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Investigative botulinum toxin formulation shows prolonged effect
, according to results of a phase 3 clinical trial presented at the virtual International Congress of Parkinson’s Disease and Movement Disorders.
The ASPEN-1 trial evaluated 301 patients with moderate to severe cervical dystonia for up to 36 weeks and found that those receiving two doses of DaxibotulinumtoxinA, known as DAXI, versus placebo improved their scores on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), said Joseph Jankovic, MD, professor of neurology and director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston.
“Botulinum neurotoxin is clearly the treatment of choice for cervical dystonia,” Dr. Jankovic said in an interview. “While the majority of patients obtain satisfactory benefit from BoNT injections, some experience adverse effects such as neck weakness and difficulty swallowing.” Another limitation of BoNT is that its effects wear off after about 3 months or less and patients have to be re-injected, he said.
“This is why I am quite encouraged by the results of the DAXI study that suggest that this formulation of BoNT (type A) may have a longer response and relatively few side effects,” he said.
Patients in the study were randomized 1:3:3 to placebo, DAXI 125U or DAXI 250U. The average TWSTRS score upon enrollment was 43.3. The placebo group had a mean ± standard error TWSTRS improvement of 4.3 ± 1.8 at 4 or 6 weeks, while the treatment groups had mean ± SE improvements of 12.7 ± 1.3 for 125U and 10.9 ± 1.2 for 250U (P = .0006 vs. placebo). They translate into improvements of 12%, 31%, and 27% for the placebo and low- and high-dose treatment groups, respectively.
“Even though paradoxically it seems the high-dose group did slightly less well than the low-dose group, there was no difference between the two groups,” Dr. Jankovic said in the presentation.
The median duration of benefit was 24 weeks in the low-dose group and 20.3 weeks in the high-dose group.
The treatment groups demonstrated similar benefit compared with placebo in TWSTRS subscales for disease severity, disability, and pain, Dr. Jankovic said. “The majority of the patients had little better, moderately better, or very much better from the botulinum toxin injection with respect to clinical global impression of change and patient global impression of change,” he said.
Likewise, both the Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) demonstrated improvement versus placebo: 77.6% and 76.9% in the 125U and 250U doses versus 45.7% for the former; and 71.2% and 73.1% versus 41.3% for the latter.
Side effects “were remarkably minimal,” Dr. Jankovic said, “but I want to call attention to the low frequency of neck weakness or dysphagia in comparison with other studies of botulinum toxin in cervical dystonia.” The rates of dysphagia were 1.6% and 3.9% in the 125U and 250U treatment groups, respectively. Sixteen of the 255 patients in the treatment groups reported muscular weakness or musculoskeletal pain, and seven had dysphagia.
The rate of dysphagia after injection is noteworthy, said David Charles, MD, professor and vice chair of neurology at Vanderbilt University in Nashville, Tenn., who was not involved in the research. “The one thing we worry about most in people with cervical dystonia are swallowing and choking – dysphagia – and the numbers are very modest: 2 out of 127 in the 125U dose and 5 of 130 in the 250U dose,” he said. “That’s a very low rate of that adverse event.”
The duration of action for both doses is “rather remarkable,” Dr. Charles said. “With the other formulations, my patients are coming back every 12 weeks for treatment; the BoNT helps so much that [these] patients make their appointments every 3 months for as far out as they can,” he said. “This could potentially mean two or three trips a year as opposed to four trips a year.”
The trial was funded by Revance Therapeutics. Dr. Jankovic is an investigator for Revance, and three coauthors are employees of Revance. Dr. Charles is a consultant to the company.
, according to results of a phase 3 clinical trial presented at the virtual International Congress of Parkinson’s Disease and Movement Disorders.
The ASPEN-1 trial evaluated 301 patients with moderate to severe cervical dystonia for up to 36 weeks and found that those receiving two doses of DaxibotulinumtoxinA, known as DAXI, versus placebo improved their scores on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), said Joseph Jankovic, MD, professor of neurology and director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston.
“Botulinum neurotoxin is clearly the treatment of choice for cervical dystonia,” Dr. Jankovic said in an interview. “While the majority of patients obtain satisfactory benefit from BoNT injections, some experience adverse effects such as neck weakness and difficulty swallowing.” Another limitation of BoNT is that its effects wear off after about 3 months or less and patients have to be re-injected, he said.
“This is why I am quite encouraged by the results of the DAXI study that suggest that this formulation of BoNT (type A) may have a longer response and relatively few side effects,” he said.
Patients in the study were randomized 1:3:3 to placebo, DAXI 125U or DAXI 250U. The average TWSTRS score upon enrollment was 43.3. The placebo group had a mean ± standard error TWSTRS improvement of 4.3 ± 1.8 at 4 or 6 weeks, while the treatment groups had mean ± SE improvements of 12.7 ± 1.3 for 125U and 10.9 ± 1.2 for 250U (P = .0006 vs. placebo). They translate into improvements of 12%, 31%, and 27% for the placebo and low- and high-dose treatment groups, respectively.
“Even though paradoxically it seems the high-dose group did slightly less well than the low-dose group, there was no difference between the two groups,” Dr. Jankovic said in the presentation.
The median duration of benefit was 24 weeks in the low-dose group and 20.3 weeks in the high-dose group.
The treatment groups demonstrated similar benefit compared with placebo in TWSTRS subscales for disease severity, disability, and pain, Dr. Jankovic said. “The majority of the patients had little better, moderately better, or very much better from the botulinum toxin injection with respect to clinical global impression of change and patient global impression of change,” he said.
Likewise, both the Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) demonstrated improvement versus placebo: 77.6% and 76.9% in the 125U and 250U doses versus 45.7% for the former; and 71.2% and 73.1% versus 41.3% for the latter.
Side effects “were remarkably minimal,” Dr. Jankovic said, “but I want to call attention to the low frequency of neck weakness or dysphagia in comparison with other studies of botulinum toxin in cervical dystonia.” The rates of dysphagia were 1.6% and 3.9% in the 125U and 250U treatment groups, respectively. Sixteen of the 255 patients in the treatment groups reported muscular weakness or musculoskeletal pain, and seven had dysphagia.
The rate of dysphagia after injection is noteworthy, said David Charles, MD, professor and vice chair of neurology at Vanderbilt University in Nashville, Tenn., who was not involved in the research. “The one thing we worry about most in people with cervical dystonia are swallowing and choking – dysphagia – and the numbers are very modest: 2 out of 127 in the 125U dose and 5 of 130 in the 250U dose,” he said. “That’s a very low rate of that adverse event.”
The duration of action for both doses is “rather remarkable,” Dr. Charles said. “With the other formulations, my patients are coming back every 12 weeks for treatment; the BoNT helps so much that [these] patients make their appointments every 3 months for as far out as they can,” he said. “This could potentially mean two or three trips a year as opposed to four trips a year.”
The trial was funded by Revance Therapeutics. Dr. Jankovic is an investigator for Revance, and three coauthors are employees of Revance. Dr. Charles is a consultant to the company.
, according to results of a phase 3 clinical trial presented at the virtual International Congress of Parkinson’s Disease and Movement Disorders.
The ASPEN-1 trial evaluated 301 patients with moderate to severe cervical dystonia for up to 36 weeks and found that those receiving two doses of DaxibotulinumtoxinA, known as DAXI, versus placebo improved their scores on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), said Joseph Jankovic, MD, professor of neurology and director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston.
“Botulinum neurotoxin is clearly the treatment of choice for cervical dystonia,” Dr. Jankovic said in an interview. “While the majority of patients obtain satisfactory benefit from BoNT injections, some experience adverse effects such as neck weakness and difficulty swallowing.” Another limitation of BoNT is that its effects wear off after about 3 months or less and patients have to be re-injected, he said.
“This is why I am quite encouraged by the results of the DAXI study that suggest that this formulation of BoNT (type A) may have a longer response and relatively few side effects,” he said.
Patients in the study were randomized 1:3:3 to placebo, DAXI 125U or DAXI 250U. The average TWSTRS score upon enrollment was 43.3. The placebo group had a mean ± standard error TWSTRS improvement of 4.3 ± 1.8 at 4 or 6 weeks, while the treatment groups had mean ± SE improvements of 12.7 ± 1.3 for 125U and 10.9 ± 1.2 for 250U (P = .0006 vs. placebo). They translate into improvements of 12%, 31%, and 27% for the placebo and low- and high-dose treatment groups, respectively.
“Even though paradoxically it seems the high-dose group did slightly less well than the low-dose group, there was no difference between the two groups,” Dr. Jankovic said in the presentation.
The median duration of benefit was 24 weeks in the low-dose group and 20.3 weeks in the high-dose group.
The treatment groups demonstrated similar benefit compared with placebo in TWSTRS subscales for disease severity, disability, and pain, Dr. Jankovic said. “The majority of the patients had little better, moderately better, or very much better from the botulinum toxin injection with respect to clinical global impression of change and patient global impression of change,” he said.
Likewise, both the Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) demonstrated improvement versus placebo: 77.6% and 76.9% in the 125U and 250U doses versus 45.7% for the former; and 71.2% and 73.1% versus 41.3% for the latter.
Side effects “were remarkably minimal,” Dr. Jankovic said, “but I want to call attention to the low frequency of neck weakness or dysphagia in comparison with other studies of botulinum toxin in cervical dystonia.” The rates of dysphagia were 1.6% and 3.9% in the 125U and 250U treatment groups, respectively. Sixteen of the 255 patients in the treatment groups reported muscular weakness or musculoskeletal pain, and seven had dysphagia.
The rate of dysphagia after injection is noteworthy, said David Charles, MD, professor and vice chair of neurology at Vanderbilt University in Nashville, Tenn., who was not involved in the research. “The one thing we worry about most in people with cervical dystonia are swallowing and choking – dysphagia – and the numbers are very modest: 2 out of 127 in the 125U dose and 5 of 130 in the 250U dose,” he said. “That’s a very low rate of that adverse event.”
The duration of action for both doses is “rather remarkable,” Dr. Charles said. “With the other formulations, my patients are coming back every 12 weeks for treatment; the BoNT helps so much that [these] patients make their appointments every 3 months for as far out as they can,” he said. “This could potentially mean two or three trips a year as opposed to four trips a year.”
The trial was funded by Revance Therapeutics. Dr. Jankovic is an investigator for Revance, and three coauthors are employees of Revance. Dr. Charles is a consultant to the company.
FROM MDS VIRTUAL CONGRESS 2021
Efforts target underrepresented populations in Parkinson’s disease genetic studies
, attendees at the International Congress of Parkinson’s Disease and Movement Disorders were told.
“Through the years, as we’ve increased the number of individuals that we’ve included in our genetic studies, the number of risk factors that we’ve been able to identify has increased exponentially,” said Ignacio F. Mata, PhD, a neurogeneticist and principal investigator with the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute. “This is all due to collaborations.”
Dr. Mata reviewed no fewer than seven initiatives that are gathering genetic data from people with Parkinson’s disease in Central and South America, India, China, Africa, Oceania, the Middle East, and Central Asia, along with efforts to target diverse populations in London and African Americans in the United States.
“One of the problems that we’ve had in the past is that most of the studies have been done just with individuals that are of European ancestry, so there’s a big gap of other populations that we haven’t been able to study,” Dr. Mata said. “And this is true for all of the current studies that are ongoing here in the United States.” That includes the Parkinson’s Progression Markers Initiative, he said, in which fewer than 6% of participants are non-European. Dr. Mata is also the lead in the Global Parkinson’s Genetics Program (GP2) for underrepresented populations.
Lack of diversity in genetic studies isn’t an issue in Parkinson’s studies alone, Dr. Mata said. “This is a generalized problem across all genetic studies,” he said, citing a 2016 analysis that found the proportion of participants in genome-wide studies was 96% European descent in 2009, shifting to 80% by 2016. “There’s still a big gap because most of the non-European populations came mostly from Asia,” Dr. Mata said, with Latinos and people of African descent representing less than 1% of the study populations.
In an interview, Dr. Mata noted there are a multitude of reasons for enrolling more diverse populations. “We’re going to be able to use genetics to create new treatments and do risk prediction – the so-called precision or personalized medicine,” he said. “We’re leaving a big chunk of the population behind if we don’t include those individuals.”
Scientific basis for diversity
There are a multitude of scientific reasons for doing so, too, said Dr. Mata. “In the whole genome we try to find gene variants that modify the risk for certain disease,” he said. “These regions can be quite large, so increasing the number of individuals that come from different genetic backgrounds can actually help us reduce the number of regions that need to be studied to find the causal variants.”
Andrew Singleton, PhD, director of the Center for Alzheimer’s and Related Dementias at the National Institute of Aging in Bethesda, Md., concurred that enrolling more diverse populations can speed up research for targeting genetic variants.
“We can use the differences in genetics to narrow down our search for variants, reduce the places where we’re looking for risk variants, and reduce the number of genes we’re looking at,” he said in an interview.
Roy Alcalay, MD, professor of neurology at Columbia University Irving Medical Center in New York, offered two more scientific reasons for more diverse study populations “in addition to being more ethically appropriate,” he said. “One is, you may identify new genes that you wouldn’t have identified otherwise; and also in the genes that already exist, you may recognize that some of the pathogenic variants may be more prevalent in populations that were unknown.”
One of the challenges in casting a wider net is that much of the research funding has been concentrated in the United States and Europe, Dr. Mata said. And even in the United States, with large, diverse populations, minority groups are underrepresented in these studies, he said, but a potential solution is emerging. “This is something that we’re learning now with COVID,” he said. “We can do a lot remotely. This should help bring some of those barriers down.”
Cultural barriers are also foreboding. “Individuals may not feel comfortable participating in research,” he said in the interview. “I see this especially in the Hispanic community; many don’t understand what they can do with genetic material, or they’re afraid it will be shared with police, and if they’re here in nonofficial immigration status, they’re afraid they could be deported. There are a lot of misconceptions about genetic research.”
An initiative of the Parkinson’s Foundation PD GENEration Study is to provide free genetic tests and give the patient a report on genetic counseling “to empower patients,” Dr. Mata said.
Solutions for targeting underrepresented groups are emerging, Dr. Singleton said. “Actually there’s a really elegant solution, which is that in the populations that we go into and work with, we make sure the ownership of those cohorts, the ownership of the science and the analysis belongs to those populations,” he said.
“Part of that is creating infrastructure on site,” Dr. Singleton added. “Another part is providing training and outreach so we can help to train a whole new generation of scientists and researchers who can work in those populations embedded within those populations. They’re really the champion of moving that research forward.”
Dr. Alcalay credited Dr. Mata for his work with cohorts in Central and South America and in reaching out to other countries to recruit more diverse populations for genetic Parkinson’s studies. “And it’s not just because it’s the politically correct thing to do, about inclusivity and diversity,” Dr. Alcalay said. “It’s because it’s really meaningful. In addition to being ethically more appropriate, it will advance the entire field.
“I also really think it’s a no-brainer,” Dr. Alcalay said. “It’s something that needs to happen.”
Dr. Mata receives grant funding from the National Institutes of Health. Dr. Singleton and Dr. Alcalay have no relevant disclosures.
, attendees at the International Congress of Parkinson’s Disease and Movement Disorders were told.
“Through the years, as we’ve increased the number of individuals that we’ve included in our genetic studies, the number of risk factors that we’ve been able to identify has increased exponentially,” said Ignacio F. Mata, PhD, a neurogeneticist and principal investigator with the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute. “This is all due to collaborations.”
Dr. Mata reviewed no fewer than seven initiatives that are gathering genetic data from people with Parkinson’s disease in Central and South America, India, China, Africa, Oceania, the Middle East, and Central Asia, along with efforts to target diverse populations in London and African Americans in the United States.
