This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University.

I want to talk about a paper that my colleagues in my division just published in Health Affairs. Amanda Zink, Lauren Taylor, and a couple of others wrote a very interesting piece, which I think has significance and importance for all those doing clinical care in American health care today.

As they pointed out, there’s a large amount of literature about what makes patients trust their doctor. There are many studies that show that, although patients sometimes have become more critical of the medical profession, in general they still try to trust their individual physician. Nurses remain in fairly high esteem among those who are getting hospital care.

What isn’t studied, as this paper properly points out, is, what can the doctor and the nurse do to trust the patient? How can that be assessed? Isn’t that just as important as saying that patients have to trust their doctors to do and comply with what they’re told?

What if doctors are afraid of violence? What if doctors are fearful that they can’t trust patients to listen, pay attention, or do what they’re being told? What if they think that patients are coming in with all kinds of disinformation, false information, or things they pick up on the Internet, so that even though you try your best to get across accurate and complete information about what to do about infectious diseases, taking care of a kid with strep throat, or whatever it might be, you’re thinking, Can I trust this patient to do what it is that I want them to do?

One particular problem that’s causing distrust is that more and more patients are showing stress and dependence on drugs and alcohol. That doesn’t make them less trustworthy per se, but it means they can’t regulate their own behavior as well.

That obviously has to be something that the physician or the nurse is thinking about. Is this person going to be able to contain anger? Is this person going to be able to handle bad news? Is this person going to deal with me when I tell them that some of the things they believe to be true about what’s good for their health care are false?

I think we have to really start to push administrators and people in positions of power to teach doctors and nurses how to defuse situations and how to make people more comfortable when they come in and the doctor suspects that they might be under the influence, impaired, or angry because of things they’ve seen on social media, whatever those might be – including concerns about racism, bigotry, and bias, which some patients are bringing into the clinic and the hospital setting.

We need more training. We’ve got to address this as a serious issue. What can we do to defuse situations where the doctor or the nurse rightly thinks that they can’t control or they can’t trust what the patient is thinking or how the patient might behave?

It’s also the case that I think we need more backup and quick access to security so that people feel safe and comfortable in providing care. We have to make sure that if you need someone to restrain a patient or to get somebody out of a situation, that they can get there quickly and respond rapidly, and that they know what to do to deescalate a situation.

It’s sad to say, but security in today’s health care world has to be something that we really test and check – not because we’re worried, as many places are, about a shooter entering the premises, which is its own bit of concern – but I’m just talking about when the doctor or the nurse says that this patient might be acting up, could get violent, or is someone I can’t trust.

My coauthors are basically saying that it’s not a one-way street. Yes, we have to figure out ways to make sure that our patients can trust what we say. Trust is absolutely the lubricant that makes health care flow. If patients don’t trust their doctors, they’re not going to do what they say. They’re not going to get their prescriptions filled. They’re not going to be compliant. They’re not going to try to lose weight or control their diabetes.

It also goes the other way. The doctor or the nurse has to trust the patient. They have to believe that they’re safe. They have to believe that the patient is capable of controlling themselves. They have to believe that the patient is capable of listening and hearing what they’re saying, and that they’re competent to follow up on instructions, including to come back if that’s what’s required.

Everybody has to feel secure in the environment in which they’re working. Security, sadly, has to be a priority if we’re going to have a health care workforce that really feels safe and comfortable dealing with a patient population that is increasingly aggressive and perhaps not as trustworthy.

That’s not news I like to read when my colleagues write it up, but it’s important and we have to take it seriously.
 

Dr. Caplan disclosed that he has served as a director, officer, partner, employee, adviser, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position), and is a contributing author and adviser for Medscape. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University.

I want to talk about a paper that my colleagues in my division just published in Health Affairs. Amanda Zink, Lauren Taylor, and a couple of others wrote a very interesting piece, which I think has significance and importance for all those doing clinical care in American health care today.

As they pointed out, there’s a large amount of literature about what makes patients trust their doctor. There are many studies that show that, although patients sometimes have become more critical of the medical profession, in general they still try to trust their individual physician. Nurses remain in fairly high esteem among those who are getting hospital care.

What isn’t studied, as this paper properly points out, is, what can the doctor and the nurse do to trust the patient? How can that be assessed? Isn’t that just as important as saying that patients have to trust their doctors to do and comply with what they’re told?

What if doctors are afraid of violence? What if doctors are fearful that they can’t trust patients to listen, pay attention, or do what they’re being told? What if they think that patients are coming in with all kinds of disinformation, false information, or things they pick up on the Internet, so that even though you try your best to get across accurate and complete information about what to do about infectious diseases, taking care of a kid with strep throat, or whatever it might be, you’re thinking, Can I trust this patient to do what it is that I want them to do?

One particular problem that’s causing distrust is that more and more patients are showing stress and dependence on drugs and alcohol. That doesn’t make them less trustworthy per se, but it means they can’t regulate their own behavior as well.

That obviously has to be something that the physician or the nurse is thinking about. Is this person going to be able to contain anger? Is this person going to be able to handle bad news? Is this person going to deal with me when I tell them that some of the things they believe to be true about what’s good for their health care are false?

I think we have to really start to push administrators and people in positions of power to teach doctors and nurses how to defuse situations and how to make people more comfortable when they come in and the doctor suspects that they might be under the influence, impaired, or angry because of things they’ve seen on social media, whatever those might be – including concerns about racism, bigotry, and bias, which some patients are bringing into the clinic and the hospital setting.

We need more training. We’ve got to address this as a serious issue. What can we do to defuse situations where the doctor or the nurse rightly thinks that they can’t control or they can’t trust what the patient is thinking or how the patient might behave?

It’s also the case that I think we need more backup and quick access to security so that people feel safe and comfortable in providing care. We have to make sure that if you need someone to restrain a patient or to get somebody out of a situation, that they can get there quickly and respond rapidly, and that they know what to do to deescalate a situation.

It’s sad to say, but security in today’s health care world has to be something that we really test and check – not because we’re worried, as many places are, about a shooter entering the premises, which is its own bit of concern – but I’m just talking about when the doctor or the nurse says that this patient might be acting up, could get violent, or is someone I can’t trust.

My coauthors are basically saying that it’s not a one-way street. Yes, we have to figure out ways to make sure that our patients can trust what we say. Trust is absolutely the lubricant that makes health care flow. If patients don’t trust their doctors, they’re not going to do what they say. They’re not going to get their prescriptions filled. They’re not going to be compliant. They’re not going to try to lose weight or control their diabetes.

It also goes the other way. The doctor or the nurse has to trust the patient. They have to believe that they’re safe. They have to believe that the patient is capable of controlling themselves. They have to believe that the patient is capable of listening and hearing what they’re saying, and that they’re competent to follow up on instructions, including to come back if that’s what’s required.

Everybody has to feel secure in the environment in which they’re working. Security, sadly, has to be a priority if we’re going to have a health care workforce that really feels safe and comfortable dealing with a patient population that is increasingly aggressive and perhaps not as trustworthy.

That’s not news I like to read when my colleagues write it up, but it’s important and we have to take it seriously.
 

Dr. Caplan disclosed that he has served as a director, officer, partner, employee, adviser, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position), and is a contributing author and adviser for Medscape. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

Hi. I’m Art Caplan. I’m at the division of medical ethics at New York University.

I want to talk about a paper that my colleagues in my division just published in Health Affairs. Amanda Zink, Lauren Taylor, and a couple of others wrote a very interesting piece, which I think has significance and importance for all those doing clinical care in American health care today.

As they pointed out, there’s a large amount of literature about what makes patients trust their doctor. There are many studies that show that, although patients sometimes have become more critical of the medical profession, in general they still try to trust their individual physician. Nurses remain in fairly high esteem among those who are getting hospital care.

What isn’t studied, as this paper properly points out, is, what can the doctor and the nurse do to trust the patient? How can that be assessed? Isn’t that just as important as saying that patients have to trust their doctors to do and comply with what they’re told?

What if doctors are afraid of violence? What if doctors are fearful that they can’t trust patients to listen, pay attention, or do what they’re being told? What if they think that patients are coming in with all kinds of disinformation, false information, or things they pick up on the Internet, so that even though you try your best to get across accurate and complete information about what to do about infectious diseases, taking care of a kid with strep throat, or whatever it might be, you’re thinking, Can I trust this patient to do what it is that I want them to do?

One particular problem that’s causing distrust is that more and more patients are showing stress and dependence on drugs and alcohol. That doesn’t make them less trustworthy per se, but it means they can’t regulate their own behavior as well.

That obviously has to be something that the physician or the nurse is thinking about. Is this person going to be able to contain anger? Is this person going to be able to handle bad news? Is this person going to deal with me when I tell them that some of the things they believe to be true about what’s good for their health care are false?

I think we have to really start to push administrators and people in positions of power to teach doctors and nurses how to defuse situations and how to make people more comfortable when they come in and the doctor suspects that they might be under the influence, impaired, or angry because of things they’ve seen on social media, whatever those might be – including concerns about racism, bigotry, and bias, which some patients are bringing into the clinic and the hospital setting.

We need more training. We’ve got to address this as a serious issue. What can we do to defuse situations where the doctor or the nurse rightly thinks that they can’t control or they can’t trust what the patient is thinking or how the patient might behave?

It’s also the case that I think we need more backup and quick access to security so that people feel safe and comfortable in providing care. We have to make sure that if you need someone to restrain a patient or to get somebody out of a situation, that they can get there quickly and respond rapidly, and that they know what to do to deescalate a situation.

It’s sad to say, but security in today’s health care world has to be something that we really test and check – not because we’re worried, as many places are, about a shooter entering the premises, which is its own bit of concern – but I’m just talking about when the doctor or the nurse says that this patient might be acting up, could get violent, or is someone I can’t trust.

My coauthors are basically saying that it’s not a one-way street. Yes, we have to figure out ways to make sure that our patients can trust what we say. Trust is absolutely the lubricant that makes health care flow. If patients don’t trust their doctors, they’re not going to do what they say. They’re not going to get their prescriptions filled. They’re not going to be compliant. They’re not going to try to lose weight or control their diabetes.

It also goes the other way. The doctor or the nurse has to trust the patient. They have to believe that they’re safe. They have to believe that the patient is capable of controlling themselves. They have to believe that the patient is capable of listening and hearing what they’re saying, and that they’re competent to follow up on instructions, including to come back if that’s what’s required.

Everybody has to feel secure in the environment in which they’re working. Security, sadly, has to be a priority if we’re going to have a health care workforce that really feels safe and comfortable dealing with a patient population that is increasingly aggressive and perhaps not as trustworthy.

That’s not news I like to read when my colleagues write it up, but it’s important and we have to take it seriously.
 

Dr. Caplan disclosed that he has served as a director, officer, partner, employee, adviser, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position), and is a contributing author and adviser for Medscape. A version of this article first appeared on Medscape.com.

Mood stabilizers protect against suicide and all-cause mortality in patients with bipolar disorder (BD), including natural mortality, with lithium emerging as the most protective agent, new research suggests.

Investigators led by Pao-Huan Chen, MD, of the department of psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in more than 25,000 patients with BD and found that those with BD had higher mortality.

However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.

“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.

“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological statuses of patients with bipolar disorder,” they add.

The study was published online in Acta Psychiatrica Scandinavica.

Research gap

Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.

Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”

To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.

The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”

Covariates included sex, age, employment status, comorbidities, and concomitant drugs.

Of the patients with BD, 4,000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.
 

Cardioprotective effects?

The standardized mortality ratios (SMRs) – the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population – were 5.26 for all causes (95% confidence interval, 5.10-5.43), 26.02 for suicide (95% CI, 24.20-27.93), and 4.68 for natural causes (95% CI, 4.51-4.85).

The cumulative mortality rate was higher among men vs. women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios, .60 and .52, respectively; both Ps < .001).

The suicide risk peaked between ages 45 and 65 years, whereas the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.

Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.

Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).

Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.

Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).

Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.

The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health of patients with BD,” the investigators note.

The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.

Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.

The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyses were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.

The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, owing to the narrow therapeutic index.”
 

First-line treatment

Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said that the data “add to a growing confluence of data from observational studies indicating that lithium especially is capable of reducing all-cause mortality, suicide mortality, and natural mortality.”

Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, agreed with the authors that lamotrigine is “not a very popular drug in Taiwan, therefore we may not have sufficient assay sensitivity to document the effect.”

But lamotrigine “does have recurrence prevention effects in BD, especially bipolar depression, and it would be expected that it would reduce suicide potentially especially in such a large sample.”

The study’s take-home message “is that the extant evidence now indicates that lithium should be a first-line treatment in persons who live with BD who are experiencing suicidal ideation and/or behavior and these data should inform algorithms of treatment selection and sequencing in clinical practice guidelines,” said Dr. McIntyre.

