Anand S. Iyer, MD, MSPH, frequently hears his patients with chronic obstructive pulmonary disease (COPD) express fear and hopelessness and describe panic and other symptoms of anxiety. He sees anxiety affect the course of COPD, worsening symptoms and outcomes.

“I had questions about what we are doing [to help patients], so I began looking into the role of palliative care to help patients assess and manage these complex emotional and psychological symptoms,” said Dr. Iyer, assistant professor in the division of pulmonology, allergy, and critical care medicine at the University of Alabama at Birmingham.

His research is now focused on the integration of palliative care principles in COPD care. For Dr. Iyer and others engaged in research and/or patient care, finding ways of identifying and managing anxiety in patients with COPD – and other chronic lung diseases – is a calling of growing urgency.

More has been published about anxiety in patients with COPD than in other pulmonary conditions – and in COPD, anxiety has long been established as a prevalent comorbidity. Prevalence rates vary from about 1 in 4, to 1 in 2 or higher, depending on the instruments used and whether clinical DSM-based diagnoses are made, Dr. Iyer said.

A 2013 systematic review of 10 studies that utilized clinical interviews based on DSM criteria, for instance, found a prevalence of clinical anxiety of 10%-55% among inpatients and 13%-46% among outpatients with COPD. The results were similar, investigators said, to studies using self-report screening tools (Respiratory Care 2013;58[5]:858-66).

In the 16 years since an ACCP workshop panel on anxiety and depression in COPD reported higher prevalence rates than for other chronic diseases and detailed a host of problems and research needs (CHEST. 2008;134;43S-56), investigators have more fully documented links to COPD outcomes, showing, for instance, that anxiety predicts exacerbations, hospitalizations, poorer adherence to therapies, poorer quality of life and higher mortality.

Dr. Iyer and other experts say anxiety is still too often a neglected comorbidity. “It’s still underdiagnosed and therefore undertreated,” said Nick Hanania, MD, MS, professor of medicine and director of the Airways Clinical Research Center at Baylor College of Medicine, Houston.

The literature on optimal approaches for management remains limited, and the role of pharmacotherapy for anxiety (and depression) in the context of COPD has not been well investigated. But there have been some advances: Screening tools have been further studied, questionnaires specific to COPD have been developed, and pulmonary rehabilitation (PR) and cognitive behavioral therapy (CBT) have both been shown to be effective in decreasing anxiety.

Researchers and academic clinicians are talking, meanwhile, about how to have to important conversations about anxiety with patients who have COPD and other chronic lung conditions, and how improve care in the face of significant health system challenges.
 

Understanding anxiety in COPD

Anxiety is often intertwined with dyspnea in a bidirectional and complex relationship, but anxiety in COPD is not always acute or limited to times of acute exacerbations.

“There’s not only the acute experience of shortness of breath or a lung change episode, but there’s an anticipation that can occur, psychologically and socially,” said Lauren Garvin, PhD, of the department of psychiatry at the University of Iowa, Iowa City. Patients worry, “what if I’m short of breath in a particular situation? What if my devices fail when I’m out somewhere?”

Patients are often living “in a state of heightened surveillance of the body,” she noted, which can be exhausting and can impact functioning.

It’s also important to appreciate that anxiety is “a continuum of experience,” said Karin Hoth, PhD, associate professor of psychiatry at the medical school, whose research includes projects focusing on psychological adjustment in COPD.

“Research historically categorizes anxiety as ‘have or don’t have.’ But there’s a continuum of experience that we’re moving toward understanding and recognizing in research,” she said. “Anxiety is part of a patient’s whole experience, no matter where one falls on the continuum.”

Female sex, current smoking, greater airflow restrictions – and in some studies, younger age – have all been associated with a greater risk of anxiety in COPD. (It may well be that women receive more attention, leaving men with higher rates of undiagnosed anxiety, Dr. Hoth said.)

Dr. Iyer stresses the complex relationship between smoking – the No. 1 cause of COPD – and anxiety. Smoking has been associated in multiple studies with an increased risk of anxiety (Brain and Behavior. 2013;3[3]:302-26), he said. (A study led by Dr. Iyer found a similar frequency of anxiety symptoms in smokers with and without COPD [Journal of Psychosomatic Research. 2019;118:18-26].)

Some patients with COPD and anxiety may smoke in order to ease their anxiety, he said, making management of anxiety an important part of the smoking cessation desired for COPD improvement.

COPD medications such as bronchodilators may cause transient symptoms of anxiety, but these are rare and short-lived, Dr. Iyer said.
 

Screening tools and conversations

“It’s not just us not thinking about anxiety that’s the problem, it’s also patients thinking that it’s just the disease [causing their anxiety symptoms],” said Dr. Hanania, a member of the 2006 ACCP panel and an author of numerous papers on COPD and anxiety and depression. “There’s quite a bit of overlap between COPD symptoms and anxiety and depression symptoms, and unless you use structured questionnaires, you may not pick it up,” he said.

Screening tools include the Generalized Anxiety Disorder 7-item (GAD-7) scale, the PHQ-9 for depression and anxiety, and the longer Primary Care Evaluation of Mental Disorders (PRIME-MD). The Hospital Anxiety and Depression Scale (HADS), Dr. Iyer noted, has been well validated for use in ambulatory settings.

Validated screening tools specific to anxiety in COPD are also now an option. Abebaw M. Yohannes, PhD, MSc, FCCP, professor in the department of physical therapy at Azuza Pacific University in Orange, Calif., and the author of numerous studies on COPD and anxiety, developed one of these tools – the 10-item Anxiety Inventory for Respiratory Disease (AIR) scale – out of concern that other surveys contain overlapping somatic symptoms (Chest. 2013;144[5]:1587-96).

“We removed the physical symptoms [of anxiety] that often manifest in patients with COPD,” he said.

Dr. Iyer said screening tools can effectively “highlight which person might be dealing with high levels of anxiety symptoms that might meet a threshold of clinical significance and require collaborative or interprofessional management,” including with psychologists and psychiatrists.

They can also open the door to conversation with patients. “I’ll often bluntly ask, do you feel anxious? Do you feel scared, or hopeless about what the future holds for you?,” he said. “Anxiety about the future plays a big role, and helping patients navigate the illness and understand early how it might look … can ease the level of anxiety.”

Asking patients about their experiences in managing their symptoms and about their psychological and emotional well-being can help to normalize anxiety – and it can be therapeutic, said Dr. Hoth and Dr. Garvin. Asking “how it’s going with the things that really matter in [their] life” is often a good question, they said.

Patients “won’t be offended if you ask,” said Dr. Hoth. “They view their mood and [whole] well-being as part of their medical condition.”

Time is a challenge, she said, but “conversation can be done little by little, as part of a philosophy of engaging the patient around their whole functioning, even if there’s not [a need or] a route to refer just then.”

Such early and integrated conversation borrows from the palliative care model. “Palliative care is a specialty, but it can also be an approach to care,” Dr. Iyer said. He is leading a National Institutes of Health–funded study on nurse-coach–led early palliative care for older adults with COPD and wants to see training opportunities for pulmonologists to learn basic palliative care skills that would equip them to better guide management of mild-moderate anxiety and other complex symptoms.
 

Pulmonary rehabilitation

For many patients with COPD who have anxiety and/or depressive symptoms, referral for nonpharmacologic therapies such as psychotherapy, cognitive-behavioral therapy (CBT), and pulmonary rehabilitation (PR) is “one of the best things you can do,” Dr. Iyer said.

“If patients haven’t done pulmonary rehabilitation, get them in. And if they have done it before, get them back into it again,” he emphasized. “Accredited programs give a holistic approach to improving your strength, your breathlessness, your mindset and understanding of your breathlessness, and your own levels of security.”

Studies addressing the impact of PR and CBT on anxiety have been mostly small and observational but have yielded encouraging findings. A 2017 review reported that PR and CBT were effective in the treatment of anxiety and dyspnea, in the short term, in the majority of 47 studies (JAMA. 2017;18[12]:1096.e1-1096.e17). And a 2019 systematic review and meta-analysis focused on PR reported that, across 11 studies comprising 734 patients, PR conferred significant benefits for anxiety and depression compared with usual care (CHEST. 2019;156[1]:80-91).

Dr. Yohannes, Dr. Hanania, and colleagues recently reported on 734 patients with clinically stable COPD who completed a community-based 8-week PR program of 2 hours a week: 1 hour of exercise and 1 hour of education, the latter of which covered anxiety, panic management, and relaxation.

Patients who had severe dyspnea and comorbid anxiety and depression prior to PR – one-third of the group compared with 20% having anxiety alone and 5% having depression alone – had the most significant improvements in dyspnea scores and anxiety and depression scores (Respir Med. Apr 9. doi: 10.1016/j.rmed.2022.106850.)

The problem is, pulmonary rehabilitation is under-reimbursed and not widely accessible. It’s logistically challenging for patients to attend therapy 2-3 times a week. And according to a recently published study by Dr. Yohannes, Dr. Hanania, and colleagues, patients with more anxiety and dyspnea may be at higher risk of dropping out (Respir Med. 2022 Jan 20. doi: 10.1016/j.rmed.2022.10674). Moreover, Dr. Iyer said, there is a shortage of programs that are accredited.

Telehealth may help on some of these fronts. The efficacy of real-time video PR for COPD is being investigated in a randomized NIH trial (now in the recruitment phase) led by pulmonologist Surya P. Bhatt, MD, also at the University of Alabama at Birmingham.

Researchers also need to investigate issues of sustainability – to learn what “works best in the long run,” Dr. Iyer said.

Dr. Yohannes and Dr. Hanania are encouraged by a recent finding that patients with COPD who completed 8 weeks of PR maintained improvements in anxiety and quality-of-life scores at 2 years. (Improvements in dyspnea and other outcomes did not persist.) (CHEST. 2021;159[3]:967-74). Prospective studies contrasting maintenance programs with no maintenance following PR, are needed, they wrote.
 

Understanding psychological interventions

Dr. Hoth and Dr. Garvin advise their pulmonologist colleagues to feel as confident as possible in describing for patients what CBT and other psychological therapies entail.

“A person [with COPD] who is experiencing something on the continuum of anxiety might be really turning inward and [assessing] unwanted internal experiences” and accompanying thoughts, sensations, emotional impacts and behaviors, Dr. Garvin said.

Among the goals, she said, are to “make shifts around those internal experiences that might invoke some more tolerance or that might shift their relationship with the experiences, or even with the diagnosis itself and all the uncertainties it carries.”

Psychological therapies can involve social support, or “breath and grounding work,” she said. “There are lots of different approaches from different providers.”

Dr. Yohannes advocates incorporating principles of CBT into PR. “In the absence of one-on-one or group [stand-alone] CBT … the principles are worth incorporating as part of the education piece [of PR],” he said. “CBT helps patients to refocus their attention. … and gives them self-confidence to engage in exercise and to function a bit more in their daily activities.”

None of those interviewed for this story reported having any relevant conflicts of interest.

Anand S. Iyer, MD, MSPH, frequently hears his patients with chronic obstructive pulmonary disease (COPD) express fear and hopelessness and describe panic and other symptoms of anxiety. He sees anxiety affect the course of COPD, worsening symptoms and outcomes.

“I had questions about what we are doing [to help patients], so I began looking into the role of palliative care to help patients assess and manage these complex emotional and psychological symptoms,” said Dr. Iyer, assistant professor in the division of pulmonology, allergy, and critical care medicine at the University of Alabama at Birmingham.

His research is now focused on the integration of palliative care principles in COPD care. For Dr. Iyer and others engaged in research and/or patient care, finding ways of identifying and managing anxiety in patients with COPD – and other chronic lung diseases – is a calling of growing urgency.

More has been published about anxiety in patients with COPD than in other pulmonary conditions – and in COPD, anxiety has long been established as a prevalent comorbidity. Prevalence rates vary from about 1 in 4, to 1 in 2 or higher, depending on the instruments used and whether clinical DSM-based diagnoses are made, Dr. Iyer said.

A 2013 systematic review of 10 studies that utilized clinical interviews based on DSM criteria, for instance, found a prevalence of clinical anxiety of 10%-55% among inpatients and 13%-46% among outpatients with COPD. The results were similar, investigators said, to studies using self-report screening tools (Respiratory Care 2013;58[5]:858-66).

In the 16 years since an ACCP workshop panel on anxiety and depression in COPD reported higher prevalence rates than for other chronic diseases and detailed a host of problems and research needs (CHEST. 2008;134;43S-56), investigators have more fully documented links to COPD outcomes, showing, for instance, that anxiety predicts exacerbations, hospitalizations, poorer adherence to therapies, poorer quality of life and higher mortality.

Dr. Iyer and other experts say anxiety is still too often a neglected comorbidity. “It’s still underdiagnosed and therefore undertreated,” said Nick Hanania, MD, MS, professor of medicine and director of the Airways Clinical Research Center at Baylor College of Medicine, Houston.