“One of the problems that we’ve had in the past is that most of the studies have been done just with individuals that are of European ancestry, so there’s a big gap of other populations that we haven’t been able to study,” Dr. Mata said. “And this is true for all of the current studies that are ongoing here in the United States.” That includes the Parkinson’s Progression Markers Initiative, he said, in which fewer than 6% of participants are non-European. Dr. Mata is also the lead in the Global Parkinson’s Genetics Program (GP2) for underrepresented populations.
Lack of diversity in genetic studies isn’t an issue in Parkinson’s studies alone, Dr. Mata said. “This is a generalized problem across all genetic studies,” he said, citing a 2016 analysis that found the proportion of participants in genome-wide studies was 96% European descent in 2009, shifting to 80% by 2016. “There’s still a big gap because most of the non-European populations came mostly from Asia,” Dr. Mata said, with Latinos and people of African descent representing less than 1% of the study populations.
In an interview, Dr. Mata noted there are a multitude of reasons for enrolling more diverse populations. “We’re going to be able to use genetics to create new treatments and do risk prediction – the so-called precision or personalized medicine,” he said. “We’re leaving a big chunk of the population behind if we don’t include those individuals.”
Scientific basis for diversity
There are a multitude of scientific reasons for doing so, too, said Dr. Mata. “In the whole genome we try to find gene variants that modify the risk for certain disease,” he said. “These regions can be quite large, so increasing the number of individuals that come from different genetic backgrounds can actually help us reduce the number of regions that need to be studied to find the causal variants.”
Andrew Singleton, PhD, director of the Center for Alzheimer’s and Related Dementias at the National Institute of Aging in Bethesda, Md., concurred that enrolling more diverse populations can speed up research for targeting genetic variants.
“We can use the differences in genetics to narrow down our search for variants, reduce the places where we’re looking for risk variants, and reduce the number of genes we’re looking at,” he said in an interview.
Roy Alcalay, MD, professor of neurology at Columbia University Irving Medical Center in New York, offered two more scientific reasons for more diverse study populations “in addition to being more ethically appropriate,” he said. “One is, you may identify new genes that you wouldn’t have identified otherwise; and also in the genes that already exist, you may recognize that some of the pathogenic variants may be more prevalent in populations that were unknown.”
One of the challenges in casting a wider net is that much of the research funding has been concentrated in the United States and Europe, Dr. Mata said. And even in the United States, with large, diverse populations, minority groups are underrepresented in these studies, he said, but a potential solution is emerging. “This is something that we’re learning now with COVID,” he said. “We can do a lot remotely. This should help bring some of those barriers down.”
Cultural barriers are also foreboding. “Individuals may not feel comfortable participating in research,” he said in the interview. “I see this especially in the Hispanic community; many don’t understand what they can do with genetic material, or they’re afraid it will be shared with police, and if they’re here in nonofficial immigration status, they’re afraid they could be deported. There are a lot of misconceptions about genetic research.”
An initiative of the Parkinson’s Foundation PD GENEration Study is to provide free genetic tests and give the patient a report on genetic counseling “to empower patients,” Dr. Mata said.
Solutions for targeting underrepresented groups are emerging, Dr. Singleton said. “Actually there’s a really elegant solution, which is that in the populations that we go into and work with, we make sure the ownership of those cohorts, the ownership of the science and the analysis belongs to those populations,” he said.
“Part of that is creating infrastructure on site,” Dr. Singleton added. “Another part is providing training and outreach so we can help to train a whole new generation of scientists and researchers who can work in those populations embedded within those populations. They’re really the champion of moving that research forward.”
Dr. Alcalay credited Dr. Mata for his work with cohorts in Central and South America and in reaching out to other countries to recruit more diverse populations for genetic Parkinson’s studies. “And it’s not just because it’s the politically correct thing to do, about inclusivity and diversity,” Dr. Alcalay said. “It’s because it’s really meaningful. In addition to being ethically more appropriate, it will advance the entire field.
“I also really think it’s a no-brainer,” Dr. Alcalay said. “It’s something that needs to happen.”
Dr. Mata receives grant funding from the National Institutes of Health. Dr. Singleton and Dr. Alcalay have no relevant disclosures.
, attendees at the International Congress of Parkinson’s Disease and Movement Disorders were told.
“Through the years, as we’ve increased the number of individuals that we’ve included in our genetic studies, the number of risk factors that we’ve been able to identify has increased exponentially,” said Ignacio F. Mata, PhD, a neurogeneticist and principal investigator with the Genomic Medicine Institute of the Cleveland Clinic Lerner Research Institute. “This is all due to collaborations.”
Dr. Mata reviewed no fewer than seven initiatives that are gathering genetic data from people with Parkinson’s disease in Central and South America, India, China, Africa, Oceania, the Middle East, and Central Asia, along with efforts to target diverse populations in London and African Americans in the United States.
“One of the problems that we’ve had in the past is that most of the studies have been done just with individuals that are of European ancestry, so there’s a big gap of other populations that we haven’t been able to study,” Dr. Mata said. “And this is true for all of the current studies that are ongoing here in the United States.” That includes the Parkinson’s Progression Markers Initiative, he said, in which fewer than 6% of participants are non-European. Dr. Mata is also the lead in the Global Parkinson’s Genetics Program (GP2) for underrepresented populations.
Lack of diversity in genetic studies isn’t an issue in Parkinson’s studies alone, Dr. Mata said. “This is a generalized problem across all genetic studies,” he said, citing a 2016 analysis that found the proportion of participants in genome-wide studies was 96% European descent in 2009, shifting to 80% by 2016. “There’s still a big gap because most of the non-European populations came mostly from Asia,” Dr. Mata said, with Latinos and people of African descent representing less than 1% of the study populations.
In an interview, Dr. Mata noted there are a multitude of reasons for enrolling more diverse populations. “We’re going to be able to use genetics to create new treatments and do risk prediction – the so-called precision or personalized medicine,” he said. “We’re leaving a big chunk of the population behind if we don’t include those individuals.”
Scientific basis for diversity
There are a multitude of scientific reasons for doing so, too, said Dr. Mata. “In the whole genome we try to find gene variants that modify the risk for certain disease,” he said. “These regions can be quite large, so increasing the number of individuals that come from different genetic backgrounds can actually help us reduce the number of regions that need to be studied to find the causal variants.”
Andrew Singleton, PhD, director of the Center for Alzheimer’s and Related Dementias at the National Institute of Aging in Bethesda, Md., concurred that enrolling more diverse populations can speed up research for targeting genetic variants.
“We can use the differences in genetics to narrow down our search for variants, reduce the places where we’re looking for risk variants, and reduce the number of genes we’re looking at,” he said in an interview.
Roy Alcalay, MD, professor of neurology at Columbia University Irving Medical Center in New York, offered two more scientific reasons for more diverse study populations “in addition to being more ethically appropriate,” he said. “One is, you may identify new genes that you wouldn’t have identified otherwise; and also in the genes that already exist, you may recognize that some of the pathogenic variants may be more prevalent in populations that were unknown.”
One of the challenges in casting a wider net is that much of the research funding has been concentrated in the United States and Europe, Dr. Mata said. And even in the United States, with large, diverse populations, minority groups are underrepresented in these studies, he said, but a potential solution is emerging. “This is something that we’re learning now with COVID,” he said. “We can do a lot remotely. This should help bring some of those barriers down.”
Cultural barriers are also foreboding. “Individuals may not feel comfortable participating in research,” he said in the interview. “I see this especially in the Hispanic community; many don’t understand what they can do with genetic material, or they’re afraid it will be shared with police, and if they’re here in nonofficial immigration status, they’re afraid they could be deported. There are a lot of misconceptions about genetic research.”
An initiative of the Parkinson’s Foundation PD GENEration Study is to provide free genetic tests and give the patient a report on genetic counseling “to empower patients,” Dr. Mata said.
Solutions for targeting underrepresented groups are emerging, Dr. Singleton said. “Actually there’s a really elegant solution, which is that in the populations that we go into and work with, we make sure the ownership of those cohorts, the ownership of the science and the analysis belongs to those populations,” he said.
“Part of that is creating infrastructure on site,” Dr. Singleton added. “Another part is providing training and outreach so we can help to train a whole new generation of scientists and researchers who can work in those populations embedded within those populations. They’re really the champion of moving that research forward.”
Dr. Alcalay credited Dr. Mata for his work with cohorts in Central and South America and in reaching out to other countries to recruit more diverse populations for genetic Parkinson’s studies. “And it’s not just because it’s the politically correct thing to do, about inclusivity and diversity,” Dr. Alcalay said. “It’s because it’s really meaningful. In addition to being ethically more appropriate, it will advance the entire field.
“I also really think it’s a no-brainer,” Dr. Alcalay said. “It’s something that needs to happen.”
Dr. Mata receives grant funding from the National Institutes of Health. Dr. Singleton and Dr. Alcalay have no relevant disclosures.
FROM MDS VIRTUAL CONGRESS 2021
Time to hit pause on ‘pausing’ puberty in gender-dysphoric youth
Teens are identifying as transgender in record numbers. In 2017, 3-4 in 100 teens in the United States reported that they are or may be transgender. A more recent 2021 study suggests that the rate of transgender identification among America’s youth may be as high as 9 in 100. All of the major gender centers in the world have reported a several-thousand-percent increase in youth presenting with gender distress.
How do we reconcile these numbers with 2013 data reporting the prevalence of adult gender dysphoria to be a rare 2-14 in 100,000? Reflection is warranted because many U.S. medical societies support providing youth who have transgender identification (over 1 million children and adolescents, using the latest estimates) with access to powerful endocrine interventions.
GnRH analogues (colloquially known as “puberty blockers”) are now available at Tanner stage 2 of puberty – a threshold crossed by females as young as 8-9 years old. Cross-sex hormones and surgeries follow, and mastectomies are now available to children as young as 13. Genital-altering surgeries, as well as the removal of the ovaries, uterus, and testes, can be obtained as soon as a patient turns 18.
What’s driving this massive increase in trans-identified youth? What are the risks, benefits, and uncertainties associated with hormonal and surgical interventions? Do such interventions improve the long-term psychological health of gender-dysphoric youth? How many will regret the irreversible changes made to their bodies during what may have been a temporary phase in their development?
We don’t know the answers to these questions, but we need to figure them out before offering such interventions. Frontline clinicians – especially those working with youth – will not be able to remain on the sidelines of this issue for much longer. Each clinician considering writing a prescription for puberty blockers or cross-sex hormones, or generating a referral for surgery, will need to answer for themselves: Just because I can, does it mean I should?
What’s contributing to the rapid rise of gender-dysphoric youth?
The etiology of the rapid rise of transgender identifications in young people is vigorously debated. Proponents of hormonal and surgical interventions for youth argue that the several-thousand-percent increase in the numbers of youth seeking gender reassignment is a reflection of more social acceptance of transgender identities, allowing more young people to “come out.” But closer examination of this claim reveals several inconsistencies.
Because adolescent and young adult females now account for 6-8 in 10 of the presenting cases (previously, prepubertal males were more common), one would expect a commensurate increase in the rate of transgender identification in older females. This has not occurred. In addition, more than three-quarters of currently presenting cases have significant mental health problems or suffer from neurocognitive comorbidities such as autism spectrum disorder or attention-deficit/hyperactivity disorder – a much higher burden of mental health comorbidities than the historical cohort with gender dysphoria.
There is legitimate concern that these comorbid mental health conditions, as well as the influence of social groups and online immersion into transgender topics, may be playing a role in the rapidly growing rate of transgender identification among these particularly vulnerable youth.
The initial study positing the theory that social influence is playing a role in the increased incidence of “late” or adolescent-onset (vs. childhood-onset) transgender-identified youth was harshly attacked by proponents of medical transitioning of youth, despite the fact that the study utilized methods similar to those used in other areas of health research. The study underwent an unprecedented second peer review and emerged with largely unchanged conclusions.
Since the study’s publication, a number of mental health clinicians working directly with gender-distressed youth have corroborated a rapid onset of transgender identification among teens with previously gender-normative childhoods.
Pioneers in gender dysphoria treatment are changing course
Several European countries that were pioneers in pediatric medical transition are now reversing course toward far more caution after their own evidence evaluations failed to show that medically transitioning gender-distressed youth improves mental health outcomes. In Sweden, following Karolinska Hospital’s announcement that it will no longer transition people under 18 outside of strictly regulated clinical trials, a number of other pediatric gender clinics followed suit and made the same decision.
In the United Kingdom, Keira Bell – a young woman who was treated with “affirmative” hormonal and surgical interventions before detransitioning – brought a challenge against the national gender clinic. Her landmark case and the UK High Court’s original judgement against the clinic have highlighted the urgency to reassess treatment approaches for the increasingly varied presentations of gender dysphoria in young people. As this article went to press, the UK’s national gender clinic won its appeal against Keira Bell, meaning that doctors there will once again be able to decide whether their patients under 16 can properly consent to puberty blockers. Keira Bell said she is disappointed with this decision and will be seeking permission to appeal to the Supreme Court. She said the medical service had become “politicized,” and added: “A global conversation has begun and has been shaped by this case. It has shone a light into the dark corners of a medical scandal that is harming children and harmed me. There is more to be done.”
And the UK National Health Service (NHS) has already commissioned an independent systematic review of data, which concluded that the evidence of benefit of hormonal interventions in gender dysphoric youth is of very low certainty and must be carefully weighed against the risks. An independent taskforce has also been convened to reassess the country’s approach to treating gender dysphoric youth.
Finland has arguably undertaken the biggest change of all. An early adopter of pediatric medical transition, researchers there noticed that adolescents who had mental health struggles at baseline failed to improve after transition. The Finnish national Gender Identity Development services issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.
Leaders of America’s medical societies have been slower to respond. Recently, the Society for Evidence-Based Gender Medicine applied to share information about youth gender transitions at the yearly meeting of the American Academy of Pediatrics (AAP). The application was denied without explanation, despite the fact that 80% of rank-and-file pediatricians who voted on AAP resolutions days earlier endorsed a resolution calling for a reassessment of the evidence and more caution regarding gender transitions of minors.
The AAP leadership apparently ignored the resounding support for this resolution, but the clear message from that vote is that frontline pediatricians do not agree with the “one size fits all” approach of automatically affirming gender-distressed youth as transgender and proceeding to gender reassignment.
What we know and don’t know
There is now growing evidence that the “gender-affirming” model, based on the unproven assumption that gender reassignment is the best way to help gender-distressed youth, is not living up to its promise. This should not be surprising. Despite more than 50 years of experience with mature adult gender transitions, there is a lack of convincing evidence that transitions improve the psychological functioning of those with gender dysphoria, and studies on regret have been plagued by high dropout rates that prevent meaningful conclusions for practitioners and patients alike. Pediatric transitions are a much more recent phenomenon, with little to no quality data to guide decision-making.
We are witnessing a growing number of vocal regretters who underwent gender reassignment as teens and young adults under “gender-affirming” care protocols in recent years. A review of stories on the subreddit r/detrans, which counts over 20,000 members (not all are detransitioners, as the forum is open to those fully detransitioned, partially detransitioned, desisted [those who identified as transgender for a period of time in their youth but no longer do], and questioning their transition) is flush with first-hand accounts of regret and should be mandatory reading for any clinician who is considering becoming a prescriber of gender-affirmative care.
Here is a brief outline of what we know – and more importantly, what we don’t know – about the practice of medically transitioning minors.