This research was supported by grants from the Ministry of Science and Technology in Taiwan and Taipei City Hospital. The authors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China, and the Milken Institute; and speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe Pharma, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.

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

Mood stabilizers protect against suicide and all-cause mortality in patients with bipolar disorder (BD), including natural mortality, with lithium emerging as the most protective agent, new research suggests.

Investigators led by Pao-Huan Chen, MD, of the department of psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in more than 25,000 patients with BD and found that those with BD had higher mortality.

However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.

“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.

“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological statuses of patients with bipolar disorder,” they add.

The study was published online in Acta Psychiatrica Scandinavica.

Research gap

Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.

Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”

To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.

The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”

Covariates included sex, age, employment status, comorbidities, and concomitant drugs.

Of the patients with BD, 4,000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.
 

Cardioprotective effects?

The standardized mortality ratios (SMRs) – the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population – were 5.26 for all causes (95% confidence interval, 5.10-5.43), 26.02 for suicide (95% CI, 24.20-27.93), and 4.68 for natural causes (95% CI, 4.51-4.85).

The cumulative mortality rate was higher among men vs. women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios, .60 and .52, respectively; both Ps < .001).

The suicide risk peaked between ages 45 and 65 years, whereas the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.

Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.

Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).

Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.

Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).

Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.

The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health of patients with BD,” the investigators note.

The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.

Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.

The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyses were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.

The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, owing to the narrow therapeutic index.”
 

First-line treatment

Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said that the data “add to a growing confluence of data from observational studies indicating that lithium especially is capable of reducing all-cause mortality, suicide mortality, and natural mortality.”

Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, agreed with the authors that lamotrigine is “not a very popular drug in Taiwan, therefore we may not have sufficient assay sensitivity to document the effect.”

But lamotrigine “does have recurrence prevention effects in BD, especially bipolar depression, and it would be expected that it would reduce suicide potentially especially in such a large sample.”

The study’s take-home message “is that the extant evidence now indicates that lithium should be a first-line treatment in persons who live with BD who are experiencing suicidal ideation and/or behavior and these data should inform algorithms of treatment selection and sequencing in clinical practice guidelines,” said Dr. McIntyre.

This research was supported by grants from the Ministry of Science and Technology in Taiwan and Taipei City Hospital. The authors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China, and the Milken Institute; and speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe Pharma, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.

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

Mood stabilizers protect against suicide and all-cause mortality in patients with bipolar disorder (BD), including natural mortality, with lithium emerging as the most protective agent, new research suggests.

Investigators led by Pao-Huan Chen, MD, of the department of psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in more than 25,000 patients with BD and found that those with BD had higher mortality.

However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.

“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.

“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological statuses of patients with bipolar disorder,” they add.

The study was published online in Acta Psychiatrica Scandinavica.

Research gap

Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.

Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”

To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.

The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”

Covariates included sex, age, employment status, comorbidities, and concomitant drugs.

Of the patients with BD, 4,000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.
 

Cardioprotective effects?

The standardized mortality ratios (SMRs) – the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population – were 5.26 for all causes (95% confidence interval, 5.10-5.43), 26.02 for suicide (95% CI, 24.20-27.93), and 4.68 for natural causes (95% CI, 4.51-4.85).

The cumulative mortality rate was higher among men vs. women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios, .60 and .52, respectively; both Ps < .001).

The suicide risk peaked between ages 45 and 65 years, whereas the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.

Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.

Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).

Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.

Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).

Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.

The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health of patients with BD,” the investigators note.

The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.

Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.

The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyses were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.

The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, owing to the narrow therapeutic index.”
 

First-line treatment

Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said that the data “add to a growing confluence of data from observational studies indicating that lithium especially is capable of reducing all-cause mortality, suicide mortality, and natural mortality.”

Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, agreed with the authors that lamotrigine is “not a very popular drug in Taiwan, therefore we may not have sufficient assay sensitivity to document the effect.”

But lamotrigine “does have recurrence prevention effects in BD, especially bipolar depression, and it would be expected that it would reduce suicide potentially especially in such a large sample.”

The study’s take-home message “is that the extant evidence now indicates that lithium should be a first-line treatment in persons who live with BD who are experiencing suicidal ideation and/or behavior and these data should inform algorithms of treatment selection and sequencing in clinical practice guidelines,” said Dr. McIntyre.

This research was supported by grants from the Ministry of Science and Technology in Taiwan and Taipei City Hospital. The authors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China, and the Milken Institute; and speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe Pharma, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.

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

The European Respiratory Society (ERS) and American Thoracic Society (ATS) just published an update to their guidelines on lung function interpretation (Stanojevic S, et al. Eur Respir J. 2022; 60: 2101499). As with any update, the document builds on past work and integrates new advances the field has seen since 2005.

The current iteration comes at a time when academics, clinicians, and epidemiologists are re-analyzing what we think we know about the complex ways race and ethnicity intersect with the practice of medicine. Several experts on lung function testing, many if not most of whom are authors on the ERS/ATS guideline, have written letters or published reviews commenting on the way accounting for race or ethnicity affects lung function interpretation.

Race/ethnicity and lung function was also the topic of an excellent session at the recent CHEST 2022 Annual Meeting in Nashville, Tennessee. Here, we’ll provide a brief review and direct the reader to relevant sources for a more detailed analysis.

Spirometry is an integral part of the diagnosis and management of a wide range of pulmonary conditions. Dr. Aaron Baugh from the University of California San Francisco (UCSF) lectured on the spirometer’s history at CHEST 2022 and detailed its interactions with race over the past 2 centuries. Other authors have chronicled this history, as well (Braun L, et al. Can J Respir Ther. 2015;51[4]:99-101). The short version is that since the British surgeon John Hutchinson created the first spirometer in 1846, race has been a part of the discussion of lung function interpretation.

In 2022, we know far more about the factors that determine lung function than we did in the 19th century. Age, height, and sex assigned at birth all explain a high percentage of the variability seen in FEV1 and FVC. When modeled, race also explains a portion of the variability, and the NHANES III investigators found its inclusion in regression equations, along with age, height, and sex, improved their precision. Case closed, right? Modern medicine is defined by phenotyping, precision, and individualized care, so why shouldn’t race be a part of lung function interpretation?

Well, it’s complicated. With the increasing recognition of health disparities across racial groups the way race is incorporated in medical practice is understandably being scrutinized. As clinicians and academics, we must analyze the root cause of differences in health outcomes between racial groups.

Publications on pulse oximetry (Gottlieb ER, et al. JAMA Intern Med. 2022; 182:849-858) and glomerular filtration rate (Williams WW, et al. N Engl J Med. 2021;385:1804-1806) have revealed some of the ways our use of instruments and equations may exacerbate or perpetuate current disparities. Even small differences in a measure like pulse oximetry could have a profound impact on clinical decisions at the individual and population levels.

The 2022 ERS/ATS lung function interpretation guidelines have abandoned the use of NHANES III as a reference set. They now recommend the equations developed by the Global Lung Initiative (GLI) for referencing to normal for spirometry, diffusion capacity, and lung volumes. For spirometry the GLI was able to integrate data from countries around the world. This allowed ethnicity to be included in their regression equations and, similar to NHANES III, they found ethnicity improved the precision of their equations. They also published an equation that did not account for country of origin that could be applied to individuals of any race/ethnicity (Quanjer PH, et al. Eur Respir J. 2014;43:505-512). This allowed for applying the GLI equations to external data sets with or without ethnicity included as a co-variate.

Given well-established discrepancies in spirometry, it should come as no surprise that applying the race/ethnicity-neutral GLI equations to non-White populations increases the percentage of patients with pulmonary defects (Moffett AT, et al. Am J Respir Crit Care Med. 2021; A1030). Other data suggest that elimination of race/ethnicity as a co-variate improves the association between percent predicted lung function and important outcomes like mortality (McCormack MC, et al. Am J Respir Crit Care Med. 2022;205:723-724). The first analysis implies that by adjusting for race/ethnicity we may be missing abnormalities, and the second suggests accuracy for outcomes is lost. So case closed, right? Let’s abandon race/ethnicity as a co- variate for our spirometry reference equations.

Perhaps, but a few caveats are in order. It’s important to note that doing so would result in a dramatic increase in abnormal findings in otherwise healthy and asymptomatic non-White individuals. This could negatively affect eligibility for employment and military service (Townsend MC, et al. Am J Respir Crit Care Med. 2022;789-790). We’ve also yet to fully explain the factors driving differences in lung function between races. If socioeconomic factors explained the entirety of the difference, it would be easier to argue for elimination of using race/ethnicity in our equations. Currently, the etiology is thought to be multifactorial and is yet to be fully explained (Braun L, et al. Eur Respir J. 2013;41:1362-1370).

The more we look for institutional racism, the more we will find it. As we realize that attaining health and wellness is more difficult for the disenfranchised, we need to ensure our current practices are part of the solution.

The ERS/ATS guidelines suggest eliminating fixed correction factors for race but do not require elimination of race/ethnicity as a co-variate in the equations selected for use. This seems very reasonable given what we know now. As pulmonary medicine academics and researchers, we need to continue to study the impact integrating race/ethnicity has on precision, accuracy, and clinical outcomes. As pulmonary medicine clinicians, we need to be aware of the reference equations being used in our lab, understand how inclusion of race/ethnicity affects findings, and act accordingly, depending on the clinical situation.
 

Dr. Ghionni is a Pulmonary/Critical Care Fellow, and Dr. Woods is Program Director – PCCM Fellowship and Associate Program Director – IM Residency, Medstar Washington Hospital Center; Dr. Woods is Associate Professor of Medicine, Georgetown University School of Medicine, Washington, DC.

The European Respiratory Society (ERS) and American Thoracic Society (ATS) just published an update to their guidelines on lung function interpretation (Stanojevic S, et al. Eur Respir J. 2022; 60: 2101499). As with any update, the document builds on past work and integrates new advances the field has seen since 2005.

The current iteration comes at a time when academics, clinicians, and epidemiologists are re-analyzing what we think we know about the complex ways race and ethnicity intersect with the practice of medicine. Several experts on lung function testing, many if not most of whom are authors on the ERS/ATS guideline, have written letters or published reviews commenting on the way accounting for race or ethnicity affects lung function interpretation.

Race/ethnicity and lung function was also the topic of an excellent session at the recent CHEST 2022 Annual Meeting in Nashville, Tennessee. Here, we’ll provide a brief review and direct the reader to relevant sources for a more detailed analysis.

Spirometry is an integral part of the diagnosis and management of a wide range of pulmonary conditions. Dr. Aaron Baugh from the University of California San Francisco (UCSF) lectured on the spirometer’s history at CHEST 2022 and detailed its interactions with race over the past 2 centuries. Other authors have chronicled this history, as well (Braun L, et al. Can J Respir Ther. 2015;51[4]:99-101). The short version is that since the British surgeon John Hutchinson created the first spirometer in 1846, race has been a part of the discussion of lung function interpretation.

In 2022, we know far more about the factors that determine lung function than we did in the 19th century. Age, height, and sex assigned at birth all explain a high percentage of the variability seen in FEV1 and FVC. When modeled, race also explains a portion of the variability, and the NHANES III investigators found its inclusion in regression equations, along with age, height, and sex, improved their precision. Case closed, right? Modern medicine is defined by phenotyping, precision, and individualized care, so why shouldn’t race be a part of lung function interpretation?

Well, it’s complicated. With the increasing recognition of health disparities across racial groups the way race is incorporated in medical practice is understandably being scrutinized. As clinicians and academics, we must analyze the root cause of differences in health outcomes between racial groups.

Publications on pulse oximetry (Gottlieb ER, et al. JAMA Intern Med. 2022; 182:849-858) and glomerular filtration rate (Williams WW, et al. N Engl J Med. 2021;385:1804-1806) have revealed some of the ways our use of instruments and equations may exacerbate or perpetuate current disparities. Even small differences in a measure like pulse oximetry could have a profound impact on clinical decisions at the individual and population levels.

The 2022 ERS/ATS lung function interpretation guidelines have abandoned the use of NHANES III as a reference set. They now recommend the equations developed by the Global Lung Initiative (GLI) for referencing to normal for spirometry, diffusion capacity, and lung volumes. For spirometry the GLI was able to integrate data from countries around the world. This allowed ethnicity to be included in their regression equations and, similar to NHANES III, they found ethnicity improved the precision of their equations. They also published an equation that did not account for country of origin that could be applied to individuals of any race/ethnicity (Quanjer PH, et al. Eur Respir J. 2014;43:505-512). This allowed for applying the GLI equations to external data sets with or without ethnicity included as a co-variate.

