said they have been feeling much more stress since the start of COVID-19, with another 45% report they were feeling somewhat more stressed.

When asked about causes of stress related directly to COVID-19, 83% cited concerns about family and friends contracting COVID-19. Also factoring into emergency physicians’ stress and burnout were concerns about their own safety (80%) and lack of personal protective equipment or other needed resources (60%).

In the poll, 29% of respondents reported having excellent access to mental health treatment and 42% reported having good access. Despite this, 30% of respondents still reported feeling there was a lot of stigma in their workplace about seeking mental health treatment, with another 43% reporting they felt there was some stigma.

Poll results also showed that 24% of respondents were very concerned about what might happen with their employment if they were to seek mental health treatment, with another 33% saying they were somewhat concerned.

In recent years there have been efforts to break down cultural roadblocks in medicine that deter many physicians from seeking mental health treatment, but more needs to be done, said Mark Rosenberg, DO, MBA, who was elected president of ACEP at last weekend’s annual meeting, ACEP20.

“The pandemic emphatically underscores our need to change the status quo when it comes to physicians’ mental health,” Dr. Rosenberg said.

As previously reported by Medscape Medical News, current efforts to remove such barriers include initiatives to limit inquiries into clinicians’ past or present mental health treatment.

In May, the influential Joint Commission issued a statement urging organizations to refrain from asking about any history of mental health conditions or treatment. The Joint Commission said it supports recommendations already made by the Federation of State Medical Boards and the American Medical Association to limit inquiries on licensing applications to conditions that currently impair a clinician’s ability to perform their job.

Also supporting these efforts is the Dr. Lorna Breen Heroes’ Foundation, created in honor of an emergency physician who died by suicide in April amid the pandemic.

Lorna Breen, MD, had been working intensely in the response to the pandemic. During one shift, she covered two EDs in Manhattan at locations 5 miles apart, according to a backgrounder on the foundation’s web site.

At an ACEP press conference this week, Dr. Breen’s brother-in-law, J. Corey Feist, JD, MBA, cofounder of the foundation, noted that some states’ licensing applications for physicians include questions that fall outside of the boundaries of the Americans With Disabilities Act. He cited an analysis of state medical boards’ initial licensing questions published in 2018 in the Journal of the American Academy of Psychiatry and the Law.

In many cases, states have posed questions that extend beyond an assessment of a physician’s current ability to care for patients, creating a needless hurdle to seeking care, wrote the paper’s lead author, Carol North, MD, of the University of Texas Southwestern Medical Center, Dallas.

“Over the years, many medical licensure boards have asked applicants intrusive questions about whether they have any psychiatric history. This has created a major problem for applicants, and unfortunately this has discouraged many of those who need psychiatric treatment from seeking it because of fear of the questions,” Dr. North and colleagues noted. They cited Ohio as an example of a state that had overhauled its approach to questioning to bring it in compliance with the ADA.

Ohio previously required applicants to answer lengthy questions about their mental health, including:

• Within the last 10 years, have you been diagnosed with or have you been treated for bipolar disorder, schizophrenia, paranoia, or any other psychotic disorder?
• Have you, since attaining the age of eighteen or within the last 10 years, whichever period is shorter, been admitted to a hospital or other facility for the treatment of bipolar disorder, schizophrenia, paranoia, or any other psychotic disorder?
• Do you have, or have you been diagnosed as having, a medical condition which in any way impairs or limits your ability to practice medicine with reasonable skill and safety?

In the new version, the single question reads: “In the past 5 years, have you been diagnosed as having, or been hospitalized for, a medical condition which in any way impairs or limits your ability to practice medicine with reasonable skill and safety?”

Other states such as New York pose no mental health questions on applications for licensure.

Still, even when states have nondiscriminatory laws, physicians may not be aware of them, said Mr. Feist at an ACEP press conference. In addition to his work with the foundation, Mr. Feist is the CEO of the University of Virginia Physicians Group.

He said his sister-in-law Dr. Breen may have worried without cause about potential consequences of seeking psychiatric treatment during the pandemic. In addition, physicians in need of psychiatric care may worry about encountering hitches with medical organizations and insurers.

“This stigma and this fear of professional action on your license or your credentialing or privileging is pervasive throughout the industry,” he said.

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

A new poll of emergency physicians on the front lines of the COVID-19 pandemic shows many are fearful of seeking mental health care for fear of stigma and the potential career impact.

wutwhanfoto/Getty Images

The results of the nationally representative poll, conducted Oct. 7-13 by the American College of Emergency Physicians, showed almost half (45%) of 862 emergency physician respondents reported being uncomfortable seeking available psychiatric care. The poll had a margin of error of plus or minus 3 percentage points.

The findings provide new insight into both the challenges of serving in emergency medicine during the pandemic and the persistent barriers to mental health care in terms of stigma and concerns about potential career setbacks.

In the poll, 42% of respondents said they have been feeling much more stress since the start of COVID-19, with another 45% report they were feeling somewhat more stressed.

When asked about causes of stress related directly to COVID-19, 83% cited concerns about family and friends contracting COVID-19. Also factoring into emergency physicians’ stress and burnout were concerns about their own safety (80%) and lack of personal protective equipment or other needed resources (60%).

In the poll, 29% of respondents reported having excellent access to mental health treatment and 42% reported having good access. Despite this, 30% of respondents still reported feeling there was a lot of stigma in their workplace about seeking mental health treatment, with another 43% reporting they felt there was some stigma.

Poll results also showed that 24% of respondents were very concerned about what might happen with their employment if they were to seek mental health treatment, with another 33% saying they were somewhat concerned.

In recent years there have been efforts to break down cultural roadblocks in medicine that deter many physicians from seeking mental health treatment, but more needs to be done, said Mark Rosenberg, DO, MBA, who was elected president of ACEP at last weekend’s annual meeting, ACEP20.

“The pandemic emphatically underscores our need to change the status quo when it comes to physicians’ mental health,” Dr. Rosenberg said.

As previously reported by Medscape Medical News, current efforts to remove such barriers include initiatives to limit inquiries into clinicians’ past or present mental health treatment.

In May, the influential Joint Commission issued a statement urging organizations to refrain from asking about any history of mental health conditions or treatment. The Joint Commission said it supports recommendations already made by the Federation of State Medical Boards and the American Medical Association to limit inquiries on licensing applications to conditions that currently impair a clinician’s ability to perform their job.

Also supporting these efforts is the Dr. Lorna Breen Heroes’ Foundation, created in honor of an emergency physician who died by suicide in April amid the pandemic.

Lorna Breen, MD, had been working intensely in the response to the pandemic. During one shift, she covered two EDs in Manhattan at locations 5 miles apart, according to a backgrounder on the foundation’s web site.

At an ACEP press conference this week, Dr. Breen’s brother-in-law, J. Corey Feist, JD, MBA, cofounder of the foundation, noted that some states’ licensing applications for physicians include questions that fall outside of the boundaries of the Americans With Disabilities Act. He cited an analysis of state medical boards’ initial licensing questions published in 2018 in the Journal of the American Academy of Psychiatry and the Law.

In many cases, states have posed questions that extend beyond an assessment of a physician’s current ability to care for patients, creating a needless hurdle to seeking care, wrote the paper’s lead author, Carol North, MD, of the University of Texas Southwestern Medical Center, Dallas.

“Over the years, many medical licensure boards have asked applicants intrusive questions about whether they have any psychiatric history. This has created a major problem for applicants, and unfortunately this has discouraged many of those who need psychiatric treatment from seeking it because of fear of the questions,” Dr. North and colleagues noted. They cited Ohio as an example of a state that had overhauled its approach to questioning to bring it in compliance with the ADA.

Ohio previously required applicants to answer lengthy questions about their mental health, including:

• Within the last 10 years, have you been diagnosed with or have you been treated for bipolar disorder, schizophrenia, paranoia, or any other psychotic disorder?
• Have you, since attaining the age of eighteen or within the last 10 years, whichever period is shorter, been admitted to a hospital or other facility for the treatment of bipolar disorder, schizophrenia, paranoia, or any other psychotic disorder?
• Do you have, or have you been diagnosed as having, a medical condition which in any way impairs or limits your ability to practice medicine with reasonable skill and safety?

In the new version, the single question reads: “In the past 5 years, have you been diagnosed as having, or been hospitalized for, a medical condition which in any way impairs or limits your ability to practice medicine with reasonable skill and safety?”

Other states such as New York pose no mental health questions on applications for licensure.

Still, even when states have nondiscriminatory laws, physicians may not be aware of them, said Mr. Feist at an ACEP press conference. In addition to his work with the foundation, Mr. Feist is the CEO of the University of Virginia Physicians Group.

He said his sister-in-law Dr. Breen may have worried without cause about potential consequences of seeking psychiatric treatment during the pandemic. In addition, physicians in need of psychiatric care may worry about encountering hitches with medical organizations and insurers.

“This stigma and this fear of professional action on your license or your credentialing or privileging is pervasive throughout the industry,” he said.

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

Two experts at IDWeek 2020 debated the best treatment for patients with the most severe type of Clostridioides difficile infection – fulminant C. diff. The discussion pitted fecal microbiota transplants (FMT) from the stool of healthy donors against traditional antibiotics.

Fulminant C. diff infection (CDI) represents about 8% of all CDI cases and is often fatal. Patients frequently don’t respond to maximum antibiotic therapy.

Should these patients be treated with FMT before surgery is considered?

“Unequivocally, yes,” said Jessica R. Allegretti, MD, MPH, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.
 

Patients face full colectomy

Fulminant infection, she says, typically requires a total abdominal colectomy with end ileostomy.

“Patients have a quite high perioperative and intraoperative mortality because this is typically an older population with significant comorbidities,” she said.

Often the patients are poor candidates for surgery, she added.

She pointed to the efficacy of FMT in studies such as one published in Gut Microbes in 2017. The study, by Monika Fischer, MD, of Indiana University, Indianapolis, and colleagues showed a 91% cure rate at 1 month in severe patients with an average of 1.5 fecal transplants, noting that was “quite remarkable” in this very sick population.

Though FMT is not approved by the US Food and Drug Administration for fulminant CDI, Dr. Allegretti said, the FDA does allow treatment under “enforcement discretion,” which means no investigational new drug license is needed specifically if treating CDI patients who haven’t responded to standard therapy, as long as proper consent has been obtained.

“This is a patient population that is likely going to die,” she said. “If you were the one in the ICU with fulminant C. diff and you’ve been on maximum therapy for 3-5 days and you’re not getting better, wouldn’t you want somebody to offer you a fecal transplant and give you the chance to recover and leave the hospital with your colon intact? The data suggest that is possible, with a high likelihood and a good safety profile.”

She said the most recent guidelines have supported FMT, and emerging guidelines coming within months “will support this as well.”
 

Unknowns with FMT

Taking the other side of the debate, Kevin Garey, PharmD, chair of the department of pharmacy practice and translational research at University of Houston College of Pharmacy, warned against trading traditional antibiotics, such as vancomycin and fidaxomicin, for the novelty of FMT.

“With the science of the microbiome and the novelty of fecal microbiota transplantation in expanding use, I think people have somewhat forgotten pharmacotherapy,” he said.

He pointed out safety concerns with FMT reported in June 2019, after which the FDA issued an alert. Two immunocompromised patients who received FMT, both from the same donor, developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli. One died.

The FDA explained that the donated FMT samples the patients received were not tested for ESBL-producing gram-negative organisms before use.

Dr. Allegretti agreed antibiotics play a role in treatment with FMT, but she argued that the safety profile of FMT remains strong and that the safety issues came from isolated incidents at a single center.

Dr. Garey countered that there are just too many unknowns with FMT.

“We will never know what the next superbug that’s going to land in an FMT is until we’ve identified that superbug in somebody – the next Candida auris, the next CRE [carbapenem-resistant Enterobacteriaceae], the next thing that’s going to show up in FMT – until we get rid of the ‘F,’ “ Dr. Garey said.

“[Until] we get microbial therapy that’s generated without the need for healthy donors, I think we’re always going to be in this problem.”

He said although FMT “has an amazing ability to alter a microbiome” it “pales in comparison” to vancomycin’s ability to do so.

Disruption of the microbiome is, without a doubt, a hallmark of C. diff, but we don’t have to run to FMT,” Dr. Garey said. “We can think about prophylaxis strategies, we can think about new drug development that spares the microbiota. The need for FMT might be a consequence of poor pharmacotherapy management, not a part of pharmacotherapy management.”

Moderator Sam Aitken, PharmD, MPH, a clinical pharmacy specialist in infectious disease at MD Anderson Cancer Center in Houston, said in an interview the speakers found some common ground.

“I think there was a general consensus between both Dr. Allegretti and Dr. Garey that both traditional therapeutics and fecal microbiota transplantation have a role to play in these patients, although there is still quite a bit of discussion around where those might be best positioned,” Dr. Aitken said.

He added, “There’s also a general consensus that there is not likely to be one right answer for all patients with multiple recurrent CDI.”

Dr. Allegretti, Dr. Garey, and Dr. Aitken have disclosed no relevant financial relationships.
 