The literature on optimal approaches for management remains limited, and the role of pharmacotherapy for anxiety (and depression) in the context of COPD has not been well investigated. But there have been some advances: Screening tools have been further studied, questionnaires specific to COPD have been developed, and pulmonary rehabilitation (PR) and cognitive behavioral therapy (CBT) have both been shown to be effective in decreasing anxiety.

Researchers and academic clinicians are talking, meanwhile, about how to have to important conversations about anxiety with patients who have COPD and other chronic lung conditions, and how improve care in the face of significant health system challenges.
 

Understanding anxiety in COPD

Anxiety is often intertwined with dyspnea in a bidirectional and complex relationship, but anxiety in COPD is not always acute or limited to times of acute exacerbations.

“There’s not only the acute experience of shortness of breath or a lung change episode, but there’s an anticipation that can occur, psychologically and socially,” said Lauren Garvin, PhD, of the department of psychiatry at the University of Iowa, Iowa City. Patients worry, “what if I’m short of breath in a particular situation? What if my devices fail when I’m out somewhere?”

Patients are often living “in a state of heightened surveillance of the body,” she noted, which can be exhausting and can impact functioning.

It’s also important to appreciate that anxiety is “a continuum of experience,” said Karin Hoth, PhD, associate professor of psychiatry at the medical school, whose research includes projects focusing on psychological adjustment in COPD.

“Research historically categorizes anxiety as ‘have or don’t have.’ But there’s a continuum of experience that we’re moving toward understanding and recognizing in research,” she said. “Anxiety is part of a patient’s whole experience, no matter where one falls on the continuum.”

Female sex, current smoking, greater airflow restrictions – and in some studies, younger age – have all been associated with a greater risk of anxiety in COPD. (It may well be that women receive more attention, leaving men with higher rates of undiagnosed anxiety, Dr. Hoth said.)

Dr. Iyer stresses the complex relationship between smoking – the No. 1 cause of COPD – and anxiety. Smoking has been associated in multiple studies with an increased risk of anxiety (Brain and Behavior. 2013;3[3]:302-26), he said. (A study led by Dr. Iyer found a similar frequency of anxiety symptoms in smokers with and without COPD [Journal of Psychosomatic Research. 2019;118:18-26].)

Some patients with COPD and anxiety may smoke in order to ease their anxiety, he said, making management of anxiety an important part of the smoking cessation desired for COPD improvement.

COPD medications such as bronchodilators may cause transient symptoms of anxiety, but these are rare and short-lived, Dr. Iyer said.
 

Screening tools and conversations

“It’s not just us not thinking about anxiety that’s the problem, it’s also patients thinking that it’s just the disease [causing their anxiety symptoms],” said Dr. Hanania, a member of the 2006 ACCP panel and an author of numerous papers on COPD and anxiety and depression. “There’s quite a bit of overlap between COPD symptoms and anxiety and depression symptoms, and unless you use structured questionnaires, you may not pick it up,” he said.

Screening tools include the Generalized Anxiety Disorder 7-item (GAD-7) scale, the PHQ-9 for depression and anxiety, and the longer Primary Care Evaluation of Mental Disorders (PRIME-MD). The Hospital Anxiety and Depression Scale (HADS), Dr. Iyer noted, has been well validated for use in ambulatory settings.

Validated screening tools specific to anxiety in COPD are also now an option. Abebaw M. Yohannes, PhD, MSc, FCCP, professor in the department of physical therapy at Azuza Pacific University in Orange, Calif., and the author of numerous studies on COPD and anxiety, developed one of these tools – the 10-item Anxiety Inventory for Respiratory Disease (AIR) scale – out of concern that other surveys contain overlapping somatic symptoms (Chest. 2013;144[5]:1587-96).

“We removed the physical symptoms [of anxiety] that often manifest in patients with COPD,” he said.

Dr. Iyer said screening tools can effectively “highlight which person might be dealing with high levels of anxiety symptoms that might meet a threshold of clinical significance and require collaborative or interprofessional management,” including with psychologists and psychiatrists.

They can also open the door to conversation with patients. “I’ll often bluntly ask, do you feel anxious? Do you feel scared, or hopeless about what the future holds for you?,” he said. “Anxiety about the future plays a big role, and helping patients navigate the illness and understand early how it might look … can ease the level of anxiety.”

Asking patients about their experiences in managing their symptoms and about their psychological and emotional well-being can help to normalize anxiety – and it can be therapeutic, said Dr. Hoth and Dr. Garvin. Asking “how it’s going with the things that really matter in [their] life” is often a good question, they said.

Patients “won’t be offended if you ask,” said Dr. Hoth. “They view their mood and [whole] well-being as part of their medical condition.”

Time is a challenge, she said, but “conversation can be done little by little, as part of a philosophy of engaging the patient around their whole functioning, even if there’s not [a need or] a route to refer just then.”

Such early and integrated conversation borrows from the palliative care model. “Palliative care is a specialty, but it can also be an approach to care,” Dr. Iyer said. He is leading a National Institutes of Health–funded study on nurse-coach–led early palliative care for older adults with COPD and wants to see training opportunities for pulmonologists to learn basic palliative care skills that would equip them to better guide management of mild-moderate anxiety and other complex symptoms.
 

Pulmonary rehabilitation

For many patients with COPD who have anxiety and/or depressive symptoms, referral for nonpharmacologic therapies such as psychotherapy, cognitive-behavioral therapy (CBT), and pulmonary rehabilitation (PR) is “one of the best things you can do,” Dr. Iyer said.

“If patients haven’t done pulmonary rehabilitation, get them in. And if they have done it before, get them back into it again,” he emphasized. “Accredited programs give a holistic approach to improving your strength, your breathlessness, your mindset and understanding of your breathlessness, and your own levels of security.”

Studies addressing the impact of PR and CBT on anxiety have been mostly small and observational but have yielded encouraging findings. A 2017 review reported that PR and CBT were effective in the treatment of anxiety and dyspnea, in the short term, in the majority of 47 studies (JAMA. 2017;18[12]:1096.e1-1096.e17). And a 2019 systematic review and meta-analysis focused on PR reported that, across 11 studies comprising 734 patients, PR conferred significant benefits for anxiety and depression compared with usual care (CHEST. 2019;156[1]:80-91).

Dr. Yohannes, Dr. Hanania, and colleagues recently reported on 734 patients with clinically stable COPD who completed a community-based 8-week PR program of 2 hours a week: 1 hour of exercise and 1 hour of education, the latter of which covered anxiety, panic management, and relaxation.

Patients who had severe dyspnea and comorbid anxiety and depression prior to PR – one-third of the group compared with 20% having anxiety alone and 5% having depression alone – had the most significant improvements in dyspnea scores and anxiety and depression scores (Respir Med. Apr 9. doi: 10.1016/j.rmed.2022.106850.)

The problem is, pulmonary rehabilitation is under-reimbursed and not widely accessible. It’s logistically challenging for patients to attend therapy 2-3 times a week. And according to a recently published study by Dr. Yohannes, Dr. Hanania, and colleagues, patients with more anxiety and dyspnea may be at higher risk of dropping out (Respir Med. 2022 Jan 20. doi: 10.1016/j.rmed.2022.10674). Moreover, Dr. Iyer said, there is a shortage of programs that are accredited.

Telehealth may help on some of these fronts. The efficacy of real-time video PR for COPD is being investigated in a randomized NIH trial (now in the recruitment phase) led by pulmonologist Surya P. Bhatt, MD, also at the University of Alabama at Birmingham.

Researchers also need to investigate issues of sustainability – to learn what “works best in the long run,” Dr. Iyer said.

Dr. Yohannes and Dr. Hanania are encouraged by a recent finding that patients with COPD who completed 8 weeks of PR maintained improvements in anxiety and quality-of-life scores at 2 years. (Improvements in dyspnea and other outcomes did not persist.) (CHEST. 2021;159[3]:967-74). Prospective studies contrasting maintenance programs with no maintenance following PR, are needed, they wrote.
 

Understanding psychological interventions

Dr. Hoth and Dr. Garvin advise their pulmonologist colleagues to feel as confident as possible in describing for patients what CBT and other psychological therapies entail.

“A person [with COPD] who is experiencing something on the continuum of anxiety might be really turning inward and [assessing] unwanted internal experiences” and accompanying thoughts, sensations, emotional impacts and behaviors, Dr. Garvin said.

Among the goals, she said, are to “make shifts around those internal experiences that might invoke some more tolerance or that might shift their relationship with the experiences, or even with the diagnosis itself and all the uncertainties it carries.”

Psychological therapies can involve social support, or “breath and grounding work,” she said. “There are lots of different approaches from different providers.”

Dr. Yohannes advocates incorporating principles of CBT into PR. “In the absence of one-on-one or group [stand-alone] CBT … the principles are worth incorporating as part of the education piece [of PR],” he said. “CBT helps patients to refocus their attention. … and gives them self-confidence to engage in exercise and to function a bit more in their daily activities.”

None of those interviewed for this story reported having any relevant conflicts of interest.

Anand S. Iyer, MD, MSPH, frequently hears his patients with chronic obstructive pulmonary disease (COPD) express fear and hopelessness and describe panic and other symptoms of anxiety. He sees anxiety affect the course of COPD, worsening symptoms and outcomes.

“I had questions about what we are doing [to help patients], so I began looking into the role of palliative care to help patients assess and manage these complex emotional and psychological symptoms,” said Dr. Iyer, assistant professor in the division of pulmonology, allergy, and critical care medicine at the University of Alabama at Birmingham.

His research is now focused on the integration of palliative care principles in COPD care. For Dr. Iyer and others engaged in research and/or patient care, finding ways of identifying and managing anxiety in patients with COPD – and other chronic lung diseases – is a calling of growing urgency.

More has been published about anxiety in patients with COPD than in other pulmonary conditions – and in COPD, anxiety has long been established as a prevalent comorbidity. Prevalence rates vary from about 1 in 4, to 1 in 2 or higher, depending on the instruments used and whether clinical DSM-based diagnoses are made, Dr. Iyer said.

A 2013 systematic review of 10 studies that utilized clinical interviews based on DSM criteria, for instance, found a prevalence of clinical anxiety of 10%-55% among inpatients and 13%-46% among outpatients with COPD. The results were similar, investigators said, to studies using self-report screening tools (Respiratory Care 2013;58[5]:858-66).

In the 16 years since an ACCP workshop panel on anxiety and depression in COPD reported higher prevalence rates than for other chronic diseases and detailed a host of problems and research needs (CHEST. 2008;134;43S-56), investigators have more fully documented links to COPD outcomes, showing, for instance, that anxiety predicts exacerbations, hospitalizations, poorer adherence to therapies, poorer quality of life and higher mortality.

Dr. Iyer and other experts say anxiety is still too often a neglected comorbidity. “It’s still underdiagnosed and therefore undertreated,” said Nick Hanania, MD, MS, professor of medicine and director of the Airways Clinical Research Center at Baylor College of Medicine, Houston.

The literature on optimal approaches for management remains limited, and the role of pharmacotherapy for anxiety (and depression) in the context of COPD has not been well investigated. But there have been some advances: Screening tools have been further studied, questionnaires specific to COPD have been developed, and pulmonary rehabilitation (PR) and cognitive behavioral therapy (CBT) have both been shown to be effective in decreasing anxiety.

Researchers and academic clinicians are talking, meanwhile, about how to have to important conversations about anxiety with patients who have COPD and other chronic lung conditions, and how improve care in the face of significant health system challenges.
 

Understanding anxiety in COPD

Anxiety is often intertwined with dyspnea in a bidirectional and complex relationship, but anxiety in COPD is not always acute or limited to times of acute exacerbations.

“There’s not only the acute experience of shortness of breath or a lung change episode, but there’s an anticipation that can occur, psychologically and socially,” said Lauren Garvin, PhD, of the department of psychiatry at the University of Iowa, Iowa City. Patients worry, “what if I’m short of breath in a particular situation? What if my devices fail when I’m out somewhere?”

Patients are often living “in a state of heightened surveillance of the body,” she noted, which can be exhausting and can impact functioning.

It’s also important to appreciate that anxiety is “a continuum of experience,” said Karin Hoth, PhD, associate professor of psychiatry at the medical school, whose research includes projects focusing on psychological adjustment in COPD.

“Research historically categorizes anxiety as ‘have or don’t have.’ But there’s a continuum of experience that we’re moving toward understanding and recognizing in research,” she said. “Anxiety is part of a patient’s whole experience, no matter where one falls on the continuum.”

Female sex, current smoking, greater airflow restrictions – and in some studies, younger age – have all been associated with a greater risk of anxiety in COPD. (It may well be that women receive more attention, leaving men with higher rates of undiagnosed anxiety, Dr. Hoth said.)

Dr. Iyer stresses the complex relationship between smoking – the No. 1 cause of COPD – and anxiety. Smoking has been associated in multiple studies with an increased risk of anxiety (Brain and Behavior. 2013;3[3]:302-26), he said. (A study led by Dr. Iyer found a similar frequency of anxiety symptoms in smokers with and without COPD [Journal of Psychosomatic Research. 2019;118:18-26].)