Given well-established discrepancies in spirometry, it should come as no surprise that applying the race/ethnicity-neutral GLI equations to non-White populations increases the percentage of patients with pulmonary defects (Moffett AT, et al. Am J Respir Crit Care Med. 2021; A1030). Other data suggest that elimination of race/ethnicity as a co-variate improves the association between percent predicted lung function and important outcomes like mortality (McCormack MC, et al. Am J Respir Crit Care Med. 2022;205:723-724). The first analysis implies that by adjusting for race/ethnicity we may be missing abnormalities, and the second suggests accuracy for outcomes is lost. So case closed, right? Let’s abandon race/ethnicity as a co- variate for our spirometry reference equations.

Perhaps, but a few caveats are in order. It’s important to note that doing so would result in a dramatic increase in abnormal findings in otherwise healthy and asymptomatic non-White individuals. This could negatively affect eligibility for employment and military service (Townsend MC, et al. Am J Respir Crit Care Med. 2022;789-790). We’ve also yet to fully explain the factors driving differences in lung function between races. If socioeconomic factors explained the entirety of the difference, it would be easier to argue for elimination of using race/ethnicity in our equations. Currently, the etiology is thought to be multifactorial and is yet to be fully explained (Braun L, et al. Eur Respir J. 2013;41:1362-1370).

The more we look for institutional racism, the more we will find it. As we realize that attaining health and wellness is more difficult for the disenfranchised, we need to ensure our current practices are part of the solution.

The ERS/ATS guidelines suggest eliminating fixed correction factors for race but do not require elimination of race/ethnicity as a co-variate in the equations selected for use. This seems very reasonable given what we know now. As pulmonary medicine academics and researchers, we need to continue to study the impact integrating race/ethnicity has on precision, accuracy, and clinical outcomes. As pulmonary medicine clinicians, we need to be aware of the reference equations being used in our lab, understand how inclusion of race/ethnicity affects findings, and act accordingly, depending on the clinical situation.
 

Dr. Ghionni is a Pulmonary/Critical Care Fellow, and Dr. Woods is Program Director – PCCM Fellowship and Associate Program Director – IM Residency, Medstar Washington Hospital Center; Dr. Woods is Associate Professor of Medicine, Georgetown University School of Medicine, Washington, DC.

The European Respiratory Society (ERS) and American Thoracic Society (ATS) just published an update to their guidelines on lung function interpretation (Stanojevic S, et al. Eur Respir J. 2022; 60: 2101499). As with any update, the document builds on past work and integrates new advances the field has seen since 2005.

The current iteration comes at a time when academics, clinicians, and epidemiologists are re-analyzing what we think we know about the complex ways race and ethnicity intersect with the practice of medicine. Several experts on lung function testing, many if not most of whom are authors on the ERS/ATS guideline, have written letters or published reviews commenting on the way accounting for race or ethnicity affects lung function interpretation.

Race/ethnicity and lung function was also the topic of an excellent session at the recent CHEST 2022 Annual Meeting in Nashville, Tennessee. Here, we’ll provide a brief review and direct the reader to relevant sources for a more detailed analysis.

Spirometry is an integral part of the diagnosis and management of a wide range of pulmonary conditions. Dr. Aaron Baugh from the University of California San Francisco (UCSF) lectured on the spirometer’s history at CHEST 2022 and detailed its interactions with race over the past 2 centuries. Other authors have chronicled this history, as well (Braun L, et al. Can J Respir Ther. 2015;51[4]:99-101). The short version is that since the British surgeon John Hutchinson created the first spirometer in 1846, race has been a part of the discussion of lung function interpretation.

In 2022, we know far more about the factors that determine lung function than we did in the 19th century. Age, height, and sex assigned at birth all explain a high percentage of the variability seen in FEV1 and FVC. When modeled, race also explains a portion of the variability, and the NHANES III investigators found its inclusion in regression equations, along with age, height, and sex, improved their precision. Case closed, right? Modern medicine is defined by phenotyping, precision, and individualized care, so why shouldn’t race be a part of lung function interpretation?

Well, it’s complicated. With the increasing recognition of health disparities across racial groups the way race is incorporated in medical practice is understandably being scrutinized. As clinicians and academics, we must analyze the root cause of differences in health outcomes between racial groups.

Publications on pulse oximetry (Gottlieb ER, et al. JAMA Intern Med. 2022; 182:849-858) and glomerular filtration rate (Williams WW, et al. N Engl J Med. 2021;385:1804-1806) have revealed some of the ways our use of instruments and equations may exacerbate or perpetuate current disparities. Even small differences in a measure like pulse oximetry could have a profound impact on clinical decisions at the individual and population levels.

The 2022 ERS/ATS lung function interpretation guidelines have abandoned the use of NHANES III as a reference set. They now recommend the equations developed by the Global Lung Initiative (GLI) for referencing to normal for spirometry, diffusion capacity, and lung volumes. For spirometry the GLI was able to integrate data from countries around the world. This allowed ethnicity to be included in their regression equations and, similar to NHANES III, they found ethnicity improved the precision of their equations. They also published an equation that did not account for country of origin that could be applied to individuals of any race/ethnicity (Quanjer PH, et al. Eur Respir J. 2014;43:505-512). This allowed for applying the GLI equations to external data sets with or without ethnicity included as a co-variate.

Given well-established discrepancies in spirometry, it should come as no surprise that applying the race/ethnicity-neutral GLI equations to non-White populations increases the percentage of patients with pulmonary defects (Moffett AT, et al. Am J Respir Crit Care Med. 2021; A1030). Other data suggest that elimination of race/ethnicity as a co-variate improves the association between percent predicted lung function and important outcomes like mortality (McCormack MC, et al. Am J Respir Crit Care Med. 2022;205:723-724). The first analysis implies that by adjusting for race/ethnicity we may be missing abnormalities, and the second suggests accuracy for outcomes is lost. So case closed, right? Let’s abandon race/ethnicity as a co- variate for our spirometry reference equations.

Perhaps, but a few caveats are in order. It’s important to note that doing so would result in a dramatic increase in abnormal findings in otherwise healthy and asymptomatic non-White individuals. This could negatively affect eligibility for employment and military service (Townsend MC, et al. Am J Respir Crit Care Med. 2022;789-790). We’ve also yet to fully explain the factors driving differences in lung function between races. If socioeconomic factors explained the entirety of the difference, it would be easier to argue for elimination of using race/ethnicity in our equations. Currently, the etiology is thought to be multifactorial and is yet to be fully explained (Braun L, et al. Eur Respir J. 2013;41:1362-1370).

The more we look for institutional racism, the more we will find it. As we realize that attaining health and wellness is more difficult for the disenfranchised, we need to ensure our current practices are part of the solution.

The ERS/ATS guidelines suggest eliminating fixed correction factors for race but do not require elimination of race/ethnicity as a co-variate in the equations selected for use. This seems very reasonable given what we know now. As pulmonary medicine academics and researchers, we need to continue to study the impact integrating race/ethnicity has on precision, accuracy, and clinical outcomes. As pulmonary medicine clinicians, we need to be aware of the reference equations being used in our lab, understand how inclusion of race/ethnicity affects findings, and act accordingly, depending on the clinical situation.
 

Dr. Ghionni is a Pulmonary/Critical Care Fellow, and Dr. Woods is Program Director – PCCM Fellowship and Associate Program Director – IM Residency, Medstar Washington Hospital Center; Dr. Woods is Associate Professor of Medicine, Georgetown University School of Medicine, Washington, DC.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

The COVID-19 pandemic has caused unprecedented and unpredictable strain on health care systems worldwide, forcing rapid organizational modifications and innovations to ensure availability of critical care resources during acute surge events. Yet, while much attention has been paid to the availability of ICU beds and ventilators, COVID-19 has insidiously and significantly harmed the most precious critical care resource of all – the human beings who are the lifeblood of critical care delivery. We are now at a crucial moment in history to better understand the pandemic’s impact on our human resources and enact changes to reverse the damage that it has inflicted on our workforce.

To understand the impact of the pandemic on critical care clinicians, we must first acknowledge the context in which they work. ICUs, where critical care delivery predominantly occurs, increasingly utilize interprofessional staffing models in which clinicians from multiple disciplines – physicians, nurses, clinical pharmacists, respiratory therapists, and dieticians, among others – bring their unique expertise to team-based clinical decisions and care delivery. Such a multidisciplinary approach helps enable the provision of more comprehensive, higher-quality critical care. In this way, the interprofessional ICU care team is an embodiment of the notion that the “whole” is more than just the sum of its parts. Therefore, we must consider the impact of the pandemic on interprofessional critical care clinicians as the team that they are.

Even before the COVID-19 pandemic, the well-being of critical care clinicians was compromised. Across multiple disciplines, they had among the highest rates of burnout syndrome of all health care professionals (Moss M, et al. Am J Respir Crit Care Med. 2016;194[1]:106-113). As the pandemic has dragged on, their well-being has only further declined. Burnout rates are at all-time highs, and symptoms of posttraumatic stress disorder, anxiety, and depression are common and have increased with each subsequent surge (Azoulay E, et al. Chest. 2021;160[3]:944-955). Offsets to burnout, such as fulfillment and recognition, have declined over time (Kerlin MP, et al. Ann Amer Thorac Soc. 2022;19[2]:329-331). These worrisome trends pose a significant threat to critical care delivery. Clinician burnout is associated with worse patient outcomes, increased medical errors, and lower patient satisfaction (Moss M, et al. Am J Respir Crit Care Med. 2016;194[1]:106-113; Poghosyan L, et al. Res Nurs Health. 2010;33[4]:288-298). It is also associated with mental illness and substance use disorders among clinicians (Dyrbye LN, et al. Ann Intern Med. 2008;149[5]:334-341). Finally, it has contributed to a workforce crisis: nearly 500,000 health care workers have left the US health care sector since the beginning of the pandemic, and approximately two-thirds of acute and critical care nurses have considered doing so (Wong E. “Why Healthcare Workers are Quitting in Droves”. The Atlantic. Accessed November 7, 2022). Such a “brain drain” of clinicians – whose expertise cannot be easily replicated or replaced – represents a staffing crisis that threatens our ability to provide high-quality, safe care for the foreseeable future.

To combat burnout, it is first necessary to identify the mechanisms by which the pandemic has induced harm. Early during the pandemic, critical care clinicians feared for their own safety with little information of how the virus was spread. At a time when the world was under lockdown, vaccines were not yet available, and hospitals were overwhelmed with surges of critically ill patients, clinicians struggled like the rest of the world to meet their own basic needs such as childcare, grocery shopping, and time with family. They experienced distress from high volumes of patients with extreme mortality rates, helplessness due to lack of treatment options, and moral injury over restrictive visitation policies (Vranas KC, et al. Chest. 2022;162[2]:331-345; Vranas KC, et al. Chest. 2021;160[5]:1714-1728). Over time, critical care clinicians have no doubt experienced further exhaustion related to the duration of the pandemic, often without adequate time to recover and process the trauma they have experienced. More recently, a new source of distress for clinicians has emerged from variability in vaccine uptake among the public. Clinicians have experienced compassion fatigue and even moral outrage toward those who chose not to receive a vaccine that is highly effective at preventing severe illness. They also suffered from ethical conflicts over how to treat unvaccinated patients and whether they should be given equal priority and access to limited therapies (Shaw D. Bioethics. 2022;36[8]:883-890).

Furthermore, the pandemic has damaged the relationship between clinicians and their institutions. Early in the pandemic, the widespread shortages of personal protective equipment harmed trust among clinicians due to their perception that their safety was not prioritized. Hospitals have also struggled with having to make rapid decisions on how to equitably allocate fixed resources in response to unanticipated and unpredictable demands, while also maintaining financial solvency. In some cases, these challenging policy decisions (eg, whether to continue elective procedures during acute surge events) lacked transparency and input from the team at the frontlines of patient care. As a result, clinicians have felt undervalued and without a voice in decisions that directly impact both the care they can provide their patients and their own well-being.

It is incumbent upon us now to take steps to repair the damage inflicted on our critical care workforce by the pandemic. To this end, there have been calls for the urgent implementation of strategies to mitigate the psychological burden experienced by critical care clinicians. However, many of these focus on interventions to increase coping strategies and resilience among individual clinicians. While programs such as mindfulness apps and resilience training are valuable, they are not sufficient. The very nature of these solutions implies that the solution (and therefore, the problem) of burnout lies in the individual clinician. Yet, as described above, many of the mechanisms of harm to clinicians’ well-being are systems-level issues that will necessarily require systems-level solutions.

Therefore, we propose a comprehensive, layered approach to begin to reverse the damage inflicted by the pandemic on critical care clinicians’ well-being, with solutions organized by ecological levels of individual clinicians, departments, institutions, and society. With this approach, we hope to address specific aspects of our critical care delivery system that, taken together, will fortify the well-being of our critical care workforce as a whole. We offer suggestions below that are both informed by existing evidence, as well as our own opinions as intensivists and researchers.
 