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

Two experts at IDWeek 2020 debated the best treatment for patients with the most severe type of Clostridioides difficile infection – fulminant C. diff. The discussion pitted fecal microbiota transplants (FMT) from the stool of healthy donors against traditional antibiotics.

Fulminant C. diff infection (CDI) represents about 8% of all CDI cases and is often fatal. Patients frequently don’t respond to maximum antibiotic therapy.

Should these patients be treated with FMT before surgery is considered?

“Unequivocally, yes,” said Jessica R. Allegretti, MD, MPH, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.
 

Patients face full colectomy

Fulminant infection, she says, typically requires a total abdominal colectomy with end ileostomy.

“Patients have a quite high perioperative and intraoperative mortality because this is typically an older population with significant comorbidities,” she said.

Often the patients are poor candidates for surgery, she added.

She pointed to the efficacy of FMT in studies such as one published in Gut Microbes in 2017. The study, by Monika Fischer, MD, of Indiana University, Indianapolis, and colleagues showed a 91% cure rate at 1 month in severe patients with an average of 1.5 fecal transplants, noting that was “quite remarkable” in this very sick population.

Though FMT is not approved by the US Food and Drug Administration for fulminant CDI, Dr. Allegretti said, the FDA does allow treatment under “enforcement discretion,” which means no investigational new drug license is needed specifically if treating CDI patients who haven’t responded to standard therapy, as long as proper consent has been obtained.

“This is a patient population that is likely going to die,” she said. “If you were the one in the ICU with fulminant C. diff and you’ve been on maximum therapy for 3-5 days and you’re not getting better, wouldn’t you want somebody to offer you a fecal transplant and give you the chance to recover and leave the hospital with your colon intact? The data suggest that is possible, with a high likelihood and a good safety profile.”

She said the most recent guidelines have supported FMT, and emerging guidelines coming within months “will support this as well.”
 

Unknowns with FMT

Taking the other side of the debate, Kevin Garey, PharmD, chair of the department of pharmacy practice and translational research at University of Houston College of Pharmacy, warned against trading traditional antibiotics, such as vancomycin and fidaxomicin, for the novelty of FMT.

“With the science of the microbiome and the novelty of fecal microbiota transplantation in expanding use, I think people have somewhat forgotten pharmacotherapy,” he said.

He pointed out safety concerns with FMT reported in June 2019, after which the FDA issued an alert. Two immunocompromised patients who received FMT, both from the same donor, developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli. One died.

The FDA explained that the donated FMT samples the patients received were not tested for ESBL-producing gram-negative organisms before use.

Dr. Allegretti agreed antibiotics play a role in treatment with FMT, but she argued that the safety profile of FMT remains strong and that the safety issues came from isolated incidents at a single center.

Dr. Garey countered that there are just too many unknowns with FMT.

“We will never know what the next superbug that’s going to land in an FMT is until we’ve identified that superbug in somebody – the next Candida auris, the next CRE [carbapenem-resistant Enterobacteriaceae], the next thing that’s going to show up in FMT – until we get rid of the ‘F,’ “ Dr. Garey said.

“[Until] we get microbial therapy that’s generated without the need for healthy donors, I think we’re always going to be in this problem.”

He said although FMT “has an amazing ability to alter a microbiome” it “pales in comparison” to vancomycin’s ability to do so.

Disruption of the microbiome is, without a doubt, a hallmark of C. diff, but we don’t have to run to FMT,” Dr. Garey said. “We can think about prophylaxis strategies, we can think about new drug development that spares the microbiota. The need for FMT might be a consequence of poor pharmacotherapy management, not a part of pharmacotherapy management.”

Moderator Sam Aitken, PharmD, MPH, a clinical pharmacy specialist in infectious disease at MD Anderson Cancer Center in Houston, said in an interview the speakers found some common ground.

“I think there was a general consensus between both Dr. Allegretti and Dr. Garey that both traditional therapeutics and fecal microbiota transplantation have a role to play in these patients, although there is still quite a bit of discussion around where those might be best positioned,” Dr. Aitken said.

He added, “There’s also a general consensus that there is not likely to be one right answer for all patients with multiple recurrent CDI.”

Dr. Allegretti, Dr. Garey, and Dr. Aitken have disclosed no relevant financial relationships.
 

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

Two experts at IDWeek 2020 debated the best treatment for patients with the most severe type of Clostridioides difficile infection – fulminant C. diff. The discussion pitted fecal microbiota transplants (FMT) from the stool of healthy donors against traditional antibiotics.

Fulminant C. diff infection (CDI) represents about 8% of all CDI cases and is often fatal. Patients frequently don’t respond to maximum antibiotic therapy.

Should these patients be treated with FMT before surgery is considered?

“Unequivocally, yes,” said Jessica R. Allegretti, MD, MPH, associate director of the Crohn’s and Colitis Center at Brigham and Women’s Hospital in Boston.
 

Patients face full colectomy

Fulminant infection, she says, typically requires a total abdominal colectomy with end ileostomy.

“Patients have a quite high perioperative and intraoperative mortality because this is typically an older population with significant comorbidities,” she said.

Often the patients are poor candidates for surgery, she added.

She pointed to the efficacy of FMT in studies such as one published in Gut Microbes in 2017. The study, by Monika Fischer, MD, of Indiana University, Indianapolis, and colleagues showed a 91% cure rate at 1 month in severe patients with an average of 1.5 fecal transplants, noting that was “quite remarkable” in this very sick population.

Though FMT is not approved by the US Food and Drug Administration for fulminant CDI, Dr. Allegretti said, the FDA does allow treatment under “enforcement discretion,” which means no investigational new drug license is needed specifically if treating CDI patients who haven’t responded to standard therapy, as long as proper consent has been obtained.

“This is a patient population that is likely going to die,” she said. “If you were the one in the ICU with fulminant C. diff and you’ve been on maximum therapy for 3-5 days and you’re not getting better, wouldn’t you want somebody to offer you a fecal transplant and give you the chance to recover and leave the hospital with your colon intact? The data suggest that is possible, with a high likelihood and a good safety profile.”

She said the most recent guidelines have supported FMT, and emerging guidelines coming within months “will support this as well.”
 

Unknowns with FMT

Taking the other side of the debate, Kevin Garey, PharmD, chair of the department of pharmacy practice and translational research at University of Houston College of Pharmacy, warned against trading traditional antibiotics, such as vancomycin and fidaxomicin, for the novelty of FMT.

“With the science of the microbiome and the novelty of fecal microbiota transplantation in expanding use, I think people have somewhat forgotten pharmacotherapy,” he said.

He pointed out safety concerns with FMT reported in June 2019, after which the FDA issued an alert. Two immunocompromised patients who received FMT, both from the same donor, developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli. One died.

The FDA explained that the donated FMT samples the patients received were not tested for ESBL-producing gram-negative organisms before use.

Dr. Allegretti agreed antibiotics play a role in treatment with FMT, but she argued that the safety profile of FMT remains strong and that the safety issues came from isolated incidents at a single center.

Dr. Garey countered that there are just too many unknowns with FMT.

“We will never know what the next superbug that’s going to land in an FMT is until we’ve identified that superbug in somebody – the next Candida auris, the next CRE [carbapenem-resistant Enterobacteriaceae], the next thing that’s going to show up in FMT – until we get rid of the ‘F,’ “ Dr. Garey said.

“[Until] we get microbial therapy that’s generated without the need for healthy donors, I think we’re always going to be in this problem.”

He said although FMT “has an amazing ability to alter a microbiome” it “pales in comparison” to vancomycin’s ability to do so.

Disruption of the microbiome is, without a doubt, a hallmark of C. diff, but we don’t have to run to FMT,” Dr. Garey said. “We can think about prophylaxis strategies, we can think about new drug development that spares the microbiota. The need for FMT might be a consequence of poor pharmacotherapy management, not a part of pharmacotherapy management.”

Moderator Sam Aitken, PharmD, MPH, a clinical pharmacy specialist in infectious disease at MD Anderson Cancer Center in Houston, said in an interview the speakers found some common ground.

“I think there was a general consensus between both Dr. Allegretti and Dr. Garey that both traditional therapeutics and fecal microbiota transplantation have a role to play in these patients, although there is still quite a bit of discussion around where those might be best positioned,” Dr. Aitken said.

He added, “There’s also a general consensus that there is not likely to be one right answer for all patients with multiple recurrent CDI.”

Dr. Allegretti, Dr. Garey, and Dr. Aitken have disclosed no relevant financial relationships.
 

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

A new consensus statement offers detailed guidelines for inpatient use of continuous glucose monitors (CGM) and automated insulin delivery (AID) systems.

Aimed at clinicians, researchers, and hospital administrators, the open-access document was recently published by a multidisciplinary international panel of 24 experts in the Journal of Diabetes Science and Technology.

The statement includes 77 separate recommendations under five headings: 1) continued use of CGM by patients already using them at home, 2) initiation of CGM in hospital, 3) continuation of AID systems in hospital by patients already using them at home, 4) logistics and hands-on care of hospitalized patients using CGM and AID systems, and 5) data management of CGM and AID systems in hospital.

“This is the most comprehensive and up-to-date guideline on the use of diabetes technology in the hospital now,” lead author Rodolfo J. Galindo, MD, told Medscape Medical News in an interview.

“Overall, most experts believe that CGM and AID have the potential to overcome the current limitations of glycemic monitoring in the hospital to improve patient outcomes, but we need research – first to get the approval and second to get widespread use,” said Galindo, medical chair of the hospital diabetes taskforce at Emory Healthcare System, Atlanta.
 

“COVID-19 changed everything”

The guideline is an update of a 2017 statement on hospital use of CGM. The new guideline adds AID systems (sometimes referred to as an artificial pancreas), which combines a CGM and insulin pump and uses an algorithm to guide insulin delivery, and is the first to be developed during the COVID-19 era.

The update had been planned prior to the pandemic, but the actual panel meeting took place in April 2020, after the US Food and Drug Administration allowed inpatient use of CGM despite lack of official approval.

“COVID-19 changed everything. ... We had to be more specific about how to implement CGM in these patients. The standard of care is hourly point-of-care glucose monitoring in the [ICU], and at least every 4 hours outside the ICU. With limited [personal protective equipment] and the burden on nursing it was unachievable,” Galindo explained.

In June 2020, Galindo and other guideline authors developed a COVID-19–specific document (also open-access), which goes more into detail about CGM and how to implement in-hospital use during the pandemic.

The current consensus guideline “provides a high-level review of the evidence by experts,” Galindo added.
 

Recommendations cover different technologies and hospital settings

The panel “strongly” advises that hospital providers consult with an inpatient diabetes team, if available, to help manage patients already using CGM prior to admission. Among other recommendations, they list several situations in which CGM data should not be relied upon for management decisions, including severe hyper- or hypoglycemia, diabetic ketoacidosis, or in patients with skin infections near the sensor site.

The panel also call for more research into outcomes for CGM continuation in the hospital and optimal implementation of both CGM and point-of-care glucose testing. For hospitals, strong recommendations include developing standard CGM data reports and workflows, as well as policies for CGM use.

Galindo pointed out: “A lot of hospitals have policies on that, but there aren’t many studies. It’s just that patients like it and it’s very hard to take it away from patients when they’re doing well.”

The section on CGM inpatient initiation is where COVID-19 plays the greatest role, which includes just one strong clinical practice recommendation: “Healthcare providers should consider prescribing CGM to reduce the need for frequent nurse contact for point-of-care glucose testing and the use of personal protective equipment for patients on isolation with highly contagious infectious diseases (eg, COVID-19).”

Strong recommendations also include a call for outcomes research and for hospitals to develop CGM protocols and educational tools for staff.

“We can do a study for approval but if administration and hospital policies aren’t there we’re not going to be able to use them,” Galindo noted.

For patients who already use AID systems – either the Medtronic 670G or Tandem Control IQ in the United States – the panel advises assessment to ensure the AID system is the most appropriate inpatient treatment, and the development of an alternative plan for diabetes management, if necessary. They also strongly recommend research in this area, and for hospitals to develop protocols for use of AID systems in various clinical situations.
 

Most detailed guidance addresses logistics and data management

Most of the strong recommendations regarding logistics are aimed at nursing staff, including receiving training in use of CGM and AID systems, confirming patient capacity, inspection of devices, and understanding when to administer a point-of-care glucose test.

Again, the panel calls for more data and for hospitals to develop policies and protocols for ensuring safe CGM and AID systems use, and when to avoid use.

Finally, they make one strong clinical recommendation regarding data management: “Healthcare providers should develop a set of core data elements and definitions for CGM data for inclusion in common data models and the electronic health record.”

That’s followed by a long list of relevant recommendations for research in the area, and for hospitals to integrate CGM and AID system data into their EHR systems.

This last area has proven particularly challenging, Galindo said. “Right now we do four point-of-care glucoses a day, and that goes right into the EHR, but with CGM it’s much more than that. How do we get all those data into the EHR and interpret it? Many steps need to be taken into consideration.”

Studies are being conducted in order to fulfill requirements for FDA approval of inpatient CGM use, he said, with data on implementation and inpatient AID system use to follow.