Most cases of early childhood-onset gender dysphoria self-resolve. Eleven out of 11 studies that followed the trajectory of gender-variant youth show that the most common outcome is natural resolution of gender dysphoria around or after puberty. Among those diagnosed as having gender identity disorder, 67% no longer met the diagnostic criteria as adults; among those subthreshold for diagnosis, 93% were not gender dysphoric as adults. Gender dysphoria in childhood is a far better predictor of future homosexuality than of future trans identity.
The future trajectory of people whose transgender identity emerged during or after puberty is entirely unknown. No one has studied future trajectories of patients whose transgender identity emerged for the first time after the onset of puberty – a previously rare but now increasingly common presentation. Growing numbers of young detransitioners and desisters are precisely from this demographic, suggesting that a transgender identity that emerges in adolescence may not be durable.
Social transition does not improve mental health outcomes. Recent studies show that while socially transitioned children can thrive in the short term, they do not fare any better than their non–socially transitioned dysphoric peers. It appears that peer relations, not the social transition status, predict mental health in gender-dysphoric children. We don’t yet know the long-term trajectories of socially transitioned minors, but emerging evidence suggests that they may be more likely to persist with gender-related distress rather than outgrow it, as previously observed. This in turn necessitates decades of invasive and risky medical interventions. In fact, the Dutch researchers who pioneered the protocol used to medically transition minors explicitly and strongly discouraged social transition of children and early adolescents.
Nearly 100% of children who begin puberty blockers will proceed to cross-sex hormones and surgeries. The two main studies that have evaluated the effects of puberty blockers on mental health found no improvements or improvements of marginal clinical significance. Both studies are also at critical risk of bias due to the absence of control groups.
Four additional studies looking at the mental health effects of puberty blockers were plagued by design limitations and also failed to show any convincing positive effects on psychological health. However, one effect of puberty blockers has been consistently replicated: At least four studies show that virtually all of the children who start puberty blockers proceed to cross-sex hormones. This suggests that rather than being a pause button, puberty blockers may serve as the “gas pedal” for gender transition.
Most of the long-term health risks are largely unknown. No long-term studies exist of patients who underwent medical transition as teens or young adults. Therefore, our ability to assess risks vs. benefits is limited. Puberty blockers have been demonstrated to significantly impair bone health, and it is not clear whether this will result in future osteoporosis. Cross-sex hormones are associated with roughly 3-5 times the risk for heart attacks and strokes, though long-term studies are of insufficient quality for accurate risk assessments. Other risks associated with these endocrine interventions will come to light as the practice continues to scale and as young people spend years and decades on these interventions. The risks to fertility are largely unknown, but it is almost certain that if puberty blockers are given at the early stages of puberty and followed by cross-sex hormones, sterility will result.
The medical pathway of “affirmative care” rests on a single Dutch study that is not applicable to the current populations of gender-dysphoric youth. Most of the youth presenting for care today would have been explicitly disqualified by the original Dutch protocol, as most have significant mental health comorbidities and post-puberty onset of trans identities. This fact has been recognized by the principal investigators of the Dutch protocol itself, who have recently begun to sound the alarm about the potential misapplication of their protocol and who suggest that psychotherapy – rather than gender reassignment – is more appropriate for many of the currently presenting cases.
On suicidality
The urgency to put gender-dysphoric youth through gender reassignment despite the dearth of evidence appears to stem from the notion that if we don’t intervene medically and in short order, these youth will commit suicide. However, studies using quality data reveal a markedly different reality.
While gender-dysphoric youth do have elevated rates of suicidality, it’s not uniquely high. In fact, it’s roughly similar to the rate of suicidality found in populations of youth referred for other mental health conditions. Quality long-term studies that explored whether transition leads to reduced suicidality have not been able to demonstrate a reduction.
Medicine has a pattern of enthusiastically embracing unproven medical interventions, only to find out years or decades later that the harms from those interventions outweigh the benefits. We owe it to our patients to be transparent about the limits of our knowledge and the fact that the “affirmative care” pathway is largely irreversible.
When the benefits of an intervention have not been shown to outweigh the risks, medical ethics dictate that such interventions should not occur outside of clinical trials. We must not conflate medical care for gender-dysphoric youth with experimental and risky interventions that are based on low-quality evidence. It’s time to hit pause on gender transitions for youth.
A brief history of the Dutch protocol
Before the mid-1990s, medical transition was primarily reserved for mature adults. However, noting the “never-disappearing masculine appearance” of many adult male transitioners, a team of Dutch researchers hypothesized that it might be appropriate to provide early intervention to a carefully selected group of adolescents before the irreversible physical changes of puberty occur.
To differentiate the majority of gender-dysphoric children who would outgrow their cross-sex identification by adulthood from the few who would probably not have resolution and would wish to transition later in life, the Dutch gender clinic designed a rigorous screening protocol, with multidisciplinary teams closely following prospective candidates for several years.
To qualify for early intervention, the adolescents had to have had persistent and severe cross-sex identification from early childhood (cases of adolescent-onset trans identity were disqualified); the distress had to worsen during puberty; and the adolescents had to be free from any other significant mental health conditions. For qualifying adolescents, puberty blockers were initiated no earlier than 12 years of age, cross-sex hormones at 16, and surgeries upon turning 18. Ongoing psychotherapy was provided through the entire assessment and intervention period.
The Dutch team published the final results of their research in 2014. The authors reported that at the average age of 21 (approximately 1.5 years post surgery), the young people were free from gender dysphoria and functioning well. Despite a postsurgical death from infection, several new diagnoses of metabolic illness, and multiple dropouts, the Western world enthusiastically embraced the early-intervention model. Concerningly, the only attempt to replicate the Dutch protocol outside of the Netherlands failed to show any psychological improvements, and to date, no long-term outcome data are available for the cohort of the 55 treated Dutch adolescents.
These progressively irreversible interventions form the basis of the “Dutch Protocol.” Currently, this protocol is being scaled in ways it was never designed for. For example, it strongly discouraged childhood social transition and did not transition adolescents with postpubertal onset of transgender identity or those with significant mental health comorbidities. Yet, treating such cases with the interventions outlined in the Dutch protocol is now common, and the age of eligibility for hormonal and surgical interventions has progressively lowered, with children as young as 8 now eligible to begin puberty blockers.
William Malone, MD, is an assistant professor of endocrinology practicing in Southern Idaho and an adviser to the Society for Evidence-Based Gender Medicine. A version of this article first appeared on Medscape.com.
Teens are identifying as transgender in record numbers. In 2017, 3-4 in 100 teens in the United States reported that they are or may be transgender. A more recent 2021 study suggests that the rate of transgender identification among America’s youth may be as high as 9 in 100. All of the major gender centers in the world have reported a several-thousand-percent increase in youth presenting with gender distress.
How do we reconcile these numbers with 2013 data reporting the prevalence of adult gender dysphoria to be a rare 2-14 in 100,000? Reflection is warranted because many U.S. medical societies support providing youth who have transgender identification (over 1 million children and adolescents, using the latest estimates) with access to powerful endocrine interventions.
GnRH analogues (colloquially known as “puberty blockers”) are now available at Tanner stage 2 of puberty – a threshold crossed by females as young as 8-9 years old. Cross-sex hormones and surgeries follow, and mastectomies are now available to children as young as 13. Genital-altering surgeries, as well as the removal of the ovaries, uterus, and testes, can be obtained as soon as a patient turns 18.
What’s driving this massive increase in trans-identified youth? What are the risks, benefits, and uncertainties associated with hormonal and surgical interventions? Do such interventions improve the long-term psychological health of gender-dysphoric youth? How many will regret the irreversible changes made to their bodies during what may have been a temporary phase in their development?
We don’t know the answers to these questions, but we need to figure them out before offering such interventions. Frontline clinicians – especially those working with youth – will not be able to remain on the sidelines of this issue for much longer. Each clinician considering writing a prescription for puberty blockers or cross-sex hormones, or generating a referral for surgery, will need to answer for themselves: Just because I can, does it mean I should?
What’s contributing to the rapid rise of gender-dysphoric youth?
The etiology of the rapid rise of transgender identifications in young people is vigorously debated. Proponents of hormonal and surgical interventions for youth argue that the several-thousand-percent increase in the numbers of youth seeking gender reassignment is a reflection of more social acceptance of transgender identities, allowing more young people to “come out.” But closer examination of this claim reveals several inconsistencies.
Because adolescent and young adult females now account for 6-8 in 10 of the presenting cases (previously, prepubertal males were more common), one would expect a commensurate increase in the rate of transgender identification in older females. This has not occurred. In addition, more than three-quarters of currently presenting cases have significant mental health problems or suffer from neurocognitive comorbidities such as autism spectrum disorder or attention-deficit/hyperactivity disorder – a much higher burden of mental health comorbidities than the historical cohort with gender dysphoria.
There is legitimate concern that these comorbid mental health conditions, as well as the influence of social groups and online immersion into transgender topics, may be playing a role in the rapidly growing rate of transgender identification among these particularly vulnerable youth.
The initial study positing the theory that social influence is playing a role in the increased incidence of “late” or adolescent-onset (vs. childhood-onset) transgender-identified youth was harshly attacked by proponents of medical transitioning of youth, despite the fact that the study utilized methods similar to those used in other areas of health research. The study underwent an unprecedented second peer review and emerged with largely unchanged conclusions.
Since the study’s publication, a number of mental health clinicians working directly with gender-distressed youth have corroborated a rapid onset of transgender identification among teens with previously gender-normative childhoods.
Pioneers in gender dysphoria treatment are changing course
Several European countries that were pioneers in pediatric medical transition are now reversing course toward far more caution after their own evidence evaluations failed to show that medically transitioning gender-distressed youth improves mental health outcomes. In Sweden, following Karolinska Hospital’s announcement that it will no longer transition people under 18 outside of strictly regulated clinical trials, a number of other pediatric gender clinics followed suit and made the same decision.
In the United Kingdom, Keira Bell – a young woman who was treated with “affirmative” hormonal and surgical interventions before detransitioning – brought a challenge against the national gender clinic. Her landmark case and the UK High Court’s original judgement against the clinic have highlighted the urgency to reassess treatment approaches for the increasingly varied presentations of gender dysphoria in young people. As this article went to press, the UK’s national gender clinic won its appeal against Keira Bell, meaning that doctors there will once again be able to decide whether their patients under 16 can properly consent to puberty blockers. Keira Bell said she is disappointed with this decision and will be seeking permission to appeal to the Supreme Court. She said the medical service had become “politicized,” and added: “A global conversation has begun and has been shaped by this case. It has shone a light into the dark corners of a medical scandal that is harming children and harmed me. There is more to be done.”
And the UK National Health Service (NHS) has already commissioned an independent systematic review of data, which concluded that the evidence of benefit of hormonal interventions in gender dysphoric youth is of very low certainty and must be carefully weighed against the risks. An independent taskforce has also been convened to reassess the country’s approach to treating gender dysphoric youth.
Finland has arguably undertaken the biggest change of all. An early adopter of pediatric medical transition, researchers there noticed that adolescents who had mental health struggles at baseline failed to improve after transition. The Finnish national Gender Identity Development services issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.
Leaders of America’s medical societies have been slower to respond. Recently, the Society for Evidence-Based Gender Medicine applied to share information about youth gender transitions at the yearly meeting of the American Academy of Pediatrics (AAP). The application was denied without explanation, despite the fact that 80% of rank-and-file pediatricians who voted on AAP resolutions days earlier endorsed a resolution calling for a reassessment of the evidence and more caution regarding gender transitions of minors.
The AAP leadership apparently ignored the resounding support for this resolution, but the clear message from that vote is that frontline pediatricians do not agree with the “one size fits all” approach of automatically affirming gender-distressed youth as transgender and proceeding to gender reassignment.
What we know and don’t know
There is now growing evidence that the “gender-affirming” model, based on the unproven assumption that gender reassignment is the best way to help gender-distressed youth, is not living up to its promise. This should not be surprising. Despite more than 50 years of experience with mature adult gender transitions, there is a lack of convincing evidence that transitions improve the psychological functioning of those with gender dysphoria, and studies on regret have been plagued by high dropout rates that prevent meaningful conclusions for practitioners and patients alike. Pediatric transitions are a much more recent phenomenon, with little to no quality data to guide decision-making.
We are witnessing a growing number of vocal regretters who underwent gender reassignment as teens and young adults under “gender-affirming” care protocols in recent years. A review of stories on the subreddit r/detrans, which counts over 20,000 members (not all are detransitioners, as the forum is open to those fully detransitioned, partially detransitioned, desisted [those who identified as transgender for a period of time in their youth but no longer do], and questioning their transition) is flush with first-hand accounts of regret and should be mandatory reading for any clinician who is considering becoming a prescriber of gender-affirmative care.
Here is a brief outline of what we know – and more importantly, what we don’t know – about the practice of medically transitioning minors.
Most cases of early childhood-onset gender dysphoria self-resolve. Eleven out of 11 studies that followed the trajectory of gender-variant youth show that the most common outcome is natural resolution of gender dysphoria around or after puberty. Among those diagnosed as having gender identity disorder, 67% no longer met the diagnostic criteria as adults; among those subthreshold for diagnosis, 93% were not gender dysphoric as adults. Gender dysphoria in childhood is a far better predictor of future homosexuality than of future trans identity.
The future trajectory of people whose transgender identity emerged during or after puberty is entirely unknown. No one has studied future trajectories of patients whose transgender identity emerged for the first time after the onset of puberty – a previously rare but now increasingly common presentation. Growing numbers of young detransitioners and desisters are precisely from this demographic, suggesting that a transgender identity that emerges in adolescence may not be durable.
Social transition does not improve mental health outcomes. Recent studies show that while socially transitioned children can thrive in the short term, they do not fare any better than their non–socially transitioned dysphoric peers. It appears that peer relations, not the social transition status, predict mental health in gender-dysphoric children. We don’t yet know the long-term trajectories of socially transitioned minors, but emerging evidence suggests that they may be more likely to persist with gender-related distress rather than outgrow it, as previously observed. This in turn necessitates decades of invasive and risky medical interventions. In fact, the Dutch researchers who pioneered the protocol used to medically transition minors explicitly and strongly discouraged social transition of children and early adolescents.
Nearly 100% of children who begin puberty blockers will proceed to cross-sex hormones and surgeries. The two main studies that have evaluated the effects of puberty blockers on mental health found no improvements or improvements of marginal clinical significance. Both studies are also at critical risk of bias due to the absence of control groups.
Four additional studies looking at the mental health effects of puberty blockers were plagued by design limitations and also failed to show any convincing positive effects on psychological health. However, one effect of puberty blockers has been consistently replicated: At least four studies show that virtually all of the children who start puberty blockers proceed to cross-sex hormones. This suggests that rather than being a pause button, puberty blockers may serve as the “gas pedal” for gender transition.
Most of the long-term health risks are largely unknown. No long-term studies exist of patients who underwent medical transition as teens or young adults. Therefore, our ability to assess risks vs. benefits is limited. Puberty blockers have been demonstrated to significantly impair bone health, and it is not clear whether this will result in future osteoporosis. Cross-sex hormones are associated with roughly 3-5 times the risk for heart attacks and strokes, though long-term studies are of insufficient quality for accurate risk assessments. Other risks associated with these endocrine interventions will come to light as the practice continues to scale and as young people spend years and decades on these interventions. The risks to fertility are largely unknown, but it is almost certain that if puberty blockers are given at the early stages of puberty and followed by cross-sex hormones, sterility will result.
The medical pathway of “affirmative care” rests on a single Dutch study that is not applicable to the current populations of gender-dysphoric youth. Most of the youth presenting for care today would have been explicitly disqualified by the original Dutch protocol, as most have significant mental health comorbidities and post-puberty onset of trans identities. This fact has been recognized by the principal investigators of the Dutch protocol itself, who have recently begun to sound the alarm about the potential misapplication of their protocol and who suggest that psychotherapy – rather than gender reassignment – is more appropriate for many of the currently presenting cases.