At the level of the individual clinician:

• Proactively provide access to mental health resources. Clinicians have limited time or energy to navigate mental health and support services and find it helpful when others proactively reach out to them.
• Provide opportunities for clinicians to experience community and support among peers. Clinicians find benefit in town halls, debrief sessions, and peer support groups, particularly during times of acute strain.

At the level of the department:

• Allow more flexibility in work schedules. Even prior to the pandemic, the lack of scheduling flexibility and the number of consecutive days worked had been identified as key contributors to burnout; these have been exacerbated during times of caseload surges, when clinicians have been asked or even required to increase their hours and work extra shifts.
• Promote a culture of psychological safety in which clinicians feel empowered to say “I cannot work” for whatever reason. This will require the establishment of formalized backup systems that easily accommodate call-outs without relying on individual clinicians to find their own coverage.

At the level of the health care system:

• Prioritize transparency, and bring administrators and clinicians together for policy decisions. Break down silos between the frontline workers involved in direct patient care and hospital executives, both to inform those decisions and demonstrate the value of clinicians’ perspectives.
• Compensate clinicians for extra work. Consider hazard pay or ensure extra time off for extra time worked.
• Make it “easier” for clinicians to do their jobs by helping them meet their basic needs. Create schedules with designated breaks during shifts. Provide adequate office space and call rooms. Facilitate access to childcare. Provide parking.
• Minimize moral injury. Develop protocols for scarce resource allocation that exclude the treatment team from making decisions about allocation of scarce resources. Avoid visitor restrictions given the harm these policies inflict on patients, families, and members of the care team.

At the level of society:

• Study mechanisms to improve communication about public health with the public. Both science and communication are essential to promoting and protecting public health; more research is needed to improve the way scientific knowledge and evidence-based recommendations are communicated to the public.

In conclusion, the COVID-19 pandemic has forever changed our critical care workforce and the way we deliver care. The time is now to act on the lessons learned from the COVID-19 pandemic through implementation of systems-level solutions to combat burnout and ensure both the health and sustainability of our critical care workforce for the season ahead.
 

Dr. Vranas is with the Center to Improve Veteran Involvement in Care, VA Portland Health Care System, the Division of Pulmonary and Critical Care, Oregon Health & Science University; Portland, OR; and the Palliative and Advanced Illness Research (PAIR) Center, University of Pennsylvania; Philadelphia, PA. Dr. Kerlin is with the Palliative and Advanced Illness Research (PAIR) Center, and Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA.

The COVID-19 pandemic has caused unprecedented and unpredictable strain on health care systems worldwide, forcing rapid organizational modifications and innovations to ensure availability of critical care resources during acute surge events. Yet, while much attention has been paid to the availability of ICU beds and ventilators, COVID-19 has insidiously and significantly harmed the most precious critical care resource of all – the human beings who are the lifeblood of critical care delivery. We are now at a crucial moment in history to better understand the pandemic’s impact on our human resources and enact changes to reverse the damage that it has inflicted on our workforce.

To understand the impact of the pandemic on critical care clinicians, we must first acknowledge the context in which they work. ICUs, where critical care delivery predominantly occurs, increasingly utilize interprofessional staffing models in which clinicians from multiple disciplines – physicians, nurses, clinical pharmacists, respiratory therapists, and dieticians, among others – bring their unique expertise to team-based clinical decisions and care delivery. Such a multidisciplinary approach helps enable the provision of more comprehensive, higher-quality critical care. In this way, the interprofessional ICU care team is an embodiment of the notion that the “whole” is more than just the sum of its parts. Therefore, we must consider the impact of the pandemic on interprofessional critical care clinicians as the team that they are.

Even before the COVID-19 pandemic, the well-being of critical care clinicians was compromised. Across multiple disciplines, they had among the highest rates of burnout syndrome of all health care professionals (Moss M, et al. Am J Respir Crit Care Med. 2016;194[1]:106-113). As the pandemic has dragged on, their well-being has only further declined. Burnout rates are at all-time highs, and symptoms of posttraumatic stress disorder, anxiety, and depression are common and have increased with each subsequent surge (Azoulay E, et al. Chest. 2021;160[3]:944-955). Offsets to burnout, such as fulfillment and recognition, have declined over time (Kerlin MP, et al. Ann Amer Thorac Soc. 2022;19[2]:329-331). These worrisome trends pose a significant threat to critical care delivery. Clinician burnout is associated with worse patient outcomes, increased medical errors, and lower patient satisfaction (Moss M, et al. Am J Respir Crit Care Med. 2016;194[1]:106-113; Poghosyan L, et al. Res Nurs Health. 2010;33[4]:288-298). It is also associated with mental illness and substance use disorders among clinicians (Dyrbye LN, et al. Ann Intern Med. 2008;149[5]:334-341). Finally, it has contributed to a workforce crisis: nearly 500,000 health care workers have left the US health care sector since the beginning of the pandemic, and approximately two-thirds of acute and critical care nurses have considered doing so (Wong E. “Why Healthcare Workers are Quitting in Droves”. The Atlantic. Accessed November 7, 2022). Such a “brain drain” of clinicians – whose expertise cannot be easily replicated or replaced – represents a staffing crisis that threatens our ability to provide high-quality, safe care for the foreseeable future.

To combat burnout, it is first necessary to identify the mechanisms by which the pandemic has induced harm. Early during the pandemic, critical care clinicians feared for their own safety with little information of how the virus was spread. At a time when the world was under lockdown, vaccines were not yet available, and hospitals were overwhelmed with surges of critically ill patients, clinicians struggled like the rest of the world to meet their own basic needs such as childcare, grocery shopping, and time with family. They experienced distress from high volumes of patients with extreme mortality rates, helplessness due to lack of treatment options, and moral injury over restrictive visitation policies (Vranas KC, et al. Chest. 2022;162[2]:331-345; Vranas KC, et al. Chest. 2021;160[5]:1714-1728). Over time, critical care clinicians have no doubt experienced further exhaustion related to the duration of the pandemic, often without adequate time to recover and process the trauma they have experienced. More recently, a new source of distress for clinicians has emerged from variability in vaccine uptake among the public. Clinicians have experienced compassion fatigue and even moral outrage toward those who chose not to receive a vaccine that is highly effective at preventing severe illness. They also suffered from ethical conflicts over how to treat unvaccinated patients and whether they should be given equal priority and access to limited therapies (Shaw D. Bioethics. 2022;36[8]:883-890).

Furthermore, the pandemic has damaged the relationship between clinicians and their institutions. Early in the pandemic, the widespread shortages of personal protective equipment harmed trust among clinicians due to their perception that their safety was not prioritized. Hospitals have also struggled with having to make rapid decisions on how to equitably allocate fixed resources in response to unanticipated and unpredictable demands, while also maintaining financial solvency. In some cases, these challenging policy decisions (eg, whether to continue elective procedures during acute surge events) lacked transparency and input from the team at the frontlines of patient care. As a result, clinicians have felt undervalued and without a voice in decisions that directly impact both the care they can provide their patients and their own well-being.

It is incumbent upon us now to take steps to repair the damage inflicted on our critical care workforce by the pandemic. To this end, there have been calls for the urgent implementation of strategies to mitigate the psychological burden experienced by critical care clinicians. However, many of these focus on interventions to increase coping strategies and resilience among individual clinicians. While programs such as mindfulness apps and resilience training are valuable, they are not sufficient. The very nature of these solutions implies that the solution (and therefore, the problem) of burnout lies in the individual clinician. Yet, as described above, many of the mechanisms of harm to clinicians’ well-being are systems-level issues that will necessarily require systems-level solutions.

Therefore, we propose a comprehensive, layered approach to begin to reverse the damage inflicted by the pandemic on critical care clinicians’ well-being, with solutions organized by ecological levels of individual clinicians, departments, institutions, and society. With this approach, we hope to address specific aspects of our critical care delivery system that, taken together, will fortify the well-being of our critical care workforce as a whole. We offer suggestions below that are both informed by existing evidence, as well as our own opinions as intensivists and researchers.
 

At the level of the individual clinician:

• Proactively provide access to mental health resources. Clinicians have limited time or energy to navigate mental health and support services and find it helpful when others proactively reach out to them.
• Provide opportunities for clinicians to experience community and support among peers. Clinicians find benefit in town halls, debrief sessions, and peer support groups, particularly during times of acute strain.

At the level of the department:

• Allow more flexibility in work schedules. Even prior to the pandemic, the lack of scheduling flexibility and the number of consecutive days worked had been identified as key contributors to burnout; these have been exacerbated during times of caseload surges, when clinicians have been asked or even required to increase their hours and work extra shifts.
• Promote a culture of psychological safety in which clinicians feel empowered to say “I cannot work” for whatever reason. This will require the establishment of formalized backup systems that easily accommodate call-outs without relying on individual clinicians to find their own coverage.

At the level of the health care system:

• Prioritize transparency, and bring administrators and clinicians together for policy decisions. Break down silos between the frontline workers involved in direct patient care and hospital executives, both to inform those decisions and demonstrate the value of clinicians’ perspectives.
• Compensate clinicians for extra work. Consider hazard pay or ensure extra time off for extra time worked.
• Make it “easier” for clinicians to do their jobs by helping them meet their basic needs. Create schedules with designated breaks during shifts. Provide adequate office space and call rooms. Facilitate access to childcare. Provide parking.
• Minimize moral injury. Develop protocols for scarce resource allocation that exclude the treatment team from making decisions about allocation of scarce resources. Avoid visitor restrictions given the harm these policies inflict on patients, families, and members of the care team.

At the level of society:

• Study mechanisms to improve communication about public health with the public. Both science and communication are essential to promoting and protecting public health; more research is needed to improve the way scientific knowledge and evidence-based recommendations are communicated to the public.

In conclusion, the COVID-19 pandemic has forever changed our critical care workforce and the way we deliver care. The time is now to act on the lessons learned from the COVID-19 pandemic through implementation of systems-level solutions to combat burnout and ensure both the health and sustainability of our critical care workforce for the season ahead.
 

Dr. Vranas is with the Center to Improve Veteran Involvement in Care, VA Portland Health Care System, the Division of Pulmonary and Critical Care, Oregon Health & Science University; Portland, OR; and the Palliative and Advanced Illness Research (PAIR) Center, University of Pennsylvania; Philadelphia, PA. Dr. Kerlin is with the Palliative and Advanced Illness Research (PAIR) Center, and Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA.

The COVID-19 pandemic has caused unprecedented and unpredictable strain on health care systems worldwide, forcing rapid organizational modifications and innovations to ensure availability of critical care resources during acute surge events. Yet, while much attention has been paid to the availability of ICU beds and ventilators, COVID-19 has insidiously and significantly harmed the most precious critical care resource of all – the human beings who are the lifeblood of critical care delivery. We are now at a crucial moment in history to better understand the pandemic’s impact on our human resources and enact changes to reverse the damage that it has inflicted on our workforce.

To understand the impact of the pandemic on critical care clinicians, we must first acknowledge the context in which they work. ICUs, where critical care delivery predominantly occurs, increasingly utilize interprofessional staffing models in which clinicians from multiple disciplines – physicians, nurses, clinical pharmacists, respiratory therapists, and dieticians, among others – bring their unique expertise to team-based clinical decisions and care delivery. Such a multidisciplinary approach helps enable the provision of more comprehensive, higher-quality critical care. In this way, the interprofessional ICU care team is an embodiment of the notion that the “whole” is more than just the sum of its parts. Therefore, we must consider the impact of the pandemic on interprofessional critical care clinicians as the team that they are.

Even before the COVID-19 pandemic, the well-being of critical care clinicians was compromised. Across multiple disciplines, they had among the highest rates of burnout syndrome of all health care professionals (Moss M, et al. Am J Respir Crit Care Med. 2016;194[1]:106-113). As the pandemic has dragged on, their well-being has only further declined. Burnout rates are at all-time highs, and symptoms of posttraumatic stress disorder, anxiety, and depression are common and have increased with each subsequent surge (Azoulay E, et al. Chest. 2021;160[3]:944-955). Offsets to burnout, such as fulfillment and recognition, have declined over time (Kerlin MP, et al. Ann Amer Thorac Soc. 2022;19[2]:329-331). These worrisome trends pose a significant threat to critical care delivery. Clinician burnout is associated with worse patient outcomes, increased medical errors, and lower patient satisfaction (Moss M, et al. Am J Respir Crit Care Med. 2016;194[1]:106-113; Poghosyan L, et al. Res Nurs Health. 2010;33[4]:288-298). It is also associated with mental illness and substance use disorders among clinicians (Dyrbye LN, et al. Ann Intern Med. 2008;149[5]:334-341). Finally, it has contributed to a workforce crisis: nearly 500,000 health care workers have left the US health care sector since the beginning of the pandemic, and approximately two-thirds of acute and critical care nurses have considered doing so (Wong E. “Why Healthcare Workers are Quitting in Droves”. The Atlantic. Accessed November 7, 2022). Such a “brain drain” of clinicians – whose expertise cannot be easily replicated or replaced – represents a staffing crisis that threatens our ability to provide high-quality, safe care for the foreseeable future.