“More data will be available, triggered by the COVID-19 pandemic. However, the use of technology in the hospital goes beyond COVID-19,” he said

Galindo has reported receiving unrestricted research support to Emory for investigator-initiated studies from Novo Nordisk and Dexcom, and consulting fees from Abbott Diabetes Care, Sanofi, Novo Nordisk, Eli Lilly, and Valeritas. He is partially supported by research grants from the NIH/NIDDK.
 

This article first appeared on Medscape.com.

A new consensus statement offers detailed guidelines for inpatient use of continuous glucose monitors (CGM) and automated insulin delivery (AID) systems.

Aimed at clinicians, researchers, and hospital administrators, the open-access document was recently published by a multidisciplinary international panel of 24 experts in the Journal of Diabetes Science and Technology.

The statement includes 77 separate recommendations under five headings: 1) continued use of CGM by patients already using them at home, 2) initiation of CGM in hospital, 3) continuation of AID systems in hospital by patients already using them at home, 4) logistics and hands-on care of hospitalized patients using CGM and AID systems, and 5) data management of CGM and AID systems in hospital.

“This is the most comprehensive and up-to-date guideline on the use of diabetes technology in the hospital now,” lead author Rodolfo J. Galindo, MD, told Medscape Medical News in an interview.

“Overall, most experts believe that CGM and AID have the potential to overcome the current limitations of glycemic monitoring in the hospital to improve patient outcomes, but we need research – first to get the approval and second to get widespread use,” said Galindo, medical chair of the hospital diabetes taskforce at Emory Healthcare System, Atlanta.
 

“COVID-19 changed everything”

The guideline is an update of a 2017 statement on hospital use of CGM. The new guideline adds AID systems (sometimes referred to as an artificial pancreas), which combines a CGM and insulin pump and uses an algorithm to guide insulin delivery, and is the first to be developed during the COVID-19 era.

The update had been planned prior to the pandemic, but the actual panel meeting took place in April 2020, after the US Food and Drug Administration allowed inpatient use of CGM despite lack of official approval.

“COVID-19 changed everything. ... We had to be more specific about how to implement CGM in these patients. The standard of care is hourly point-of-care glucose monitoring in the [ICU], and at least every 4 hours outside the ICU. With limited [personal protective equipment] and the burden on nursing it was unachievable,” Galindo explained.

In June 2020, Galindo and other guideline authors developed a COVID-19–specific document (also open-access), which goes more into detail about CGM and how to implement in-hospital use during the pandemic.

The current consensus guideline “provides a high-level review of the evidence by experts,” Galindo added.
 

Recommendations cover different technologies and hospital settings

The panel “strongly” advises that hospital providers consult with an inpatient diabetes team, if available, to help manage patients already using CGM prior to admission. Among other recommendations, they list several situations in which CGM data should not be relied upon for management decisions, including severe hyper- or hypoglycemia, diabetic ketoacidosis, or in patients with skin infections near the sensor site.

The panel also call for more research into outcomes for CGM continuation in the hospital and optimal implementation of both CGM and point-of-care glucose testing. For hospitals, strong recommendations include developing standard CGM data reports and workflows, as well as policies for CGM use.

Galindo pointed out: “A lot of hospitals have policies on that, but there aren’t many studies. It’s just that patients like it and it’s very hard to take it away from patients when they’re doing well.”

The section on CGM inpatient initiation is where COVID-19 plays the greatest role, which includes just one strong clinical practice recommendation: “Healthcare providers should consider prescribing CGM to reduce the need for frequent nurse contact for point-of-care glucose testing and the use of personal protective equipment for patients on isolation with highly contagious infectious diseases (eg, COVID-19).”

Strong recommendations also include a call for outcomes research and for hospitals to develop CGM protocols and educational tools for staff.

“We can do a study for approval but if administration and hospital policies aren’t there we’re not going to be able to use them,” Galindo noted.

For patients who already use AID systems – either the Medtronic 670G or Tandem Control IQ in the United States – the panel advises assessment to ensure the AID system is the most appropriate inpatient treatment, and the development of an alternative plan for diabetes management, if necessary. They also strongly recommend research in this area, and for hospitals to develop protocols for use of AID systems in various clinical situations.
 

Most detailed guidance addresses logistics and data management

Most of the strong recommendations regarding logistics are aimed at nursing staff, including receiving training in use of CGM and AID systems, confirming patient capacity, inspection of devices, and understanding when to administer a point-of-care glucose test.

Again, the panel calls for more data and for hospitals to develop policies and protocols for ensuring safe CGM and AID systems use, and when to avoid use.

Finally, they make one strong clinical recommendation regarding data management: “Healthcare providers should develop a set of core data elements and definitions for CGM data for inclusion in common data models and the electronic health record.”

That’s followed by a long list of relevant recommendations for research in the area, and for hospitals to integrate CGM and AID system data into their EHR systems.

This last area has proven particularly challenging, Galindo said. “Right now we do four point-of-care glucoses a day, and that goes right into the EHR, but with CGM it’s much more than that. How do we get all those data into the EHR and interpret it? Many steps need to be taken into consideration.”

Studies are being conducted in order to fulfill requirements for FDA approval of inpatient CGM use, he said, with data on implementation and inpatient AID system use to follow.

“More data will be available, triggered by the COVID-19 pandemic. However, the use of technology in the hospital goes beyond COVID-19,” he said

Galindo has reported receiving unrestricted research support to Emory for investigator-initiated studies from Novo Nordisk and Dexcom, and consulting fees from Abbott Diabetes Care, Sanofi, Novo Nordisk, Eli Lilly, and Valeritas. He is partially supported by research grants from the NIH/NIDDK.
 

This article first appeared on Medscape.com.

A new consensus statement offers detailed guidelines for inpatient use of continuous glucose monitors (CGM) and automated insulin delivery (AID) systems.

Aimed at clinicians, researchers, and hospital administrators, the open-access document was recently published by a multidisciplinary international panel of 24 experts in the Journal of Diabetes Science and Technology.

The statement includes 77 separate recommendations under five headings: 1) continued use of CGM by patients already using them at home, 2) initiation of CGM in hospital, 3) continuation of AID systems in hospital by patients already using them at home, 4) logistics and hands-on care of hospitalized patients using CGM and AID systems, and 5) data management of CGM and AID systems in hospital.

“This is the most comprehensive and up-to-date guideline on the use of diabetes technology in the hospital now,” lead author Rodolfo J. Galindo, MD, told Medscape Medical News in an interview.

“Overall, most experts believe that CGM and AID have the potential to overcome the current limitations of glycemic monitoring in the hospital to improve patient outcomes, but we need research – first to get the approval and second to get widespread use,” said Galindo, medical chair of the hospital diabetes taskforce at Emory Healthcare System, Atlanta.
 

“COVID-19 changed everything”

The guideline is an update of a 2017 statement on hospital use of CGM. The new guideline adds AID systems (sometimes referred to as an artificial pancreas), which combines a CGM and insulin pump and uses an algorithm to guide insulin delivery, and is the first to be developed during the COVID-19 era.

The update had been planned prior to the pandemic, but the actual panel meeting took place in April 2020, after the US Food and Drug Administration allowed inpatient use of CGM despite lack of official approval.

“COVID-19 changed everything. ... We had to be more specific about how to implement CGM in these patients. The standard of care is hourly point-of-care glucose monitoring in the [ICU], and at least every 4 hours outside the ICU. With limited [personal protective equipment] and the burden on nursing it was unachievable,” Galindo explained.

In June 2020, Galindo and other guideline authors developed a COVID-19–specific document (also open-access), which goes more into detail about CGM and how to implement in-hospital use during the pandemic.

The current consensus guideline “provides a high-level review of the evidence by experts,” Galindo added.
 

Recommendations cover different technologies and hospital settings

The panel “strongly” advises that hospital providers consult with an inpatient diabetes team, if available, to help manage patients already using CGM prior to admission. Among other recommendations, they list several situations in which CGM data should not be relied upon for management decisions, including severe hyper- or hypoglycemia, diabetic ketoacidosis, or in patients with skin infections near the sensor site.

The panel also call for more research into outcomes for CGM continuation in the hospital and optimal implementation of both CGM and point-of-care glucose testing. For hospitals, strong recommendations include developing standard CGM data reports and workflows, as well as policies for CGM use.

Galindo pointed out: “A lot of hospitals have policies on that, but there aren’t many studies. It’s just that patients like it and it’s very hard to take it away from patients when they’re doing well.”

The section on CGM inpatient initiation is where COVID-19 plays the greatest role, which includes just one strong clinical practice recommendation: “Healthcare providers should consider prescribing CGM to reduce the need for frequent nurse contact for point-of-care glucose testing and the use of personal protective equipment for patients on isolation with highly contagious infectious diseases (eg, COVID-19).”

Strong recommendations also include a call for outcomes research and for hospitals to develop CGM protocols and educational tools for staff.

“We can do a study for approval but if administration and hospital policies aren’t there we’re not going to be able to use them,” Galindo noted.

For patients who already use AID systems – either the Medtronic 670G or Tandem Control IQ in the United States – the panel advises assessment to ensure the AID system is the most appropriate inpatient treatment, and the development of an alternative plan for diabetes management, if necessary. They also strongly recommend research in this area, and for hospitals to develop protocols for use of AID systems in various clinical situations.
 

Most detailed guidance addresses logistics and data management

Most of the strong recommendations regarding logistics are aimed at nursing staff, including receiving training in use of CGM and AID systems, confirming patient capacity, inspection of devices, and understanding when to administer a point-of-care glucose test.

Again, the panel calls for more data and for hospitals to develop policies and protocols for ensuring safe CGM and AID systems use, and when to avoid use.

Finally, they make one strong clinical recommendation regarding data management: “Healthcare providers should develop a set of core data elements and definitions for CGM data for inclusion in common data models and the electronic health record.”

That’s followed by a long list of relevant recommendations for research in the area, and for hospitals to integrate CGM and AID system data into their EHR systems.

This last area has proven particularly challenging, Galindo said. “Right now we do four point-of-care glucoses a day, and that goes right into the EHR, but with CGM it’s much more than that. How do we get all those data into the EHR and interpret it? Many steps need to be taken into consideration.”

Studies are being conducted in order to fulfill requirements for FDA approval of inpatient CGM use, he said, with data on implementation and inpatient AID system use to follow.

“More data will be available, triggered by the COVID-19 pandemic. However, the use of technology in the hospital goes beyond COVID-19,” he said

Galindo has reported receiving unrestricted research support to Emory for investigator-initiated studies from Novo Nordisk and Dexcom, and consulting fees from Abbott Diabetes Care, Sanofi, Novo Nordisk, Eli Lilly, and Valeritas. He is partially supported by research grants from the NIH/NIDDK.
 

This article first appeared on Medscape.com.

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

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

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

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

For patients with diabetic kidney disease, finerenone, an agent from a new class of selective, nonsteroidal mineralocorticoid receptor antagonists, led to significant reductions in combined adverse renal outcomes and in combined adverse cardiovascular outcomes in the pivotal FIDELIO-DKD trial.

And the safety results showed a good level of tolerability. The rate of hyperkalemia was higher with finerenone than with placebo, but the rate of drug discontinuations for elevated potassium was lower than that seen with spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA).

“An ideal drug would cause no hyperkalemia, but the absolute risk we saw is a fraction of what we see with spironolactone in this vulnerable patient population,” said Rajiv Agarwal, MD, from Indiana in Indianapolis, during a press briefing.

After a median follow-up of 2.6 years, finerenone was associated with a 3.4% absolute reduction in the rate of combined adverse renal events, the study’s primary end point, which comprised kidney failure, renal death, and a drop in estimated glomerular filtration rate (eGFR) of at least 40% from baseline. This produced a significant relative risk reduction of 18%, with a number needed to treat of 32 to prevent one of these events, Dr. Agarwal reported at Kidney Week 2020. Findings from the FIDELIO-DKD trial were published simultaneously in the New England Journal of Medicine.

Finerenone was also associated with an absolute 2.4% reduction in the rate of combined adverse cardiovascular events, the study’s “key secondary end point,” which included cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure. This translated into a significant relative risk reduction of 14% and a number needed to treat of 42 to prevent one of these events.

FIDELIO-DKD assessed 5,734 patients with type 2 diabetes and chronic kidney disease from more than 1,000 sites in 48 countries, including the United States, from 2015 to 2018. In the study cohort, average age was slightly more than 65 years, average baseline systolic blood pressure was 138 mm Hg, average duration of diabetes was nearly 17 years, average baseline glycated hemoglobin (A1c) was 7.7%, and fewer than 5% of patients were Black, 25% were Asian, and about 63% were White.
 

A suggestion of less severe hyperkalemia

Finerenone was well tolerated by the participants, and the findings suggest that it caused less clinically meaningful hyperkalemia than spironolactone, the most established and widely used MRA.

Like all MRA drugs, finerenone led to an increase in serum potassium in all patient subgroups – in this case 0.2 mmol/L – unlike placebo, said Dr. Agarwal.

The overall incidence of hyperkalemia was 16% in the 2,827 evaluable patients in the finerenone group and 8% in the 2,831 evaluable patients in the placebo group. Fewer than 10% of patients in the trial received a potassium-binding agent.