Some patients with COPD and anxiety may smoke in order to ease their anxiety, he said, making management of anxiety an important part of the smoking cessation desired for COPD improvement.

COPD medications such as bronchodilators may cause transient symptoms of anxiety, but these are rare and short-lived, Dr. Iyer said.
 

Screening tools and conversations

“It’s not just us not thinking about anxiety that’s the problem, it’s also patients thinking that it’s just the disease [causing their anxiety symptoms],” said Dr. Hanania, a member of the 2006 ACCP panel and an author of numerous papers on COPD and anxiety and depression. “There’s quite a bit of overlap between COPD symptoms and anxiety and depression symptoms, and unless you use structured questionnaires, you may not pick it up,” he said.

Screening tools include the Generalized Anxiety Disorder 7-item (GAD-7) scale, the PHQ-9 for depression and anxiety, and the longer Primary Care Evaluation of Mental Disorders (PRIME-MD). The Hospital Anxiety and Depression Scale (HADS), Dr. Iyer noted, has been well validated for use in ambulatory settings.

Validated screening tools specific to anxiety in COPD are also now an option. Abebaw M. Yohannes, PhD, MSc, FCCP, professor in the department of physical therapy at Azuza Pacific University in Orange, Calif., and the author of numerous studies on COPD and anxiety, developed one of these tools – the 10-item Anxiety Inventory for Respiratory Disease (AIR) scale – out of concern that other surveys contain overlapping somatic symptoms (Chest. 2013;144[5]:1587-96).

“We removed the physical symptoms [of anxiety] that often manifest in patients with COPD,” he said.

Dr. Iyer said screening tools can effectively “highlight which person might be dealing with high levels of anxiety symptoms that might meet a threshold of clinical significance and require collaborative or interprofessional management,” including with psychologists and psychiatrists.

They can also open the door to conversation with patients. “I’ll often bluntly ask, do you feel anxious? Do you feel scared, or hopeless about what the future holds for you?,” he said. “Anxiety about the future plays a big role, and helping patients navigate the illness and understand early how it might look … can ease the level of anxiety.”

Asking patients about their experiences in managing their symptoms and about their psychological and emotional well-being can help to normalize anxiety – and it can be therapeutic, said Dr. Hoth and Dr. Garvin. Asking “how it’s going with the things that really matter in [their] life” is often a good question, they said.

Patients “won’t be offended if you ask,” said Dr. Hoth. “They view their mood and [whole] well-being as part of their medical condition.”

Time is a challenge, she said, but “conversation can be done little by little, as part of a philosophy of engaging the patient around their whole functioning, even if there’s not [a need or] a route to refer just then.”

Such early and integrated conversation borrows from the palliative care model. “Palliative care is a specialty, but it can also be an approach to care,” Dr. Iyer said. He is leading a National Institutes of Health–funded study on nurse-coach–led early palliative care for older adults with COPD and wants to see training opportunities for pulmonologists to learn basic palliative care skills that would equip them to better guide management of mild-moderate anxiety and other complex symptoms.
 

Pulmonary rehabilitation

For many patients with COPD who have anxiety and/or depressive symptoms, referral for nonpharmacologic therapies such as psychotherapy, cognitive-behavioral therapy (CBT), and pulmonary rehabilitation (PR) is “one of the best things you can do,” Dr. Iyer said.

“If patients haven’t done pulmonary rehabilitation, get them in. And if they have done it before, get them back into it again,” he emphasized. “Accredited programs give a holistic approach to improving your strength, your breathlessness, your mindset and understanding of your breathlessness, and your own levels of security.”

Studies addressing the impact of PR and CBT on anxiety have been mostly small and observational but have yielded encouraging findings. A 2017 review reported that PR and CBT were effective in the treatment of anxiety and dyspnea, in the short term, in the majority of 47 studies (JAMA. 2017;18[12]:1096.e1-1096.e17). And a 2019 systematic review and meta-analysis focused on PR reported that, across 11 studies comprising 734 patients, PR conferred significant benefits for anxiety and depression compared with usual care (CHEST. 2019;156[1]:80-91).

Dr. Yohannes, Dr. Hanania, and colleagues recently reported on 734 patients with clinically stable COPD who completed a community-based 8-week PR program of 2 hours a week: 1 hour of exercise and 1 hour of education, the latter of which covered anxiety, panic management, and relaxation.

Patients who had severe dyspnea and comorbid anxiety and depression prior to PR – one-third of the group compared with 20% having anxiety alone and 5% having depression alone – had the most significant improvements in dyspnea scores and anxiety and depression scores (Respir Med. Apr 9. doi: 10.1016/j.rmed.2022.106850.)

The problem is, pulmonary rehabilitation is under-reimbursed and not widely accessible. It’s logistically challenging for patients to attend therapy 2-3 times a week. And according to a recently published study by Dr. Yohannes, Dr. Hanania, and colleagues, patients with more anxiety and dyspnea may be at higher risk of dropping out (Respir Med. 2022 Jan 20. doi: 10.1016/j.rmed.2022.10674). Moreover, Dr. Iyer said, there is a shortage of programs that are accredited.

Telehealth may help on some of these fronts. The efficacy of real-time video PR for COPD is being investigated in a randomized NIH trial (now in the recruitment phase) led by pulmonologist Surya P. Bhatt, MD, also at the University of Alabama at Birmingham.

Researchers also need to investigate issues of sustainability – to learn what “works best in the long run,” Dr. Iyer said.

Dr. Yohannes and Dr. Hanania are encouraged by a recent finding that patients with COPD who completed 8 weeks of PR maintained improvements in anxiety and quality-of-life scores at 2 years. (Improvements in dyspnea and other outcomes did not persist.) (CHEST. 2021;159[3]:967-74). Prospective studies contrasting maintenance programs with no maintenance following PR, are needed, they wrote.
 

Understanding psychological interventions

Dr. Hoth and Dr. Garvin advise their pulmonologist colleagues to feel as confident as possible in describing for patients what CBT and other psychological therapies entail.

“A person [with COPD] who is experiencing something on the continuum of anxiety might be really turning inward and [assessing] unwanted internal experiences” and accompanying thoughts, sensations, emotional impacts and behaviors, Dr. Garvin said.

Among the goals, she said, are to “make shifts around those internal experiences that might invoke some more tolerance or that might shift their relationship with the experiences, or even with the diagnosis itself and all the uncertainties it carries.”

Psychological therapies can involve social support, or “breath and grounding work,” she said. “There are lots of different approaches from different providers.”

Dr. Yohannes advocates incorporating principles of CBT into PR. “In the absence of one-on-one or group [stand-alone] CBT … the principles are worth incorporating as part of the education piece [of PR],” he said. “CBT helps patients to refocus their attention. … and gives them self-confidence to engage in exercise and to function a bit more in their daily activities.”

None of those interviewed for this story reported having any relevant conflicts of interest.

In June of this year, the World Health Organization launched a policy report to confront the increasingly strong and lasting impacts that climate change is having directly and indirectly on people’s mental health and psychosocial well-being.

In addition to the increasingly high incidence of mental disorders (for instance, emotional distress, stress, depression, and suicidal behavior) affecting people worldwide, the WHO warned of new, emerging syndromes that are directly related to climate change, such as “ecotrauma.” This term refers to anxiety in the face of the apocalyptic scenario predicted to result from the transformation of ecosystems by anthropogenic activity.

Two weeks after the release of the policy report, which integrates key policies for countries to address one of the biggest challenges, the WHO published its largest review of global mental health since the turn of the century. The work provides a model for governments, academics, health professionals, and civil society to become key players when dealing with the mental health problems that our society is going through.

Bernhard_Staehli/Thinkstock

As the document highlights, almost 1 billion people, including 14% of the world’s adolescents, were living with a mental health disorder in 2019. Suicide accounted for more than 1 in 100 deaths, and 58% of cases occurred before age 50 years. Mental health disorders are already the leading cause of disability in the world, and people with serious but preventable diseases die on average 10-20 years earlier than the general population.

The COVID-19 crisis has significantly aggravated mental health disorders, especially in populations such as minors. Consequently, many experts refer to this public health phenomenon as the new major pandemic. “I’m not sure it’s correct to call a set of mental health problems a pandemic, but the reality is that many countries are ignoring or largely forgetting this crisis,” Sarah Sheppard, WHO communications officer, told this news organization. According to Ms. Sheppard, “stigma and lack of understanding are key drivers of these problems and have been one of the reasons for the lack of mental health funding for decades. Mental health receives less than 1% of international health aid.” We recently interviewed Ms. Sheppard about these challenges.

Univadis: As the data provided in the recently released Mental Health and Climate Change Policy Brief indicate, there are large gaps in many countries between mental health needs and the services and systems available to address them. Where can we start to change this reality?

Ms. Sheppard: The simplest answer to improve the situation we face begins with a change in people’s priorities when it comes to valuing mental health. This would lead to greater investment in human and financial resources for mental health services and systems. However, the challenge lies in the complexity of the problem. In the report we just published, we provide comprehensive recommendations on how to transform mental health systems for all, such as trying to integrate climate change considerations into policies and programs for mental health or building on existing global commitments, including the Sustainable Development Goals (SDGs) or the Paris Agreement.

Univadis: Is there evidence that mental illnesses and disorders affect some populations more than others, such as women, for example?

Ms. Sheppard: The prevalence of mental disorders varies according to conditions and according to sex and age. In general, I don’t think we can say that mental health conditions or disorders affect women more than men. There are groups at risk, but vulnerability depends on the context and varies a lot. Of course, social determinants such as poverty, unstable housing, and exposure to adversity can significantly increase risk.

Univadis: According to the statistics recently provided by the WHO, changes in the environment are directly and indirectly affecting people’s mental health and psychosocial well-being. The new report highlights the gap between countries when it comes to addressing this complex problem. Is there any country that is carrying out political or innovative initiatives in this regard?

Ms. Sheppard: Yes, there are many case studies in the policy brief that highlight important work in the area. There are strong examples that are highlighted in the summary. One of them is India and its resilient cities program. Focused on the reduction of disaster risk, climate resilience, and mental health and psychosocial support at city level, this project resulted from a collaboration between the United Nations Development Program and the Indian National Institute of Mental Health and Neurosciences, which began in 2017.

Univadis: In addition to its effects on mental health, we are seeing how climate change is causing the appearance and resurgence of zoonoses, such as the pandemic caused by coronavirus and now monkeypox.

Ms. Sheppard: Mike Ryan, head of emergency situations at WHO, stated at the beginning of June that the increase in zoonoses raises the risk of new pandemics. Infections transmitted from animals to humans, such as Ebola, COVID-19, or monkeypox, have multiplied in recent years. Climate change alters the conditions for pathogens and zoonotic disease vectors and their distribution. The intensification of travel, for example, allows them to spread more quickly and in a more uncontrolled way.

Human health, including mental health, is connected to animal health. As various materials available to us from our World Health Day 2022 campaign examine, the links between planetary health and human health are inextricable.

Univadis: How is it possible that while scientific progress advances and more powerful and efficient technologies are developed, we become increasingly vulnerable to environmental phenomena?

Ms. Sheppard: Scientific advancement improves our understanding of the quality and scale of the health impacts of climate change, including the identification of the most vulnerable groups, as well as the adaptation and mitigation measures that would work to reduce the consequences on health. At the same time, climate change is widespread, rapid, and intensifying. Technological advances have a role to play in mitigation, particularly those tools that reduce our dependence on burning fossil fuels, as well as adaptation to climate change. For example, early warning systems for extreme weather events could reduce those vulnerabilities your question mentioned.

On the other hand, the measures proposed by the latest report on mental health and climate change have multiple effects. Some are particularly powerful and are not overly dependent on new technology. These include changing our mode of transport to low-emission, physically active ways to get around (walking, cycling), the benefits of which are already more than proven for both the environment and human health.

This article was translated from Univadis Spain.

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

In June of this year, the World Health Organization launched a policy report to confront the increasingly strong and lasting impacts that climate change is having directly and indirectly on people’s mental health and psychosocial well-being.

In addition to the increasingly high incidence of mental disorders (for instance, emotional distress, stress, depression, and suicidal behavior) affecting people worldwide, the WHO warned of new, emerging syndromes that are directly related to climate change, such as “ecotrauma.” This term refers to anxiety in the face of the apocalyptic scenario predicted to result from the transformation of ecosystems by anthropogenic activity.

Two weeks after the release of the policy report, which integrates key policies for countries to address one of the biggest challenges, the WHO published its largest review of global mental health since the turn of the century. The work provides a model for governments, academics, health professionals, and civil society to become key players when dealing with the mental health problems that our society is going through.

Bernhard_Staehli/Thinkstock

As the document highlights, almost 1 billion people, including 14% of the world’s adolescents, were living with a mental health disorder in 2019. Suicide accounted for more than 1 in 100 deaths, and 58% of cases occurred before age 50 years. Mental health disorders are already the leading cause of disability in the world, and people with serious but preventable diseases die on average 10-20 years earlier than the general population.