To combat burnout, it is first necessary to identify the mechanisms by which the pandemic has induced harm. Early during the pandemic, critical care clinicians feared for their own safety with little information of how the virus was spread. At a time when the world was under lockdown, vaccines were not yet available, and hospitals were overwhelmed with surges of critically ill patients, clinicians struggled like the rest of the world to meet their own basic needs such as childcare, grocery shopping, and time with family. They experienced distress from high volumes of patients with extreme mortality rates, helplessness due to lack of treatment options, and moral injury over restrictive visitation policies (Vranas KC, et al. Chest. 2022;162[2]:331-345; Vranas KC, et al. Chest. 2021;160[5]:1714-1728). Over time, critical care clinicians have no doubt experienced further exhaustion related to the duration of the pandemic, often without adequate time to recover and process the trauma they have experienced. More recently, a new source of distress for clinicians has emerged from variability in vaccine uptake among the public. Clinicians have experienced compassion fatigue and even moral outrage toward those who chose not to receive a vaccine that is highly effective at preventing severe illness. They also suffered from ethical conflicts over how to treat unvaccinated patients and whether they should be given equal priority and access to limited therapies (Shaw D. Bioethics. 2022;36[8]:883-890).

Furthermore, the pandemic has damaged the relationship between clinicians and their institutions. Early in the pandemic, the widespread shortages of personal protective equipment harmed trust among clinicians due to their perception that their safety was not prioritized. Hospitals have also struggled with having to make rapid decisions on how to equitably allocate fixed resources in response to unanticipated and unpredictable demands, while also maintaining financial solvency. In some cases, these challenging policy decisions (eg, whether to continue elective procedures during acute surge events) lacked transparency and input from the team at the frontlines of patient care. As a result, clinicians have felt undervalued and without a voice in decisions that directly impact both the care they can provide their patients and their own well-being.

It is incumbent upon us now to take steps to repair the damage inflicted on our critical care workforce by the pandemic. To this end, there have been calls for the urgent implementation of strategies to mitigate the psychological burden experienced by critical care clinicians. However, many of these focus on interventions to increase coping strategies and resilience among individual clinicians. While programs such as mindfulness apps and resilience training are valuable, they are not sufficient. The very nature of these solutions implies that the solution (and therefore, the problem) of burnout lies in the individual clinician. Yet, as described above, many of the mechanisms of harm to clinicians’ well-being are systems-level issues that will necessarily require systems-level solutions.

Therefore, we propose a comprehensive, layered approach to begin to reverse the damage inflicted by the pandemic on critical care clinicians’ well-being, with solutions organized by ecological levels of individual clinicians, departments, institutions, and society. With this approach, we hope to address specific aspects of our critical care delivery system that, taken together, will fortify the well-being of our critical care workforce as a whole. We offer suggestions below that are both informed by existing evidence, as well as our own opinions as intensivists and researchers.
 

At the level of the individual clinician:

• Proactively provide access to mental health resources. Clinicians have limited time or energy to navigate mental health and support services and find it helpful when others proactively reach out to them.
• Provide opportunities for clinicians to experience community and support among peers. Clinicians find benefit in town halls, debrief sessions, and peer support groups, particularly during times of acute strain.

At the level of the department:

• Allow more flexibility in work schedules. Even prior to the pandemic, the lack of scheduling flexibility and the number of consecutive days worked had been identified as key contributors to burnout; these have been exacerbated during times of caseload surges, when clinicians have been asked or even required to increase their hours and work extra shifts.
• Promote a culture of psychological safety in which clinicians feel empowered to say “I cannot work” for whatever reason. This will require the establishment of formalized backup systems that easily accommodate call-outs without relying on individual clinicians to find their own coverage.

At the level of the health care system:

• Prioritize transparency, and bring administrators and clinicians together for policy decisions. Break down silos between the frontline workers involved in direct patient care and hospital executives, both to inform those decisions and demonstrate the value of clinicians’ perspectives.
• Compensate clinicians for extra work. Consider hazard pay or ensure extra time off for extra time worked.
• Make it “easier” for clinicians to do their jobs by helping them meet their basic needs. Create schedules with designated breaks during shifts. Provide adequate office space and call rooms. Facilitate access to childcare. Provide parking.
• Minimize moral injury. Develop protocols for scarce resource allocation that exclude the treatment team from making decisions about allocation of scarce resources. Avoid visitor restrictions given the harm these policies inflict on patients, families, and members of the care team.

At the level of society:

• Study mechanisms to improve communication about public health with the public. Both science and communication are essential to promoting and protecting public health; more research is needed to improve the way scientific knowledge and evidence-based recommendations are communicated to the public.

In conclusion, the COVID-19 pandemic has forever changed our critical care workforce and the way we deliver care. The time is now to act on the lessons learned from the COVID-19 pandemic through implementation of systems-level solutions to combat burnout and ensure both the health and sustainability of our critical care workforce for the season ahead.
 

Dr. Vranas is with the Center to Improve Veteran Involvement in Care, VA Portland Health Care System, the Division of Pulmonary and Critical Care, Oregon Health & Science University; Portland, OR; and the Palliative and Advanced Illness Research (PAIR) Center, University of Pennsylvania; Philadelphia, PA. Dr. Kerlin is with the Palliative and Advanced Illness Research (PAIR) Center, and Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA.

Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.

“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.

“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.

“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.

The study was published online in The Lancet Oncology.

“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.

“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”

“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”

Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”

She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
 

Dose/response relationship

The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.

The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.

During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.

The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.

“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.

These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.

“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
 

Keeping dose to a minimum

The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.

“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.

“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”

The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.

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

Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.

“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.

“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.

“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.

The study was published online in The Lancet Oncology.

“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.

“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”

“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”

Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”

She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
 

Dose/response relationship

The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.

The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.

During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.

The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.

“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.

These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.

“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
 

Keeping dose to a minimum

The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.

“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.

“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”

The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.

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

Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.

“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.

“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.

“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.

The study was published online in The Lancet Oncology.

“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.

“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”

“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”

Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”

She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
 

Dose/response relationship

The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.

The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.

During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.

The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.

“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.

These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.

“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
 

Keeping dose to a minimum

The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.

“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.

“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”

The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.

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

A digital intervention may offer a new and effective treatment option for panic disorder (PD) and posttraumatic stress disorder, new research suggests.

The 28-day home-based treatment, known as the capnometry guided respiratory intervention (CGRI), uses an app-based feedback protocol to normalize respiration and increase patients’ ability to cope with symptoms of stress, anxiety, and panic by providing real time breath-to-breath feedback of respiratory rate and carbon dioxide (CO₂) levels via a nasal cannula.

Freespira

Results from the large real-world study showed that over 65% of patients with PD and over 72% of those with PTSD responded to the treatment. In addition, almost 75% of participants adhered to the study protocol, with low dropout rates.

“The brief duration of treatment, high adherence rates, and clinical benefit suggests that CGRI provides an important addition to treatment options for PD and PTSD,” the investigators write.

The study was published online in Frontiers in Digital Health.
 

‘New kid on the block’

The “respiratory dysregulation hypothesis” links CO₂ sensitivity to panic attacks and PD, and similar reactivity has been identified in PTSD, but a “common limitation of psychotherapeutic and pharmacologic approaches to PD and PTSD is that neither address the role of respiratory physiology and breathing style,” the investigators note.

The most widely studied treatment for PTSD is trauma-focused psychotherapy, in which the patient reviews and revisits the trauma, but it has a high dropout rate, study investigator Michael Telch, PhD, director of the Laboratory for the Study of Anxiety Disorders, University of Texas, Austin, told this news organization.

He described CGRI for PTSD as a “relatively new kid on the block, so to speak.” The intervention was cleared by the U.S. Food and Drug Administration for treatment of PD and PTSD in 2013 and 2018, respectively, and is currently available through the Veterans Administration for veterans with PTSD. It is also covered by some commercial insurance plans.

“The underlying assumption [of CGRI] is that a person can learn to develop skills for controlling some of their physiological reactions that are triggered as a result of trauma,” said Dr. Telch.

The device uses a biofeedback approach to give patients “greater control over their physiological reactions, such as hyperventilation and increased respiration rate, and the focus is on providing a sense of mastery,” he said.

Participants with PTSD were assigned to a health coach. The device was delivered to the patient’s home, and patients met with the trained coach weekly and could check in between visits via text or e-mail. Twice-daily sessions were recommended.

“The coach gets feedback about what’s happening with the patient’s respiration and end-tidal CO₂ levels [etCO₂] and instructs participants how to keep their respiration rate and etCO₂ at a more normal level,” said Dr. Telch.

The CGRI “teaches a specific breathing style via a system providing real-time feedback of respiratory rate (RR) and exhaled carbon dioxide levels facilitated by data capture,” the authors note.
 

Sense of mastery

Of the 1,569 participants, 1,395 had PD and 174 had PTSD (mean age, 39.2 [standard deviation, 13.9] years and 40.9 [SD, 14.9] years, respectively; 76% and 73% female, respectively). Those with PD completed the Panic Disorder Severity Scale (PDSS) and those with PTSD completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), before and after the intervention.

The treatment response rate for PD was defined as a 40% or greater reduction in PDSS total scores, whereas treatment response rate for PTSD was defined as a 10-point or greater reduction in PCL-5 scores.

At baseline, patients were classified either as normocapnic or hypocapnic (etCO₂ ≥ 37 or < 37, respectively), with 65% classified as normocapnic and 35% classified as hypocapnic.

Among patients with PD, there was a 50.2% mean pre- to posttreatment reduction in total PDSS scores (P < .001; d = 1.31), with a treatment response rate of 65.3% of patients.

Among patients with PTSD, there was a 41.1% pre- to posttreatment reduction in total PCL-5 scores (P < .001; d = 1.16), with a treatment response rate of 72.4%.

When investigators analyzed the response at the individual level, they found that 55.7% of patients with PD and 53.5% of those with PTSD were classified as treatment responders. This determination was based on a two-pronged approach that first calculated the Reliable Change Index (RCI) for each participant, and, in participants showing statistically reliable improvement, whether the posttreatment score was closer to the distribution of scores for patients without or with the given disorder.

“Patients with both normal and below-normal baseline exhaled CO2 levels experienced comparable benefit,” the authors report.

‘A viable alternative’

Commenting on the research, Charles Marmar, MD, chair and Peter H. Schub Professor of Psychiatry, department of psychiatry, New York University, said that the study has some limitations, probably the most significant of which is that most participants had normal baseline CO₂ levels.

“The treatment is fundamentally designed for people who hyperventilate and blow off too much CO₂ so they can breathe in a more calm, relaxed way, but most people in the trial had normal CO₂ to begin with,” said Dr. Marmar, who was not involved with the study.

“It’s likely that the major benefits were the relaxation from doing the breathing exercises rather than the change in CO₂ levels,” he speculated.

The treatment is “probably a good thing for those patients who actually have abnormal CO₂ levels. This treatment could be used in precision medicine, where you tailor treatments to those who actually need them rather than giving the same treatment to everyone,” he said.

“For patients who don’t respond to trauma-focused therapy or it’s too aversive for them to undergo, this new intervention provides a viable alternative,” Dr. Telch added.

The study was internally funded by Freespira. Dr. Telch is a scientific advisor at Freespira and receives compensation by way of stock options. The other authors’ disclosures are listed on the original paper. Dr. Marmar has declared no relevant financial relationships.

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

A digital intervention may offer a new and effective treatment option for panic disorder (PD) and posttraumatic stress disorder, new research suggests.

The 28-day home-based treatment, known as the capnometry guided respiratory intervention (CGRI), uses an app-based feedback protocol to normalize respiration and increase patients’ ability to cope with symptoms of stress, anxiety, and panic by providing real time breath-to-breath feedback of respiratory rate and carbon dioxide (CO₂) levels via a nasal cannula.

Freespira

Results from the large real-world study showed that over 65% of patients with PD and over 72% of those with PTSD responded to the treatment. In addition, almost 75% of participants adhered to the study protocol, with low dropout rates.

“The brief duration of treatment, high adherence rates, and clinical benefit suggests that CGRI provides an important addition to treatment options for PD and PTSD,” the investigators write.

The study was published online in Frontiers in Digital Health.
 

‘New kid on the block’

The “respiratory dysregulation hypothesis” links CO₂ sensitivity to panic attacks and PD, and similar reactivity has been identified in PTSD, but a “common limitation of psychotherapeutic and pharmacologic approaches to PD and PTSD is that neither address the role of respiratory physiology and breathing style,” the investigators note.