The rate of hyperkalemia leading to treatment discontinuation was higher in the finerenone group than in the placebo group (2.3% vs. 0.9%).

That 2.3% rate is 10 times lower than the 23.0% rate of hyperkalemia-related treatment discontinuation in patients who received spironolactone and no potassium-binding agent, said Dr. Agarwal, citing a previous study he was involved with.

He hypothesized that finerenone might cause less clinically meaningful hyperkalemia because it creates no active metabolites that linger in the body, whereas spironolactone produces active metabolites with a half life of about 1 week.

“The risk for hyperkalemia is clearly increased with finerenone compared with placebo, and in the absence of head-to-head studies, it’s hard to know how it compares with spironolactone or eplerenone [Inspra],” the other agents in the MRA class, said Mikhail N. Kosiborod, MD, from the University of Missouri–Kansas City.

“The rates of hyperkalemia observed in FIDELIO-DKD were overall comparable to what we would expect from eplerenone. But the rate of serious hyperkalemia was quite low with finerenone, which is reassuring,” Dr. Kosiborod said in an interview.

And the adverse-effect profile showed that finerenone “is as safe as you could expect from an MRA,” said Janani Rangaswami, MD, from the Einstein Medical Center in Philadelphia.

The rate of hyperkalemia should be interpreted in the context of the high risk the enrolled patients faced, given that they all had moderate to severe diabetic kidney disease with albuminuria and, in some cases, eGFR rates as low as 25 mL/min per 1.73m², she explained. In addition, all patients were on maximally tolerated treatment with either an angiotensin-converting–enzyme inhibitor or an angiotensin receptor blocker to inhibit the renin angiotensin system (RAS).

“Considering this background, it’s a very acceptable adverse-event profile,” Dr. Rangaswami said in an interview.
 

Renal drugs that could work together

More than 99% of patients in FIDELIO-DKD were on an RAS inhibitor, but fewer than 5% were on a sodium glucose cotransporter 2 (SGLT2) inhibitor at baseline, and fewer than 10% started on this drug class during the course of the study.

Despite that, both Dr. Kosiborod and Dr. Rangaswami are enthusiastic about the prospect of using the three drugs in combination to maximize renal and cardiovascular benefits in FIDELIO-DKD–type patients. Recent results from the CREDENCE study of canagliflozin (Invokana) and from the DAPA-CKD study of dapagluflozin (Farxiga) have established SGLT2 inhibitors – at least those two – as key agents for patients with chronic kidney disease.

Dual treatment with an RAS inhibitor and an SGLT2 inhibitor is “clearly established” for patients with diabetic kidney disease, said Dr. Agarwal.

“After CREDENCE, DAPA-CKD, and now FIDELIO-DKD, we need to seriously consider triple therapy as the future of treatment for diabetic kidney disease to prevent both cardiovascular and kidney complications,” said Dr. Kosiborod. The approach will mimic the multidrug therapy that’s now standard for patients with heart failure with reduced ejection fraction (HFrEF). But he cautioned that this triple combination needs further testing.

“Triple therapy will be the standard of care” for patients with diabetic kidney disease, Dr. Rangaswami agreed, but she cautioned that she would not currently expand the target population for finerenone to patients without type 2 diabetes or to patients without the level of albuminuria required for entry into FIDELIO-DKD: at least 30 mg/g of creatinine per day. And patients with HFrEF were excluded from FIDELIO-DKD, so that limitation on finerenone use should remain for the time being, she added.

Dr. Rangaswami said she is optimistic about the potential efficacy of finerenone added to an SGLT2 inhibitor because of the likelihood that the two drug classes work in different but complementary ways. SGLT2 inhibitors seem to exert their renal protective effects largely through hemodynamic effects, whereas it is likely that finerenone exerts its effects largely as an anti-inflammatory and antifibrotic agent, she speculated. The FIDELIO-DKD results appear to rule out any major effect of finerenone on blood pressure lowering because average systolic pressure fell by only about 2 mm Hg in the treatment group.

“The benefits of finerenone for cardiorenal outcomes are substantial and clinically meaningful,” Dr. Kosiborod said. “We cannot assume that other MRAs, such as spironolactone, provide similar benefits,” he cautioned, but the results are “very good news for patients with type 2 diabetes and chronic kidney disease. We now have another effective intervention with a different mechanism of action.”

FIDELIO-DKD was sponsored by Bayer, the company developing finerenone (BAY 94-8862). Dr. Agarwal has been a consultant to and has received honoraria from Bayer and from several other companies. Dr. Kosiborod has been a consultant to Bayer and to AstraZeneca, Boehringer Ingelheim, Jansse, Merck, and Vifor and has received research funding from AstraZeneca and Boehringer Ingelheim. Dr. Rangaswami has disclosed no relevant financial relationships.
 

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

A new formulation of an existing antibacterial agent and a potential therapeutic approach to a challenging clinical problem were the focus of a session on potentially practice-changing clinical trials in antimicrobial therapy presented during IDWeek 2020, an annual scientific meeting on infectious diseases.

“I know it has been a big year for viral disease of course, with COVID, but there has been some really good work that has gone on in the bacterial space, and of course as those of you who are on service know, you may have your fair share of COVID patients, but these are infections that we still deal with on a daily basis,” said Michael Satlin, MD, an infectious disease specialist at Weill Cornell Medicine in New York.

He combed through studies published during the previous 12 months in leading medical journals, including the New England Journal of Medicine, JAMA network publications, Lancet Infectious Diseases, Lancet Respiratory Medicine, Clinical Infectious Diseases, and Clinical Microbiology and Infection, looking for randomized trials of interventions to treat bacterial infections, and selecting those most likely to change practice of U.S. infectious diseases practitioners.

He excluded meta-analyses, post hoc analyses, evaluations of diagnostic tests, stewardship, or any studies presented previously at IDWeek.

Two of the trials he highlighted are described here.
 

Fosfomycin for injection

In the United States, fosfomycin, the only antibiotic in its class, is currently available only in an oral sachet formulation (Monurol), “and typically we’ve only given this for patients with cystitis because we know that we don’t achieve significant levels [of drug] in the kidney or in the bloodstream for other types of infections,” Dr. Satlin said.

In Europe, however fosfomycin for injection (ZTI-01) has been available for several years.

“There’s been a lot of interest in fosfomycin because it has a different mechanism of action from other agents. It’s an epoxide antibiotic that inhibits early peptidoglycan synthesis by binding to MurA,” he explained.

The phase 2/3 randomized ZEUS trial compared ZTI-01 with piperacillin/tazobactam (pip/taz) for treatment of complicated urinary tract infection (UTI) including acute pyelonephritis.

A total of 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI or acute pyelonephritis were randomized to 6 g of ZTI-01 every 8 hours or 4.5 g of intravenous pip/taz every 8 hours for a fixed 7-day course with no oral switch; patients with concomitant bacteremia (about 9% of the study population) could receive the assigned therapy for up to 14 days.

The primary endpoint of noninferiority of ZTI-01 was met and clinical cure rates were high and similar between the treatments, at approximately 91% each. Treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mostly mild and transient.

The hypokalemia seen in the trial may be attributable to the high salt load of fosfomycin relative to pip/taz, Dr. Satlin said.

“How might this change your practice? Well, if IV fosfomycin is ever FDA [Food and Drug Administration] approved – and my understanding is that the delays have been more related to manufacturing than scientific quality of data – it could potentially be an alternative to beta-lactams and fluoroquinolones” and has activity against most extend spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae, he said.

Fosfomycin susceptibility testing is challenging, however, with no Clinical & Laboratory Standards Institute (CLSI) or FDA breakpoints for Enterobacterales other than Escherichia coli, and there are questions about the step-down therapy.

“Do you just give a 3-gram sachet chaser when they walk out the door? Do you switch to another agent? I think that needs to be worked out,” he said.
 

Inhaled amikacin

“We know that some IV antibiotics, particularly for resistant organisms, may not achieve sufficient concentrations in the lung to treat pneumonia. We know that inhaled antibiotics can give a lot of concentration of that drug right at the at the site of infection, but we don’t really have [randomized controlled trial] data to see whether it really helps,” Dr. Satlin said.

The INHALE trial was a double-blind, placebo-controlled superiority trial to see whether adding inhaled amikacin to IV standard-of-care antibiotics could improve outcomes for mechanically ventilated patients with gram-negative pneumonia.

The investigators enrolled 725 adults who were receiving mechanical ventilation for pneumonia, 45% of who had ventilator-associated pneumonia (VAP). Of the total cohort, 508 patients analyzed for efficacy had gram-negative pathogens, including 32% with Pseudomonas aeurginosa, 29% with Acinetobacter baumannii, 30% with E. coli, and the remainder with Klebsiella pneumoniae.

Patients were randomized to standard-of-care intravenous antibiotics plus either inhaled amikacin 400 mg twice daily for 10 days or inhaled saline placebo.

“Of note, the median standard-of-care antibiotics in this study was 18 days, which is certainly longer than what our guidelines recommend.”

There was no significant difference between study arms in the primary endpoint of survival at days 28-32 for all patients who had received at least one dose of study drug, were infected with a gram-negative pathogen, and an Acute Physiology and Chronic Health Evaluation (APACHE) II score of at 10 or higher at diagnosis. The respective survival rates for the inhaled amikacin and placebo groups were 75% and 77%. The incidence of treatment-emergent adverse events or serious treatment-emergent adverse events were similar between the two treatment arms.

“No matter how you sliced and diced it – days of mechanical ventilation, duration of ICU stay – essentially they looked the same. Even for [extensively drug resistant] pathogens where you might expect that you’d see the benefit of inhaled amikacin, they didn’t really see a mortality benefit in this study,” Dr. Satlin said.

The study is practice changing, he said “because I think inhaled aminoglycosides should not be routinely added to the standard of care IV antibiotics for pneumonia in ventilated patients,” he said.

It’s still unclear whether inhaled aminoglycosides might play a role in the treatment of select patients infected with organisms resistant to all beta-lactams and fluoroquinolones, he added.
 

Tempting strategy

“Adding inhaled antibiotics is a tempting strategy for treatment of ventilated pneumonia, which often has poor outcomes,” commented Thomas Holland, MD, a hospitalist and infectious disease specialist at Duke University Hospital in Durham, N.C. “This is valuable and practical information as clinicians choose antibiotics regimens for this difficult-to-treat syndrome,” he said in an interview.

Dr. Holland comoderated the session in which Dr. Satlin presented the study findings and opinions.

No funding source for the presentation was reported. Dr. Satlin reported consulting for Shionogi and Achaogen and research grants from Allergan, Merck, and BioFire Diagnostics. Dr. Holland disclosed consulting fees and other material support from Basilea Pharmaceutica, Genetech, Karius and Theravance.

A new formulation of an existing antibacterial agent and a potential therapeutic approach to a challenging clinical problem were the focus of a session on potentially practice-changing clinical trials in antimicrobial therapy presented during IDWeek 2020, an annual scientific meeting on infectious diseases.

“I know it has been a big year for viral disease of course, with COVID, but there has been some really good work that has gone on in the bacterial space, and of course as those of you who are on service know, you may have your fair share of COVID patients, but these are infections that we still deal with on a daily basis,” said Michael Satlin, MD, an infectious disease specialist at Weill Cornell Medicine in New York.

He combed through studies published during the previous 12 months in leading medical journals, including the New England Journal of Medicine, JAMA network publications, Lancet Infectious Diseases, Lancet Respiratory Medicine, Clinical Infectious Diseases, and Clinical Microbiology and Infection, looking for randomized trials of interventions to treat bacterial infections, and selecting those most likely to change practice of U.S. infectious diseases practitioners.

He excluded meta-analyses, post hoc analyses, evaluations of diagnostic tests, stewardship, or any studies presented previously at IDWeek.

Two of the trials he highlighted are described here.
 

Fosfomycin for injection

In the United States, fosfomycin, the only antibiotic in its class, is currently available only in an oral sachet formulation (Monurol), “and typically we’ve only given this for patients with cystitis because we know that we don’t achieve significant levels [of drug] in the kidney or in the bloodstream for other types of infections,” Dr. Satlin said.

In Europe, however fosfomycin for injection (ZTI-01) has been available for several years.

“There’s been a lot of interest in fosfomycin because it has a different mechanism of action from other agents. It’s an epoxide antibiotic that inhibits early peptidoglycan synthesis by binding to MurA,” he explained.

The phase 2/3 randomized ZEUS trial compared ZTI-01 with piperacillin/tazobactam (pip/taz) for treatment of complicated urinary tract infection (UTI) including acute pyelonephritis.

A total of 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI or acute pyelonephritis were randomized to 6 g of ZTI-01 every 8 hours or 4.5 g of intravenous pip/taz every 8 hours for a fixed 7-day course with no oral switch; patients with concomitant bacteremia (about 9% of the study population) could receive the assigned therapy for up to 14 days.

The primary endpoint of noninferiority of ZTI-01 was met and clinical cure rates were high and similar between the treatments, at approximately 91% each. Treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mostly mild and transient.