On suicidality
The urgency to put gender-dysphoric youth through gender reassignment despite the dearth of evidence appears to stem from the notion that if we don’t intervene medically and in short order, these youth will commit suicide. However, studies using quality data reveal a markedly different reality.
While gender-dysphoric youth do have elevated rates of suicidality, it’s not uniquely high. In fact, it’s roughly similar to the rate of suicidality found in populations of youth referred for other mental health conditions. Quality long-term studies that explored whether transition leads to reduced suicidality have not been able to demonstrate a reduction.
Medicine has a pattern of enthusiastically embracing unproven medical interventions, only to find out years or decades later that the harms from those interventions outweigh the benefits. We owe it to our patients to be transparent about the limits of our knowledge and the fact that the “affirmative care” pathway is largely irreversible.
When the benefits of an intervention have not been shown to outweigh the risks, medical ethics dictate that such interventions should not occur outside of clinical trials. We must not conflate medical care for gender-dysphoric youth with experimental and risky interventions that are based on low-quality evidence. It’s time to hit pause on gender transitions for youth.
A brief history of the Dutch protocol
Before the mid-1990s, medical transition was primarily reserved for mature adults. However, noting the “never-disappearing masculine appearance” of many adult male transitioners, a team of Dutch researchers hypothesized that it might be appropriate to provide early intervention to a carefully selected group of adolescents before the irreversible physical changes of puberty occur.
To differentiate the majority of gender-dysphoric children who would outgrow their cross-sex identification by adulthood from the few who would probably not have resolution and would wish to transition later in life, the Dutch gender clinic designed a rigorous screening protocol, with multidisciplinary teams closely following prospective candidates for several years.
To qualify for early intervention, the adolescents had to have had persistent and severe cross-sex identification from early childhood (cases of adolescent-onset trans identity were disqualified); the distress had to worsen during puberty; and the adolescents had to be free from any other significant mental health conditions. For qualifying adolescents, puberty blockers were initiated no earlier than 12 years of age, cross-sex hormones at 16, and surgeries upon turning 18. Ongoing psychotherapy was provided through the entire assessment and intervention period.
The Dutch team published the final results of their research in 2014. The authors reported that at the average age of 21 (approximately 1.5 years post surgery), the young people were free from gender dysphoria and functioning well. Despite a postsurgical death from infection, several new diagnoses of metabolic illness, and multiple dropouts, the Western world enthusiastically embraced the early-intervention model. Concerningly, the only attempt to replicate the Dutch protocol outside of the Netherlands failed to show any psychological improvements, and to date, no long-term outcome data are available for the cohort of the 55 treated Dutch adolescents.
These progressively irreversible interventions form the basis of the “Dutch Protocol.” Currently, this protocol is being scaled in ways it was never designed for. For example, it strongly discouraged childhood social transition and did not transition adolescents with postpubertal onset of transgender identity or those with significant mental health comorbidities. Yet, treating such cases with the interventions outlined in the Dutch protocol is now common, and the age of eligibility for hormonal and surgical interventions has progressively lowered, with children as young as 8 now eligible to begin puberty blockers.
William Malone, MD, is an assistant professor of endocrinology practicing in Southern Idaho and an adviser to the Society for Evidence-Based Gender Medicine. A version of this article first appeared on Medscape.com.
Teens are identifying as transgender in record numbers. In 2017, 3-4 in 100 teens in the United States reported that they are or may be transgender. A more recent 2021 study suggests that the rate of transgender identification among America’s youth may be as high as 9 in 100. All of the major gender centers in the world have reported a several-thousand-percent increase in youth presenting with gender distress.
How do we reconcile these numbers with 2013 data reporting the prevalence of adult gender dysphoria to be a rare 2-14 in 100,000? Reflection is warranted because many U.S. medical societies support providing youth who have transgender identification (over 1 million children and adolescents, using the latest estimates) with access to powerful endocrine interventions.
GnRH analogues (colloquially known as “puberty blockers”) are now available at Tanner stage 2 of puberty – a threshold crossed by females as young as 8-9 years old. Cross-sex hormones and surgeries follow, and mastectomies are now available to children as young as 13. Genital-altering surgeries, as well as the removal of the ovaries, uterus, and testes, can be obtained as soon as a patient turns 18.
What’s driving this massive increase in trans-identified youth? What are the risks, benefits, and uncertainties associated with hormonal and surgical interventions? Do such interventions improve the long-term psychological health of gender-dysphoric youth? How many will regret the irreversible changes made to their bodies during what may have been a temporary phase in their development?
We don’t know the answers to these questions, but we need to figure them out before offering such interventions. Frontline clinicians – especially those working with youth – will not be able to remain on the sidelines of this issue for much longer. Each clinician considering writing a prescription for puberty blockers or cross-sex hormones, or generating a referral for surgery, will need to answer for themselves: Just because I can, does it mean I should?
What’s contributing to the rapid rise of gender-dysphoric youth?
The etiology of the rapid rise of transgender identifications in young people is vigorously debated. Proponents of hormonal and surgical interventions for youth argue that the several-thousand-percent increase in the numbers of youth seeking gender reassignment is a reflection of more social acceptance of transgender identities, allowing more young people to “come out.” But closer examination of this claim reveals several inconsistencies.
Because adolescent and young adult females now account for 6-8 in 10 of the presenting cases (previously, prepubertal males were more common), one would expect a commensurate increase in the rate of transgender identification in older females. This has not occurred. In addition, more than three-quarters of currently presenting cases have significant mental health problems or suffer from neurocognitive comorbidities such as autism spectrum disorder or attention-deficit/hyperactivity disorder – a much higher burden of mental health comorbidities than the historical cohort with gender dysphoria.
There is legitimate concern that these comorbid mental health conditions, as well as the influence of social groups and online immersion into transgender topics, may be playing a role in the rapidly growing rate of transgender identification among these particularly vulnerable youth.
The initial study positing the theory that social influence is playing a role in the increased incidence of “late” or adolescent-onset (vs. childhood-onset) transgender-identified youth was harshly attacked by proponents of medical transitioning of youth, despite the fact that the study utilized methods similar to those used in other areas of health research. The study underwent an unprecedented second peer review and emerged with largely unchanged conclusions.
Since the study’s publication, a number of mental health clinicians working directly with gender-distressed youth have corroborated a rapid onset of transgender identification among teens with previously gender-normative childhoods.
Pioneers in gender dysphoria treatment are changing course
Several European countries that were pioneers in pediatric medical transition are now reversing course toward far more caution after their own evidence evaluations failed to show that medically transitioning gender-distressed youth improves mental health outcomes. In Sweden, following Karolinska Hospital’s announcement that it will no longer transition people under 18 outside of strictly regulated clinical trials, a number of other pediatric gender clinics followed suit and made the same decision.
In the United Kingdom, Keira Bell – a young woman who was treated with “affirmative” hormonal and surgical interventions before detransitioning – brought a challenge against the national gender clinic. Her landmark case and the UK High Court’s original judgement against the clinic have highlighted the urgency to reassess treatment approaches for the increasingly varied presentations of gender dysphoria in young people. As this article went to press, the UK’s national gender clinic won its appeal against Keira Bell, meaning that doctors there will once again be able to decide whether their patients under 16 can properly consent to puberty blockers. Keira Bell said she is disappointed with this decision and will be seeking permission to appeal to the Supreme Court. She said the medical service had become “politicized,” and added: “A global conversation has begun and has been shaped by this case. It has shone a light into the dark corners of a medical scandal that is harming children and harmed me. There is more to be done.”
And the UK National Health Service (NHS) has already commissioned an independent systematic review of data, which concluded that the evidence of benefit of hormonal interventions in gender dysphoric youth is of very low certainty and must be carefully weighed against the risks. An independent taskforce has also been convened to reassess the country’s approach to treating gender dysphoric youth.
Finland has arguably undertaken the biggest change of all. An early adopter of pediatric medical transition, researchers there noticed that adolescents who had mental health struggles at baseline failed to improve after transition. The Finnish national Gender Identity Development services issued new treatment guidelines in 2020 stating that psychotherapy, rather than gender reassignment, should be the first line of treatment for gender-dysphoric youth.
Leaders of America’s medical societies have been slower to respond. Recently, the Society for Evidence-Based Gender Medicine applied to share information about youth gender transitions at the yearly meeting of the American Academy of Pediatrics (AAP). The application was denied without explanation, despite the fact that 80% of rank-and-file pediatricians who voted on AAP resolutions days earlier endorsed a resolution calling for a reassessment of the evidence and more caution regarding gender transitions of minors.
The AAP leadership apparently ignored the resounding support for this resolution, but the clear message from that vote is that frontline pediatricians do not agree with the “one size fits all” approach of automatically affirming gender-distressed youth as transgender and proceeding to gender reassignment.
What we know and don’t know
There is now growing evidence that the “gender-affirming” model, based on the unproven assumption that gender reassignment is the best way to help gender-distressed youth, is not living up to its promise. This should not be surprising. Despite more than 50 years of experience with mature adult gender transitions, there is a lack of convincing evidence that transitions improve the psychological functioning of those with gender dysphoria, and studies on regret have been plagued by high dropout rates that prevent meaningful conclusions for practitioners and patients alike. Pediatric transitions are a much more recent phenomenon, with little to no quality data to guide decision-making.
We are witnessing a growing number of vocal regretters who underwent gender reassignment as teens and young adults under “gender-affirming” care protocols in recent years. A review of stories on the subreddit r/detrans, which counts over 20,000 members (not all are detransitioners, as the forum is open to those fully detransitioned, partially detransitioned, desisted [those who identified as transgender for a period of time in their youth but no longer do], and questioning their transition) is flush with first-hand accounts of regret and should be mandatory reading for any clinician who is considering becoming a prescriber of gender-affirmative care.
Here is a brief outline of what we know – and more importantly, what we don’t know – about the practice of medically transitioning minors.
Most cases of early childhood-onset gender dysphoria self-resolve. Eleven out of 11 studies that followed the trajectory of gender-variant youth show that the most common outcome is natural resolution of gender dysphoria around or after puberty. Among those diagnosed as having gender identity disorder, 67% no longer met the diagnostic criteria as adults; among those subthreshold for diagnosis, 93% were not gender dysphoric as adults. Gender dysphoria in childhood is a far better predictor of future homosexuality than of future trans identity.
The future trajectory of people whose transgender identity emerged during or after puberty is entirely unknown. No one has studied future trajectories of patients whose transgender identity emerged for the first time after the onset of puberty – a previously rare but now increasingly common presentation. Growing numbers of young detransitioners and desisters are precisely from this demographic, suggesting that a transgender identity that emerges in adolescence may not be durable.
Social transition does not improve mental health outcomes. Recent studies show that while socially transitioned children can thrive in the short term, they do not fare any better than their non–socially transitioned dysphoric peers. It appears that peer relations, not the social transition status, predict mental health in gender-dysphoric children. We don’t yet know the long-term trajectories of socially transitioned minors, but emerging evidence suggests that they may be more likely to persist with gender-related distress rather than outgrow it, as previously observed. This in turn necessitates decades of invasive and risky medical interventions. In fact, the Dutch researchers who pioneered the protocol used to medically transition minors explicitly and strongly discouraged social transition of children and early adolescents.
Nearly 100% of children who begin puberty blockers will proceed to cross-sex hormones and surgeries. The two main studies that have evaluated the effects of puberty blockers on mental health found no improvements or improvements of marginal clinical significance. Both studies are also at critical risk of bias due to the absence of control groups.
Four additional studies looking at the mental health effects of puberty blockers were plagued by design limitations and also failed to show any convincing positive effects on psychological health. However, one effect of puberty blockers has been consistently replicated: At least four studies show that virtually all of the children who start puberty blockers proceed to cross-sex hormones. This suggests that rather than being a pause button, puberty blockers may serve as the “gas pedal” for gender transition.
Most of the long-term health risks are largely unknown. No long-term studies exist of patients who underwent medical transition as teens or young adults. Therefore, our ability to assess risks vs. benefits is limited. Puberty blockers have been demonstrated to significantly impair bone health, and it is not clear whether this will result in future osteoporosis. Cross-sex hormones are associated with roughly 3-5 times the risk for heart attacks and strokes, though long-term studies are of insufficient quality for accurate risk assessments. Other risks associated with these endocrine interventions will come to light as the practice continues to scale and as young people spend years and decades on these interventions. The risks to fertility are largely unknown, but it is almost certain that if puberty blockers are given at the early stages of puberty and followed by cross-sex hormones, sterility will result.
The medical pathway of “affirmative care” rests on a single Dutch study that is not applicable to the current populations of gender-dysphoric youth. Most of the youth presenting for care today would have been explicitly disqualified by the original Dutch protocol, as most have significant mental health comorbidities and post-puberty onset of trans identities. This fact has been recognized by the principal investigators of the Dutch protocol itself, who have recently begun to sound the alarm about the potential misapplication of their protocol and who suggest that psychotherapy – rather than gender reassignment – is more appropriate for many of the currently presenting cases.
On suicidality
The urgency to put gender-dysphoric youth through gender reassignment despite the dearth of evidence appears to stem from the notion that if we don’t intervene medically and in short order, these youth will commit suicide. However, studies using quality data reveal a markedly different reality.
While gender-dysphoric youth do have elevated rates of suicidality, it’s not uniquely high. In fact, it’s roughly similar to the rate of suicidality found in populations of youth referred for other mental health conditions. Quality long-term studies that explored whether transition leads to reduced suicidality have not been able to demonstrate a reduction.
Medicine has a pattern of enthusiastically embracing unproven medical interventions, only to find out years or decades later that the harms from those interventions outweigh the benefits. We owe it to our patients to be transparent about the limits of our knowledge and the fact that the “affirmative care” pathway is largely irreversible.
When the benefits of an intervention have not been shown to outweigh the risks, medical ethics dictate that such interventions should not occur outside of clinical trials. We must not conflate medical care for gender-dysphoric youth with experimental and risky interventions that are based on low-quality evidence. It’s time to hit pause on gender transitions for youth.
A brief history of the Dutch protocol
Before the mid-1990s, medical transition was primarily reserved for mature adults. However, noting the “never-disappearing masculine appearance” of many adult male transitioners, a team of Dutch researchers hypothesized that it might be appropriate to provide early intervention to a carefully selected group of adolescents before the irreversible physical changes of puberty occur.
To differentiate the majority of gender-dysphoric children who would outgrow their cross-sex identification by adulthood from the few who would probably not have resolution and would wish to transition later in life, the Dutch gender clinic designed a rigorous screening protocol, with multidisciplinary teams closely following prospective candidates for several years.
To qualify for early intervention, the adolescents had to have had persistent and severe cross-sex identification from early childhood (cases of adolescent-onset trans identity were disqualified); the distress had to worsen during puberty; and the adolescents had to be free from any other significant mental health conditions. For qualifying adolescents, puberty blockers were initiated no earlier than 12 years of age, cross-sex hormones at 16, and surgeries upon turning 18. Ongoing psychotherapy was provided through the entire assessment and intervention period.
The Dutch team published the final results of their research in 2014. The authors reported that at the average age of 21 (approximately 1.5 years post surgery), the young people were free from gender dysphoria and functioning well. Despite a postsurgical death from infection, several new diagnoses of metabolic illness, and multiple dropouts, the Western world enthusiastically embraced the early-intervention model. Concerningly, the only attempt to replicate the Dutch protocol outside of the Netherlands failed to show any psychological improvements, and to date, no long-term outcome data are available for the cohort of the 55 treated Dutch adolescents.