The COVID-19 crisis has significantly aggravated mental health disorders, especially in populations such as minors. Consequently, many experts refer to this public health phenomenon as the new major pandemic. “I’m not sure it’s correct to call a set of mental health problems a pandemic, but the reality is that many countries are ignoring or largely forgetting this crisis,” Sarah Sheppard, WHO communications officer, told this news organization. According to Ms. Sheppard, “stigma and lack of understanding are key drivers of these problems and have been one of the reasons for the lack of mental health funding for decades. Mental health receives less than 1% of international health aid.” We recently interviewed Ms. Sheppard about these challenges.

Univadis: As the data provided in the recently released Mental Health and Climate Change Policy Brief indicate, there are large gaps in many countries between mental health needs and the services and systems available to address them. Where can we start to change this reality?

Ms. Sheppard: The simplest answer to improve the situation we face begins with a change in people’s priorities when it comes to valuing mental health. This would lead to greater investment in human and financial resources for mental health services and systems. However, the challenge lies in the complexity of the problem. In the report we just published, we provide comprehensive recommendations on how to transform mental health systems for all, such as trying to integrate climate change considerations into policies and programs for mental health or building on existing global commitments, including the Sustainable Development Goals (SDGs) or the Paris Agreement.

Univadis: Is there evidence that mental illnesses and disorders affect some populations more than others, such as women, for example?

Ms. Sheppard: The prevalence of mental disorders varies according to conditions and according to sex and age. In general, I don’t think we can say that mental health conditions or disorders affect women more than men. There are groups at risk, but vulnerability depends on the context and varies a lot. Of course, social determinants such as poverty, unstable housing, and exposure to adversity can significantly increase risk.

Univadis: According to the statistics recently provided by the WHO, changes in the environment are directly and indirectly affecting people’s mental health and psychosocial well-being. The new report highlights the gap between countries when it comes to addressing this complex problem. Is there any country that is carrying out political or innovative initiatives in this regard?

Ms. Sheppard: Yes, there are many case studies in the policy brief that highlight important work in the area. There are strong examples that are highlighted in the summary. One of them is India and its resilient cities program. Focused on the reduction of disaster risk, climate resilience, and mental health and psychosocial support at city level, this project resulted from a collaboration between the United Nations Development Program and the Indian National Institute of Mental Health and Neurosciences, which began in 2017.

Univadis: In addition to its effects on mental health, we are seeing how climate change is causing the appearance and resurgence of zoonoses, such as the pandemic caused by coronavirus and now monkeypox.

Ms. Sheppard: Mike Ryan, head of emergency situations at WHO, stated at the beginning of June that the increase in zoonoses raises the risk of new pandemics. Infections transmitted from animals to humans, such as Ebola, COVID-19, or monkeypox, have multiplied in recent years. Climate change alters the conditions for pathogens and zoonotic disease vectors and their distribution. The intensification of travel, for example, allows them to spread more quickly and in a more uncontrolled way.

Human health, including mental health, is connected to animal health. As various materials available to us from our World Health Day 2022 campaign examine, the links between planetary health and human health are inextricable.

Univadis: How is it possible that while scientific progress advances and more powerful and efficient technologies are developed, we become increasingly vulnerable to environmental phenomena?

Ms. Sheppard: Scientific advancement improves our understanding of the quality and scale of the health impacts of climate change, including the identification of the most vulnerable groups, as well as the adaptation and mitigation measures that would work to reduce the consequences on health. At the same time, climate change is widespread, rapid, and intensifying. Technological advances have a role to play in mitigation, particularly those tools that reduce our dependence on burning fossil fuels, as well as adaptation to climate change. For example, early warning systems for extreme weather events could reduce those vulnerabilities your question mentioned.

On the other hand, the measures proposed by the latest report on mental health and climate change have multiple effects. Some are particularly powerful and are not overly dependent on new technology. These include changing our mode of transport to low-emission, physically active ways to get around (walking, cycling), the benefits of which are already more than proven for both the environment and human health.

This article was translated from Univadis Spain.

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

In June of this year, the World Health Organization launched a policy report to confront the increasingly strong and lasting impacts that climate change is having directly and indirectly on people’s mental health and psychosocial well-being.

In addition to the increasingly high incidence of mental disorders (for instance, emotional distress, stress, depression, and suicidal behavior) affecting people worldwide, the WHO warned of new, emerging syndromes that are directly related to climate change, such as “ecotrauma.” This term refers to anxiety in the face of the apocalyptic scenario predicted to result from the transformation of ecosystems by anthropogenic activity.

Two weeks after the release of the policy report, which integrates key policies for countries to address one of the biggest challenges, the WHO published its largest review of global mental health since the turn of the century. The work provides a model for governments, academics, health professionals, and civil society to become key players when dealing with the mental health problems that our society is going through.

Bernhard_Staehli/Thinkstock

As the document highlights, almost 1 billion people, including 14% of the world’s adolescents, were living with a mental health disorder in 2019. Suicide accounted for more than 1 in 100 deaths, and 58% of cases occurred before age 50 years. Mental health disorders are already the leading cause of disability in the world, and people with serious but preventable diseases die on average 10-20 years earlier than the general population.

The COVID-19 crisis has significantly aggravated mental health disorders, especially in populations such as minors. Consequently, many experts refer to this public health phenomenon as the new major pandemic. “I’m not sure it’s correct to call a set of mental health problems a pandemic, but the reality is that many countries are ignoring or largely forgetting this crisis,” Sarah Sheppard, WHO communications officer, told this news organization. According to Ms. Sheppard, “stigma and lack of understanding are key drivers of these problems and have been one of the reasons for the lack of mental health funding for decades. Mental health receives less than 1% of international health aid.” We recently interviewed Ms. Sheppard about these challenges.

Univadis: As the data provided in the recently released Mental Health and Climate Change Policy Brief indicate, there are large gaps in many countries between mental health needs and the services and systems available to address them. Where can we start to change this reality?

Ms. Sheppard: The simplest answer to improve the situation we face begins with a change in people’s priorities when it comes to valuing mental health. This would lead to greater investment in human and financial resources for mental health services and systems. However, the challenge lies in the complexity of the problem. In the report we just published, we provide comprehensive recommendations on how to transform mental health systems for all, such as trying to integrate climate change considerations into policies and programs for mental health or building on existing global commitments, including the Sustainable Development Goals (SDGs) or the Paris Agreement.

Univadis: Is there evidence that mental illnesses and disorders affect some populations more than others, such as women, for example?

Ms. Sheppard: The prevalence of mental disorders varies according to conditions and according to sex and age. In general, I don’t think we can say that mental health conditions or disorders affect women more than men. There are groups at risk, but vulnerability depends on the context and varies a lot. Of course, social determinants such as poverty, unstable housing, and exposure to adversity can significantly increase risk.

Univadis: According to the statistics recently provided by the WHO, changes in the environment are directly and indirectly affecting people’s mental health and psychosocial well-being. The new report highlights the gap between countries when it comes to addressing this complex problem. Is there any country that is carrying out political or innovative initiatives in this regard?

Ms. Sheppard: Yes, there are many case studies in the policy brief that highlight important work in the area. There are strong examples that are highlighted in the summary. One of them is India and its resilient cities program. Focused on the reduction of disaster risk, climate resilience, and mental health and psychosocial support at city level, this project resulted from a collaboration between the United Nations Development Program and the Indian National Institute of Mental Health and Neurosciences, which began in 2017.

Univadis: In addition to its effects on mental health, we are seeing how climate change is causing the appearance and resurgence of zoonoses, such as the pandemic caused by coronavirus and now monkeypox.

Ms. Sheppard: Mike Ryan, head of emergency situations at WHO, stated at the beginning of June that the increase in zoonoses raises the risk of new pandemics. Infections transmitted from animals to humans, such as Ebola, COVID-19, or monkeypox, have multiplied in recent years. Climate change alters the conditions for pathogens and zoonotic disease vectors and their distribution. The intensification of travel, for example, allows them to spread more quickly and in a more uncontrolled way.

Human health, including mental health, is connected to animal health. As various materials available to us from our World Health Day 2022 campaign examine, the links between planetary health and human health are inextricable.

Univadis: How is it possible that while scientific progress advances and more powerful and efficient technologies are developed, we become increasingly vulnerable to environmental phenomena?

Ms. Sheppard: Scientific advancement improves our understanding of the quality and scale of the health impacts of climate change, including the identification of the most vulnerable groups, as well as the adaptation and mitigation measures that would work to reduce the consequences on health. At the same time, climate change is widespread, rapid, and intensifying. Technological advances have a role to play in mitigation, particularly those tools that reduce our dependence on burning fossil fuels, as well as adaptation to climate change. For example, early warning systems for extreme weather events could reduce those vulnerabilities your question mentioned.

On the other hand, the measures proposed by the latest report on mental health and climate change have multiple effects. Some are particularly powerful and are not overly dependent on new technology. These include changing our mode of transport to low-emission, physically active ways to get around (walking, cycling), the benefits of which are already more than proven for both the environment and human health.

This article was translated from Univadis Spain.

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

Patients with hemophilia B face a lifelong need for regular factor IX injections. But in 9 of 10 patients treated with a novel gene therapy, this need was eliminated.

“Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” lead author Pratima Chowdary, MD, of the Royal Free Hospital, University College London Cancer Institute, commented in a press statement.

The team reported new results with the investigational gene therapy FLT180a in a study published in the New England Journal of Medicine.

“We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a,” the authors reported. “In all but one patient, gene therapy led to durable factor IX expression, eliminated the need for factor IX prophylaxis, and eliminated spontaneous bleeding leading to factor IX replacement.”

FLT180a (Freeline Therapeutics) is a liver-directed, adeno-associated virus (AAV) gene therapy designed to normalize levels of the factor IX protein that is needed for coagulation; however, it is produced in dangerously low levels in people with hemophilia B as a result of gene mutations.

Under the current standard of care, patients with hemophilia B require lifelong prophylaxis of regular intravenous injections with recombinant factor IX replacement therapy, and they commonly continue to experience potentially severe joint pain.

While factor-replacement therapies with longer half-lives have emerged, the prophylaxis is still invasive and extremely expensive, with the average price tag in the United States of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
 

Novel gene therapy

Hemophilia B is a rare and inherited genetic bleeding disorder caused by defects in the gene responsible for factor IX protein, which is needed for blood clotting.

AAV gene therapy delivers a functional copy of this gene directly to patient tissues to compensate for one that is not working properly. It leads to the synthesis of factor IX proteins and a one-time gene therapy infusion can achieve long-lasting effects, the team explained in a press release.

The results they reported come from the phase 1/2 multicenter B-AMAZE open-label trial. It involved 10 patients (all age 18 and older) with severe or moderately severe hemophilia B, defined as having a factor IX level of 2% or less that of normal values.

All patients received one-off gene therapy infusion, at one of four FLT180a doses.

All patients also received immunosuppression to prevent the body from rejecting the vector gene therapy. This consisted of glucocorticoids with or without tacrolimus for a period of ranging from several weeks to several months.

Following the FLT180a infusion, all patients showed dose-dependent increases in factor IX levels. After a median follow-up of 27.2 months (range, 19.1-42.4 months), nearly all the patients (9 of 10) continued to show sustained factor IX activity.

Steady production of factor IX activity started at month 12, with low bleeding frequency that allowed these nine patients to no longer require weekly injections of the protein.

Five of the patients had factor IX levels in the normal range, from 51% to 78%; three patients had lower increases of 23%-43% of the normal range, and one patient who had received the highest dose, had a level that was 260% of normal.

The exception was one patient who required a return to factor IX prophylaxis. He had  experienced a failure in the immunosuppression regimen due to a delay in the recognition of an immune response at approximately 22 weeks after treatment, the authors reported.

The therapy was generally well tolerated, with no infusion reactions or discontinuations of infusions. As of the study cutoff, no inhibitors of factor IX were detected.

Of the adverse events, about 10% were determined to be related to the gene therapy. The most common event associated with the gene therapy was increases in liver aminotransferase, which is a concern with AAV gene therapies, the authors commented.

Otherwise, 24% of adverse events were determined to be related to the immunosuppression, and were consistent with the known safety profiles of glucocorticoids and tacrolimus.

Late increases in aminotransferase levels were reported among patients who had received prolonged tacrolimus beyond the tapering of glucocorticoid treatment.

The one serious adverse event that was reported involved an arteriovenous fistula thrombosis, which occurred in the patient who had received the highest dose of gene therapy and who showed the highest factor IX levels.

The current findings, along with data from another recent study involving gene therapy for patients with hemophilia A, emphasized that “immune responses can occur later than previously expected and may coincide with the withdrawal of immunosuppression,” the authors cautioned.

“Consistent best practices for monitoring aminotransferase levels and deciding when ALT increases warrant intervention remain a critical topic for the field,” they noted.

Meanwhile, the patients in this B-AMAZE trial all remain enrolled in a long-term follow-up study to assess the safety and durability of FLT180a over 15 years.