The hypokalemia seen in the trial may be attributable to the high salt load of fosfomycin relative to pip/taz, Dr. Satlin said.

“How might this change your practice? Well, if IV fosfomycin is ever FDA [Food and Drug Administration] approved – and my understanding is that the delays have been more related to manufacturing than scientific quality of data – it could potentially be an alternative to beta-lactams and fluoroquinolones” and has activity against most extend spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae, he said.

Fosfomycin susceptibility testing is challenging, however, with no Clinical & Laboratory Standards Institute (CLSI) or FDA breakpoints for Enterobacterales other than Escherichia coli, and there are questions about the step-down therapy.

“Do you just give a 3-gram sachet chaser when they walk out the door? Do you switch to another agent? I think that needs to be worked out,” he said.
 

Inhaled amikacin

“We know that some IV antibiotics, particularly for resistant organisms, may not achieve sufficient concentrations in the lung to treat pneumonia. We know that inhaled antibiotics can give a lot of concentration of that drug right at the at the site of infection, but we don’t really have [randomized controlled trial] data to see whether it really helps,” Dr. Satlin said.

The INHALE trial was a double-blind, placebo-controlled superiority trial to see whether adding inhaled amikacin to IV standard-of-care antibiotics could improve outcomes for mechanically ventilated patients with gram-negative pneumonia.

The investigators enrolled 725 adults who were receiving mechanical ventilation for pneumonia, 45% of who had ventilator-associated pneumonia (VAP). Of the total cohort, 508 patients analyzed for efficacy had gram-negative pathogens, including 32% with Pseudomonas aeurginosa, 29% with Acinetobacter baumannii, 30% with E. coli, and the remainder with Klebsiella pneumoniae.

Patients were randomized to standard-of-care intravenous antibiotics plus either inhaled amikacin 400 mg twice daily for 10 days or inhaled saline placebo.

“Of note, the median standard-of-care antibiotics in this study was 18 days, which is certainly longer than what our guidelines recommend.”

There was no significant difference between study arms in the primary endpoint of survival at days 28-32 for all patients who had received at least one dose of study drug, were infected with a gram-negative pathogen, and an Acute Physiology and Chronic Health Evaluation (APACHE) II score of at 10 or higher at diagnosis. The respective survival rates for the inhaled amikacin and placebo groups were 75% and 77%. The incidence of treatment-emergent adverse events or serious treatment-emergent adverse events were similar between the two treatment arms.

“No matter how you sliced and diced it – days of mechanical ventilation, duration of ICU stay – essentially they looked the same. Even for [extensively drug resistant] pathogens where you might expect that you’d see the benefit of inhaled amikacin, they didn’t really see a mortality benefit in this study,” Dr. Satlin said.

The study is practice changing, he said “because I think inhaled aminoglycosides should not be routinely added to the standard of care IV antibiotics for pneumonia in ventilated patients,” he said.

It’s still unclear whether inhaled aminoglycosides might play a role in the treatment of select patients infected with organisms resistant to all beta-lactams and fluoroquinolones, he added.
 

Tempting strategy

“Adding inhaled antibiotics is a tempting strategy for treatment of ventilated pneumonia, which often has poor outcomes,” commented Thomas Holland, MD, a hospitalist and infectious disease specialist at Duke University Hospital in Durham, N.C. “This is valuable and practical information as clinicians choose antibiotics regimens for this difficult-to-treat syndrome,” he said in an interview.

Dr. Holland comoderated the session in which Dr. Satlin presented the study findings and opinions.

No funding source for the presentation was reported. Dr. Satlin reported consulting for Shionogi and Achaogen and research grants from Allergan, Merck, and BioFire Diagnostics. Dr. Holland disclosed consulting fees and other material support from Basilea Pharmaceutica, Genetech, Karius and Theravance.

A new formulation of an existing antibacterial agent and a potential therapeutic approach to a challenging clinical problem were the focus of a session on potentially practice-changing clinical trials in antimicrobial therapy presented during IDWeek 2020, an annual scientific meeting on infectious diseases.

“I know it has been a big year for viral disease of course, with COVID, but there has been some really good work that has gone on in the bacterial space, and of course as those of you who are on service know, you may have your fair share of COVID patients, but these are infections that we still deal with on a daily basis,” said Michael Satlin, MD, an infectious disease specialist at Weill Cornell Medicine in New York.

He combed through studies published during the previous 12 months in leading medical journals, including the New England Journal of Medicine, JAMA network publications, Lancet Infectious Diseases, Lancet Respiratory Medicine, Clinical Infectious Diseases, and Clinical Microbiology and Infection, looking for randomized trials of interventions to treat bacterial infections, and selecting those most likely to change practice of U.S. infectious diseases practitioners.

He excluded meta-analyses, post hoc analyses, evaluations of diagnostic tests, stewardship, or any studies presented previously at IDWeek.

Two of the trials he highlighted are described here.
 

Fosfomycin for injection

In the United States, fosfomycin, the only antibiotic in its class, is currently available only in an oral sachet formulation (Monurol), “and typically we’ve only given this for patients with cystitis because we know that we don’t achieve significant levels [of drug] in the kidney or in the bloodstream for other types of infections,” Dr. Satlin said.

In Europe, however fosfomycin for injection (ZTI-01) has been available for several years.

“There’s been a lot of interest in fosfomycin because it has a different mechanism of action from other agents. It’s an epoxide antibiotic that inhibits early peptidoglycan synthesis by binding to MurA,” he explained.

The phase 2/3 randomized ZEUS trial compared ZTI-01 with piperacillin/tazobactam (pip/taz) for treatment of complicated urinary tract infection (UTI) including acute pyelonephritis.

A total of 465 hospitalized adults with suspected or microbiologically confirmed complicated UTI or acute pyelonephritis were randomized to 6 g of ZTI-01 every 8 hours or 4.5 g of intravenous pip/taz every 8 hours for a fixed 7-day course with no oral switch; patients with concomitant bacteremia (about 9% of the study population) could receive the assigned therapy for up to 14 days.

The primary endpoint of noninferiority of ZTI-01 was met and clinical cure rates were high and similar between the treatments, at approximately 91% each. Treatment-emergent adverse events, including hypokalemia and elevated serum aminotransferases, were mostly mild and transient.

The hypokalemia seen in the trial may be attributable to the high salt load of fosfomycin relative to pip/taz, Dr. Satlin said.

“How might this change your practice? Well, if IV fosfomycin is ever FDA [Food and Drug Administration] approved – and my understanding is that the delays have been more related to manufacturing than scientific quality of data – it could potentially be an alternative to beta-lactams and fluoroquinolones” and has activity against most extend spectrum beta-lactamase (ESBL)–producing Enterobacteriaceae, he said.

Fosfomycin susceptibility testing is challenging, however, with no Clinical & Laboratory Standards Institute (CLSI) or FDA breakpoints for Enterobacterales other than Escherichia coli, and there are questions about the step-down therapy.

“Do you just give a 3-gram sachet chaser when they walk out the door? Do you switch to another agent? I think that needs to be worked out,” he said.
 

Inhaled amikacin

“We know that some IV antibiotics, particularly for resistant organisms, may not achieve sufficient concentrations in the lung to treat pneumonia. We know that inhaled antibiotics can give a lot of concentration of that drug right at the at the site of infection, but we don’t really have [randomized controlled trial] data to see whether it really helps,” Dr. Satlin said.

The INHALE trial was a double-blind, placebo-controlled superiority trial to see whether adding inhaled amikacin to IV standard-of-care antibiotics could improve outcomes for mechanically ventilated patients with gram-negative pneumonia.

The investigators enrolled 725 adults who were receiving mechanical ventilation for pneumonia, 45% of who had ventilator-associated pneumonia (VAP). Of the total cohort, 508 patients analyzed for efficacy had gram-negative pathogens, including 32% with Pseudomonas aeurginosa, 29% with Acinetobacter baumannii, 30% with E. coli, and the remainder with Klebsiella pneumoniae.

Patients were randomized to standard-of-care intravenous antibiotics plus either inhaled amikacin 400 mg twice daily for 10 days or inhaled saline placebo.

“Of note, the median standard-of-care antibiotics in this study was 18 days, which is certainly longer than what our guidelines recommend.”

There was no significant difference between study arms in the primary endpoint of survival at days 28-32 for all patients who had received at least one dose of study drug, were infected with a gram-negative pathogen, and an Acute Physiology and Chronic Health Evaluation (APACHE) II score of at 10 or higher at diagnosis. The respective survival rates for the inhaled amikacin and placebo groups were 75% and 77%. The incidence of treatment-emergent adverse events or serious treatment-emergent adverse events were similar between the two treatment arms.

“No matter how you sliced and diced it – days of mechanical ventilation, duration of ICU stay – essentially they looked the same. Even for [extensively drug resistant] pathogens where you might expect that you’d see the benefit of inhaled amikacin, they didn’t really see a mortality benefit in this study,” Dr. Satlin said.

The study is practice changing, he said “because I think inhaled aminoglycosides should not be routinely added to the standard of care IV antibiotics for pneumonia in ventilated patients,” he said.

It’s still unclear whether inhaled aminoglycosides might play a role in the treatment of select patients infected with organisms resistant to all beta-lactams and fluoroquinolones, he added.
 

Tempting strategy

“Adding inhaled antibiotics is a tempting strategy for treatment of ventilated pneumonia, which often has poor outcomes,” commented Thomas Holland, MD, a hospitalist and infectious disease specialist at Duke University Hospital in Durham, N.C. “This is valuable and practical information as clinicians choose antibiotics regimens for this difficult-to-treat syndrome,” he said in an interview.

Dr. Holland comoderated the session in which Dr. Satlin presented the study findings and opinions.

No funding source for the presentation was reported. Dr. Satlin reported consulting for Shionogi and Achaogen and research grants from Allergan, Merck, and BioFire Diagnostics. Dr. Holland disclosed consulting fees and other material support from Basilea Pharmaceutica, Genetech, Karius and Theravance.

The patient was given a diagnosis of prurigo pigmentosa based on the characteristic pruritic rash that had developed after the patient started a strict ketogenic diet.

Prurigo pigmentosa is a benign, pruritic rash that most commonly presents with erythematous or hyperpigmented, symmetrically distributed urticarial papules and plaques on the chest and back. Females represent approximately 70% of cases with a predominant age range of 11 to 30. It more commonly is seen in people of Asian descent.

While the pathophysiology remains unknown, the rash most commonly occurs in association with diabetes, ketosis, and more recently with ketogenic diets. Despite occurring in only a fraction of patients on the ketogenic diet, the characteristic presentation has led to the alternative name of the “keto rash” in online nutritional forums and blogs.

The diagnosis is made clinically, so the appearance of a symmetric pruritic, hyperpigmented rash on the chest and back should prompt the physician to ask about any recent changes in diet. Laboratory analysis is unnecessary, as a complete blood count, basic metabolic panel, and liver function panel are almost always normal.

Other conditions can mimic prurigo pigmentosa such as urticaria, irritant contact dermatitis, confluent and reticulated papillomatosis, and pityriasis rosea.

Primary treatment includes resumption of a normal diet. This often leads to rapid resolution of pruritis. Residual hyperpigmentation may take months to fade. If additional treatment is required, minocycline 100 to 200 mg/d has been reported most effective, likely due to its anti-inflammatory properties. Topical corticosteroids and oral antihistamines provide symptomatic relief in some patients.

This patient had resolution of the pruritis and urticarial lesions within 2 days of resuming a normal diet; however, residual asymptomatic hyperpigmentation persisted. A retrial of the ketogenic diet initiated a flare of the rash in the same distribution. It rapidly resolved with carbohydrate intake.

‌

This case was adapted from: Croom D, Barlow T, Landers JT. Pruritic rash on chest and back. J Fam Pract. 2019;68:113-114,116

The patient was given a diagnosis of prurigo pigmentosa based on the characteristic pruritic rash that had developed after the patient started a strict ketogenic diet.

Prurigo pigmentosa is a benign, pruritic rash that most commonly presents with erythematous or hyperpigmented, symmetrically distributed urticarial papules and plaques on the chest and back. Females represent approximately 70% of cases with a predominant age range of 11 to 30. It more commonly is seen in people of Asian descent.

While the pathophysiology remains unknown, the rash most commonly occurs in association with diabetes, ketosis, and more recently with ketogenic diets. Despite occurring in only a fraction of patients on the ketogenic diet, the characteristic presentation has led to the alternative name of the “keto rash” in online nutritional forums and blogs.

The diagnosis is made clinically, so the appearance of a symmetric pruritic, hyperpigmented rash on the chest and back should prompt the physician to ask about any recent changes in diet. Laboratory analysis is unnecessary, as a complete blood count, basic metabolic panel, and liver function panel are almost always normal.

Other conditions can mimic prurigo pigmentosa such as urticaria, irritant contact dermatitis, confluent and reticulated papillomatosis, and pityriasis rosea.

Primary treatment includes resumption of a normal diet. This often leads to rapid resolution of pruritis. Residual hyperpigmentation may take months to fade. If additional treatment is required, minocycline 100 to 200 mg/d has been reported most effective, likely due to its anti-inflammatory properties. Topical corticosteroids and oral antihistamines provide symptomatic relief in some patients.