These progressively irreversible interventions form the basis of the “Dutch Protocol.” Currently, this protocol is being scaled in ways it was never designed for. For example, it strongly discouraged childhood social transition and did not transition adolescents with postpubertal onset of transgender identity or those with significant mental health comorbidities. Yet, treating such cases with the interventions outlined in the Dutch protocol is now common, and the age of eligibility for hormonal and surgical interventions has progressively lowered, with children as young as 8 now eligible to begin puberty blockers.
William Malone, MD, is an assistant professor of endocrinology practicing in Southern Idaho and an adviser to the Society for Evidence-Based Gender Medicine. A version of this article first appeared on Medscape.com.
Synthetic triglyceride shows potential in Huntington’s disease
, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.
“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”
TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.
TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).
Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).
Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
‘The first good news’
Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.
“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”
She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.
As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.
However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.
Dr. Mochel said that the findings are prompting the investigators to consider just that.
Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.
, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.
“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”
TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.
TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).
Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).
Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
‘The first good news’
Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.
“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”
She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.
As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.
However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.
Dr. Mochel said that the findings are prompting the investigators to consider just that.
Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.
, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.
Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.
“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”
TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.
TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).
Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).
Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
‘The first good news’
Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.
“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”
She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.
As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.
However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.
Dr. Mochel said that the findings are prompting the investigators to consider just that.
Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.
FROM MDS VIRTUAL CONGRESS 2021
Mean leadership
The differences between the mean and median of leadership data
Let me apologize for misleading all of you; this is not an article about malignant physician leaders; instead, it goes over the numbers and trends uncovered by the 2020 State of Hospital Medicine report (SoHM).1 The hospital medicine leader ends up doing many tasks like planning, growth, collaboration, finance, recruiting, scheduling, onboarding, coaching, and most near and dear to our hearts, putting out the fires and conflict resolution.
Ratio of leadership FTE to physician hospitalists FTE
If my pun has already put you off, you can avoid reading the rest of the piece and go to the 2020 SoHM to look at pages 52 (Table 3.7c), 121 (Table 4.7c), and 166 (Table 5.7c). It has a newly added table (3.7c), and it is phenomenal; it is the ratio of leadership FTE to physician hospitalists FTE. As an avid user of SoHM, I always ended up doing a makeshift calculation to “guesstimate” this number. Now that we have it calculated for us and the ultimate revelation lies in its narrow range across all groups. We might differ in the region, employment type, academics, teaching, or size, but this range is relatively narrow.
The median ratio of leadership FTE to total FTE lies between 2% and 5% in pediatric groups and between 3% and 6% for most adult groups. The only two outliers are on the adult side, with less than 5 FTE and multistate management companies. The higher median for the less than 5 FTE group size is understandable because of the small number of hospitalist FTEs that the leader’s time must be spread over. Even a small amount of dedicated leadership time will result in a high ratio of leader time to hospitalist clinical time if the group is very small. The multistate management company is probably a result of multiple layers of physician leadership (for example, regional medical directors) and travel-related time adjustments. Still, it raises the question of why the local leadership is not developed to decrease the leadership cost and better access.
Another helpful pattern is the decrease in standard deviation with the increase in group size. The hospital medicine leaders and CEOs of the hospital need to watch this number closely; any extremes on high or low side would be indicators for a deep dive in leadership structure and health.
Total number and total dedicated FTE for all physician leaders
Once we start seeing the differences between the mean and median of leadership data, we can see the median is relatively static while the mean has increased year after year and took a big jump in the 2020 SoHM. The chart below shows trends for the number of individuals in leadership positions (“Total No” and total FTEs allocated to leadership (“Total FTE”) over the last several surveys. The data is heavily skewed toward the right (positive); so, it makes sense to use the median in this case rather than mean. A few factors could explain the right skew of data.
- Large groups of 30 or more hospitalists are increasing, and so is their leadership need.
- There is more recognition of the need for dedicated leadership individuals and FTE.
- The leadership is getting less concentrated among just one or a few leaders.
- Outliers on the high side.
- Lower bounds of 0 or 0.1 FTE.
Highest-ranked leader dedicated FTE and premium compensation
Another pleasing trend is an increase in dedicated FTE for the highest-paid leader. Like any skill-set development, leadership requires the investment of deliberate practice, financial acumen, negotiation skills, and increased vulnerability. Time helps way more in developing these skill sets than money. SoHM trends show increase in dedicated FTE for the highest physician leader over the years and static premium compensation.
At last, we can say median leadership is always better than “mean” leadership in skewed data. Pun apart, every group needs leadership, and SoHM offers a nice window to the trends in leadership amongst many practice groups. It is a valuable resource for every group.
Dr. Chadha is chief of the division of hospital medicine at the University of Kentucky Healthcare, Lexington. He actively leads efforts of recruiting, practice analysis, and operation of the group. He is finishing his first tenure in the Practice Analysis Committee. He is often found spending a lot more than required time with spreadsheets and graphs.
Reference
1. 2020 State of Hospital Medicine. www.hospitalmedicine.org/practice-management/shms-state-of-hospital-medicine/
The differences between the mean and median of leadership data
The differences between the mean and median of leadership data
Let me apologize for misleading all of you; this is not an article about malignant physician leaders; instead, it goes over the numbers and trends uncovered by the 2020 State of Hospital Medicine report (SoHM).1 The hospital medicine leader ends up doing many tasks like planning, growth, collaboration, finance, recruiting, scheduling, onboarding, coaching, and most near and dear to our hearts, putting out the fires and conflict resolution.
Ratio of leadership FTE to physician hospitalists FTE
If my pun has already put you off, you can avoid reading the rest of the piece and go to the 2020 SoHM to look at pages 52 (Table 3.7c), 121 (Table 4.7c), and 166 (Table 5.7c). It has a newly added table (3.7c), and it is phenomenal; it is the ratio of leadership FTE to physician hospitalists FTE. As an avid user of SoHM, I always ended up doing a makeshift calculation to “guesstimate” this number. Now that we have it calculated for us and the ultimate revelation lies in its narrow range across all groups. We might differ in the region, employment type, academics, teaching, or size, but this range is relatively narrow.
The median ratio of leadership FTE to total FTE lies between 2% and 5% in pediatric groups and between 3% and 6% for most adult groups. The only two outliers are on the adult side, with less than 5 FTE and multistate management companies. The higher median for the less than 5 FTE group size is understandable because of the small number of hospitalist FTEs that the leader’s time must be spread over. Even a small amount of dedicated leadership time will result in a high ratio of leader time to hospitalist clinical time if the group is very small. The multistate management company is probably a result of multiple layers of physician leadership (for example, regional medical directors) and travel-related time adjustments. Still, it raises the question of why the local leadership is not developed to decrease the leadership cost and better access.
Another helpful pattern is the decrease in standard deviation with the increase in group size. The hospital medicine leaders and CEOs of the hospital need to watch this number closely; any extremes on high or low side would be indicators for a deep dive in leadership structure and health.
Total number and total dedicated FTE for all physician leaders
Once we start seeing the differences between the mean and median of leadership data, we can see the median is relatively static while the mean has increased year after year and took a big jump in the 2020 SoHM. The chart below shows trends for the number of individuals in leadership positions (“Total No” and total FTEs allocated to leadership (“Total FTE”) over the last several surveys. The data is heavily skewed toward the right (positive); so, it makes sense to use the median in this case rather than mean. A few factors could explain the right skew of data.
- Large groups of 30 or more hospitalists are increasing, and so is their leadership need.
- There is more recognition of the need for dedicated leadership individuals and FTE.
- The leadership is getting less concentrated among just one or a few leaders.
- Outliers on the high side.
- Lower bounds of 0 or 0.1 FTE.
Highest-ranked leader dedicated FTE and premium compensation
Another pleasing trend is an increase in dedicated FTE for the highest-paid leader. Like any skill-set development, leadership requires the investment of deliberate practice, financial acumen, negotiation skills, and increased vulnerability. Time helps way more in developing these skill sets than money. SoHM trends show increase in dedicated FTE for the highest physician leader over the years and static premium compensation.
At last, we can say median leadership is always better than “mean” leadership in skewed data. Pun apart, every group needs leadership, and SoHM offers a nice window to the trends in leadership amongst many practice groups. It is a valuable resource for every group.
Dr. Chadha is chief of the division of hospital medicine at the University of Kentucky Healthcare, Lexington. He actively leads efforts of recruiting, practice analysis, and operation of the group. He is finishing his first tenure in the Practice Analysis Committee. He is often found spending a lot more than required time with spreadsheets and graphs.
Reference
1. 2020 State of Hospital Medicine. www.hospitalmedicine.org/practice-management/shms-state-of-hospital-medicine/
Let me apologize for misleading all of you; this is not an article about malignant physician leaders; instead, it goes over the numbers and trends uncovered by the 2020 State of Hospital Medicine report (SoHM).1 The hospital medicine leader ends up doing many tasks like planning, growth, collaboration, finance, recruiting, scheduling, onboarding, coaching, and most near and dear to our hearts, putting out the fires and conflict resolution.
Ratio of leadership FTE to physician hospitalists FTE
If my pun has already put you off, you can avoid reading the rest of the piece and go to the 2020 SoHM to look at pages 52 (Table 3.7c), 121 (Table 4.7c), and 166 (Table 5.7c). It has a newly added table (3.7c), and it is phenomenal; it is the ratio of leadership FTE to physician hospitalists FTE. As an avid user of SoHM, I always ended up doing a makeshift calculation to “guesstimate” this number. Now that we have it calculated for us and the ultimate revelation lies in its narrow range across all groups. We might differ in the region, employment type, academics, teaching, or size, but this range is relatively narrow.
The median ratio of leadership FTE to total FTE lies between 2% and 5% in pediatric groups and between 3% and 6% for most adult groups. The only two outliers are on the adult side, with less than 5 FTE and multistate management companies. The higher median for the less than 5 FTE group size is understandable because of the small number of hospitalist FTEs that the leader’s time must be spread over. Even a small amount of dedicated leadership time will result in a high ratio of leader time to hospitalist clinical time if the group is very small. The multistate management company is probably a result of multiple layers of physician leadership (for example, regional medical directors) and travel-related time adjustments. Still, it raises the question of why the local leadership is not developed to decrease the leadership cost and better access.
Another helpful pattern is the decrease in standard deviation with the increase in group size. The hospital medicine leaders and CEOs of the hospital need to watch this number closely; any extremes on high or low side would be indicators for a deep dive in leadership structure and health.
Total number and total dedicated FTE for all physician leaders
Once we start seeing the differences between the mean and median of leadership data, we can see the median is relatively static while the mean has increased year after year and took a big jump in the 2020 SoHM. The chart below shows trends for the number of individuals in leadership positions (“Total No” and total FTEs allocated to leadership (“Total FTE”) over the last several surveys. The data is heavily skewed toward the right (positive); so, it makes sense to use the median in this case rather than mean. A few factors could explain the right skew of data.
- Large groups of 30 or more hospitalists are increasing, and so is their leadership need.
- There is more recognition of the need for dedicated leadership individuals and FTE.
- The leadership is getting less concentrated among just one or a few leaders.
- Outliers on the high side.
- Lower bounds of 0 or 0.1 FTE.
Highest-ranked leader dedicated FTE and premium compensation
Another pleasing trend is an increase in dedicated FTE for the highest-paid leader. Like any skill-set development, leadership requires the investment of deliberate practice, financial acumen, negotiation skills, and increased vulnerability. Time helps way more in developing these skill sets than money. SoHM trends show increase in dedicated FTE for the highest physician leader over the years and static premium compensation.
At last, we can say median leadership is always better than “mean” leadership in skewed data. Pun apart, every group needs leadership, and SoHM offers a nice window to the trends in leadership amongst many practice groups. It is a valuable resource for every group.
Dr. Chadha is chief of the division of hospital medicine at the University of Kentucky Healthcare, Lexington. He actively leads efforts of recruiting, practice analysis, and operation of the group. He is finishing his first tenure in the Practice Analysis Committee. He is often found spending a lot more than required time with spreadsheets and graphs.
Reference
1. 2020 State of Hospital Medicine. www.hospitalmedicine.org/practice-management/shms-state-of-hospital-medicine/
Pandemic restrictions ignite innovative pivot for psychiatry
As medical school faculty members – and our students – know well, the COVID-19 pandemic forced us to become creative and shift much of our curricula online. Many hospitals chose to limit medical student rotations because of safety concerns. Students fell victim to canceled psychiatry rotations and electives during the pandemic’s early days. Privacy issues, combined with stigma tied to mental illness, made this shift to virtual instruction particularly challenging. But as a field, we persevered! And, as we learned during our shift toward telemedicine, many of the changes we made in medical education are probably here to stay.
Our team at the New York Institute of Technology College of Osteopathic Medicine (NYITCOM) was able to implement a novel curriculum that allowed our students to learn psychiatry and maintain high-quality medical school education.
We developed an online course for third-year students’ rotation in psychiatry, with several modules that focused on a variety of psychiatric topics and disorders, including the basic classifications and categories of depression, anxiety, personality disorders, and psychotic disorders. There were also video encounters available showing actual patient encounters. On completion of the online module, a faculty session was held to discuss topics of concern/confusion to the students, areas of interest, and a variety of related topics, such as professionalism in psychiatry, essentials of the mental status exam, management of diverse populations, and COVID repercussions in psychiatry.
For fourth-year students, we developed a telemedicine psychiatry elective, which allowed the students to observe psychiatric evaluations, psychiatric medication review visits, and even follow-up psychotherapy sessions, with the school’s clinical psychologists. The new method was minimally invasive, and it was accepted by patients and welcomed by the students.
During a time when hospitals were limiting onsite student rotations and discouraging patient contact, medical students still needed to experience patient interactions. As the director of the school’s Center for Behavioral Health, I designed an additional program that allowed students to participate in observing patients who presented with psychiatric complaints and symptoms. It had to be confidential in nature, accessible, and safe.
I recalled my own training in a hospital setting, where students and residents were allowed to observe a patient being evaluated by an attending, through a one-way mirror. It was a method that was acceptable at the time in a hospital, but unfortunately, not in a private office setting. As such, students and residents experienced such an interaction in acute inpatient and/or outpatient clinics of a hospital. The experience was invaluable.
The concept was simple, yet very efficient. The clinicians in the Center for Behavioral Health were seeing all patients with psychiatric needs via a HIPAA-compliant telemedicine platform. Access was granted for students – with the patient’s consent – and they “entered the session” without being seen or heard. This presented little to no distraction to the patient, and the student was able to observe a range of clinical sessions.
The course also provided online supplemental modules, including essential psychiatric topics, psychopharmacology, and a psychotherapeutic module that discussed a myriad of therapeutic interventions. In addition, the student was supervised weekly by the course director, the psychopharmacologist, and the clinical psychologist. The course director provided daily wrap-up reviews as well.
Originally, this new approach was envisioned as a temporary solution for use during the pandemic. But it has become clear that this approach would be beneficial post pandemic as well. Most of the students who participated in the course were actually interested in pursuing psychiatry as their future specialty. It allowed them to observe a population of patients firsthand that they might encounter in private practice, as opposed to only hospital settings.
Being present in a session with a patient with psychiatric symptoms and diagnoses has always been a challenge. Many patients refuse to have another medical professional in the room because of the intimate details being discussed and their associated stigma. The patients’ inability to see or hear the student during the sessions allows them to ignore the students’ presence – or at least not be intimidated by it. This, therefore, allows the students access and affords them a unique and memorable educational experience.
The pandemic curtailed and altered medical students’ traditional exposure to patients, but we found innovative ways to redefine it. As difficult as COVID-19 has been for the health care community, we have been able to use the restrictions forced by the pandemic to identify innovative ways to improve the education of our medical students.