The trial was sponsored by University College London and funded by Freeline Therapeutics. Dr. Chowdary disclosed various relationships with industry.

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

Patients with hemophilia B face a lifelong need for regular factor IX injections. But in 9 of 10 patients treated with a novel gene therapy, this need was eliminated.

“Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” lead author Pratima Chowdary, MD, of the Royal Free Hospital, University College London Cancer Institute, commented in a press statement.

The team reported new results with the investigational gene therapy FLT180a in a study published in the New England Journal of Medicine.

“We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a,” the authors reported. “In all but one patient, gene therapy led to durable factor IX expression, eliminated the need for factor IX prophylaxis, and eliminated spontaneous bleeding leading to factor IX replacement.”

FLT180a (Freeline Therapeutics) is a liver-directed, adeno-associated virus (AAV) gene therapy designed to normalize levels of the factor IX protein that is needed for coagulation; however, it is produced in dangerously low levels in people with hemophilia B as a result of gene mutations.

Under the current standard of care, patients with hemophilia B require lifelong prophylaxis of regular intravenous injections with recombinant factor IX replacement therapy, and they commonly continue to experience potentially severe joint pain.

While factor-replacement therapies with longer half-lives have emerged, the prophylaxis is still invasive and extremely expensive, with the average price tag in the United States of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
 

Novel gene therapy

Hemophilia B is a rare and inherited genetic bleeding disorder caused by defects in the gene responsible for factor IX protein, which is needed for blood clotting.

AAV gene therapy delivers a functional copy of this gene directly to patient tissues to compensate for one that is not working properly. It leads to the synthesis of factor IX proteins and a one-time gene therapy infusion can achieve long-lasting effects, the team explained in a press release.

The results they reported come from the phase 1/2 multicenter B-AMAZE open-label trial. It involved 10 patients (all age 18 and older) with severe or moderately severe hemophilia B, defined as having a factor IX level of 2% or less that of normal values.

All patients received one-off gene therapy infusion, at one of four FLT180a doses.

All patients also received immunosuppression to prevent the body from rejecting the vector gene therapy. This consisted of glucocorticoids with or without tacrolimus for a period of ranging from several weeks to several months.

Following the FLT180a infusion, all patients showed dose-dependent increases in factor IX levels. After a median follow-up of 27.2 months (range, 19.1-42.4 months), nearly all the patients (9 of 10) continued to show sustained factor IX activity.

Steady production of factor IX activity started at month 12, with low bleeding frequency that allowed these nine patients to no longer require weekly injections of the protein.

Five of the patients had factor IX levels in the normal range, from 51% to 78%; three patients had lower increases of 23%-43% of the normal range, and one patient who had received the highest dose, had a level that was 260% of normal.

The exception was one patient who required a return to factor IX prophylaxis. He had  experienced a failure in the immunosuppression regimen due to a delay in the recognition of an immune response at approximately 22 weeks after treatment, the authors reported.

The therapy was generally well tolerated, with no infusion reactions or discontinuations of infusions. As of the study cutoff, no inhibitors of factor IX were detected.

Of the adverse events, about 10% were determined to be related to the gene therapy. The most common event associated with the gene therapy was increases in liver aminotransferase, which is a concern with AAV gene therapies, the authors commented.

Otherwise, 24% of adverse events were determined to be related to the immunosuppression, and were consistent with the known safety profiles of glucocorticoids and tacrolimus.

Late increases in aminotransferase levels were reported among patients who had received prolonged tacrolimus beyond the tapering of glucocorticoid treatment.

The one serious adverse event that was reported involved an arteriovenous fistula thrombosis, which occurred in the patient who had received the highest dose of gene therapy and who showed the highest factor IX levels.

The current findings, along with data from another recent study involving gene therapy for patients with hemophilia A, emphasized that “immune responses can occur later than previously expected and may coincide with the withdrawal of immunosuppression,” the authors cautioned.

“Consistent best practices for monitoring aminotransferase levels and deciding when ALT increases warrant intervention remain a critical topic for the field,” they noted.

Meanwhile, the patients in this B-AMAZE trial all remain enrolled in a long-term follow-up study to assess the safety and durability of FLT180a over 15 years.

The trial was sponsored by University College London and funded by Freeline Therapeutics. Dr. Chowdary disclosed various relationships with industry.

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

Patients with hemophilia B face a lifelong need for regular factor IX injections. But in 9 of 10 patients treated with a novel gene therapy, this need was eliminated.

“Removing the need for hemophilia patients to regularly inject themselves with the missing protein is an important step in improving their quality of life,” lead author Pratima Chowdary, MD, of the Royal Free Hospital, University College London Cancer Institute, commented in a press statement.

The team reported new results with the investigational gene therapy FLT180a in a study published in the New England Journal of Medicine.

“We found that normal factor IX levels can be achieved in patients with severe or moderately severe hemophilia B with the use of relatively low vector doses of FLT180a,” the authors reported. “In all but one patient, gene therapy led to durable factor IX expression, eliminated the need for factor IX prophylaxis, and eliminated spontaneous bleeding leading to factor IX replacement.”

FLT180a (Freeline Therapeutics) is a liver-directed, adeno-associated virus (AAV) gene therapy designed to normalize levels of the factor IX protein that is needed for coagulation; however, it is produced in dangerously low levels in people with hemophilia B as a result of gene mutations.

Under the current standard of care, patients with hemophilia B require lifelong prophylaxis of regular intravenous injections with recombinant factor IX replacement therapy, and they commonly continue to experience potentially severe joint pain.

While factor-replacement therapies with longer half-lives have emerged, the prophylaxis is still invasive and extremely expensive, with the average price tag in the United States of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
 

Novel gene therapy

Hemophilia B is a rare and inherited genetic bleeding disorder caused by defects in the gene responsible for factor IX protein, which is needed for blood clotting.

AAV gene therapy delivers a functional copy of this gene directly to patient tissues to compensate for one that is not working properly. It leads to the synthesis of factor IX proteins and a one-time gene therapy infusion can achieve long-lasting effects, the team explained in a press release.

The results they reported come from the phase 1/2 multicenter B-AMAZE open-label trial. It involved 10 patients (all age 18 and older) with severe or moderately severe hemophilia B, defined as having a factor IX level of 2% or less that of normal values.

All patients received one-off gene therapy infusion, at one of four FLT180a doses.

All patients also received immunosuppression to prevent the body from rejecting the vector gene therapy. This consisted of glucocorticoids with or without tacrolimus for a period of ranging from several weeks to several months.

Following the FLT180a infusion, all patients showed dose-dependent increases in factor IX levels. After a median follow-up of 27.2 months (range, 19.1-42.4 months), nearly all the patients (9 of 10) continued to show sustained factor IX activity.

Steady production of factor IX activity started at month 12, with low bleeding frequency that allowed these nine patients to no longer require weekly injections of the protein.

Five of the patients had factor IX levels in the normal range, from 51% to 78%; three patients had lower increases of 23%-43% of the normal range, and one patient who had received the highest dose, had a level that was 260% of normal.

The exception was one patient who required a return to factor IX prophylaxis. He had  experienced a failure in the immunosuppression regimen due to a delay in the recognition of an immune response at approximately 22 weeks after treatment, the authors reported.

The therapy was generally well tolerated, with no infusion reactions or discontinuations of infusions. As of the study cutoff, no inhibitors of factor IX were detected.

Of the adverse events, about 10% were determined to be related to the gene therapy. The most common event associated with the gene therapy was increases in liver aminotransferase, which is a concern with AAV gene therapies, the authors commented.

Otherwise, 24% of adverse events were determined to be related to the immunosuppression, and were consistent with the known safety profiles of glucocorticoids and tacrolimus.

Late increases in aminotransferase levels were reported among patients who had received prolonged tacrolimus beyond the tapering of glucocorticoid treatment.

The one serious adverse event that was reported involved an arteriovenous fistula thrombosis, which occurred in the patient who had received the highest dose of gene therapy and who showed the highest factor IX levels.

The current findings, along with data from another recent study involving gene therapy for patients with hemophilia A, emphasized that “immune responses can occur later than previously expected and may coincide with the withdrawal of immunosuppression,” the authors cautioned.

“Consistent best practices for monitoring aminotransferase levels and deciding when ALT increases warrant intervention remain a critical topic for the field,” they noted.

Meanwhile, the patients in this B-AMAZE trial all remain enrolled in a long-term follow-up study to assess the safety and durability of FLT180a over 15 years.

The trial was sponsored by University College London and funded by Freeline Therapeutics. Dr. Chowdary disclosed various relationships with industry.

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

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

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

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

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

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

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

The Food and Drug Administration has cleared for marketing the first devices indicated for endoscopic sleeve gastroplasty (ESG) and endoscopic bariatric revision, according to the manufacturer.

The Apollo ESG, Apollo ESG Sx, Apollo Revise, and Apollo Revise Sx systems made by Apollo Endosurgery were reviewed through the de novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type.

“The Apollo ESG and Apollo Revise systems offer a compelling mix of effectiveness, safety, durability, and convenience for treatment of patients with obesity,” Chas McKhann, president and CEO of the company, said in a news release.

“The authorization of these new endoscopic systems represents a major step forward in addressing the global obesity epidemic,” Mr. McKhann added.

The Apollo ESG and Apollo ESG Sx systems are intended for use by trained gastroenterologists or surgeons to facilitate weight loss in adults with obesity who have failed to lose weight or maintain weight loss through more conservative measures, the company says.

The Apollo Revise and Apollo Revise Sx systems allow gastroenterologists or surgeons to perform transoral outlet reduction (TORe) as a revision to a previous bariatric procedure.

Studies have shown that 10 years after bariatric surgery, patients have regained an average of 20%-30% of weight they initially lost. Bariatric revision procedures are the fastest growing segment of the bariatric surgery market.

TORe is an endoscopic procedure performed to revise a previous gastric bypass and like ESG, can be performed as a same-day procedure without incisions or scars.

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

The Food and Drug Administration has cleared for marketing the first devices indicated for endoscopic sleeve gastroplasty (ESG) and endoscopic bariatric revision, according to the manufacturer.

The Apollo ESG, Apollo ESG Sx, Apollo Revise, and Apollo Revise Sx systems made by Apollo Endosurgery were reviewed through the de novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type.

“The Apollo ESG and Apollo Revise systems offer a compelling mix of effectiveness, safety, durability, and convenience for treatment of patients with obesity,” Chas McKhann, president and CEO of the company, said in a news release.

“The authorization of these new endoscopic systems represents a major step forward in addressing the global obesity epidemic,” Mr. McKhann added.

The Apollo ESG and Apollo ESG Sx systems are intended for use by trained gastroenterologists or surgeons to facilitate weight loss in adults with obesity who have failed to lose weight or maintain weight loss through more conservative measures, the company says.

The Apollo Revise and Apollo Revise Sx systems allow gastroenterologists or surgeons to perform transoral outlet reduction (TORe) as a revision to a previous bariatric procedure.

Studies have shown that 10 years after bariatric surgery, patients have regained an average of 20%-30% of weight they initially lost. Bariatric revision procedures are the fastest growing segment of the bariatric surgery market.

TORe is an endoscopic procedure performed to revise a previous gastric bypass and like ESG, can be performed as a same-day procedure without incisions or scars.

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

The Food and Drug Administration has cleared for marketing the first devices indicated for endoscopic sleeve gastroplasty (ESG) and endoscopic bariatric revision, according to the manufacturer.

The Apollo ESG, Apollo ESG Sx, Apollo Revise, and Apollo Revise Sx systems made by Apollo Endosurgery were reviewed through the de novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type.

“The Apollo ESG and Apollo Revise systems offer a compelling mix of effectiveness, safety, durability, and convenience for treatment of patients with obesity,” Chas McKhann, president and CEO of the company, said in a news release.

“The authorization of these new endoscopic systems represents a major step forward in addressing the global obesity epidemic,” Mr. McKhann added.

The Apollo ESG and Apollo ESG Sx systems are intended for use by trained gastroenterologists or surgeons to facilitate weight loss in adults with obesity who have failed to lose weight or maintain weight loss through more conservative measures, the company says.

The Apollo Revise and Apollo Revise Sx systems allow gastroenterologists or surgeons to perform transoral outlet reduction (TORe) as a revision to a previous bariatric procedure.

Studies have shown that 10 years after bariatric surgery, patients have regained an average of 20%-30% of weight they initially lost. Bariatric revision procedures are the fastest growing segment of the bariatric surgery market.

TORe is an endoscopic procedure performed to revise a previous gastric bypass and like ESG, can be performed as a same-day procedure without incisions or scars.

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

Taking up gardening is linked to improved mood and decreased stress, new research suggests.

The results of the small pilot study add to the growing body of evidence supporting the therapeutic value of gardening, study investigator Charles Guy, PhD, professor emeritus, University of Florida Institute of Food and Agricultural Sciences, Gainesville, told this news organization.

“If we can see therapeutic benefits among healthy individuals in a rigorously designed study, where variability was as controlled as you will see in this field, then now is the time to invest in some large-scale multi-institutional studies,” Dr. Guy added.