This patient had resolution of the pruritis and urticarial lesions within 2 days of resuming a normal diet; however, residual asymptomatic hyperpigmentation persisted. A retrial of the ketogenic diet initiated a flare of the rash in the same distribution. It rapidly resolved with carbohydrate intake.

‌

This case was adapted from: Croom D, Barlow T, Landers JT. Pruritic rash on chest and back. J Fam Pract. 2019;68:113-114,116

The patient was given a diagnosis of prurigo pigmentosa based on the characteristic pruritic rash that had developed after the patient started a strict ketogenic diet.

Prurigo pigmentosa is a benign, pruritic rash that most commonly presents with erythematous or hyperpigmented, symmetrically distributed urticarial papules and plaques on the chest and back. Females represent approximately 70% of cases with a predominant age range of 11 to 30. It more commonly is seen in people of Asian descent.

While the pathophysiology remains unknown, the rash most commonly occurs in association with diabetes, ketosis, and more recently with ketogenic diets. Despite occurring in only a fraction of patients on the ketogenic diet, the characteristic presentation has led to the alternative name of the “keto rash” in online nutritional forums and blogs.

The diagnosis is made clinically, so the appearance of a symmetric pruritic, hyperpigmented rash on the chest and back should prompt the physician to ask about any recent changes in diet. Laboratory analysis is unnecessary, as a complete blood count, basic metabolic panel, and liver function panel are almost always normal.

Other conditions can mimic prurigo pigmentosa such as urticaria, irritant contact dermatitis, confluent and reticulated papillomatosis, and pityriasis rosea.

Primary treatment includes resumption of a normal diet. This often leads to rapid resolution of pruritis. Residual hyperpigmentation may take months to fade. If additional treatment is required, minocycline 100 to 200 mg/d has been reported most effective, likely due to its anti-inflammatory properties. Topical corticosteroids and oral antihistamines provide symptomatic relief in some patients.

This patient had resolution of the pruritis and urticarial lesions within 2 days of resuming a normal diet; however, residual asymptomatic hyperpigmentation persisted. A retrial of the ketogenic diet initiated a flare of the rash in the same distribution. It rapidly resolved with carbohydrate intake.

‌

This case was adapted from: Croom D, Barlow T, Landers JT. Pruritic rash on chest and back. J Fam Pract. 2019;68:113-114,116

Tocilizumab (Actemra/RoActemra) was not found to have any clear role as a treatment for COVID-19 in four new studies.

Three randomized controlled trials showed that the drug either had no benefit or only a modest one, contradicting a large retrospective study that had hinted at a more robust effect.

“This is not a blockbuster,” said David Cennimo, MD, an infectious disease expert at Rutgers New Jersey Medical School, Newark, New Jersey. “This is not something that’s going to revolutionize our treatment of COVID-19.”

But some researchers still regard these studies as showing evidence that the drug benefits certain patients with severe inflammation.

The immune response to SARS-CoV-2 includes elevated levels of the cytokine interleukin-6 (IL-6). In some patients, this response becomes a nonspecific inflammation, a “cytokine storm,” involving edema and inflammatory cell infiltration in the lungs. These cases are among the most severe.

Dexamethasone has proved effective in controlling this inflammation in some patients. Researchers have theorized that a more targeted suppression of IL-6 could be even more effective or work in cases that don’t respond to dexamethasone.

A recombinant monoclonal antibody, tocilizumab blocks IL-6 receptors. It is approved by the US Food and Drug Administration for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T-cell therapy.

Current National Institutes of Health (NIH) guidelines recommend against the use of tocilizumab as a treatment for COVID-19, despite earlier observational studies that suggested the drug might help patients with moderate to severe disease. Controlled trials were lacking until now.

The most hopeful results in this batch came from the CORIMUNO-19 platform of open-label, randomized controlled trials of immune modulatory treatments for moderate or severe COVID-19 in France.

Published in JAMA Internal Medicine , the trial recruited patients from nine French hospitals. Patients were eligible if they required at least 3 L/min of oxygen without ventilation or admission to the intensive care unit.

The investigators randomly assigned 64 patients to receive tocilizumab 8 mg/kg body weight intravenously plus usual care and 67 patients to usual care alone. Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

After 4 days, the investigators scored patients on the World Health Organization 10-point Clinical Progression Scale. Twelve of the patients who received tocilizumab scored higher than 5 vs 19 of the patients in the usual care group, with higher scores indicating clinical deterioration.

After 14 days, 24% of the patients taking tocilizumab required either noninvasive ventilation or mechanical ventilation or had died, vs 36% in the usual care group (median posterior hazard ratio [HR], 0.58; 90% credible interval, 0.33 – 1.00).

“We reduced the risk of dying or requiring mechanical ventilation, so for me, the study was positive,” said Olivier Hermine, MD, PhD, a professor of hematology at Paris Descartes University in Paris, France.

However, there was no difference in mortality at 28 days. Hermine hopes to have longer-term outcomes soon, he told Medscape Medical News.

A second randomized controlled trial, also published in JAMA Internal Medicine , provided less hope. In this RCT-TCZ-COVID-19 Study Group trial, conducted at 24 Italian centers, patients were enrolled if their partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ratios were between 200 and 300 mm Hg and if their inflammatory phenotypes were defined by fever and elevated C-reactive protein level.

The investigators randomly assigned 60 patients to receive tocilizumab 8 mg/kg up to a maximum of 800 mg within 8 hours of randomization, followed by a second dose after 12 hours. They assigned 66 patients to a control group that received supportive care until clinical worsening, at which point patients could receive tocilizumab as a rescue therapy.

Of the patients who received tocilizumab, 28.3% showed clinical worsening within 14 days, compared to 27.0% in the control group (rate ratio, 1.05; 95% CI, 0.59 – 1.86). There was no significant difference between the groups in terms of the proportion admitted to intensive care. The researchers stopped the trial prematurely because tocilizumab did not seem to be making a difference.

The BACC Bay Tocilizumab Trial was conducted at seven Boston hospitals. The results, which were published in The New England Journal of Medicine, were also discouraging.

In that trial, enrolled patients met two sets of parameters. First, the patients had at least one of the following signs: C-reactive protein level higher than 50 mg/L, ferritin level higher than 500 ng/mL, D-dimer level higher than 1000 ng/mL, or a lactate dehydrogenase level higher than 250 U/L. Second, the patients had to have at least two of the following signs: body temperature >38° C, pulmonary infiltrates, or the need for supplemental oxygen to maintain an oxygen saturation greater than 92%.

The investigators randomly assigned 161 patients to receive intravenous tocilizumab 8 mg/kg up to 800 mg and 81 to receive a placebo.

They didn’t find a statistically significant difference between the groups. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% CI, 0.38 – 1.81; P = .64). The hazard ratio for disease worsening was 1.11 (95% CI, 0.59 – 2.10; P = .73). At 14 days, the conditions of 18.0% of the patients who received tocilizumab and 14.9% of the patients who received the placebo worsened.

In contrast to these randomized trials, STOP-COVID, a retrospective analysis of 3924 patients, also published in JAMA Internal Medicine, found that the risk for death was lower for patients treated with tocilizumab compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56 – 0.92) over a median follow-up period of 27 days.

Also on the bright side, none of the new studies showed significant adverse reactions to tocilizumab.

More randomized clinical trials are underway. In press releases announcing topline data, Roche reported mostly negative results in its phase 3 COVACTA trial but noted a 44% reduction in the risk for progression to death or ventilation in its phase 3 IMPACTA trial. Roche did not comment on the ethnicity of its COVACTA patients; it said IMPACTA enrolled a majority of Hispanic patients and included large representations of Native American and Black patients.
 

Results don’t support routine use

Commenting on the new studies, editorialists in both JAMA Internal Medicine and The New England Journal of Medicine concluded that the tocilizumab results were not strong enough to support routine use.

“My take-home point from looking at all of these together is that, even if it does help, it’s most likely in a small subset of the population and/or a small effect,” Cennimo told Medscape Medical News.

But the NIH recommendation against tocilizumab goes too far, argued Cristina Mussini, MD, a professor of infectious diseases at the University of Modena and Reggio Emilia in Italy, who is a coauthor of a cohort study of tocilizumab and served on the CORIMUNO-19 Data Safety and Monitoring Board.

“I really think it’s too early to recommend against it because at least two clinical trials showed protection against mechanical ventilation and death,” she said.

She prescribes tocilizumab for patients who have not been helped by dexamethasone. “It’s just a rescue drug,” she told Medscape Medical News. “It’s not something you use for everybody, but it’s the only weapon we have now when the patient is really going to the intensive care unit.”

The BACC Bay Tocilizumab Trial was funded by Genentech/Roche. Genentech/Roche provided the drug for the CORIMUNO and RCT-TCZ-COVID-19 trials. The STOP-COVID study was supported by grants from the NIH and by the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor. Cennimo, Hermine, and Mussini have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Tocilizumab (Actemra/RoActemra) was not found to have any clear role as a treatment for COVID-19 in four new studies.

Three randomized controlled trials showed that the drug either had no benefit or only a modest one, contradicting a large retrospective study that had hinted at a more robust effect.

“This is not a blockbuster,” said David Cennimo, MD, an infectious disease expert at Rutgers New Jersey Medical School, Newark, New Jersey. “This is not something that’s going to revolutionize our treatment of COVID-19.”

But some researchers still regard these studies as showing evidence that the drug benefits certain patients with severe inflammation.

The immune response to SARS-CoV-2 includes elevated levels of the cytokine interleukin-6 (IL-6). In some patients, this response becomes a nonspecific inflammation, a “cytokine storm,” involving edema and inflammatory cell infiltration in the lungs. These cases are among the most severe.

Dexamethasone has proved effective in controlling this inflammation in some patients. Researchers have theorized that a more targeted suppression of IL-6 could be even more effective or work in cases that don’t respond to dexamethasone.

A recombinant monoclonal antibody, tocilizumab blocks IL-6 receptors. It is approved by the US Food and Drug Administration for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T-cell therapy.

Current National Institutes of Health (NIH) guidelines recommend against the use of tocilizumab as a treatment for COVID-19, despite earlier observational studies that suggested the drug might help patients with moderate to severe disease. Controlled trials were lacking until now.

The most hopeful results in this batch came from the CORIMUNO-19 platform of open-label, randomized controlled trials of immune modulatory treatments for moderate or severe COVID-19 in France.

Published in JAMA Internal Medicine , the trial recruited patients from nine French hospitals. Patients were eligible if they required at least 3 L/min of oxygen without ventilation or admission to the intensive care unit.

The investigators randomly assigned 64 patients to receive tocilizumab 8 mg/kg body weight intravenously plus usual care and 67 patients to usual care alone. Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

After 4 days, the investigators scored patients on the World Health Organization 10-point Clinical Progression Scale. Twelve of the patients who received tocilizumab scored higher than 5 vs 19 of the patients in the usual care group, with higher scores indicating clinical deterioration.

After 14 days, 24% of the patients taking tocilizumab required either noninvasive ventilation or mechanical ventilation or had died, vs 36% in the usual care group (median posterior hazard ratio [HR], 0.58; 90% credible interval, 0.33 – 1.00).

“We reduced the risk of dying or requiring mechanical ventilation, so for me, the study was positive,” said Olivier Hermine, MD, PhD, a professor of hematology at Paris Descartes University in Paris, France.

However, there was no difference in mortality at 28 days. Hermine hopes to have longer-term outcomes soon, he told Medscape Medical News.

A second randomized controlled trial, also published in JAMA Internal Medicine , provided less hope. In this RCT-TCZ-COVID-19 Study Group trial, conducted at 24 Italian centers, patients were enrolled if their partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ratios were between 200 and 300 mm Hg and if their inflammatory phenotypes were defined by fever and elevated C-reactive protein level.

The investigators randomly assigned 60 patients to receive tocilizumab 8 mg/kg up to a maximum of 800 mg within 8 hours of randomization, followed by a second dose after 12 hours. They assigned 66 patients to a control group that received supportive care until clinical worsening, at which point patients could receive tocilizumab as a rescue therapy.

Of the patients who received tocilizumab, 28.3% showed clinical worsening within 14 days, compared to 27.0% in the control group (rate ratio, 1.05; 95% CI, 0.59 – 1.86). There was no significant difference between the groups in terms of the proportion admitted to intensive care. The researchers stopped the trial prematurely because tocilizumab did not seem to be making a difference.

The BACC Bay Tocilizumab Trial was conducted at seven Boston hospitals. The results, which were published in The New England Journal of Medicine, were also discouraging.

In that trial, enrolled patients met two sets of parameters. First, the patients had at least one of the following signs: C-reactive protein level higher than 50 mg/L, ferritin level higher than 500 ng/mL, D-dimer level higher than 1000 ng/mL, or a lactate dehydrogenase level higher than 250 U/L. Second, the patients had to have at least two of the following signs: body temperature >38° C, pulmonary infiltrates, or the need for supplemental oxygen to maintain an oxygen saturation greater than 92%.