The most widely studied treatment for PTSD is trauma-focused psychotherapy, in which the patient reviews and revisits the trauma, but it has a high dropout rate, study investigator Michael Telch, PhD, director of the Laboratory for the Study of Anxiety Disorders, University of Texas, Austin, told this news organization.

He described CGRI for PTSD as a “relatively new kid on the block, so to speak.” The intervention was cleared by the U.S. Food and Drug Administration for treatment of PD and PTSD in 2013 and 2018, respectively, and is currently available through the Veterans Administration for veterans with PTSD. It is also covered by some commercial insurance plans.

“The underlying assumption [of CGRI] is that a person can learn to develop skills for controlling some of their physiological reactions that are triggered as a result of trauma,” said Dr. Telch.

The device uses a biofeedback approach to give patients “greater control over their physiological reactions, such as hyperventilation and increased respiration rate, and the focus is on providing a sense of mastery,” he said.

Participants with PTSD were assigned to a health coach. The device was delivered to the patient’s home, and patients met with the trained coach weekly and could check in between visits via text or e-mail. Twice-daily sessions were recommended.

“The coach gets feedback about what’s happening with the patient’s respiration and end-tidal CO₂ levels [etCO₂] and instructs participants how to keep their respiration rate and etCO₂ at a more normal level,” said Dr. Telch.

The CGRI “teaches a specific breathing style via a system providing real-time feedback of respiratory rate (RR) and exhaled carbon dioxide levels facilitated by data capture,” the authors note.
 

Sense of mastery

Of the 1,569 participants, 1,395 had PD and 174 had PTSD (mean age, 39.2 [standard deviation, 13.9] years and 40.9 [SD, 14.9] years, respectively; 76% and 73% female, respectively). Those with PD completed the Panic Disorder Severity Scale (PDSS) and those with PTSD completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), before and after the intervention.

The treatment response rate for PD was defined as a 40% or greater reduction in PDSS total scores, whereas treatment response rate for PTSD was defined as a 10-point or greater reduction in PCL-5 scores.

At baseline, patients were classified either as normocapnic or hypocapnic (etCO₂ ≥ 37 or < 37, respectively), with 65% classified as normocapnic and 35% classified as hypocapnic.

Among patients with PD, there was a 50.2% mean pre- to posttreatment reduction in total PDSS scores (P < .001; d = 1.31), with a treatment response rate of 65.3% of patients.

Among patients with PTSD, there was a 41.1% pre- to posttreatment reduction in total PCL-5 scores (P < .001; d = 1.16), with a treatment response rate of 72.4%.

When investigators analyzed the response at the individual level, they found that 55.7% of patients with PD and 53.5% of those with PTSD were classified as treatment responders. This determination was based on a two-pronged approach that first calculated the Reliable Change Index (RCI) for each participant, and, in participants showing statistically reliable improvement, whether the posttreatment score was closer to the distribution of scores for patients without or with the given disorder.

“Patients with both normal and below-normal baseline exhaled CO2 levels experienced comparable benefit,” the authors report.

‘A viable alternative’

Commenting on the research, Charles Marmar, MD, chair and Peter H. Schub Professor of Psychiatry, department of psychiatry, New York University, said that the study has some limitations, probably the most significant of which is that most participants had normal baseline CO₂ levels.

“The treatment is fundamentally designed for people who hyperventilate and blow off too much CO₂ so they can breathe in a more calm, relaxed way, but most people in the trial had normal CO₂ to begin with,” said Dr. Marmar, who was not involved with the study.

“It’s likely that the major benefits were the relaxation from doing the breathing exercises rather than the change in CO₂ levels,” he speculated.

The treatment is “probably a good thing for those patients who actually have abnormal CO₂ levels. This treatment could be used in precision medicine, where you tailor treatments to those who actually need them rather than giving the same treatment to everyone,” he said.

“For patients who don’t respond to trauma-focused therapy or it’s too aversive for them to undergo, this new intervention provides a viable alternative,” Dr. Telch added.

The study was internally funded by Freespira. Dr. Telch is a scientific advisor at Freespira and receives compensation by way of stock options. The other authors’ disclosures are listed on the original paper. Dr. Marmar has declared no relevant financial relationships.

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

A digital intervention may offer a new and effective treatment option for panic disorder (PD) and posttraumatic stress disorder, new research suggests.

The 28-day home-based treatment, known as the capnometry guided respiratory intervention (CGRI), uses an app-based feedback protocol to normalize respiration and increase patients’ ability to cope with symptoms of stress, anxiety, and panic by providing real time breath-to-breath feedback of respiratory rate and carbon dioxide (CO₂) levels via a nasal cannula.

Freespira

Results from the large real-world study showed that over 65% of patients with PD and over 72% of those with PTSD responded to the treatment. In addition, almost 75% of participants adhered to the study protocol, with low dropout rates.

“The brief duration of treatment, high adherence rates, and clinical benefit suggests that CGRI provides an important addition to treatment options for PD and PTSD,” the investigators write.

The study was published online in Frontiers in Digital Health.
 

‘New kid on the block’

The “respiratory dysregulation hypothesis” links CO₂ sensitivity to panic attacks and PD, and similar reactivity has been identified in PTSD, but a “common limitation of psychotherapeutic and pharmacologic approaches to PD and PTSD is that neither address the role of respiratory physiology and breathing style,” the investigators note.

The most widely studied treatment for PTSD is trauma-focused psychotherapy, in which the patient reviews and revisits the trauma, but it has a high dropout rate, study investigator Michael Telch, PhD, director of the Laboratory for the Study of Anxiety Disorders, University of Texas, Austin, told this news organization.

He described CGRI for PTSD as a “relatively new kid on the block, so to speak.” The intervention was cleared by the U.S. Food and Drug Administration for treatment of PD and PTSD in 2013 and 2018, respectively, and is currently available through the Veterans Administration for veterans with PTSD. It is also covered by some commercial insurance plans.

“The underlying assumption [of CGRI] is that a person can learn to develop skills for controlling some of their physiological reactions that are triggered as a result of trauma,” said Dr. Telch.

The device uses a biofeedback approach to give patients “greater control over their physiological reactions, such as hyperventilation and increased respiration rate, and the focus is on providing a sense of mastery,” he said.

Participants with PTSD were assigned to a health coach. The device was delivered to the patient’s home, and patients met with the trained coach weekly and could check in between visits via text or e-mail. Twice-daily sessions were recommended.

“The coach gets feedback about what’s happening with the patient’s respiration and end-tidal CO₂ levels [etCO₂] and instructs participants how to keep their respiration rate and etCO₂ at a more normal level,” said Dr. Telch.

The CGRI “teaches a specific breathing style via a system providing real-time feedback of respiratory rate (RR) and exhaled carbon dioxide levels facilitated by data capture,” the authors note.
 

Sense of mastery

Of the 1,569 participants, 1,395 had PD and 174 had PTSD (mean age, 39.2 [standard deviation, 13.9] years and 40.9 [SD, 14.9] years, respectively; 76% and 73% female, respectively). Those with PD completed the Panic Disorder Severity Scale (PDSS) and those with PTSD completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), before and after the intervention.

The treatment response rate for PD was defined as a 40% or greater reduction in PDSS total scores, whereas treatment response rate for PTSD was defined as a 10-point or greater reduction in PCL-5 scores.

At baseline, patients were classified either as normocapnic or hypocapnic (etCO₂ ≥ 37 or < 37, respectively), with 65% classified as normocapnic and 35% classified as hypocapnic.

Among patients with PD, there was a 50.2% mean pre- to posttreatment reduction in total PDSS scores (P < .001; d = 1.31), with a treatment response rate of 65.3% of patients.

Among patients with PTSD, there was a 41.1% pre- to posttreatment reduction in total PCL-5 scores (P < .001; d = 1.16), with a treatment response rate of 72.4%.

When investigators analyzed the response at the individual level, they found that 55.7% of patients with PD and 53.5% of those with PTSD were classified as treatment responders. This determination was based on a two-pronged approach that first calculated the Reliable Change Index (RCI) for each participant, and, in participants showing statistically reliable improvement, whether the posttreatment score was closer to the distribution of scores for patients without or with the given disorder.

“Patients with both normal and below-normal baseline exhaled CO2 levels experienced comparable benefit,” the authors report.

‘A viable alternative’

Commenting on the research, Charles Marmar, MD, chair and Peter H. Schub Professor of Psychiatry, department of psychiatry, New York University, said that the study has some limitations, probably the most significant of which is that most participants had normal baseline CO₂ levels.

“The treatment is fundamentally designed for people who hyperventilate and blow off too much CO₂ so they can breathe in a more calm, relaxed way, but most people in the trial had normal CO₂ to begin with,” said Dr. Marmar, who was not involved with the study.

“It’s likely that the major benefits were the relaxation from doing the breathing exercises rather than the change in CO₂ levels,” he speculated.

The treatment is “probably a good thing for those patients who actually have abnormal CO₂ levels. This treatment could be used in precision medicine, where you tailor treatments to those who actually need them rather than giving the same treatment to everyone,” he said.

“For patients who don’t respond to trauma-focused therapy or it’s too aversive for them to undergo, this new intervention provides a viable alternative,” Dr. Telch added.

The study was internally funded by Freespira. Dr. Telch is a scientific advisor at Freespira and receives compensation by way of stock options. The other authors’ disclosures are listed on the original paper. Dr. Marmar has declared no relevant financial relationships.

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

CHICAGO – A smartphone app that delivers nutritional cognitive behavioral therapy (CBT) to people with type 2 diabetes produced an average 0.29 percentage point drop in hemoglobin A1c during 180 days of use compared with controls, and an average 0.37 percentage point reduction in A1c compared with baseline values in a randomized, pivotal trial with 669 adults.

Use of the app for 180 days also significantly linked with a reduced need for additional medications, reduced weight and blood pressure, and improved patient-reported outcomes, and it led to fewer adverse effects than seen in control subjects, Marc P. Bonaca, MD, reported at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The findings also showed a clear dose-response relationship: The more CBT lessons a person completed with the app, the greater the A1c reduction.

The results suggest that the app, called BT-001, “potentially provides a scalable treatment option for patients with type 2 diabetes,” concluded Dr. Bonaca.

On the basis of the results from this trial, also called BT-001, the company developing the app, Better Therapeutics, announced in September 2022 that it had filed a classification request with the Food and Drug Administration that would allow marketing authorization for the BT-001 app. Better Therapeutics envisions that once authorized by the FDA, the app would be available to people with type 2 diabetes by prescriptions written by health care providers and that the cost for the app would be covered by health insurance, explained a company spokesperson.
 

A ‘modest positive impact’

“CBT is an empirically supported psychotherapy for a variety of emotional disorders, and it has been adapted to target specific emotional distress in the context of chronic illness,” said Amit Shapira, PhD, a clinical psychologist at the Joslin Diabetes Center in Boston who has not been involved in the BT-001 studies. A CBT protocol designed for diabetes, CBT for Adherence and Depression, “has been shown to have a positive impact on depression symptoms and glycemic control in adults with type 2 diabetes,” Dr. Shapira said in an interview.

Based on published results, the BT-001 app “seems to have a modest positive impact on glycemic control, especially among people who completed more than 10 [lesson] modules.” The evidence appears to suggest that the app “might be a good supplement to working with a behavioral health counselor.”

The BT-001 trial enrolled 669 adults with type 2 diabetes for an average of 11 years and an A1c of 7%-10.9% with an average level of 8.2%. Participants had to be on a stable medication regimen for at least 3 months but not using insulin, and their treatment regimens could undergo adjustment during the trial. At baseline, each subject was on an average of 2.1 antidiabetes medications, including 90% on metformin and 42% on a sulfonylurea. The researchers also highlighted that the enrolled cohort of people with type 2 diabetes had a demographic profile that was “generally representative” of U.S. adults with type 2 diabetes.

The researchers told the 326 people who were randomized to the active intervention group to use the app but subjects were free to determine their frequency of use. The app introduced a new lesson module weekly that took 10-20 minutes to complete, and each weekly lesson came with associated exercises aimed at practicing skills related to behavioral beliefs.

The study’s primary efficacy endpoint was the average change from baseline in A1c compared with the 343 control participants after 90 days of app use, and 610 of the 669 enrolled participants (91%) had paired baseline and 90-day measurements. At 90 days, people in the app group had an average 0.28 percentage point decrease in their A1c compared with an average 0.11 percentage point increase among the controls, a between-group difference of 0.39 percentage points. Both the reduction from baseline with app use and the reduction relative to the controls were significant. These results appeared in an article published online in in Diabetes Care.