In addition to serving as director of the Center for Behavioral Health at NYITCOM in Old Westbury, N.Y., Dr. Jarkon is assistant professor in the department of family medicine. She has no disclosures.
As medical school faculty members – and our students – know well, the COVID-19 pandemic forced us to become creative and shift much of our curricula online. Many hospitals chose to limit medical student rotations because of safety concerns. Students fell victim to canceled psychiatry rotations and electives during the pandemic’s early days. Privacy issues, combined with stigma tied to mental illness, made this shift to virtual instruction particularly challenging. But as a field, we persevered! And, as we learned during our shift toward telemedicine, many of the changes we made in medical education are probably here to stay.
Our team at the New York Institute of Technology College of Osteopathic Medicine (NYITCOM) was able to implement a novel curriculum that allowed our students to learn psychiatry and maintain high-quality medical school education.
We developed an online course for third-year students’ rotation in psychiatry, with several modules that focused on a variety of psychiatric topics and disorders, including the basic classifications and categories of depression, anxiety, personality disorders, and psychotic disorders. There were also video encounters available showing actual patient encounters. On completion of the online module, a faculty session was held to discuss topics of concern/confusion to the students, areas of interest, and a variety of related topics, such as professionalism in psychiatry, essentials of the mental status exam, management of diverse populations, and COVID repercussions in psychiatry.
For fourth-year students, we developed a telemedicine psychiatry elective, which allowed the students to observe psychiatric evaluations, psychiatric medication review visits, and even follow-up psychotherapy sessions, with the school’s clinical psychologists. The new method was minimally invasive, and it was accepted by patients and welcomed by the students.
During a time when hospitals were limiting onsite student rotations and discouraging patient contact, medical students still needed to experience patient interactions. As the director of the school’s Center for Behavioral Health, I designed an additional program that allowed students to participate in observing patients who presented with psychiatric complaints and symptoms. It had to be confidential in nature, accessible, and safe.
I recalled my own training in a hospital setting, where students and residents were allowed to observe a patient being evaluated by an attending, through a one-way mirror. It was a method that was acceptable at the time in a hospital, but unfortunately, not in a private office setting. As such, students and residents experienced such an interaction in acute inpatient and/or outpatient clinics of a hospital. The experience was invaluable.
The concept was simple, yet very efficient. The clinicians in the Center for Behavioral Health were seeing all patients with psychiatric needs via a HIPAA-compliant telemedicine platform. Access was granted for students – with the patient’s consent – and they “entered the session” without being seen or heard. This presented little to no distraction to the patient, and the student was able to observe a range of clinical sessions.
The course also provided online supplemental modules, including essential psychiatric topics, psychopharmacology, and a psychotherapeutic module that discussed a myriad of therapeutic interventions. In addition, the student was supervised weekly by the course director, the psychopharmacologist, and the clinical psychologist. The course director provided daily wrap-up reviews as well.
Originally, this new approach was envisioned as a temporary solution for use during the pandemic. But it has become clear that this approach would be beneficial post pandemic as well. Most of the students who participated in the course were actually interested in pursuing psychiatry as their future specialty. It allowed them to observe a population of patients firsthand that they might encounter in private practice, as opposed to only hospital settings.
Being present in a session with a patient with psychiatric symptoms and diagnoses has always been a challenge. Many patients refuse to have another medical professional in the room because of the intimate details being discussed and their associated stigma. The patients’ inability to see or hear the student during the sessions allows them to ignore the students’ presence – or at least not be intimidated by it. This, therefore, allows the students access and affords them a unique and memorable educational experience.
The pandemic curtailed and altered medical students’ traditional exposure to patients, but we found innovative ways to redefine it. As difficult as COVID-19 has been for the health care community, we have been able to use the restrictions forced by the pandemic to identify innovative ways to improve the education of our medical students.
In addition to serving as director of the Center for Behavioral Health at NYITCOM in Old Westbury, N.Y., Dr. Jarkon is assistant professor in the department of family medicine. She has no disclosures.
As medical school faculty members – and our students – know well, the COVID-19 pandemic forced us to become creative and shift much of our curricula online. Many hospitals chose to limit medical student rotations because of safety concerns. Students fell victim to canceled psychiatry rotations and electives during the pandemic’s early days. Privacy issues, combined with stigma tied to mental illness, made this shift to virtual instruction particularly challenging. But as a field, we persevered! And, as we learned during our shift toward telemedicine, many of the changes we made in medical education are probably here to stay.
Our team at the New York Institute of Technology College of Osteopathic Medicine (NYITCOM) was able to implement a novel curriculum that allowed our students to learn psychiatry and maintain high-quality medical school education.
We developed an online course for third-year students’ rotation in psychiatry, with several modules that focused on a variety of psychiatric topics and disorders, including the basic classifications and categories of depression, anxiety, personality disorders, and psychotic disorders. There were also video encounters available showing actual patient encounters. On completion of the online module, a faculty session was held to discuss topics of concern/confusion to the students, areas of interest, and a variety of related topics, such as professionalism in psychiatry, essentials of the mental status exam, management of diverse populations, and COVID repercussions in psychiatry.
For fourth-year students, we developed a telemedicine psychiatry elective, which allowed the students to observe psychiatric evaluations, psychiatric medication review visits, and even follow-up psychotherapy sessions, with the school’s clinical psychologists. The new method was minimally invasive, and it was accepted by patients and welcomed by the students.
During a time when hospitals were limiting onsite student rotations and discouraging patient contact, medical students still needed to experience patient interactions. As the director of the school’s Center for Behavioral Health, I designed an additional program that allowed students to participate in observing patients who presented with psychiatric complaints and symptoms. It had to be confidential in nature, accessible, and safe.
I recalled my own training in a hospital setting, where students and residents were allowed to observe a patient being evaluated by an attending, through a one-way mirror. It was a method that was acceptable at the time in a hospital, but unfortunately, not in a private office setting. As such, students and residents experienced such an interaction in acute inpatient and/or outpatient clinics of a hospital. The experience was invaluable.
The concept was simple, yet very efficient. The clinicians in the Center for Behavioral Health were seeing all patients with psychiatric needs via a HIPAA-compliant telemedicine platform. Access was granted for students – with the patient’s consent – and they “entered the session” without being seen or heard. This presented little to no distraction to the patient, and the student was able to observe a range of clinical sessions.
The course also provided online supplemental modules, including essential psychiatric topics, psychopharmacology, and a psychotherapeutic module that discussed a myriad of therapeutic interventions. In addition, the student was supervised weekly by the course director, the psychopharmacologist, and the clinical psychologist. The course director provided daily wrap-up reviews as well.
Originally, this new approach was envisioned as a temporary solution for use during the pandemic. But it has become clear that this approach would be beneficial post pandemic as well. Most of the students who participated in the course were actually interested in pursuing psychiatry as their future specialty. It allowed them to observe a population of patients firsthand that they might encounter in private practice, as opposed to only hospital settings.
Being present in a session with a patient with psychiatric symptoms and diagnoses has always been a challenge. Many patients refuse to have another medical professional in the room because of the intimate details being discussed and their associated stigma. The patients’ inability to see or hear the student during the sessions allows them to ignore the students’ presence – or at least not be intimidated by it. This, therefore, allows the students access and affords them a unique and memorable educational experience.
The pandemic curtailed and altered medical students’ traditional exposure to patients, but we found innovative ways to redefine it. As difficult as COVID-19 has been for the health care community, we have been able to use the restrictions forced by the pandemic to identify innovative ways to improve the education of our medical students.
In addition to serving as director of the Center for Behavioral Health at NYITCOM in Old Westbury, N.Y., Dr. Jarkon is assistant professor in the department of family medicine. She has no disclosures.
Cardiogenic shock teams again tied to lower mortality
A large multicenter study provides further evidence supporting the rationale for multidisciplinary teams for cardiogenic shock, one of the most lethal diseases in cardiovascular medicine.
The analysis of 24 critical care ICUs in the Critical Care Cardiology Trials Network showed that the presence of a shock team was independently associated with a 28% lower risk for CICU mortality (23% vs. 29%; odds ratio, 0.72; P = .016).
Patients treated by a shock team also had significantly shorter CICU stays and less need for mechanical ventilation or renal replacement therapy, as reported in the Journal of the American College of Cardiology.
“It’s observational, but the association that we’re seeing here, just because of our sample size, is the strongest that’s been published yet,” lead author Alexander Papolos, MD, MedStar Washington Hospital Center, said in an interview.
Although a causal relationship cannot be drawn, the authors suggest several factors that could explain the findings, including a shock team’s ability to rapidly diagnose and treat cardiogenic shock before multiorgan dysfunction occurs.
Centers with shock teams also used significantly more pulmonary artery catheters (60% vs. 49%; adjusted OR, 1.86; P < .001) and placed them earlier (0.3 vs. 0.66 days; P = .019).
Pulmonary artery catheter (PAC) use has declined after earlier trials like ESCAPE showed little or no benefit in other acutely ill patient groups, but positive results have been reported recently in cardiogenic shock, where a PAC is needed to determine the severity of the lesion and the phenotype, Dr. Papolos observed.
A 2018 study showed PAC use was tied to increased survival among patients with acute myocardial infarction cardiogenic shock (AMI-CS) supported with the Impella (Abiomed) device. Additionally, a 2021 study by the Cardiogenic Shock Working Group demonstrated a dose-dependent survival response based on the completeness of hemodynamic assessment by PAC prior to initiating mechanical circulatory support (MCS).
A third factor might be that a structured, team-based evaluation can facilitate timely and optimal MCS device selection, deployment, and management, suggested Dr. Papolos.
Centers with shock teams used more advanced types of MCS – defined as Impella, TandemHeart (LivaNova), extracorporeal membrane oxygenation, and temporary or durable surgical ventricular assist devices – than those without a shock team (53% vs. 43%; adjusted OR, 1.73; P = .005) and did so more often as the initial device (42% vs. 28%; P = .002).
Overall MCS use was lower at shock team centers (35% vs. 43%), driven by less frequent use of intra-aortic balloon pumps (58% vs. 72%).
“The standard, basic MCS has always been the balloon pump because it’s something that’s easy to put in at the cath lab or at the bedside,” Dr. Papolos said. “So, if you take away having all of the information and having the right people at the table to discuss what the best level of support is, then you’re going to end up with balloon pumps, and that’s what we saw here.”
The study involved 6,872 consecutive medical admissions at 24 level 1 CICU centers during an annual 2-month period from 2017 to 2019. Of these, 1,242 admissions were for cardiogenic shock and 546 (44%) were treated at one of 10 centers with a shock team.
Shock team centers had higher-acuity patients than centers without a shock team (Sequential Organ Failure Assessment score, 4 vs. 3) but a similar proportion of patients with AMI-CS (27% vs. 28%).
Among all admissions, CICU mortality was not significantly different between centers with and without a shock team.
For cardiogenic shock patients treated at centers with and without a shock team, the median CICU stay was 4.0 and 5.1 days, respectively, mechanical ventilation was used in 41% and 52%, respectively, and new renal replacement therapy in 11% and 19%, respectively (P < .001 for all).
Shock team centers used significantly more PACs for AMI-CS and non–AMI-CS admissions; advanced MCS therapy was also greater in the AMI-CS subgroup.
Lower CICU mortality at shock team centers persisted among patients with non-AMI-CS (adjusted OR, 0.67; P = .017) and AMI-CS (adjusted OR, 0.79; P = .344).
“This analysis supports that all AHA level 1 cardiac ICUs should strongly consider having a shock team,” Dr. Papolos said.
Evidence from single centers and the National Cardiogenic Shock Initiative has shown improved survival with a cardiogenic shock algorithm, but this is the first report specifically comparing no shock teams with shock teams, Perwaiz Meraj, MD, Northwell Health, Manhansett, N.Y., told this news organization.
“People may say that it’s just another paper that’s saying, ‘shock teams, shock teams, rah, rah, rah,’ but it’s important for all of us to really take a close look under the covers and see how are we best managing these patients, what teams are we putting together, and to create systems of care, where if you’re at a center that really doesn’t have the capabilities of doing this, then you should partner up with a center that does,” he said.
Notably, the 10 shock teams were present only in medium or large urban, academic medical centers with more than 500 beds. Although they followed individual protocols, survey results show service-line representation, structure, and operations were similar across centers.
They all had a centralized way to activate the shock team, the service was 24/7, and members came from areas such as critical care cardiology (100%), cardiac surgery (100%), interventional cardiology (90%), advanced heart failure (80%), and extracorporeal membrane oxygenation service (70%).
Limitations of the study include the possibility of residual confounding, the fact that the registry did not capture patients with cardiogenic shock managed outside the CICU or the time of onset of cardiogenic shock, and data were limited on inotropic strategies, sedation practices, and ventilator management, the authors wrote.
“Although many critics will continue to discuss the lack of randomized controlled trials in cardiogenic shock, this paper supports the process previously outlined of a multidisciplinary team-based approach improving survival,” Dr. Meraj and William W. O’Neill, MD, director of the Center for Structural Heart Disease and Henry Ford Health System, Detroit, and the force behind the National Cardiogenic Shock Initiative, wrote in an accompanying editorial.
They point out that the report doesn’t address the escalation of care based on invasive hemodynamics in the CICU and the protocols to prevent acute vascular/limb complications (ALI) that can arise from the use of MCS.
“Many procedural techniques and novel CICU models exist to mitigate the risk of ALI in CS patients with MCS,” they wrote. “Finally, escalation of care and support is vital to the continued success of any shock team and center.”
One coauthor has served as a consultant to Abbott. Another has served as a consultant to the Abiomed critical care advisory board. All other authors reported having no relevant financial relationships. Dr. Meraj has received research and grant funding from Abiomed, Medtronic, CSI, and Boston Scientific. Dr. O’Neill has received consulting/speaker honoraria from Abiomed, Boston Scientific, and Abbott.
A version of this article first appeared on Medscape.com.
A large multicenter study provides further evidence supporting the rationale for multidisciplinary teams for cardiogenic shock, one of the most lethal diseases in cardiovascular medicine.
The analysis of 24 critical care ICUs in the Critical Care Cardiology Trials Network showed that the presence of a shock team was independently associated with a 28% lower risk for CICU mortality (23% vs. 29%; odds ratio, 0.72; P = .016).
Patients treated by a shock team also had significantly shorter CICU stays and less need for mechanical ventilation or renal replacement therapy, as reported in the Journal of the American College of Cardiology.
“It’s observational, but the association that we’re seeing here, just because of our sample size, is the strongest that’s been published yet,” lead author Alexander Papolos, MD, MedStar Washington Hospital Center, said in an interview.
Although a causal relationship cannot be drawn, the authors suggest several factors that could explain the findings, including a shock team’s ability to rapidly diagnose and treat cardiogenic shock before multiorgan dysfunction occurs.
Centers with shock teams also used significantly more pulmonary artery catheters (60% vs. 49%; adjusted OR, 1.86; P < .001) and placed them earlier (0.3 vs. 0.66 days; P = .019).
Pulmonary artery catheter (PAC) use has declined after earlier trials like ESCAPE showed little or no benefit in other acutely ill patient groups, but positive results have been reported recently in cardiogenic shock, where a PAC is needed to determine the severity of the lesion and the phenotype, Dr. Papolos observed.
A 2018 study showed PAC use was tied to increased survival among patients with acute myocardial infarction cardiogenic shock (AMI-CS) supported with the Impella (Abiomed) device. Additionally, a 2021 study by the Cardiogenic Shock Working Group demonstrated a dose-dependent survival response based on the completeness of hemodynamic assessment by PAC prior to initiating mechanical circulatory support (MCS).
A third factor might be that a structured, team-based evaluation can facilitate timely and optimal MCS device selection, deployment, and management, suggested Dr. Papolos.