The investigators randomly assigned 161 patients to receive intravenous tocilizumab 8 mg/kg up to 800 mg and 81 to receive a placebo.

They didn’t find a statistically significant difference between the groups. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% CI, 0.38 – 1.81; P = .64). The hazard ratio for disease worsening was 1.11 (95% CI, 0.59 – 2.10; P = .73). At 14 days, the conditions of 18.0% of the patients who received tocilizumab and 14.9% of the patients who received the placebo worsened.

In contrast to these randomized trials, STOP-COVID, a retrospective analysis of 3924 patients, also published in JAMA Internal Medicine, found that the risk for death was lower for patients treated with tocilizumab compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56 – 0.92) over a median follow-up period of 27 days.

Also on the bright side, none of the new studies showed significant adverse reactions to tocilizumab.

More randomized clinical trials are underway. In press releases announcing topline data, Roche reported mostly negative results in its phase 3 COVACTA trial but noted a 44% reduction in the risk for progression to death or ventilation in its phase 3 IMPACTA trial. Roche did not comment on the ethnicity of its COVACTA patients; it said IMPACTA enrolled a majority of Hispanic patients and included large representations of Native American and Black patients.
 

Results don’t support routine use

Commenting on the new studies, editorialists in both JAMA Internal Medicine and The New England Journal of Medicine concluded that the tocilizumab results were not strong enough to support routine use.

“My take-home point from looking at all of these together is that, even if it does help, it’s most likely in a small subset of the population and/or a small effect,” Cennimo told Medscape Medical News.

But the NIH recommendation against tocilizumab goes too far, argued Cristina Mussini, MD, a professor of infectious diseases at the University of Modena and Reggio Emilia in Italy, who is a coauthor of a cohort study of tocilizumab and served on the CORIMUNO-19 Data Safety and Monitoring Board.

“I really think it’s too early to recommend against it because at least two clinical trials showed protection against mechanical ventilation and death,” she said.

She prescribes tocilizumab for patients who have not been helped by dexamethasone. “It’s just a rescue drug,” she told Medscape Medical News. “It’s not something you use for everybody, but it’s the only weapon we have now when the patient is really going to the intensive care unit.”

The BACC Bay Tocilizumab Trial was funded by Genentech/Roche. Genentech/Roche provided the drug for the CORIMUNO and RCT-TCZ-COVID-19 trials. The STOP-COVID study was supported by grants from the NIH and by the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor. Cennimo, Hermine, and Mussini have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Tocilizumab (Actemra/RoActemra) was not found to have any clear role as a treatment for COVID-19 in four new studies.

Three randomized controlled trials showed that the drug either had no benefit or only a modest one, contradicting a large retrospective study that had hinted at a more robust effect.

“This is not a blockbuster,” said David Cennimo, MD, an infectious disease expert at Rutgers New Jersey Medical School, Newark, New Jersey. “This is not something that’s going to revolutionize our treatment of COVID-19.”

But some researchers still regard these studies as showing evidence that the drug benefits certain patients with severe inflammation.

The immune response to SARS-CoV-2 includes elevated levels of the cytokine interleukin-6 (IL-6). In some patients, this response becomes a nonspecific inflammation, a “cytokine storm,” involving edema and inflammatory cell infiltration in the lungs. These cases are among the most severe.

Dexamethasone has proved effective in controlling this inflammation in some patients. Researchers have theorized that a more targeted suppression of IL-6 could be even more effective or work in cases that don’t respond to dexamethasone.

A recombinant monoclonal antibody, tocilizumab blocks IL-6 receptors. It is approved by the US Food and Drug Administration for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T-cell therapy.

Current National Institutes of Health (NIH) guidelines recommend against the use of tocilizumab as a treatment for COVID-19, despite earlier observational studies that suggested the drug might help patients with moderate to severe disease. Controlled trials were lacking until now.

The most hopeful results in this batch came from the CORIMUNO-19 platform of open-label, randomized controlled trials of immune modulatory treatments for moderate or severe COVID-19 in France.

Published in JAMA Internal Medicine , the trial recruited patients from nine French hospitals. Patients were eligible if they required at least 3 L/min of oxygen without ventilation or admission to the intensive care unit.

The investigators randomly assigned 64 patients to receive tocilizumab 8 mg/kg body weight intravenously plus usual care and 67 patients to usual care alone. Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.

After 4 days, the investigators scored patients on the World Health Organization 10-point Clinical Progression Scale. Twelve of the patients who received tocilizumab scored higher than 5 vs 19 of the patients in the usual care group, with higher scores indicating clinical deterioration.

After 14 days, 24% of the patients taking tocilizumab required either noninvasive ventilation or mechanical ventilation or had died, vs 36% in the usual care group (median posterior hazard ratio [HR], 0.58; 90% credible interval, 0.33 – 1.00).

“We reduced the risk of dying or requiring mechanical ventilation, so for me, the study was positive,” said Olivier Hermine, MD, PhD, a professor of hematology at Paris Descartes University in Paris, France.

However, there was no difference in mortality at 28 days. Hermine hopes to have longer-term outcomes soon, he told Medscape Medical News.

A second randomized controlled trial, also published in JAMA Internal Medicine , provided less hope. In this RCT-TCZ-COVID-19 Study Group trial, conducted at 24 Italian centers, patients were enrolled if their partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ratios were between 200 and 300 mm Hg and if their inflammatory phenotypes were defined by fever and elevated C-reactive protein level.

The investigators randomly assigned 60 patients to receive tocilizumab 8 mg/kg up to a maximum of 800 mg within 8 hours of randomization, followed by a second dose after 12 hours. They assigned 66 patients to a control group that received supportive care until clinical worsening, at which point patients could receive tocilizumab as a rescue therapy.

Of the patients who received tocilizumab, 28.3% showed clinical worsening within 14 days, compared to 27.0% in the control group (rate ratio, 1.05; 95% CI, 0.59 – 1.86). There was no significant difference between the groups in terms of the proportion admitted to intensive care. The researchers stopped the trial prematurely because tocilizumab did not seem to be making a difference.

The BACC Bay Tocilizumab Trial was conducted at seven Boston hospitals. The results, which were published in The New England Journal of Medicine, were also discouraging.

In that trial, enrolled patients met two sets of parameters. First, the patients had at least one of the following signs: C-reactive protein level higher than 50 mg/L, ferritin level higher than 500 ng/mL, D-dimer level higher than 1000 ng/mL, or a lactate dehydrogenase level higher than 250 U/L. Second, the patients had to have at least two of the following signs: body temperature >38° C, pulmonary infiltrates, or the need for supplemental oxygen to maintain an oxygen saturation greater than 92%.

The investigators randomly assigned 161 patients to receive intravenous tocilizumab 8 mg/kg up to 800 mg and 81 to receive a placebo.

They didn’t find a statistically significant difference between the groups. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% CI, 0.38 – 1.81; P = .64). The hazard ratio for disease worsening was 1.11 (95% CI, 0.59 – 2.10; P = .73). At 14 days, the conditions of 18.0% of the patients who received tocilizumab and 14.9% of the patients who received the placebo worsened.

In contrast to these randomized trials, STOP-COVID, a retrospective analysis of 3924 patients, also published in JAMA Internal Medicine, found that the risk for death was lower for patients treated with tocilizumab compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56 – 0.92) over a median follow-up period of 27 days.

Also on the bright side, none of the new studies showed significant adverse reactions to tocilizumab.

More randomized clinical trials are underway. In press releases announcing topline data, Roche reported mostly negative results in its phase 3 COVACTA trial but noted a 44% reduction in the risk for progression to death or ventilation in its phase 3 IMPACTA trial. Roche did not comment on the ethnicity of its COVACTA patients; it said IMPACTA enrolled a majority of Hispanic patients and included large representations of Native American and Black patients.
 

Results don’t support routine use

Commenting on the new studies, editorialists in both JAMA Internal Medicine and The New England Journal of Medicine concluded that the tocilizumab results were not strong enough to support routine use.

“My take-home point from looking at all of these together is that, even if it does help, it’s most likely in a small subset of the population and/or a small effect,” Cennimo told Medscape Medical News.

But the NIH recommendation against tocilizumab goes too far, argued Cristina Mussini, MD, a professor of infectious diseases at the University of Modena and Reggio Emilia in Italy, who is a coauthor of a cohort study of tocilizumab and served on the CORIMUNO-19 Data Safety and Monitoring Board.

“I really think it’s too early to recommend against it because at least two clinical trials showed protection against mechanical ventilation and death,” she said.

She prescribes tocilizumab for patients who have not been helped by dexamethasone. “It’s just a rescue drug,” she told Medscape Medical News. “It’s not something you use for everybody, but it’s the only weapon we have now when the patient is really going to the intensive care unit.”

The BACC Bay Tocilizumab Trial was funded by Genentech/Roche. Genentech/Roche provided the drug for the CORIMUNO and RCT-TCZ-COVID-19 trials. The STOP-COVID study was supported by grants from the NIH and by the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor. Cennimo, Hermine, and Mussini have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

The American College of Cardiology (ACC) has released a new Expert Consensus Decision Pathway (ECDP) on the management of conduction disturbances after transcatheter aortic valve replacement (TAVR).

The document provides guidance to clinicians in identifying and managing this common complication of TAVR, covering the pre-TAVR, periprocedural and post-TAVR periods.

“Conduction disturbances after TAVR are common and there is currently heterogeneity in how they’re managed, ranging from a casual observational approach to invasive electrophysiological studies and preemptive pacemaker implantation,” said writing committee chair Scott Lilly, MD, PhD, from the Ohio State Wexner Medical Center in Columbus.

“We felt this kind of collaborative effort to review what little research there is on this topic and come to [an] expert consensus was long overdue,” he added.

The document was published online Oct. 21 in the Journal of the American College of Cardiology.

Dr. Lilly stressed in an interview that this effort is an ECDP and not a guideline “because there is not data out there to solidly stand on and say, ‘This is the way we should do things.’ “

His hope is that this document will generate more discussion on this topic and spur some (probably National Institutes of Health–sponsored) clinical trials to better guide practice.
 

Not uncommon and not decreasing

Complete heart block requiring permanent pacemaker (PPM) implantation is seen in about 15% of patients within 30 days after TAVR. While this is a clear indication for PPM, there is no consensus on the management of less severe conduction disturbances such as new bundle branch or transient complete atrioventricular (AV) heart block.

Unlike the rates of bleeding, vascular injury, and stroke, which have decreased over time, the rates of in-hospital PPM implantation after TAVR have not changed significantly since commercialization in 2012. This is a concern because TAVR is increasingly used in younger, lower-risk patients.

“The pacemaker rate really hasn’t improved at a clip we would like to see if it was going to be a durable technology,” Dr. Lilly said.

Consensus regarding a reasonable strategy to manage cardiac conduction disturbances after TAVR has been elusive. This is a result of several things: a dearth of adequately powered, randomized controlled trials; the often transient nature of the conduction disturbances; evolving technologies; and the interplay of cardiology subspecialties involved.

The 2013 European Society of Cardiology guidelines address pacing post-TAVR, but do not provide in-depth discussion on the topic. This is the first effort sponsored by a cardiovascular society in the United States to review the existing data and experience and propose evidence-based expert guidance.
 

Pre-TAVR assessment

Pre-TAVR assessment should consider the patient’s risk for postprocedure conduction disturbances, the authors said. Since bradyarrythmias and aortic stenosis may present similarly (fatigue, lightheadedness, and syncope being hallmarks of both), a careful history is needed to determine if bradyarrhythmia is present.

An electrocardiogram (ECG) or ambulatory rhythm monitoring may identify baseline conduction abnormalities and help predict the need for post-TAVR PPM.

“In this section, we underscored some of the literature that has raised awareness about the presence of preexisting arrhythmias in TAVR patients and suggest that monitoring in selected patients before the procedure is reasonable, particularly those presenting with syncope or lightheadedness,” said Dr. Lilly.
 

Intraprocedural management

On the day of the procedure, patients determined to have elevated risk for complete AV heart block require careful perioperative ECG and hemodynamic monitoring. Regardless of preexisting risk, said the authors that all patients should be monitored on a telemetry unit during the procedure with ability to do emergency pacing if necessary.

“In the periprocedural section, we address the role of electrophysiological studies for identifying patients at high-risk of subsequent heart block,” said Dr. Lilly. “That’s a practice that’s occurring at a number of centers, but the data out there is insufficient to establish it as a pacemaker indication. Routine EP testing for patients deemed at risk for conduction disturbances after TAVR is not guideline-based and more research is needed.”

The document also outlines the effects of medications and anesthesia on postprocedure conduction abnormalities.
 

Post-TAVR management

The authors define post-TAVR management as continuing through 30-days after discharge.

The ECDP carefully outlines which patients can be discharged without monitoring and those for whom outpatient monitoring can be considered.

“If I’m going to pick one thing from this section, it’s the monitoring piece. A lot of patients that have a conduction disturbance right after TAVR – but you’re not sure if it’s going to progress and require a pacemaker – might stay in the hospital for an extended time waiting to see if the heart holds up,” reported Dr. Lilly.