At the scientific sessions, Dr. Bonaca presented additional outcome data after 180 days of app use. He reported an average 0.37 percentage point reduction from baseline in A1c among app users and a 0.08 percentage point decrease from baseline among the controls, for a net 0.29 percentage point incremental decline with the app, a significant difference. At 180 days, 50% of the people in the app group had an A1c decline from baseline of at least 0.4 percentage points compared with 34% of the controls, a significant difference.


 

A dose-response relationship

Notably, app use showed a clear dose-response pattern. During 180 days of app availability, people who used the app fewer than 10 times had an average reduction from baseline in their A1c of less than 0.1 percentage points. Among those who used the app 10-20 times (a subgroup with roughly one-third of the people randomized to app use) average A1c reduction increased to about 0.4 percentage points, and among those who used the app more than 20 times, also one-third of the intervention group, the average A1c reduction from baseline was about 0.6 percentage points.

“It would be interesting to learn more about the adults who engaged with the app” and had a higher use rate “to provide more targeted care” with the app to people who match the profiles of those who were more likely to use the app during the trial, said Dr. Shapira.

Dr. Bonaca, a cardiologist and vascular medicine specialist and executive director of CPC Clinical Research and CPC Community Health, an academic research organization created by and affiliated with the University of Colorado Anschutz Medical Campus in Aurora, Colo., reported several other 180-day outcomes in the BT-001 trial:

• A 33% relative decrease in the percentage of subjects who needed during the study an additional antidiabetes medication or increased dosages of their baseline medications, which occurred at a rate of 21% among the controls and 14% among those who used the app.
• An average weight loss from baseline of 5.5 pounds using the app compared with an average 1.9 pound decrease among controls, a significant difference.
• A decline in average systolic blood pressure of 4.7 mm Hg with app use compared with a 1.8 mm Hg average decline among the controls, a significant difference.
• Significant incremental average improvements in a self-reported Short Form-12 physical component score with the app compared with controls, and increased average improvement in the PHQ9 self-reported measure of depression in app users compared with controls.
• Significantly fewer treatment-emergent adverse effects, and significantly fewer serious treatment-emergent adverse effects among the app users compared with the controls.

‘Ready for clinical use’

Based on these findings, “in my view the app is ready for [routine] clinical use,” declared Judith Hsia, MD, a cardiologist and professor of medicine at the University of Colorado in Aurora, and with Dr. Bonaca a co-lead investigator for the study.

The BT-001 app can serve as “an addition to the toolkit of diabetes treatments,” Dr. Hsia said in an interview. One key advantage of the app is that, once approved, it could be available to many more people with type 2 diabetes than would be able to receive CBT directly from a therapist. Another potential plus for the CBT app is that “the effects should be durable in contrast to medications,” which must be taken on an ongoing basis to maintain effectiveness. In addition, the safety profile “is favorable compared with drug therapies, which should appeal to health care providers,” said Dr. Hsia, chief science officer for CPC Clinical Research.

However, Dr. Shapira cited the issue that therapeutic apps “raise privacy and licensing liability concerns.”

The BT-001 trial was sponsored by Better Therapeutics, the company developing the app. CPC Clinical Research receives research and consulting funding from numerous companies. Dr. Bonaca has been a consultant to Audentes, and is a stockholder of Medtronic and Pfizer. Dr. Shapira had no disclosures. Dr. Hsia is a stockholder of AstraZeneca.

CHICAGO – A smartphone app that delivers nutritional cognitive behavioral therapy (CBT) to people with type 2 diabetes produced an average 0.29 percentage point drop in hemoglobin A1c during 180 days of use compared with controls, and an average 0.37 percentage point reduction in A1c compared with baseline values in a randomized, pivotal trial with 669 adults.

Use of the app for 180 days also significantly linked with a reduced need for additional medications, reduced weight and blood pressure, and improved patient-reported outcomes, and it led to fewer adverse effects than seen in control subjects, Marc P. Bonaca, MD, reported at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The findings also showed a clear dose-response relationship: The more CBT lessons a person completed with the app, the greater the A1c reduction.

The results suggest that the app, called BT-001, “potentially provides a scalable treatment option for patients with type 2 diabetes,” concluded Dr. Bonaca.

On the basis of the results from this trial, also called BT-001, the company developing the app, Better Therapeutics, announced in September 2022 that it had filed a classification request with the Food and Drug Administration that would allow marketing authorization for the BT-001 app. Better Therapeutics envisions that once authorized by the FDA, the app would be available to people with type 2 diabetes by prescriptions written by health care providers and that the cost for the app would be covered by health insurance, explained a company spokesperson.
 

A ‘modest positive impact’

“CBT is an empirically supported psychotherapy for a variety of emotional disorders, and it has been adapted to target specific emotional distress in the context of chronic illness,” said Amit Shapira, PhD, a clinical psychologist at the Joslin Diabetes Center in Boston who has not been involved in the BT-001 studies. A CBT protocol designed for diabetes, CBT for Adherence and Depression, “has been shown to have a positive impact on depression symptoms and glycemic control in adults with type 2 diabetes,” Dr. Shapira said in an interview.

Based on published results, the BT-001 app “seems to have a modest positive impact on glycemic control, especially among people who completed more than 10 [lesson] modules.” The evidence appears to suggest that the app “might be a good supplement to working with a behavioral health counselor.”

The BT-001 trial enrolled 669 adults with type 2 diabetes for an average of 11 years and an A1c of 7%-10.9% with an average level of 8.2%. Participants had to be on a stable medication regimen for at least 3 months but not using insulin, and their treatment regimens could undergo adjustment during the trial. At baseline, each subject was on an average of 2.1 antidiabetes medications, including 90% on metformin and 42% on a sulfonylurea. The researchers also highlighted that the enrolled cohort of people with type 2 diabetes had a demographic profile that was “generally representative” of U.S. adults with type 2 diabetes.

The researchers told the 326 people who were randomized to the active intervention group to use the app but subjects were free to determine their frequency of use. The app introduced a new lesson module weekly that took 10-20 minutes to complete, and each weekly lesson came with associated exercises aimed at practicing skills related to behavioral beliefs.

The study’s primary efficacy endpoint was the average change from baseline in A1c compared with the 343 control participants after 90 days of app use, and 610 of the 669 enrolled participants (91%) had paired baseline and 90-day measurements. At 90 days, people in the app group had an average 0.28 percentage point decrease in their A1c compared with an average 0.11 percentage point increase among the controls, a between-group difference of 0.39 percentage points. Both the reduction from baseline with app use and the reduction relative to the controls were significant. These results appeared in an article published online in in Diabetes Care.

At the scientific sessions, Dr. Bonaca presented additional outcome data after 180 days of app use. He reported an average 0.37 percentage point reduction from baseline in A1c among app users and a 0.08 percentage point decrease from baseline among the controls, for a net 0.29 percentage point incremental decline with the app, a significant difference. At 180 days, 50% of the people in the app group had an A1c decline from baseline of at least 0.4 percentage points compared with 34% of the controls, a significant difference.


 

A dose-response relationship

Notably, app use showed a clear dose-response pattern. During 180 days of app availability, people who used the app fewer than 10 times had an average reduction from baseline in their A1c of less than 0.1 percentage points. Among those who used the app 10-20 times (a subgroup with roughly one-third of the people randomized to app use) average A1c reduction increased to about 0.4 percentage points, and among those who used the app more than 20 times, also one-third of the intervention group, the average A1c reduction from baseline was about 0.6 percentage points.

“It would be interesting to learn more about the adults who engaged with the app” and had a higher use rate “to provide more targeted care” with the app to people who match the profiles of those who were more likely to use the app during the trial, said Dr. Shapira.

Dr. Bonaca, a cardiologist and vascular medicine specialist and executive director of CPC Clinical Research and CPC Community Health, an academic research organization created by and affiliated with the University of Colorado Anschutz Medical Campus in Aurora, Colo., reported several other 180-day outcomes in the BT-001 trial:

• A 33% relative decrease in the percentage of subjects who needed during the study an additional antidiabetes medication or increased dosages of their baseline medications, which occurred at a rate of 21% among the controls and 14% among those who used the app.
• An average weight loss from baseline of 5.5 pounds using the app compared with an average 1.9 pound decrease among controls, a significant difference.
• A decline in average systolic blood pressure of 4.7 mm Hg with app use compared with a 1.8 mm Hg average decline among the controls, a significant difference.
• Significant incremental average improvements in a self-reported Short Form-12 physical component score with the app compared with controls, and increased average improvement in the PHQ9 self-reported measure of depression in app users compared with controls.
• Significantly fewer treatment-emergent adverse effects, and significantly fewer serious treatment-emergent adverse effects among the app users compared with the controls.

‘Ready for clinical use’

Based on these findings, “in my view the app is ready for [routine] clinical use,” declared Judith Hsia, MD, a cardiologist and professor of medicine at the University of Colorado in Aurora, and with Dr. Bonaca a co-lead investigator for the study.

The BT-001 app can serve as “an addition to the toolkit of diabetes treatments,” Dr. Hsia said in an interview. One key advantage of the app is that, once approved, it could be available to many more people with type 2 diabetes than would be able to receive CBT directly from a therapist. Another potential plus for the CBT app is that “the effects should be durable in contrast to medications,” which must be taken on an ongoing basis to maintain effectiveness. In addition, the safety profile “is favorable compared with drug therapies, which should appeal to health care providers,” said Dr. Hsia, chief science officer for CPC Clinical Research.

However, Dr. Shapira cited the issue that therapeutic apps “raise privacy and licensing liability concerns.”

The BT-001 trial was sponsored by Better Therapeutics, the company developing the app. CPC Clinical Research receives research and consulting funding from numerous companies. Dr. Bonaca has been a consultant to Audentes, and is a stockholder of Medtronic and Pfizer. Dr. Shapira had no disclosures. Dr. Hsia is a stockholder of AstraZeneca.

CHICAGO – A smartphone app that delivers nutritional cognitive behavioral therapy (CBT) to people with type 2 diabetes produced an average 0.29 percentage point drop in hemoglobin A1c during 180 days of use compared with controls, and an average 0.37 percentage point reduction in A1c compared with baseline values in a randomized, pivotal trial with 669 adults.

Use of the app for 180 days also significantly linked with a reduced need for additional medications, reduced weight and blood pressure, and improved patient-reported outcomes, and it led to fewer adverse effects than seen in control subjects, Marc P. Bonaca, MD, reported at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The findings also showed a clear dose-response relationship: The more CBT lessons a person completed with the app, the greater the A1c reduction.

The results suggest that the app, called BT-001, “potentially provides a scalable treatment option for patients with type 2 diabetes,” concluded Dr. Bonaca.

On the basis of the results from this trial, also called BT-001, the company developing the app, Better Therapeutics, announced in September 2022 that it had filed a classification request with the Food and Drug Administration that would allow marketing authorization for the BT-001 app. Better Therapeutics envisions that once authorized by the FDA, the app would be available to people with type 2 diabetes by prescriptions written by health care providers and that the cost for the app would be covered by health insurance, explained a company spokesperson.
 

A ‘modest positive impact’

“CBT is an empirically supported psychotherapy for a variety of emotional disorders, and it has been adapted to target specific emotional distress in the context of chronic illness,” said Amit Shapira, PhD, a clinical psychologist at the Joslin Diabetes Center in Boston who has not been involved in the BT-001 studies. A CBT protocol designed for diabetes, CBT for Adherence and Depression, “has been shown to have a positive impact on depression symptoms and glycemic control in adults with type 2 diabetes,” Dr. Shapira said in an interview.

Based on published results, the BT-001 app “seems to have a modest positive impact on glycemic control, especially among people who completed more than 10 [lesson] modules.” The evidence appears to suggest that the app “might be a good supplement to working with a behavioral health counselor.”

The BT-001 trial enrolled 669 adults with type 2 diabetes for an average of 11 years and an A1c of 7%-10.9% with an average level of 8.2%. Participants had to be on a stable medication regimen for at least 3 months but not using insulin, and their treatment regimens could undergo adjustment during the trial. At baseline, each subject was on an average of 2.1 antidiabetes medications, including 90% on metformin and 42% on a sulfonylurea. The researchers also highlighted that the enrolled cohort of people with type 2 diabetes had a demographic profile that was “generally representative” of U.S. adults with type 2 diabetes.

The researchers told the 326 people who were randomized to the active intervention group to use the app but subjects were free to determine their frequency of use. The app introduced a new lesson module weekly that took 10-20 minutes to complete, and each weekly lesson came with associated exercises aimed at practicing skills related to behavioral beliefs.