Centers with shock teams used more advanced types of MCS – defined as Impella, TandemHeart (LivaNova), extracorporeal membrane oxygenation, and temporary or durable surgical ventricular assist devices – than those without a shock team (53% vs. 43%; adjusted OR, 1.73; P = .005) and did so more often as the initial device (42% vs. 28%; P = .002).
Overall MCS use was lower at shock team centers (35% vs. 43%), driven by less frequent use of intra-aortic balloon pumps (58% vs. 72%).
“The standard, basic MCS has always been the balloon pump because it’s something that’s easy to put in at the cath lab or at the bedside,” Dr. Papolos said. “So, if you take away having all of the information and having the right people at the table to discuss what the best level of support is, then you’re going to end up with balloon pumps, and that’s what we saw here.”
The study involved 6,872 consecutive medical admissions at 24 level 1 CICU centers during an annual 2-month period from 2017 to 2019. Of these, 1,242 admissions were for cardiogenic shock and 546 (44%) were treated at one of 10 centers with a shock team.
Shock team centers had higher-acuity patients than centers without a shock team (Sequential Organ Failure Assessment score, 4 vs. 3) but a similar proportion of patients with AMI-CS (27% vs. 28%).
Among all admissions, CICU mortality was not significantly different between centers with and without a shock team.
For cardiogenic shock patients treated at centers with and without a shock team, the median CICU stay was 4.0 and 5.1 days, respectively, mechanical ventilation was used in 41% and 52%, respectively, and new renal replacement therapy in 11% and 19%, respectively (P < .001 for all).
Shock team centers used significantly more PACs for AMI-CS and non–AMI-CS admissions; advanced MCS therapy was also greater in the AMI-CS subgroup.
Lower CICU mortality at shock team centers persisted among patients with non-AMI-CS (adjusted OR, 0.67; P = .017) and AMI-CS (adjusted OR, 0.79; P = .344).
“This analysis supports that all AHA level 1 cardiac ICUs should strongly consider having a shock team,” Dr. Papolos said.
Evidence from single centers and the National Cardiogenic Shock Initiative has shown improved survival with a cardiogenic shock algorithm, but this is the first report specifically comparing no shock teams with shock teams, Perwaiz Meraj, MD, Northwell Health, Manhansett, N.Y., told this news organization.
“People may say that it’s just another paper that’s saying, ‘shock teams, shock teams, rah, rah, rah,’ but it’s important for all of us to really take a close look under the covers and see how are we best managing these patients, what teams are we putting together, and to create systems of care, where if you’re at a center that really doesn’t have the capabilities of doing this, then you should partner up with a center that does,” he said.
Notably, the 10 shock teams were present only in medium or large urban, academic medical centers with more than 500 beds. Although they followed individual protocols, survey results show service-line representation, structure, and operations were similar across centers.
They all had a centralized way to activate the shock team, the service was 24/7, and members came from areas such as critical care cardiology (100%), cardiac surgery (100%), interventional cardiology (90%), advanced heart failure (80%), and extracorporeal membrane oxygenation service (70%).
Limitations of the study include the possibility of residual confounding, the fact that the registry did not capture patients with cardiogenic shock managed outside the CICU or the time of onset of cardiogenic shock, and data were limited on inotropic strategies, sedation practices, and ventilator management, the authors wrote.
“Although many critics will continue to discuss the lack of randomized controlled trials in cardiogenic shock, this paper supports the process previously outlined of a multidisciplinary team-based approach improving survival,” Dr. Meraj and William W. O’Neill, MD, director of the Center for Structural Heart Disease and Henry Ford Health System, Detroit, and the force behind the National Cardiogenic Shock Initiative, wrote in an accompanying editorial.
They point out that the report doesn’t address the escalation of care based on invasive hemodynamics in the CICU and the protocols to prevent acute vascular/limb complications (ALI) that can arise from the use of MCS.
“Many procedural techniques and novel CICU models exist to mitigate the risk of ALI in CS patients with MCS,” they wrote. “Finally, escalation of care and support is vital to the continued success of any shock team and center.”
One coauthor has served as a consultant to Abbott. Another has served as a consultant to the Abiomed critical care advisory board. All other authors reported having no relevant financial relationships. Dr. Meraj has received research and grant funding from Abiomed, Medtronic, CSI, and Boston Scientific. Dr. O’Neill has received consulting/speaker honoraria from Abiomed, Boston Scientific, and Abbott.
A version of this article first appeared on Medscape.com.
A large multicenter study provides further evidence supporting the rationale for multidisciplinary teams for cardiogenic shock, one of the most lethal diseases in cardiovascular medicine.
The analysis of 24 critical care ICUs in the Critical Care Cardiology Trials Network showed that the presence of a shock team was independently associated with a 28% lower risk for CICU mortality (23% vs. 29%; odds ratio, 0.72; P = .016).
Patients treated by a shock team also had significantly shorter CICU stays and less need for mechanical ventilation or renal replacement therapy, as reported in the Journal of the American College of Cardiology.
“It’s observational, but the association that we’re seeing here, just because of our sample size, is the strongest that’s been published yet,” lead author Alexander Papolos, MD, MedStar Washington Hospital Center, said in an interview.
Although a causal relationship cannot be drawn, the authors suggest several factors that could explain the findings, including a shock team’s ability to rapidly diagnose and treat cardiogenic shock before multiorgan dysfunction occurs.
Centers with shock teams also used significantly more pulmonary artery catheters (60% vs. 49%; adjusted OR, 1.86; P < .001) and placed them earlier (0.3 vs. 0.66 days; P = .019).
Pulmonary artery catheter (PAC) use has declined after earlier trials like ESCAPE showed little or no benefit in other acutely ill patient groups, but positive results have been reported recently in cardiogenic shock, where a PAC is needed to determine the severity of the lesion and the phenotype, Dr. Papolos observed.
A 2018 study showed PAC use was tied to increased survival among patients with acute myocardial infarction cardiogenic shock (AMI-CS) supported with the Impella (Abiomed) device. Additionally, a 2021 study by the Cardiogenic Shock Working Group demonstrated a dose-dependent survival response based on the completeness of hemodynamic assessment by PAC prior to initiating mechanical circulatory support (MCS).
A third factor might be that a structured, team-based evaluation can facilitate timely and optimal MCS device selection, deployment, and management, suggested Dr. Papolos.
Centers with shock teams used more advanced types of MCS – defined as Impella, TandemHeart (LivaNova), extracorporeal membrane oxygenation, and temporary or durable surgical ventricular assist devices – than those without a shock team (53% vs. 43%; adjusted OR, 1.73; P = .005) and did so more often as the initial device (42% vs. 28%; P = .002).
Overall MCS use was lower at shock team centers (35% vs. 43%), driven by less frequent use of intra-aortic balloon pumps (58% vs. 72%).
“The standard, basic MCS has always been the balloon pump because it’s something that’s easy to put in at the cath lab or at the bedside,” Dr. Papolos said. “So, if you take away having all of the information and having the right people at the table to discuss what the best level of support is, then you’re going to end up with balloon pumps, and that’s what we saw here.”
The study involved 6,872 consecutive medical admissions at 24 level 1 CICU centers during an annual 2-month period from 2017 to 2019. Of these, 1,242 admissions were for cardiogenic shock and 546 (44%) were treated at one of 10 centers with a shock team.
Shock team centers had higher-acuity patients than centers without a shock team (Sequential Organ Failure Assessment score, 4 vs. 3) but a similar proportion of patients with AMI-CS (27% vs. 28%).
Among all admissions, CICU mortality was not significantly different between centers with and without a shock team.
For cardiogenic shock patients treated at centers with and without a shock team, the median CICU stay was 4.0 and 5.1 days, respectively, mechanical ventilation was used in 41% and 52%, respectively, and new renal replacement therapy in 11% and 19%, respectively (P < .001 for all).
Shock team centers used significantly more PACs for AMI-CS and non–AMI-CS admissions; advanced MCS therapy was also greater in the AMI-CS subgroup.
Lower CICU mortality at shock team centers persisted among patients with non-AMI-CS (adjusted OR, 0.67; P = .017) and AMI-CS (adjusted OR, 0.79; P = .344).
“This analysis supports that all AHA level 1 cardiac ICUs should strongly consider having a shock team,” Dr. Papolos said.
Evidence from single centers and the National Cardiogenic Shock Initiative has shown improved survival with a cardiogenic shock algorithm, but this is the first report specifically comparing no shock teams with shock teams, Perwaiz Meraj, MD, Northwell Health, Manhansett, N.Y., told this news organization.
“People may say that it’s just another paper that’s saying, ‘shock teams, shock teams, rah, rah, rah,’ but it’s important for all of us to really take a close look under the covers and see how are we best managing these patients, what teams are we putting together, and to create systems of care, where if you’re at a center that really doesn’t have the capabilities of doing this, then you should partner up with a center that does,” he said.
Notably, the 10 shock teams were present only in medium or large urban, academic medical centers with more than 500 beds. Although they followed individual protocols, survey results show service-line representation, structure, and operations were similar across centers.
They all had a centralized way to activate the shock team, the service was 24/7, and members came from areas such as critical care cardiology (100%), cardiac surgery (100%), interventional cardiology (90%), advanced heart failure (80%), and extracorporeal membrane oxygenation service (70%).
Limitations of the study include the possibility of residual confounding, the fact that the registry did not capture patients with cardiogenic shock managed outside the CICU or the time of onset of cardiogenic shock, and data were limited on inotropic strategies, sedation practices, and ventilator management, the authors wrote.
“Although many critics will continue to discuss the lack of randomized controlled trials in cardiogenic shock, this paper supports the process previously outlined of a multidisciplinary team-based approach improving survival,” Dr. Meraj and William W. O’Neill, MD, director of the Center for Structural Heart Disease and Henry Ford Health System, Detroit, and the force behind the National Cardiogenic Shock Initiative, wrote in an accompanying editorial.
They point out that the report doesn’t address the escalation of care based on invasive hemodynamics in the CICU and the protocols to prevent acute vascular/limb complications (ALI) that can arise from the use of MCS.
“Many procedural techniques and novel CICU models exist to mitigate the risk of ALI in CS patients with MCS,” they wrote. “Finally, escalation of care and support is vital to the continued success of any shock team and center.”
One coauthor has served as a consultant to Abbott. Another has served as a consultant to the Abiomed critical care advisory board. All other authors reported having no relevant financial relationships. Dr. Meraj has received research and grant funding from Abiomed, Medtronic, CSI, and Boston Scientific. Dr. O’Neill has received consulting/speaker honoraria from Abiomed, Boston Scientific, and Abbott.
A version of this article first appeared on Medscape.com.
Consensus statement warns against acetaminophen use during pregnancy
Pregnant women should use paracetamol/acetaminophen only with a medical indication and at the lowest effective dose for the shortest possible time, according to an international consensus statement published online Sept. 23 in Nature Reviews Endocrinology.
With global rates of use high and risks considered negligible, the expert panel of 13 U.S. and European authors call for focused research into how this analgesic and febrifuge may impair fetal development and lead to adverse outcomes in children. They outline several precautionary measures to be taken in the meantime.
According to first author and epidemiologist Ann Z. Bauer, ScD, a postdoctoral research fellow at the University of Massachusetts in Lowell, and colleagues, this drug is used by an estimated 65% of pregnant women in the United States, and more than 50% worldwide. It is currently the active ingredient in more than 600 prescription and nonprescription medications, including Tylenol, which historically has been deemed safe in all trimesters of pregnancy.
But a growing body of experimental and epidemiological evidence suggests prenatal exposure to paracetamol (N-acetyl-p-aminophenol, or APAP) might alter fetal development and elevate the risks of neurodevelopmental, reproductive and urogenital disorders in both sexes. Exposure in utero has been linked, for example, to potential behavioral problems in children.
The new recommendations are based on a review of experimental animal and cell-based research as well as human epidemiological data published from January 1995 to October 2020. The authors include clinicians, epidemiologists, and scientists specializing in toxicology, endocrinology, reproductive medicine and neurodevelopment.
Recommendations
Although the new guidance does not differ markedly from current advice, the authors believe stronger communication and greater awareness of risks are needed. In addition to restricting use of this medication to low doses for short periods when medically necessary, expectant mothers should receive counseling before conception or early in pregnancy. If uncertain about its use, they should consult their physicians or pharmacists.
In other recommendations, the panel said:
- The 2015 FDA Drug Safety Communication recommendations should be updated based on evaluation of all available scientific evidence.
- The European Medicines Agency Pharmacovigilance Risk Assessment Committee should review the most recent epidemiologic and experimental research and issue an updated Drug Safety Communication.
- Obstetric and gynecological associations should update their guidance after reviewing all available research.
- The Acetaminophen Awareness Coalition (“Know Your Dose” Campaign) should add standardized warnings and specifically advise pregnant women to forgo APAP unless it’s medically indicated.
- All sales of APAP-containing medications should be accompanied by recommendations specifically for use in pregnancy. This information should include warning labels on packaging, and if possible, APAP should be sold only in pharmacies (as in France).
Mechanism of action
APAP is an endocrine disruptor (Neuroscientist. 2020 Sep 11. doi: 10.1177/1073858420952046). “Chemicals that disrupt the endocrine system are concerning because they can interfere with the activity of endogenous hormones that are essential for healthy neurological, urogenital, and reproductive development,” researchers wrote.
“The precise mechanism is not clear but its toxicity is thought to be due mainly to hormone disruption,” Dr. Bauer said in an interview.
Moreover, APAP readily crosses the placenta and blood–brain barrier, and changes in APAP metabolism during pregnancy might make women and their fetuses more vulnerable to its toxic effects. For instance, the molar dose fraction of APAP converted to the oxidative metabolite N-acetyl-p-benzoquinone imine increases during pregnancy. In addition to its hepatotoxicity, this poisonous byproduct is thought to be a genotoxin that increases DNA cleavage by acting on the enzyme topoisomerase II.
Asked for her perspective on the statement, Kjersti Aagaard, MD, PhD, a professor of obstetrics and gynecology at Baylor College of Medicine and Texas Children’s Hospital in Houston, called the expert panel’s statement thoughtful and comprehensive, but she urged caution in interpreting the role of acetaminophen.
The challenge in linking any commonly used medication to adverse effects and congenital defects, she said, is “teasing out an association from causation. Given the commonality of the use of acetaminophen with the relative rarity of the outcomes, it is clear that not all cases of exposure result in adverse outcomes.”
As for judicious use, she said, one would be to reduce a high fever, which can cause miscarriage, neural tube defects, and potential heart disease in adulthood. Acetaminophen is the drug of choice in this case since nonsteroidal anti-inflammatory drugs such as ibuprofen are not recommended owing to their known risks to the fetal heart.
Dr. Aagaard emphasized that while acetaminophen use is temporally associated with learning and behavioral problems, and urogenital disorders at birth in male infants such as like hypospadias, so is exposure to multiple environmental chemicals and pollutants, as well as climate change. “It would be a real mistake with real life implications if we associated any congenital disease or disorder with a commonly used medication with known benefits if the true causal link lies elsewhere.”
She said the precautionary statements fall into the time-honored therapeutic principle of first do no harm. “However, the call for research action must be undertaken earnestly and sincerely.”
According to Dr. Bauer, the statement’s essential take-home message is that “physicians should educate themselves and educate women about what we’re learning about the risks of acetaminophen in pregnancy.” Risk can be minimized by using the lowest effective dose for the shortest time and only when medically indicated. “Pregnant women should speak to their physicians about acetaminophen. It’s about empowerment and making smart decisions,” she said.
This study received no specific funding. Coauthor Dr. R.T. Mitchell is supported by a UK Research Institute fellowship.