“But a number of centers are now discharging people at 1 or 2 days, which begs the question: What do you do with these folks? Our group has published data showing that 30-day monitoring in select patients is a safe approach,” said Dr. Lilly.

There are shortcomings, however, in existing data, and recommendations will likely change as more data are collected, he explained.

As well, there remains uncertainty in how conduction block should be managed after TAVR, and clinical judgment is “foundational” in this, wrote the authors.

“This document is meant to help programs deal with these situations right now, acknowledging full and well, that really good randomized clinical data is not available,” said Dr. Lilly.

Dr. Lilly has disclosed no relevant financial relationships. The work of the writing committee was supported exclusively by the American College of Cardiology without commercial support.
 

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

The American College of Cardiology (ACC) has released a new Expert Consensus Decision Pathway (ECDP) on the management of conduction disturbances after transcatheter aortic valve replacement (TAVR).

The document provides guidance to clinicians in identifying and managing this common complication of TAVR, covering the pre-TAVR, periprocedural and post-TAVR periods.

“Conduction disturbances after TAVR are common and there is currently heterogeneity in how they’re managed, ranging from a casual observational approach to invasive electrophysiological studies and preemptive pacemaker implantation,” said writing committee chair Scott Lilly, MD, PhD, from the Ohio State Wexner Medical Center in Columbus.

“We felt this kind of collaborative effort to review what little research there is on this topic and come to [an] expert consensus was long overdue,” he added.

The document was published online Oct. 21 in the Journal of the American College of Cardiology.

Dr. Lilly stressed in an interview that this effort is an ECDP and not a guideline “because there is not data out there to solidly stand on and say, ‘This is the way we should do things.’ “

His hope is that this document will generate more discussion on this topic and spur some (probably National Institutes of Health–sponsored) clinical trials to better guide practice.
 

Not uncommon and not decreasing

Complete heart block requiring permanent pacemaker (PPM) implantation is seen in about 15% of patients within 30 days after TAVR. While this is a clear indication for PPM, there is no consensus on the management of less severe conduction disturbances such as new bundle branch or transient complete atrioventricular (AV) heart block.

Unlike the rates of bleeding, vascular injury, and stroke, which have decreased over time, the rates of in-hospital PPM implantation after TAVR have not changed significantly since commercialization in 2012. This is a concern because TAVR is increasingly used in younger, lower-risk patients.

“The pacemaker rate really hasn’t improved at a clip we would like to see if it was going to be a durable technology,” Dr. Lilly said.

Consensus regarding a reasonable strategy to manage cardiac conduction disturbances after TAVR has been elusive. This is a result of several things: a dearth of adequately powered, randomized controlled trials; the often transient nature of the conduction disturbances; evolving technologies; and the interplay of cardiology subspecialties involved.

The 2013 European Society of Cardiology guidelines address pacing post-TAVR, but do not provide in-depth discussion on the topic. This is the first effort sponsored by a cardiovascular society in the United States to review the existing data and experience and propose evidence-based expert guidance.
 

Pre-TAVR assessment

Pre-TAVR assessment should consider the patient’s risk for postprocedure conduction disturbances, the authors said. Since bradyarrythmias and aortic stenosis may present similarly (fatigue, lightheadedness, and syncope being hallmarks of both), a careful history is needed to determine if bradyarrhythmia is present.

An electrocardiogram (ECG) or ambulatory rhythm monitoring may identify baseline conduction abnormalities and help predict the need for post-TAVR PPM.

“In this section, we underscored some of the literature that has raised awareness about the presence of preexisting arrhythmias in TAVR patients and suggest that monitoring in selected patients before the procedure is reasonable, particularly those presenting with syncope or lightheadedness,” said Dr. Lilly.
 

Intraprocedural management

On the day of the procedure, patients determined to have elevated risk for complete AV heart block require careful perioperative ECG and hemodynamic monitoring. Regardless of preexisting risk, said the authors that all patients should be monitored on a telemetry unit during the procedure with ability to do emergency pacing if necessary.

“In the periprocedural section, we address the role of electrophysiological studies for identifying patients at high-risk of subsequent heart block,” said Dr. Lilly. “That’s a practice that’s occurring at a number of centers, but the data out there is insufficient to establish it as a pacemaker indication. Routine EP testing for patients deemed at risk for conduction disturbances after TAVR is not guideline-based and more research is needed.”

The document also outlines the effects of medications and anesthesia on postprocedure conduction abnormalities.
 

Post-TAVR management

The authors define post-TAVR management as continuing through 30-days after discharge.

The ECDP carefully outlines which patients can be discharged without monitoring and those for whom outpatient monitoring can be considered.

“If I’m going to pick one thing from this section, it’s the monitoring piece. A lot of patients that have a conduction disturbance right after TAVR – but you’re not sure if it’s going to progress and require a pacemaker – might stay in the hospital for an extended time waiting to see if the heart holds up,” reported Dr. Lilly.

“But a number of centers are now discharging people at 1 or 2 days, which begs the question: What do you do with these folks? Our group has published data showing that 30-day monitoring in select patients is a safe approach,” said Dr. Lilly.

There are shortcomings, however, in existing data, and recommendations will likely change as more data are collected, he explained.

As well, there remains uncertainty in how conduction block should be managed after TAVR, and clinical judgment is “foundational” in this, wrote the authors.

“This document is meant to help programs deal with these situations right now, acknowledging full and well, that really good randomized clinical data is not available,” said Dr. Lilly.

Dr. Lilly has disclosed no relevant financial relationships. The work of the writing committee was supported exclusively by the American College of Cardiology without commercial support.
 

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

The American College of Cardiology (ACC) has released a new Expert Consensus Decision Pathway (ECDP) on the management of conduction disturbances after transcatheter aortic valve replacement (TAVR).

The document provides guidance to clinicians in identifying and managing this common complication of TAVR, covering the pre-TAVR, periprocedural and post-TAVR periods.

“Conduction disturbances after TAVR are common and there is currently heterogeneity in how they’re managed, ranging from a casual observational approach to invasive electrophysiological studies and preemptive pacemaker implantation,” said writing committee chair Scott Lilly, MD, PhD, from the Ohio State Wexner Medical Center in Columbus.

“We felt this kind of collaborative effort to review what little research there is on this topic and come to [an] expert consensus was long overdue,” he added.

The document was published online Oct. 21 in the Journal of the American College of Cardiology.

Dr. Lilly stressed in an interview that this effort is an ECDP and not a guideline “because there is not data out there to solidly stand on and say, ‘This is the way we should do things.’ “

His hope is that this document will generate more discussion on this topic and spur some (probably National Institutes of Health–sponsored) clinical trials to better guide practice.
 

Not uncommon and not decreasing

Complete heart block requiring permanent pacemaker (PPM) implantation is seen in about 15% of patients within 30 days after TAVR. While this is a clear indication for PPM, there is no consensus on the management of less severe conduction disturbances such as new bundle branch or transient complete atrioventricular (AV) heart block.

Unlike the rates of bleeding, vascular injury, and stroke, which have decreased over time, the rates of in-hospital PPM implantation after TAVR have not changed significantly since commercialization in 2012. This is a concern because TAVR is increasingly used in younger, lower-risk patients.

“The pacemaker rate really hasn’t improved at a clip we would like to see if it was going to be a durable technology,” Dr. Lilly said.

Consensus regarding a reasonable strategy to manage cardiac conduction disturbances after TAVR has been elusive. This is a result of several things: a dearth of adequately powered, randomized controlled trials; the often transient nature of the conduction disturbances; evolving technologies; and the interplay of cardiology subspecialties involved.

The 2013 European Society of Cardiology guidelines address pacing post-TAVR, but do not provide in-depth discussion on the topic. This is the first effort sponsored by a cardiovascular society in the United States to review the existing data and experience and propose evidence-based expert guidance.
 

Pre-TAVR assessment

Pre-TAVR assessment should consider the patient’s risk for postprocedure conduction disturbances, the authors said. Since bradyarrythmias and aortic stenosis may present similarly (fatigue, lightheadedness, and syncope being hallmarks of both), a careful history is needed to determine if bradyarrhythmia is present.

An electrocardiogram (ECG) or ambulatory rhythm monitoring may identify baseline conduction abnormalities and help predict the need for post-TAVR PPM.

“In this section, we underscored some of the literature that has raised awareness about the presence of preexisting arrhythmias in TAVR patients and suggest that monitoring in selected patients before the procedure is reasonable, particularly those presenting with syncope or lightheadedness,” said Dr. Lilly.
 

Intraprocedural management

On the day of the procedure, patients determined to have elevated risk for complete AV heart block require careful perioperative ECG and hemodynamic monitoring. Regardless of preexisting risk, said the authors that all patients should be monitored on a telemetry unit during the procedure with ability to do emergency pacing if necessary.

“In the periprocedural section, we address the role of electrophysiological studies for identifying patients at high-risk of subsequent heart block,” said Dr. Lilly. “That’s a practice that’s occurring at a number of centers, but the data out there is insufficient to establish it as a pacemaker indication. Routine EP testing for patients deemed at risk for conduction disturbances after TAVR is not guideline-based and more research is needed.”

The document also outlines the effects of medications and anesthesia on postprocedure conduction abnormalities.
 

Post-TAVR management

The authors define post-TAVR management as continuing through 30-days after discharge.

The ECDP carefully outlines which patients can be discharged without monitoring and those for whom outpatient monitoring can be considered.

“If I’m going to pick one thing from this section, it’s the monitoring piece. A lot of patients that have a conduction disturbance right after TAVR – but you’re not sure if it’s going to progress and require a pacemaker – might stay in the hospital for an extended time waiting to see if the heart holds up,” reported Dr. Lilly.

“But a number of centers are now discharging people at 1 or 2 days, which begs the question: What do you do with these folks? Our group has published data showing that 30-day monitoring in select patients is a safe approach,” said Dr. Lilly.

There are shortcomings, however, in existing data, and recommendations will likely change as more data are collected, he explained.

As well, there remains uncertainty in how conduction block should be managed after TAVR, and clinical judgment is “foundational” in this, wrote the authors.

“This document is meant to help programs deal with these situations right now, acknowledging full and well, that really good randomized clinical data is not available,” said Dr. Lilly.

Dr. Lilly has disclosed no relevant financial relationships. The work of the writing committee was supported exclusively by the American College of Cardiology without commercial support.
 

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

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

Eli Lilly announced it will halt its ACTIV-3 trial evaluating the antibody bamlanivimab in combination with remdesivir for people hospitalized with COVID-19, after new evidence regarding efficacy emerged.

The new data from the National Institutes of Health suggest that the experimental neutralizing antibody therapy does not offer significant clinical benefit for people with more advanced COVID-19 illness, according to a company statement.

Eli Lilly also announced it plans to continue its other trials evaluating the antibody, including those assessing a potential role in treating people in the earlier stages of COVID-19.

“While there was insufficient evidence that bamlanivimab improved clinical outcomes when added to other treatments in hospitalized patients with COVID-19, we remain confident based on data from Lilly’s BLAZE-1 study that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19,” the statement reads.

The ACTIV-3 trial was paused on October 13 after a data and safety monitoring board cited safety concerns.

The most recent data update that triggered an end to the trial did not reveal any significant differences in safety, though.  
 

This article first appeared on Medscape.com.

Eli Lilly announced it will halt its ACTIV-3 trial evaluating the antibody bamlanivimab in combination with remdesivir for people hospitalized with COVID-19, after new evidence regarding efficacy emerged.

The new data from the National Institutes of Health suggest that the experimental neutralizing antibody therapy does not offer significant clinical benefit for people with more advanced COVID-19 illness, according to a company statement.

Eli Lilly also announced it plans to continue its other trials evaluating the antibody, including those assessing a potential role in treating people in the earlier stages of COVID-19.

“While there was insufficient evidence that bamlanivimab improved clinical outcomes when added to other treatments in hospitalized patients with COVID-19, we remain confident based on data from Lilly’s BLAZE-1 study that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19,” the statement reads.

The ACTIV-3 trial was paused on October 13 after a data and safety monitoring board cited safety concerns.

The most recent data update that triggered an end to the trial did not reveal any significant differences in safety, though.  
 

This article first appeared on Medscape.com.

Eli Lilly announced it will halt its ACTIV-3 trial evaluating the antibody bamlanivimab in combination with remdesivir for people hospitalized with COVID-19, after new evidence regarding efficacy emerged.

The new data from the National Institutes of Health suggest that the experimental neutralizing antibody therapy does not offer significant clinical benefit for people with more advanced COVID-19 illness, according to a company statement.

Eli Lilly also announced it plans to continue its other trials evaluating the antibody, including those assessing a potential role in treating people in the earlier stages of COVID-19.

“While there was insufficient evidence that bamlanivimab improved clinical outcomes when added to other treatments in hospitalized patients with COVID-19, we remain confident based on data from Lilly’s BLAZE-1 study that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19,” the statement reads.

The ACTIV-3 trial was paused on October 13 after a data and safety monitoring board cited safety concerns.

The most recent data update that triggered an end to the trial did not reveal any significant differences in safety, though.  
 

This article first appeared on Medscape.com.