The study’s primary efficacy endpoint was the average change from baseline in A1c compared with the 343 control participants after 90 days of app use, and 610 of the 669 enrolled participants (91%) had paired baseline and 90-day measurements. At 90 days, people in the app group had an average 0.28 percentage point decrease in their A1c compared with an average 0.11 percentage point increase among the controls, a between-group difference of 0.39 percentage points. Both the reduction from baseline with app use and the reduction relative to the controls were significant. These results appeared in an article published online in in Diabetes Care.

At the scientific sessions, Dr. Bonaca presented additional outcome data after 180 days of app use. He reported an average 0.37 percentage point reduction from baseline in A1c among app users and a 0.08 percentage point decrease from baseline among the controls, for a net 0.29 percentage point incremental decline with the app, a significant difference. At 180 days, 50% of the people in the app group had an A1c decline from baseline of at least 0.4 percentage points compared with 34% of the controls, a significant difference.


 

A dose-response relationship

Notably, app use showed a clear dose-response pattern. During 180 days of app availability, people who used the app fewer than 10 times had an average reduction from baseline in their A1c of less than 0.1 percentage points. Among those who used the app 10-20 times (a subgroup with roughly one-third of the people randomized to app use) average A1c reduction increased to about 0.4 percentage points, and among those who used the app more than 20 times, also one-third of the intervention group, the average A1c reduction from baseline was about 0.6 percentage points.

“It would be interesting to learn more about the adults who engaged with the app” and had a higher use rate “to provide more targeted care” with the app to people who match the profiles of those who were more likely to use the app during the trial, said Dr. Shapira.

Dr. Bonaca, a cardiologist and vascular medicine specialist and executive director of CPC Clinical Research and CPC Community Health, an academic research organization created by and affiliated with the University of Colorado Anschutz Medical Campus in Aurora, Colo., reported several other 180-day outcomes in the BT-001 trial:

• A 33% relative decrease in the percentage of subjects who needed during the study an additional antidiabetes medication or increased dosages of their baseline medications, which occurred at a rate of 21% among the controls and 14% among those who used the app.
• An average weight loss from baseline of 5.5 pounds using the app compared with an average 1.9 pound decrease among controls, a significant difference.
• A decline in average systolic blood pressure of 4.7 mm Hg with app use compared with a 1.8 mm Hg average decline among the controls, a significant difference.
• Significant incremental average improvements in a self-reported Short Form-12 physical component score with the app compared with controls, and increased average improvement in the PHQ9 self-reported measure of depression in app users compared with controls.
• Significantly fewer treatment-emergent adverse effects, and significantly fewer serious treatment-emergent adverse effects among the app users compared with the controls.

‘Ready for clinical use’

Based on these findings, “in my view the app is ready for [routine] clinical use,” declared Judith Hsia, MD, a cardiologist and professor of medicine at the University of Colorado in Aurora, and with Dr. Bonaca a co-lead investigator for the study.

The BT-001 app can serve as “an addition to the toolkit of diabetes treatments,” Dr. Hsia said in an interview. One key advantage of the app is that, once approved, it could be available to many more people with type 2 diabetes than would be able to receive CBT directly from a therapist. Another potential plus for the CBT app is that “the effects should be durable in contrast to medications,” which must be taken on an ongoing basis to maintain effectiveness. In addition, the safety profile “is favorable compared with drug therapies, which should appeal to health care providers,” said Dr. Hsia, chief science officer for CPC Clinical Research.

However, Dr. Shapira cited the issue that therapeutic apps “raise privacy and licensing liability concerns.”

The BT-001 trial was sponsored by Better Therapeutics, the company developing the app. CPC Clinical Research receives research and consulting funding from numerous companies. Dr. Bonaca has been a consultant to Audentes, and is a stockholder of Medtronic and Pfizer. Dr. Shapira had no disclosures. Dr. Hsia is a stockholder of AstraZeneca.

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

A new generation of treatments appears to have caused U.S. melanoma mortality rates to plunge between 2013 and 2017 for the first time in 4 decades, a new study finds, although the dip appeared to stabilize over the next 2 years.

“This data is very encouraging and represents the real-world effectiveness of these newer therapies, which include immunotherapies and targeted therapies,” hematologist/oncologist Navkirat Kahlon, MD, MPH, of Seacoast Cancer Center and Massachusetts General Brigham Wentworth-Douglass Hospital, Dover, N.H., one of the study authors, said in an interview. In clinical trials, these new treatments “have been very effective ... so the timing as well as magnitude of drop seen in melanoma-specific population mortality was not at all surprising. But it’s still very exciting.”

The report, published in JAMA Network Open, tracked mortality rates for the deadliest form of skin cancer from 1975 to 2019. The researchers launched the study to better understand outcomes in cutaneous melanoma following the rise of new therapies that now provide options in addition to chemotherapy. “With the use of novel therapies, the survival of these patients has increased from a few weeks or months to many years in clinical trials,” Dr. Kahlon said. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world U.S. population is deriving the same benefit.”

New drugs introduced in recent years include immunotherapy agents such as ipilimumab and targeted therapies such as vemurafenib.

The researchers analyzed age-adjusted melanoma outcome data from the Surveillance, Epidemiology, and End Results (SEER) database. In 1975, the long-term melanoma mortality rate for melanoma was 2.07 per 100,000 people (95% confidence interval [CI], 2.00-2.13). It rose to 2.65 (95% CI, 2.58-2.65) in 1988 and 2.67 (95% CI, 2.61-2.72) in 2013, then fell to 2.09 (95% CI, 2.05-2.14) in 2017 and 2.01 (95% CI, 1.97-2.06) in 2019.

Per the analysis, the rate grew at an annual percentage change (APC) of 1.65% (95% CI, 1.30%-2.00%, P < .001) from 1975 to 1988 and remained stable from 1988 to 2013 (P = .85). Then it fell by an APC of 6.28% (95% CI, –8.52% to –3.97%, P < .001) from 2013 to 2017. There was no statistically significant difference between 2017 and 2019, although “the trend was downward,” the authors noted.

“Our study didn’t study the parameters that can answer the question about how many more years of life patients are getting or how many lives aren’t lost,” Dr. Kahlon said in the interview. “But looking at other studies and clinical trial data, the prognosis of these patients with a historical median overall survival of a few weeks to months has improved to many months to years.”

But why do melanoma mortality rates remain roughly about the same as they were in 1975? “The incidence of melanoma has continued to rise,” she said. “Also, over time, we have become better at collecting more accurate information, so the [rate] in 1975 could potentially be an underestimated rate.”

In an interview, dermatologist Adewole “Ade” Adamson, MD, MPP, of the University of Texas at Austin, noted that a 2020 study examined melanoma death rates in Whites – who are most affected by melanoma – and found similar trends from 2013 to 2016. “Nothing about these [new] findings surprises me as they have been shown before. However, these confirmatory findings are reassuring because they show the powerful effect of novel treatments at a population level.”

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.

SAN Antonio – How do you shoot at an invisible target? It seems counterintuitive, but trastuzumab deruxtecan (T-DXd) (Enhertu), which combines an antibody targeted to HER2 with a toxic payload, showed promising preliminary activity against localized hormone receptor–positive breast cancers with only low levels of HER2 expression (HR+/HER2-low).

In the investigator-initiated TRIO-US B-12 TALENT study looking at neoadjuvant T-DXd either alone or in combination with the hormone therapy anastrazole, the objective response rate (ORR) with T-DXd alone was 68%, compared with 58% for T-DXd plus anastrazole, reported Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital Cancer Center in Boston. He recently presented the study findings at the 2022 San Antonio Breast Cancer Symposium.

“The study provides a rich platform for additional translational research to evaluate more sensitive methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in residual disease which would guide subsequent therapeutic strategies, including combination therapy,” he said in an oral abstract session at the meeting.
 

Not-so-innocent bystander

In an interview, Dr. Bardia explained that the T-DXd may have efficacy in HER2-low cancers because of a bystander effect.

“With these antibody drug conjugates, if you have the antigen, the ADC binds to the antigen, gets internalized, and releases the payload, but the payload has a bystander effect ... it’s membrane permeable, so it can go outside and affect other cells that do not express the antigen. So for HER2-low tumors, even if there is HER2 heterogeneity or if there are some cells that do not express HER2, this would work because of the bystander effect,” he said.

Although neoadjuvant chemotherapy with an anthracycline and taxane is often used to treat patients with high-risk localized HR-positive breast cancer, the therapy is associated with low pathologic complete response (pCR) rates, radiological response rates of around 50%, and significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and leukemia risk, Dr. Bardia said.
 

At cross purposes

The trial included both a T-DXd monotherapy arm and a second arm containing the antibody drug conjugate (ADC) with endocrine therapy. The rationale for the latter is that there is documented “cross-talk” between the estrogen receptor (ER) and HER2.

“In tumors that become endocrine resistant, you see an increase in the HER2 pathway, and if you block ER, you see that HER2 goes up and vice versa. If you just block HER2 alone, the expression of ER can go up, and if you block the PI3 kinase alone, the expression of ER goes up,” he said.

Dual blockade can be effective with antibody-based therapy or with tyrosine kinase inhibitors, but with an ADC, the dual blockade strategy may be less effective, Dr. Bardia said, “because if you have an ADC, you need HER2, the ADC binds to HER2, then gives the payload to the cancer cells and essentially kills the cancer cells,” Dr. Bardia explained in a media briefing held prior to his presentation.

In fact, the T-DXd–anastrozole combination was associated with a lower overall response rate in the study than T-DXd alone, but Dr. Bardia cautioned about overinterpreting these results, as the study included only 39 patients.
 

Study details

The investigators enrolled 58 patients – 56 pre- and postmenopausal women and 2 men – with HR+/HER2-low tumors determined by local and/or central review, and operable stage II or III cancers.

After stratification by HER2 expression level and menopausal status, the patients were randomized to receive either T-DXd alone at a dose of 5.4 mg/kg, or with T-DXd at the same dose plus anastrozole, with men and premenopausal women also receiving a gonadotropin-releasing hormone analog.

The protocol originally called for six cycles of therapy, but was amended in February 2022 to increase the number to eight for newly enrolled participants and patients who were already on study treatment but had not yet had surgery.

The majority of patients in each arm had invasive ductal cancers, and most had HER2 expression on immunohistochemistry (IHC) of 1+, which is generally considered to be HER2-negative. However, there was only modest concordance between local and central review in determining HER2 expression levels, Dr. Bardia noted. Indeed, the entire question of HER2-low cancers, whether they compose a separate clinical entity from other cancers and how to standardize testing, was the subject of a special session at this year’s SABCS.
 

Results

Overall response rate, the primary endpoint, was 68% in the T-DXd arm and 58% in the T-DXd plus anastrazole arm.

Although the low response rate with the combination suggests that endocrine therapy may not be helpful in this patient population, it’s still too early to say so conclusively, Dr. Bardia said.

Looking at the change in HER2 expression by IHC from baseline to surgery, they found that 48.6% of patients had a change in HER2 IHC expression after T-DXd treatment, and that nearly 90% of these patients had a decrease in expression levels.

Among 42 patients with available data on residual cancer burden (RCB) at the time of data cutoff, one patient in the T-DXd alone arm with stage 3A disease had an RCB of 0, equivalent to a pathologic complete response (pCR). There were no other RCB 0 tumors after surgery in either study arm. The rate of combined RCB and RCB 1 (near pCR) was about 15% in each arm.

In all, 3 of the 58 patients in the study (5.2%) required dose reductions because of adverse events. There were no cases of grade 3 or greater pneumonitis, and no cases of either cardiomyopathy or neuropathy.
 

Way better than chemotherapy?

“It was very exciting when we got the DESTINY-Breast04 results showing this impressive activity of trastuzumab deruxtecan in this HER2-low entity, and now we know that hormone-positive [tumors], the majority of them are HER2-low. It was really encouraging, it was practice changing, but we were left wondering about this HER2-low entity, and can we act on it in the earlier setting,” commented Jason A. Mouabbi, MD, from the University of Texas MD Anderson Cancer Center in Houston.

“The beauty of the TRIO-US B-12 TALENT study is that it looked at the neoadjuvant setting where we know those patients who are hormone-positive usually do not respond well to chemotherapy,” he said in an interview.

He said that although the study didn’t compare T-DXd to chemotherapy, “it’s an excellent first start.”

An overall response rate near 70% “is something amazing. I’m really excited to see it against chemo. I think it’s going to do way better,” Dr. Mouabbi said.

The study was conducted by the Translational Research In Oncology (TRIO)-US network. Funding was provided by Daiichi Sankyo, the maker of trastuzumab deruxtecan (Enhertu). Dr. Bardia serves as a consultant or advisory board member for Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo, AstraZeneca, and Eli Lilly, and has received research funding from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead Sciences, Daiichi Sankyo, AstraZeneca, and Eli Lilly.

Dr. Mouabbi disclosed honoraria from BostonGene, Cardinal Health, Napo Pharmaceuticals, and Fresenius Kabi.