The study was published online in PLOS ONE.
 

Horticulture as therapy

Horticulture therapy involves engaging in gardening and plant-based activities facilitated by a trained therapist. Previous studies found that this intervention reduces apathy and improves cognitive function in some populations.

The current study included healthy, nonsmoking, and non–drug-using women, whose average age was about 32.5 years and whose body mass index was less than 32. The participants had no chronic conditions and were not allergic to pollen or plants.

Virtually all previous studies of therapeutic gardening included participants who had been diagnosed with conditions such as depression, chronic pain, or PTSD. “If we can see a therapeutic benefit with perfectly healthy people, then this is likely to have a therapeutic effect with whatever clinical population you might be interested in looking at,” said Dr. Guy.

In addition, including only women reduced variability, which is important in a small study, he said.

The researchers randomly assigned 20 participants to the gardening intervention and 20 to an art intervention. Each intervention consisted of twice-weekly 60-minute sessions for 4 weeks and a single follow-up session.

The art group was asked not to visit art galleries, museums, arts and crafts events, or art-related websites. Those in the gardening group were told not to visit parks or botanical gardens, not to engage in gardening activities, and not to visit gardening websites.

Activities in both groups involved a similar level of physical, cognitive, and social engagement. Gardeners were taught how to plant seeds and transplant and harvest edible crops, such as tomatoes, beans, and basil. Those in the art group learned papermaking and storytelling through drawing, printmaking, and mixed media collage.

At the beginning and end of the study, participants completed six questionnaires: the Profile of Mood States 2-A (POMS) short form, the Perceived Stress Scale (PSS), the Beck Depression Inventory II (BDI-II), the State-Trait Anxiety Inventory for Adults, the Satisfaction With Participation in Discretionary Social Activities, and the 36-item Short-Form Survey.

Participants wore wrist cuff blood pressure and heart rate monitors.

The analysis included 15 persons in the gardening group and 17 in the art group.

Participants in both interventions improved on several scales. For example, the mean preintervention POMS TMD (T score) for gardeners was 53.1, which was reduced to a mean of 46.9 post intervention (P = .018). In the art group, the means score was 53.5 before the intervention and 47.0 after the intervention (P = .009).

For the PSS, mean scores went from 14.9 to 9.4 (P = .002) for gardening and from 15.8 to 10.0 (P = .001) for artmaking.

For the BDI-II, mean scores dropped from 8.2 to 2.8 (P = .001) for gardening and from 9.0 to 5.1 (P = .009) for art.

However, gardening was associated with less trait anxiety than artmaking. “We concluded that both interventions were roughly equally therapeutic, with one glaring exception, and that was with trait anxiety, where the gardening resulted in statistical separation from the art group,” said Dr. Guy.

There appeared to be dose responses for total mood disturbance, perceived stress, and depression symptomatology for both gardening and artmaking.

Neither intervention affected heart rate or blood pressure. A larger sample might be needed to detect treatment differences in healthy women, the investigators noted.

The therapeutic benefit of gardening may lie in the role of plants in human evolution, during which “we relied on plants for shelter; we relied on them for protection; we relied on them obviously for nutrition,” said Dr. Guy.

The study results support carrying out large, well-designed, rigorously designed trials “that will definitively and conclusively demonstrate treatment effects with quantitative descriptions of those treatment effects with respect to dosage,” he said.
 

Good for the mind

Commenting on the study, Sir Richard Thompson, MD, past president, Royal College of Physicians, London, who has written about the health benefits of gardening, said this new study provides “more evidence that both gardening and art therapy are good for the mind” with mostly equal benefits for the two interventions.

Anuradha Dullewe Wijeyeratne

“A much larger study would be needed to strengthen their case, but it fits in with much of the literature,” said Dr. Thompson.

However, he acknowledged the difficulty of carrying out scientifically robust studies in the field of alternative medicine, which “tends to be frowned upon” by some scientists.

Dr. Thompson identified some drawbacks of the study. In trying to measure so many parameters, the authors “may have had to resort to complex statistical analyses,” which may have led to some outcome changes being statistically positive by chance.

He noted that the study was small and that the gardening arm was “artificial” in that it was carried out in a greenhouse. “Maybe being outside would have been more beneficial; it would be interesting to test that hypothesis.”

As well, he pointed out initial differences between the two groups, including income and initial blood pressure, but he doubts these were significant.

He agreed that changes in cardiovascular parameters wouldn’t be expected in healthy young women, “as there’s little room for improvement.

“I wonder whether more improvement might have been seen in participants who were already suffering from anxiety, depression, etc.”

The study was supported by the Horticulture Research Institute, the Gene and Barbara Batson Endowed Nursery Fund, Florida Nursery Growers and Landscape Association, the Institute of Food and Agricultural Sciences, Wilmot Botanical Gardens, the Center for Arts in Medicine, Health Shands Arts in Medicine, and the department of environmental horticulture at the University of Florida. The authors disclosed no relevant financial relationships.

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

Taking up gardening is linked to improved mood and decreased stress, new research suggests.

The results of the small pilot study add to the growing body of evidence supporting the therapeutic value of gardening, study investigator Charles Guy, PhD, professor emeritus, University of Florida Institute of Food and Agricultural Sciences, Gainesville, told this news organization.

“If we can see therapeutic benefits among healthy individuals in a rigorously designed study, where variability was as controlled as you will see in this field, then now is the time to invest in some large-scale multi-institutional studies,” Dr. Guy added.

The study was published online in PLOS ONE.
 

Horticulture as therapy

Horticulture therapy involves engaging in gardening and plant-based activities facilitated by a trained therapist. Previous studies found that this intervention reduces apathy and improves cognitive function in some populations.

The current study included healthy, nonsmoking, and non–drug-using women, whose average age was about 32.5 years and whose body mass index was less than 32. The participants had no chronic conditions and were not allergic to pollen or plants.

Virtually all previous studies of therapeutic gardening included participants who had been diagnosed with conditions such as depression, chronic pain, or PTSD. “If we can see a therapeutic benefit with perfectly healthy people, then this is likely to have a therapeutic effect with whatever clinical population you might be interested in looking at,” said Dr. Guy.

In addition, including only women reduced variability, which is important in a small study, he said.

The researchers randomly assigned 20 participants to the gardening intervention and 20 to an art intervention. Each intervention consisted of twice-weekly 60-minute sessions for 4 weeks and a single follow-up session.

The art group was asked not to visit art galleries, museums, arts and crafts events, or art-related websites. Those in the gardening group were told not to visit parks or botanical gardens, not to engage in gardening activities, and not to visit gardening websites.

Activities in both groups involved a similar level of physical, cognitive, and social engagement. Gardeners were taught how to plant seeds and transplant and harvest edible crops, such as tomatoes, beans, and basil. Those in the art group learned papermaking and storytelling through drawing, printmaking, and mixed media collage.

At the beginning and end of the study, participants completed six questionnaires: the Profile of Mood States 2-A (POMS) short form, the Perceived Stress Scale (PSS), the Beck Depression Inventory II (BDI-II), the State-Trait Anxiety Inventory for Adults, the Satisfaction With Participation in Discretionary Social Activities, and the 36-item Short-Form Survey.

Participants wore wrist cuff blood pressure and heart rate monitors.

The analysis included 15 persons in the gardening group and 17 in the art group.

Participants in both interventions improved on several scales. For example, the mean preintervention POMS TMD (T score) for gardeners was 53.1, which was reduced to a mean of 46.9 post intervention (P = .018). In the art group, the means score was 53.5 before the intervention and 47.0 after the intervention (P = .009).

For the PSS, mean scores went from 14.9 to 9.4 (P = .002) for gardening and from 15.8 to 10.0 (P = .001) for artmaking.

For the BDI-II, mean scores dropped from 8.2 to 2.8 (P = .001) for gardening and from 9.0 to 5.1 (P = .009) for art.

However, gardening was associated with less trait anxiety than artmaking. “We concluded that both interventions were roughly equally therapeutic, with one glaring exception, and that was with trait anxiety, where the gardening resulted in statistical separation from the art group,” said Dr. Guy.

There appeared to be dose responses for total mood disturbance, perceived stress, and depression symptomatology for both gardening and artmaking.

Neither intervention affected heart rate or blood pressure. A larger sample might be needed to detect treatment differences in healthy women, the investigators noted.

The therapeutic benefit of gardening may lie in the role of plants in human evolution, during which “we relied on plants for shelter; we relied on them for protection; we relied on them obviously for nutrition,” said Dr. Guy.

The study results support carrying out large, well-designed, rigorously designed trials “that will definitively and conclusively demonstrate treatment effects with quantitative descriptions of those treatment effects with respect to dosage,” he said.
 

Good for the mind

Commenting on the study, Sir Richard Thompson, MD, past president, Royal College of Physicians, London, who has written about the health benefits of gardening, said this new study provides “more evidence that both gardening and art therapy are good for the mind” with mostly equal benefits for the two interventions.

Anuradha Dullewe Wijeyeratne

“A much larger study would be needed to strengthen their case, but it fits in with much of the literature,” said Dr. Thompson.

However, he acknowledged the difficulty of carrying out scientifically robust studies in the field of alternative medicine, which “tends to be frowned upon” by some scientists.

Dr. Thompson identified some drawbacks of the study. In trying to measure so many parameters, the authors “may have had to resort to complex statistical analyses,” which may have led to some outcome changes being statistically positive by chance.

He noted that the study was small and that the gardening arm was “artificial” in that it was carried out in a greenhouse. “Maybe being outside would have been more beneficial; it would be interesting to test that hypothesis.”

As well, he pointed out initial differences between the two groups, including income and initial blood pressure, but he doubts these were significant.

He agreed that changes in cardiovascular parameters wouldn’t be expected in healthy young women, “as there’s little room for improvement.

“I wonder whether more improvement might have been seen in participants who were already suffering from anxiety, depression, etc.”

The study was supported by the Horticulture Research Institute, the Gene and Barbara Batson Endowed Nursery Fund, Florida Nursery Growers and Landscape Association, the Institute of Food and Agricultural Sciences, Wilmot Botanical Gardens, the Center for Arts in Medicine, Health Shands Arts in Medicine, and the department of environmental horticulture at the University of Florida. The authors disclosed no relevant financial relationships.

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

Taking up gardening is linked to improved mood and decreased stress, new research suggests.

The results of the small pilot study add to the growing body of evidence supporting the therapeutic value of gardening, study investigator Charles Guy, PhD, professor emeritus, University of Florida Institute of Food and Agricultural Sciences, Gainesville, told this news organization.

“If we can see therapeutic benefits among healthy individuals in a rigorously designed study, where variability was as controlled as you will see in this field, then now is the time to invest in some large-scale multi-institutional studies,” Dr. Guy added.

The study was published online in PLOS ONE.
 

Horticulture as therapy

Horticulture therapy involves engaging in gardening and plant-based activities facilitated by a trained therapist. Previous studies found that this intervention reduces apathy and improves cognitive function in some populations.

The current study included healthy, nonsmoking, and non–drug-using women, whose average age was about 32.5 years and whose body mass index was less than 32. The participants had no chronic conditions and were not allergic to pollen or plants.

Virtually all previous studies of therapeutic gardening included participants who had been diagnosed with conditions such as depression, chronic pain, or PTSD. “If we can see a therapeutic benefit with perfectly healthy people, then this is likely to have a therapeutic effect with whatever clinical population you might be interested in looking at,” said Dr. Guy.

In addition, including only women reduced variability, which is important in a small study, he said.

The researchers randomly assigned 20 participants to the gardening intervention and 20 to an art intervention. Each intervention consisted of twice-weekly 60-minute sessions for 4 weeks and a single follow-up session.

The art group was asked not to visit art galleries, museums, arts and crafts events, or art-related websites. Those in the gardening group were told not to visit parks or botanical gardens, not to engage in gardening activities, and not to visit gardening websites.

Activities in both groups involved a similar level of physical, cognitive, and social engagement. Gardeners were taught how to plant seeds and transplant and harvest edible crops, such as tomatoes, beans, and basil. Those in the art group learned papermaking and storytelling through drawing, printmaking, and mixed media collage.

At the beginning and end of the study, participants completed six questionnaires: the Profile of Mood States 2-A (POMS) short form, the Perceived Stress Scale (PSS), the Beck Depression Inventory II (BDI-II), the State-Trait Anxiety Inventory for Adults, the Satisfaction With Participation in Discretionary Social Activities, and the 36-item Short-Form Survey.

Participants wore wrist cuff blood pressure and heart rate monitors.

The analysis included 15 persons in the gardening group and 17 in the art group.

Participants in both interventions improved on several scales. For example, the mean preintervention POMS TMD (T score) for gardeners was 53.1, which was reduced to a mean of 46.9 post intervention (P = .018). In the art group, the means score was 53.5 before the intervention and 47.0 after the intervention (P = .009).