Pregnant women should use paracetamol/acetaminophen only with a medical indication and at the lowest effective dose for the shortest possible time, according to an international consensus statement published online Sept. 23 in Nature Reviews Endocrinology.
With global rates of use high and risks considered negligible, the expert panel of 13 U.S. and European authors call for focused research into how this analgesic and febrifuge may impair fetal development and lead to adverse outcomes in children. They outline several precautionary measures to be taken in the meantime.
According to first author and epidemiologist Ann Z. Bauer, ScD, a postdoctoral research fellow at the University of Massachusetts in Lowell, and colleagues, this drug is used by an estimated 65% of pregnant women in the United States, and more than 50% worldwide. It is currently the active ingredient in more than 600 prescription and nonprescription medications, including Tylenol, which historically has been deemed safe in all trimesters of pregnancy.
But a growing body of experimental and epidemiological evidence suggests prenatal exposure to paracetamol (N-acetyl-p-aminophenol, or APAP) might alter fetal development and elevate the risks of neurodevelopmental, reproductive and urogenital disorders in both sexes. Exposure in utero has been linked, for example, to potential behavioral problems in children.
The new recommendations are based on a review of experimental animal and cell-based research as well as human epidemiological data published from January 1995 to October 2020. The authors include clinicians, epidemiologists, and scientists specializing in toxicology, endocrinology, reproductive medicine and neurodevelopment.
Recommendations
Although the new guidance does not differ markedly from current advice, the authors believe stronger communication and greater awareness of risks are needed. In addition to restricting use of this medication to low doses for short periods when medically necessary, expectant mothers should receive counseling before conception or early in pregnancy. If uncertain about its use, they should consult their physicians or pharmacists.
In other recommendations, the panel said:
- The 2015 FDA Drug Safety Communication recommendations should be updated based on evaluation of all available scientific evidence.
- The European Medicines Agency Pharmacovigilance Risk Assessment Committee should review the most recent epidemiologic and experimental research and issue an updated Drug Safety Communication.
- Obstetric and gynecological associations should update their guidance after reviewing all available research.
- The Acetaminophen Awareness Coalition (“Know Your Dose” Campaign) should add standardized warnings and specifically advise pregnant women to forgo APAP unless it’s medically indicated.
- All sales of APAP-containing medications should be accompanied by recommendations specifically for use in pregnancy. This information should include warning labels on packaging, and if possible, APAP should be sold only in pharmacies (as in France).
Mechanism of action
APAP is an endocrine disruptor (Neuroscientist. 2020 Sep 11. doi: 10.1177/1073858420952046). “Chemicals that disrupt the endocrine system are concerning because they can interfere with the activity of endogenous hormones that are essential for healthy neurological, urogenital, and reproductive development,” researchers wrote.
“The precise mechanism is not clear but its toxicity is thought to be due mainly to hormone disruption,” Dr. Bauer said in an interview.
Moreover, APAP readily crosses the placenta and blood–brain barrier, and changes in APAP metabolism during pregnancy might make women and their fetuses more vulnerable to its toxic effects. For instance, the molar dose fraction of APAP converted to the oxidative metabolite N-acetyl-p-benzoquinone imine increases during pregnancy. In addition to its hepatotoxicity, this poisonous byproduct is thought to be a genotoxin that increases DNA cleavage by acting on the enzyme topoisomerase II.
Asked for her perspective on the statement, Kjersti Aagaard, MD, PhD, a professor of obstetrics and gynecology at Baylor College of Medicine and Texas Children’s Hospital in Houston, called the expert panel’s statement thoughtful and comprehensive, but she urged caution in interpreting the role of acetaminophen.
The challenge in linking any commonly used medication to adverse effects and congenital defects, she said, is “teasing out an association from causation. Given the commonality of the use of acetaminophen with the relative rarity of the outcomes, it is clear that not all cases of exposure result in adverse outcomes.”
As for judicious use, she said, one would be to reduce a high fever, which can cause miscarriage, neural tube defects, and potential heart disease in adulthood. Acetaminophen is the drug of choice in this case since nonsteroidal anti-inflammatory drugs such as ibuprofen are not recommended owing to their known risks to the fetal heart.
Dr. Aagaard emphasized that while acetaminophen use is temporally associated with learning and behavioral problems, and urogenital disorders at birth in male infants such as like hypospadias, so is exposure to multiple environmental chemicals and pollutants, as well as climate change. “It would be a real mistake with real life implications if we associated any congenital disease or disorder with a commonly used medication with known benefits if the true causal link lies elsewhere.”
She said the precautionary statements fall into the time-honored therapeutic principle of first do no harm. “However, the call for research action must be undertaken earnestly and sincerely.”
According to Dr. Bauer, the statement’s essential take-home message is that “physicians should educate themselves and educate women about what we’re learning about the risks of acetaminophen in pregnancy.” Risk can be minimized by using the lowest effective dose for the shortest time and only when medically indicated. “Pregnant women should speak to their physicians about acetaminophen. It’s about empowerment and making smart decisions,” she said.
This study received no specific funding. Coauthor Dr. R.T. Mitchell is supported by a UK Research Institute fellowship.
Pregnant women should use paracetamol/acetaminophen only with a medical indication and at the lowest effective dose for the shortest possible time, according to an international consensus statement published online Sept. 23 in Nature Reviews Endocrinology.
With global rates of use high and risks considered negligible, the expert panel of 13 U.S. and European authors call for focused research into how this analgesic and febrifuge may impair fetal development and lead to adverse outcomes in children. They outline several precautionary measures to be taken in the meantime.
According to first author and epidemiologist Ann Z. Bauer, ScD, a postdoctoral research fellow at the University of Massachusetts in Lowell, and colleagues, this drug is used by an estimated 65% of pregnant women in the United States, and more than 50% worldwide. It is currently the active ingredient in more than 600 prescription and nonprescription medications, including Tylenol, which historically has been deemed safe in all trimesters of pregnancy.
But a growing body of experimental and epidemiological evidence suggests prenatal exposure to paracetamol (N-acetyl-p-aminophenol, or APAP) might alter fetal development and elevate the risks of neurodevelopmental, reproductive and urogenital disorders in both sexes. Exposure in utero has been linked, for example, to potential behavioral problems in children.
The new recommendations are based on a review of experimental animal and cell-based research as well as human epidemiological data published from January 1995 to October 2020. The authors include clinicians, epidemiologists, and scientists specializing in toxicology, endocrinology, reproductive medicine and neurodevelopment.
Recommendations
Although the new guidance does not differ markedly from current advice, the authors believe stronger communication and greater awareness of risks are needed. In addition to restricting use of this medication to low doses for short periods when medically necessary, expectant mothers should receive counseling before conception or early in pregnancy. If uncertain about its use, they should consult their physicians or pharmacists.
In other recommendations, the panel said:
- The 2015 FDA Drug Safety Communication recommendations should be updated based on evaluation of all available scientific evidence.
- The European Medicines Agency Pharmacovigilance Risk Assessment Committee should review the most recent epidemiologic and experimental research and issue an updated Drug Safety Communication.
- Obstetric and gynecological associations should update their guidance after reviewing all available research.
- The Acetaminophen Awareness Coalition (“Know Your Dose” Campaign) should add standardized warnings and specifically advise pregnant women to forgo APAP unless it’s medically indicated.
- All sales of APAP-containing medications should be accompanied by recommendations specifically for use in pregnancy. This information should include warning labels on packaging, and if possible, APAP should be sold only in pharmacies (as in France).
Mechanism of action
APAP is an endocrine disruptor (Neuroscientist. 2020 Sep 11. doi: 10.1177/1073858420952046). “Chemicals that disrupt the endocrine system are concerning because they can interfere with the activity of endogenous hormones that are essential for healthy neurological, urogenital, and reproductive development,” researchers wrote.
“The precise mechanism is not clear but its toxicity is thought to be due mainly to hormone disruption,” Dr. Bauer said in an interview.
Moreover, APAP readily crosses the placenta and blood–brain barrier, and changes in APAP metabolism during pregnancy might make women and their fetuses more vulnerable to its toxic effects. For instance, the molar dose fraction of APAP converted to the oxidative metabolite N-acetyl-p-benzoquinone imine increases during pregnancy. In addition to its hepatotoxicity, this poisonous byproduct is thought to be a genotoxin that increases DNA cleavage by acting on the enzyme topoisomerase II.
Asked for her perspective on the statement, Kjersti Aagaard, MD, PhD, a professor of obstetrics and gynecology at Baylor College of Medicine and Texas Children’s Hospital in Houston, called the expert panel’s statement thoughtful and comprehensive, but she urged caution in interpreting the role of acetaminophen.
The challenge in linking any commonly used medication to adverse effects and congenital defects, she said, is “teasing out an association from causation. Given the commonality of the use of acetaminophen with the relative rarity of the outcomes, it is clear that not all cases of exposure result in adverse outcomes.”
As for judicious use, she said, one would be to reduce a high fever, which can cause miscarriage, neural tube defects, and potential heart disease in adulthood. Acetaminophen is the drug of choice in this case since nonsteroidal anti-inflammatory drugs such as ibuprofen are not recommended owing to their known risks to the fetal heart.
Dr. Aagaard emphasized that while acetaminophen use is temporally associated with learning and behavioral problems, and urogenital disorders at birth in male infants such as like hypospadias, so is exposure to multiple environmental chemicals and pollutants, as well as climate change. “It would be a real mistake with real life implications if we associated any congenital disease or disorder with a commonly used medication with known benefits if the true causal link lies elsewhere.”
She said the precautionary statements fall into the time-honored therapeutic principle of first do no harm. “However, the call for research action must be undertaken earnestly and sincerely.”
According to Dr. Bauer, the statement’s essential take-home message is that “physicians should educate themselves and educate women about what we’re learning about the risks of acetaminophen in pregnancy.” Risk can be minimized by using the lowest effective dose for the shortest time and only when medically indicated. “Pregnant women should speak to their physicians about acetaminophen. It’s about empowerment and making smart decisions,” she said.
This study received no specific funding. Coauthor Dr. R.T. Mitchell is supported by a UK Research Institute fellowship.
Datopotamab deruxtecan for advanced NSCLC encouraging so far
according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).
Limited benefit from existing treatments
Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.
TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
Subgroup with AGAs
The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.
Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”
The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
Further evaluation ongoing
Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.
Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”
Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”
The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).
Limited benefit from existing treatments
Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.
TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
Subgroup with AGAs
The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.
Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”
The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
Further evaluation ongoing
Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.
Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”
Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”
The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).
Limited benefit from existing treatments
Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.
TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
Subgroup with AGAs
The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.
Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”
The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
Further evaluation ongoing
Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.
Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”
Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”
The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
FROM ESMO 2021
TULIP trial shows extended survival in HER2+ metastatic breast cancer
, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).
Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer progression-free survival with SYD985
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).
A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
Another option
“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”
“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”
The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).
Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer progression-free survival with SYD985
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).
A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
Another option
“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”
“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”
The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
, according to Cristina Saura Manich, MD, Hospital Universitario Valle de Hebrón, Barcelona. In TULIP, trastuzumab duocarmazine (SYD985, Byondis B.V., NL) was compared with physician’s choice of chemotherapy, Dr. Saura said at the virtual European Society for Medical Oncology Congress 2021 on Sept. 18 (abstract LBA15).
Trastuzumab duocarmazine, Dr. Manich noted, is a novel HER2-targeting antibody–drug conjugate based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Its three-way mechanism of action includes uptake of the antibody–drug conjugate by internalization and intracellular release of the payload, and two bystander effects: proteolytic cleavage and subsequent release of payload in the tumor microenvironment and diffusion of active payload to neighboring tumor cells.
Two or more prior therapies for metastatic breast cancer
TULIP investigators enrolled 437 patients from 83 sites in 11 countries with HER2-positive locally advanced or metastatic breast cancer who had received two or more therapies for metastatic disease (treatment for brain metastases allowed). They were randomized 2:1 to SYD985 (1.2 mg/kg IV every 21 days [n = 291]) or physician’s choice (PC) [n = 146] of one of three trastuzumab-containing combinations or lapatinib plus capecitabine. Treatment was continued until progression or unacceptable toxicity. The primary endpoint was centrally assessed PFS.
Longer progression-free survival with SYD985
Median age was 57 years, and the median number of prior metastatic breast cancer regimens was 4.7. Centrally reviewed progression-free survival was significantly longer in the SYD985 group at 7.0 months (5.4-7.2) versus 4.9 months (4.0-5.5) for PC (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.49-0.84, P = .002). Subgroup analysis, also centrally reviewed, revealed numerical advantage for SYD985 over physician choice across all categories (except for ECOG status 2). Analysis of progression-free survival by investigators showed a similar benefit for SYD985 (6.9 months versus 4.6 months, HR, 0.60, P < .001).
A first look at median overall survival showed a nonsignificant advantage for SYD985 (20.4 months versus 16.3 months (HR, 0.83, 95% CI, 0.62-1.09, P = .153). The overall response rate (partial or complete response) was similar between groups at 27.8% for SYD985 and 29.5% for PC, with reductions in target lesion measurement at 70.2% and 32.2% for SYD985 and physician choice, respectively. The clinical benefit rates were 38.5% for SYD985 and 32.2% for physician choice.
Ocular toxicity
Most patients had at least one treatment-related adverse event (96.5% SD985, 96.4% PC), and grade 3 or higher event rates were similar between groups (52.8% SYD985, 48.2% PC). The most frequently reported adverse events for SYD985 were ocular toxicity, with conjunctivitis reported in 38.2%, and keratitis in 38.2%, with fatigue at 33.3%; for physician’s choice these were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease pneumonitis was reported for 7.6% (5.2% grade 1-2) of patients treated with SYD985, including two grade 5 events. Eye toxicity led to discontinuations in 20.8% of SYD985 patients, dose modifications in 22.9%, with dose modifications for interstitial lung disease/pneumonitis in 5.2% of SYD985 patients. Six fatalities (2.1%) were reported in the SYD985 group, with four attributed to treatment. Assessment of health-related quality of life showed no significant difference between groups.
Dr. Manich outlined risk mitigation strategies. Patients with prior keratitis were excluded and patients were given prophylactic lubricating eye drops and regular eye exams by ophthalmologists. Treatment was discontinued if grade 3 or higher keratitis developed, and was delayed if grade 3 conjunctivitis developed until it reduced to grade 2. Also, patients with prior pneumonitis were excluded and CT lung scans were evaluated for lung changes. New or worsening respiratory symptoms triggered a full diagnostic workup. Treatment was discontinued for grade 2 or higher pneumonitis and delayed until resolution for grade 1 pneumonitis.
Another option
“It is encouraging to observe clinically meaningful and potentially practice changing PFS improvements in patients receiving treatment in the third line and beyond,” said Aditya Bardia, MD, of Massachusetts General Hospital and Harvard Medical School, Boston. “Several agents have been approved as treatments for HER2-positive metastatic breast cancer in recent years – including T-DXd, neratinib, tucatinib, and margetuximab – and [vic-]trastuzumab duocarmazine could eventually be another option.”
“At this time, there is only a minor 2-month difference in progression-free survival and a nonsignificant overall survival difference,” said Fatima Cardoso, MD, of Champalimaud Cancer Center, Lisbon, Portugal. “With the high incidence of ocular toxicity and four toxic deaths, we cannot recommend this drug for clinical practice, in my opinion.”
Dr. Manich concluded, “SYD985 can provide a new treatment option for patients with pretreated locally advanced or metastatic HER2-positive metastatic breast cancer.”
The study was funded by Byondis B.V. The authors disclosed numerous pharmaceutical-related financial interests.
This article was updated Sept. 24, 2021.
FROM ESMO 2021