For the PSS, mean scores went from 14.9 to 9.4 (P = .002) for gardening and from 15.8 to 10.0 (P = .001) for artmaking.

For the BDI-II, mean scores dropped from 8.2 to 2.8 (P = .001) for gardening and from 9.0 to 5.1 (P = .009) for art.

However, gardening was associated with less trait anxiety than artmaking. “We concluded that both interventions were roughly equally therapeutic, with one glaring exception, and that was with trait anxiety, where the gardening resulted in statistical separation from the art group,” said Dr. Guy.

There appeared to be dose responses for total mood disturbance, perceived stress, and depression symptomatology for both gardening and artmaking.

Neither intervention affected heart rate or blood pressure. A larger sample might be needed to detect treatment differences in healthy women, the investigators noted.

The therapeutic benefit of gardening may lie in the role of plants in human evolution, during which “we relied on plants for shelter; we relied on them for protection; we relied on them obviously for nutrition,” said Dr. Guy.

The study results support carrying out large, well-designed, rigorously designed trials “that will definitively and conclusively demonstrate treatment effects with quantitative descriptions of those treatment effects with respect to dosage,” he said.
 

Good for the mind

Commenting on the study, Sir Richard Thompson, MD, past president, Royal College of Physicians, London, who has written about the health benefits of gardening, said this new study provides “more evidence that both gardening and art therapy are good for the mind” with mostly equal benefits for the two interventions.

Anuradha Dullewe Wijeyeratne

“A much larger study would be needed to strengthen their case, but it fits in with much of the literature,” said Dr. Thompson.

However, he acknowledged the difficulty of carrying out scientifically robust studies in the field of alternative medicine, which “tends to be frowned upon” by some scientists.

Dr. Thompson identified some drawbacks of the study. In trying to measure so many parameters, the authors “may have had to resort to complex statistical analyses,” which may have led to some outcome changes being statistically positive by chance.

He noted that the study was small and that the gardening arm was “artificial” in that it was carried out in a greenhouse. “Maybe being outside would have been more beneficial; it would be interesting to test that hypothesis.”

As well, he pointed out initial differences between the two groups, including income and initial blood pressure, but he doubts these were significant.

He agreed that changes in cardiovascular parameters wouldn’t be expected in healthy young women, “as there’s little room for improvement.

“I wonder whether more improvement might have been seen in participants who were already suffering from anxiety, depression, etc.”

The study was supported by the Horticulture Research Institute, the Gene and Barbara Batson Endowed Nursery Fund, Florida Nursery Growers and Landscape Association, the Institute of Food and Agricultural Sciences, Wilmot Botanical Gardens, the Center for Arts in Medicine, Health Shands Arts in Medicine, and the department of environmental horticulture at the University of Florida. The authors disclosed no relevant financial relationships.

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

Segmental rather than total colectomy may be a safe and effective choice for some patients with colonic Crohn’s disease (cCD), showing significantly lower rates of repeat surgery and reduced need for stoma, according to long-term data.

Gianluca Pellino, MD, with the department of advanced medical and surgical sciences, Università degli Studi della Campania “Luigi Vanvitelli” in Naples, Italy, led the study, which was published in the Journal of Crohn’s and Colitis.

CD of the colon has gotten less attention than the more prevalent small bowel disease, according to the authors, but it can be debilitating and permanently reduce quality of life. Isolated cCD incidence ranges between 14% and 32% of all CD cases from the start of disease. Historically, extensive resection has been linked with longer disease-free intervals, and reduced repeat surgeries compared with segmental resections. However, most of the data have included low-quality evidence and reports typically have not adequately considered the role of biologics or advances in perioperative management of patients with cCD, the authors wrote.

The Segmental Colectomy for Crohn’s disease (SCOTCH) international study included a retrospective analysis of data from six European Inflammatory Bowel Disease referral centers on patients operated on between 2000 and 2019 who had either segmental or total colectomy for cCD.

Among 687 patients (301 male; 386 female), segmental colectomy was performed in 285 (41.5%) of cases and total colectomy in 402 (58.5%). The 15-year surgical recurrence rate was 44% among patients who had TC and 27% for patients with segmental colectomy (P = .006).

The SCOTCH study found that segmental colectomy may be performed safely and effectively and reduce the need for stoma in cCD patients without increasing risk of repeat surgeries compared with total colectomy, which was the primary measure investigators studied.

The findings of this study also suggest that biologics, when used early and correctly, may allow more conservative options for cCD, with a fivefold reduction in surgical recurrence risk in patients who have one to three large bowel locations.

Morbidity and mortality were similar in the SC and TC groups.

Among the limitations of the study are that the total colectomy patients in the study had indications for total colectomy that were also higher risk factors for recurrence – for instance, perianal disease.

The authors wrote, “The differences between patients who underwent SC vs TC might have accounted for the choice of one treatment over the other. It is however difficult to obtain a homogenous population of cCD patients.” They also cite the difficulties in gathering enough patients for randomized trials.

“These findings need to be discussed with the patients, and the choice of operation should be individualised,” they concluded. “Multidisciplinary management of patients with cCD is of critical importance to achieve optimal long-term results of bowel-sparing approaches.”

Miguel Regueiro, MD, chair of the department of gastroenterology, hepatology, and nutrition at the Cleveland Clinic, who was not part of the study, told this publication the findings should be considered confirmatory rather than suggestive of practice change.

“If a patient has a limited segment of Crohn’s, for example ileocecal Crohn’s – a common phenotype – then the standard of care is a segmental resection and primary anastomosis,” he said. “If the patient has more extensive CD – perianal fistula, colonic-only CD – they’re more likely to undergo a total colectomy. This study confirms that.“

The authors and Dr. Regueiro declared no relevant financial relationships.

Segmental rather than total colectomy may be a safe and effective choice for some patients with colonic Crohn’s disease (cCD), showing significantly lower rates of repeat surgery and reduced need for stoma, according to long-term data.

Gianluca Pellino, MD, with the department of advanced medical and surgical sciences, Università degli Studi della Campania “Luigi Vanvitelli” in Naples, Italy, led the study, which was published in the Journal of Crohn’s and Colitis.

CD of the colon has gotten less attention than the more prevalent small bowel disease, according to the authors, but it can be debilitating and permanently reduce quality of life. Isolated cCD incidence ranges between 14% and 32% of all CD cases from the start of disease. Historically, extensive resection has been linked with longer disease-free intervals, and reduced repeat surgeries compared with segmental resections. However, most of the data have included low-quality evidence and reports typically have not adequately considered the role of biologics or advances in perioperative management of patients with cCD, the authors wrote.

The Segmental Colectomy for Crohn’s disease (SCOTCH) international study included a retrospective analysis of data from six European Inflammatory Bowel Disease referral centers on patients operated on between 2000 and 2019 who had either segmental or total colectomy for cCD.

Among 687 patients (301 male; 386 female), segmental colectomy was performed in 285 (41.5%) of cases and total colectomy in 402 (58.5%). The 15-year surgical recurrence rate was 44% among patients who had TC and 27% for patients with segmental colectomy (P = .006).

The SCOTCH study found that segmental colectomy may be performed safely and effectively and reduce the need for stoma in cCD patients without increasing risk of repeat surgeries compared with total colectomy, which was the primary measure investigators studied.

The findings of this study also suggest that biologics, when used early and correctly, may allow more conservative options for cCD, with a fivefold reduction in surgical recurrence risk in patients who have one to three large bowel locations.

Morbidity and mortality were similar in the SC and TC groups.

Among the limitations of the study are that the total colectomy patients in the study had indications for total colectomy that were also higher risk factors for recurrence – for instance, perianal disease.

The authors wrote, “The differences between patients who underwent SC vs TC might have accounted for the choice of one treatment over the other. It is however difficult to obtain a homogenous population of cCD patients.” They also cite the difficulties in gathering enough patients for randomized trials.

“These findings need to be discussed with the patients, and the choice of operation should be individualised,” they concluded. “Multidisciplinary management of patients with cCD is of critical importance to achieve optimal long-term results of bowel-sparing approaches.”

Miguel Regueiro, MD, chair of the department of gastroenterology, hepatology, and nutrition at the Cleveland Clinic, who was not part of the study, told this publication the findings should be considered confirmatory rather than suggestive of practice change.

“If a patient has a limited segment of Crohn’s, for example ileocecal Crohn’s – a common phenotype – then the standard of care is a segmental resection and primary anastomosis,” he said. “If the patient has more extensive CD – perianal fistula, colonic-only CD – they’re more likely to undergo a total colectomy. This study confirms that.“

The authors and Dr. Regueiro declared no relevant financial relationships.

Segmental rather than total colectomy may be a safe and effective choice for some patients with colonic Crohn’s disease (cCD), showing significantly lower rates of repeat surgery and reduced need for stoma, according to long-term data.

Gianluca Pellino, MD, with the department of advanced medical and surgical sciences, Università degli Studi della Campania “Luigi Vanvitelli” in Naples, Italy, led the study, which was published in the Journal of Crohn’s and Colitis.

CD of the colon has gotten less attention than the more prevalent small bowel disease, according to the authors, but it can be debilitating and permanently reduce quality of life. Isolated cCD incidence ranges between 14% and 32% of all CD cases from the start of disease. Historically, extensive resection has been linked with longer disease-free intervals, and reduced repeat surgeries compared with segmental resections. However, most of the data have included low-quality evidence and reports typically have not adequately considered the role of biologics or advances in perioperative management of patients with cCD, the authors wrote.

The Segmental Colectomy for Crohn’s disease (SCOTCH) international study included a retrospective analysis of data from six European Inflammatory Bowel Disease referral centers on patients operated on between 2000 and 2019 who had either segmental or total colectomy for cCD.

Among 687 patients (301 male; 386 female), segmental colectomy was performed in 285 (41.5%) of cases and total colectomy in 402 (58.5%). The 15-year surgical recurrence rate was 44% among patients who had TC and 27% for patients with segmental colectomy (P = .006).

The SCOTCH study found that segmental colectomy may be performed safely and effectively and reduce the need for stoma in cCD patients without increasing risk of repeat surgeries compared with total colectomy, which was the primary measure investigators studied.

The findings of this study also suggest that biologics, when used early and correctly, may allow more conservative options for cCD, with a fivefold reduction in surgical recurrence risk in patients who have one to three large bowel locations.

Morbidity and mortality were similar in the SC and TC groups.

Among the limitations of the study are that the total colectomy patients in the study had indications for total colectomy that were also higher risk factors for recurrence – for instance, perianal disease.

The authors wrote, “The differences between patients who underwent SC vs TC might have accounted for the choice of one treatment over the other. It is however difficult to obtain a homogenous population of cCD patients.” They also cite the difficulties in gathering enough patients for randomized trials.

“These findings need to be discussed with the patients, and the choice of operation should be individualised,” they concluded. “Multidisciplinary management of patients with cCD is of critical importance to achieve optimal long-term results of bowel-sparing approaches.”

Miguel Regueiro, MD, chair of the department of gastroenterology, hepatology, and nutrition at the Cleveland Clinic, who was not part of the study, told this publication the findings should be considered confirmatory rather than suggestive of practice change.

“If a patient has a limited segment of Crohn’s, for example ileocecal Crohn’s – a common phenotype – then the standard of care is a segmental resection and primary anastomosis,” he said. “If the patient has more extensive CD – perianal fistula, colonic-only CD – they’re more likely to undergo a total colectomy. This study confirms that.“

The authors and Dr. Regueiro declared no relevant financial relationships.

For patients with advanced hepatocellular carcinoma (HCC), immune checkpoint inhibitors (ICIs) may be the safer choice over tyrosine kinase inhibitors (TKIs), shows a new systematic review and meta-analysis.

The study, which was published online in JAMA Network Open, found that ICIs were associated with fewer serious adverse events, such as death, illness requiring hospitalization or illness leading to disability.

The findings are based on a meta-analysis of 30 randomized clinical trials and 12,921 patients. The analysis found a greater frequency of serious adverse events among those treated with TKIs than those treated with ICIs, though the rates of less serious liver-related adverse events were similar.

“When considering objective response rates, combination therapy with atezolizumab and bevacizumab or lenvatinib alone likely offer the most promise in the neoadjuvant setting in terms of objective response and toxic effects without preventing patients from reaching surgery,” the authors wrote.

Most newly diagnosed cases of HCC are unresectable, which leads to palliative treatment. When disease is advanced, systemic treatment is generally chosen, and new options introduced in the past decade have boosted survival. Many of these approaches feature ICIs and TKIs.

HCC therapy continues to evolve, with targeted surgical and locoregional therapies like ablation and embolization, and it’s important to understand how side effects from ICIs and TKIs might impact follow-on procedures.

Neoadjuvant therapy can avoid delays to adjuvant chemotherapy that might occur due to surgical complications. Neoadjuvant therapy also has the potential to downstage the disease from advanced to resectable, and it can provide greater opportunity for patient selection based on both tumor biology and patient characteristics.

However, advanced HCC is a complicated condition. Patients typically have cirrhosis and require an adequate functional liver remnant. Neoadjuvant locoregional treatment has been studied in HCC. A systematic review of 55 studies found no significant difference in disease-free or overall survival between preoperative or postoperative transarterial chemoembolization in resectable HCC. There is some weak evidence that locoregional therapies may achieve downstaging or maintain candidacy past 6 months.

The median age of participants was 62 years. Among the included studies, on average, 84% of patients were male. The mean fraction of patients with disease originating outside the liver was 61%, and the mean percentage with microvascular invasion was 28%. A mean of 82% had stage C according to Barcelona Clinic Liver Center staging.

21% of patients who received TKIs (95% confidence interval, 16%-26%) experienced liver toxicities versus 24% (95% CI, 13%-35%) of patients receiving ICIs. Severe adverse events were more common with TKIs, with a frequency of 46% (95% CI, 40%-51%), compared with 24% of those who received ICIs (95% CI, 13%-35%).

TKIs other than sorafenib were associated with higher rates of severe adverse events (risk ratio, 1.24; 95% CI, 1.07-1.44). ICIs and sorafenib had similar rates of liver toxic effects and severe adverse events.

The study has some limitations, including variations within the included studies in the way adverse events were reported, and there was variation in the inclusion criteria.

For patients with advanced hepatocellular carcinoma (HCC), immune checkpoint inhibitors (ICIs) may be the safer choice over tyrosine kinase inhibitors (TKIs), shows a new systematic review and meta-analysis.

The study, which was published online in JAMA Network Open, found that ICIs were associated with fewer serious adverse events, such as death, illness requiring hospitalization or illness leading to disability.

The findings are based on a meta-analysis of 30 randomized clinical trials and 12,921 patients. The analysis found a greater frequency of serious adverse events among those treated with TKIs than those treated with ICIs, though the rates of less serious liver-related adverse events were similar.

“When considering objective response rates, combination therapy with atezolizumab and bevacizumab or lenvatinib alone likely offer the most promise in the neoadjuvant setting in terms of objective response and toxic effects without preventing patients from reaching surgery,” the authors wrote.

Most newly diagnosed cases of HCC are unresectable, which leads to palliative treatment. When disease is advanced, systemic treatment is generally chosen, and new options introduced in the past decade have boosted survival. Many of these approaches feature ICIs and TKIs.

HCC therapy continues to evolve, with targeted surgical and locoregional therapies like ablation and embolization, and it’s important to understand how side effects from ICIs and TKIs might impact follow-on procedures.

Neoadjuvant therapy can avoid delays to adjuvant chemotherapy that might occur due to surgical complications. Neoadjuvant therapy also has the potential to downstage the disease from advanced to resectable, and it can provide greater opportunity for patient selection based on both tumor biology and patient characteristics.

However, advanced HCC is a complicated condition. Patients typically have cirrhosis and require an adequate functional liver remnant. Neoadjuvant locoregional treatment has been studied in HCC. A systematic review of 55 studies found no significant difference in disease-free or overall survival between preoperative or postoperative transarterial chemoembolization in resectable HCC. There is some weak evidence that locoregional therapies may achieve downstaging or maintain candidacy past 6 months.

The median age of participants was 62 years. Among the included studies, on average, 84% of patients were male. The mean fraction of patients with disease originating outside the liver was 61%, and the mean percentage with microvascular invasion was 28%. A mean of 82% had stage C according to Barcelona Clinic Liver Center staging.

21% of patients who received TKIs (95% confidence interval, 16%-26%) experienced liver toxicities versus 24% (95% CI, 13%-35%) of patients receiving ICIs. Severe adverse events were more common with TKIs, with a frequency of 46% (95% CI, 40%-51%), compared with 24% of those who received ICIs (95% CI, 13%-35%).

TKIs other than sorafenib were associated with higher rates of severe adverse events (risk ratio, 1.24; 95% CI, 1.07-1.44). ICIs and sorafenib had similar rates of liver toxic effects and severe adverse events.

The study has some limitations, including variations within the included studies in the way adverse events were reported, and there was variation in the inclusion criteria.

For patients with advanced hepatocellular carcinoma (HCC), immune checkpoint inhibitors (ICIs) may be the safer choice over tyrosine kinase inhibitors (TKIs), shows a new systematic review and meta-analysis.

The study, which was published online in JAMA Network Open, found that ICIs were associated with fewer serious adverse events, such as death, illness requiring hospitalization or illness leading to disability.

The findings are based on a meta-analysis of 30 randomized clinical trials and 12,921 patients. The analysis found a greater frequency of serious adverse events among those treated with TKIs than those treated with ICIs, though the rates of less serious liver-related adverse events were similar.

“When considering objective response rates, combination therapy with atezolizumab and bevacizumab or lenvatinib alone likely offer the most promise in the neoadjuvant setting in terms of objective response and toxic effects without preventing patients from reaching surgery,” the authors wrote.

Most newly diagnosed cases of HCC are unresectable, which leads to palliative treatment. When disease is advanced, systemic treatment is generally chosen, and new options introduced in the past decade have boosted survival. Many of these approaches feature ICIs and TKIs.

HCC therapy continues to evolve, with targeted surgical and locoregional therapies like ablation and embolization, and it’s important to understand how side effects from ICIs and TKIs might impact follow-on procedures.

Neoadjuvant therapy can avoid delays to adjuvant chemotherapy that might occur due to surgical complications. Neoadjuvant therapy also has the potential to downstage the disease from advanced to resectable, and it can provide greater opportunity for patient selection based on both tumor biology and patient characteristics.

However, advanced HCC is a complicated condition. Patients typically have cirrhosis and require an adequate functional liver remnant. Neoadjuvant locoregional treatment has been studied in HCC. A systematic review of 55 studies found no significant difference in disease-free or overall survival between preoperative or postoperative transarterial chemoembolization in resectable HCC. There is some weak evidence that locoregional therapies may achieve downstaging or maintain candidacy past 6 months.

The median age of participants was 62 years. Among the included studies, on average, 84% of patients were male. The mean fraction of patients with disease originating outside the liver was 61%, and the mean percentage with microvascular invasion was 28%. A mean of 82% had stage C according to Barcelona Clinic Liver Center staging.

21% of patients who received TKIs (95% confidence interval, 16%-26%) experienced liver toxicities versus 24% (95% CI, 13%-35%) of patients receiving ICIs. Severe adverse events were more common with TKIs, with a frequency of 46% (95% CI, 40%-51%), compared with 24% of those who received ICIs (95% CI, 13%-35%).

TKIs other than sorafenib were associated with higher rates of severe adverse events (risk ratio, 1.24; 95% CI, 1.07-1.44). ICIs and sorafenib had similar rates of liver toxic effects and severe adverse events.

The study has some limitations, including variations within the included studies in the way adverse events were reported, and there was variation in the inclusion criteria.

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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

The long-struggling field of cardiac xenotransplantation has had a very good year.

In January, the University of Maryland made history by keeping a 57-year-old man deemed too sick for a human heart transplant alive for 2 months with a genetically engineered pig heart. On July 12, New York University surgeons reported that heart function was “completely normal with excellent contractility” in two brain-dead patients with pig hearts beating in their chests for 72 hours.

NYU Langone Health

The NYU team approached the project with a decedent model in mind and, after discussions with their IRB equivalent, settled on a 72-hour window because that’s the time they typically keep people ventilated when trying to place their organs, explained Robert A. Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute.

“There’s no real ethical argument for that,” he said in an interview. The consideration is what the family is willing to do when trying to balance doing “something very altruistic and good versus having closure.”

Some families have religious beliefs that burial or interment has to occur very rapidly, whereas others, including one of the family donors, were willing to have the research go on much longer, Dr. Montgomery said. Indeed, the next protocol is being written to consider maintaining the bodies for 2-4 weeks.

“People do vary and you have to kind of accommodate that variation,” he said. “For some people, this isn’t going to be what they’re going to want and that’s why you have to go through the consent process.”
 

Informed authorization

Arthur L. Caplan, PhD, director of medical ethics at the NYU Langone Medical Center, said the Uniform Anatomical Gift Act recognizes an individual’s right to be an organ donor for transplant and research, but it “mentions nothing about maintaining you in a dead state artificially for research purposes.”

“It’s a major shift in what people are thinking about doing when they die or their relatives die,” he said.

Because organ donation is controlled at the state, not federal, level, the possibility of donating organs for xenotransplantation, like medical aid in dying, will vary between states, observed Dr. Caplan. The best way to ensure that patients whose organs are found to be unsuitable for transplantation have the option is to change state laws.

He noted that cases are already springing up where people are requesting postmortem sperm or egg donations without direct consents from the person who died. “So we have this new area opening up of handling the use of the dead body and we need to bring the law into sync with the possibilities that are out there.”

In terms of informed authorization (informed consent is reserved for the living), Dr. Caplan said there should be written evidence the person wanted to be a donor and, while not required by law, all survivors should give their permission and understand what’s going to be done in terms of the experiment, such as the use of animal parts, when the body will be returned, and the possibility of zoonotic viral infection.

“They have to fully accept that the person is dead and we’re just maintaining them artificially,” he said. “There’s no maintaining anyone who’s alive. That’s a source of a lot of confusion.”

Special committees also need to be appointed with voices from people in organ procurement, law, theology, and patient groups to monitor practice to ensure people who have given permission understood the process, that families have their questions answered independent of the research team, and that clear limits are set on how long experiments will last.

As to what those limits should be: “I think in terms of a week or 2,” Dr. Caplan said. “Obviously we could maintain bodies longer and people have. But I think, culturally in our society, going much past that starts to perhaps stress emotionally, psychologically, family and friends about getting closure.”

“I’m not as comfortable when people say things like, ‘How about 2 months?’ ” he said. “That’s a long time to sort of accept the fact that somebody has died but you can’t complete all the things that go along with the death.”

Dr. Caplan is also uncomfortable with the use of one-off emergency authorizations, as used for Maryland resident David Bennett Sr., who was rejected for standard heart transplantation and required mechanical circulatory support to stay alive.

“It’s too premature, I believe, even to try and rescue someone,” he said. “We need to learn more from the deceased models.”
 

A better model

Dr. Montgomery noted that primates are very imperfect models for predicting what’s going to happen in humans, and that in order to do xenotransplantation in living humans, there are only two pathways – the one-off emergency authorization or a clinical phase 1 trial.

The decedent model, he said, “will make human trials safer because it’s an intermediate step. You don’t have a living human’s life on the line when you’re trying to do iterative changes and improve the procedure.”

Joe Carrotta for NYU Langone Health

The team, for example, omitted a perfusion pump that was used in the Maryland case and would likely have made its way into phase 1 trials based on baboon data that suggested it was important to have the heart on the pump for hours before it was transplanted, he said. “We didn’t do any of that. We just did it like we would do a regular heart transplant and it started right up, immediately, and started to work.”

The researchers did not release details on the immunosuppression regimen, but noted that, unlike Maryland, they also did not use the experimental anti-CD40 antibody to tamp down the recipients’ immune system.

Although Mr. Bennett’s autopsy did not show any conventional sign of graft rejection, the transplanted pig heart was infected with porcine cytomegalovirus (PCMV) and Mr. Bennett showed traces of DNA from PCMV in his circulation.
 

Nailing down safety

Dr. Montgomery said he wouldn’t rule out xenotransplantation in a living human, but that the safety issues need to be nailed down. “I think that the tests used on the pig that was the donor for the Bennett case were not sensitive enough for latent virus, and that’s how it slipped through. So there was a bit of going back to the drawing board, really looking at each of the tests, and being sure we had the sensitivity to pick up a latent virus.”

He noted that United Therapeutics, which funded the research and provided the engineered pigs through its subsidiary Revivicor, has created and validated a more sensitive polymerase chain reaction test that covers some 35 different pathogens, microbes, and parasites. NYU has also developed its own platform to repeat the testing and for monitoring after the transplant. “The ones that we’re currently using would have picked up the virus.”

Stuart Russell, MD, a professor of medicine who specializes in advanced HF at Duke University, Durham, N.C., said “the biggest thing from my perspective is those two amazing families that were willing let this happen. ... If 20 years from now, this is what we’re doing, it’s related to these families being this generous at a really tough time in their lives.”

Dr. Russell said he awaits publication of the data on what the pathology of the heart looks like, but that the experiments “help to give us a lot of reassurance that we don’t need to worry about hyperacute rejection,” which by definition is going to happen in the first 24-48 hours.

That said, longer-term data is essential to potential safety issues. Notably, among the 10 genetic modifications made to the pigs, four were porcine gene knockouts, including a growth hormone receptor knockout to prevent abnormal organ growth inside the recipient’s chest. As a result, the organs seem to be small for the age of the pig and just don’t grow that well, admitted Dr. Montgomery, who said they are currently analyzing this with echocardiography.

Dr. Russell said this may create a sizing issue, but also “if you have a heart that’s more stressed in the pig, from the point of being a donor, maybe it’s not as good a heart as if it was growing normally. But that kind of stuff, I think, is going to take more than two cases and longer-term data to sort out.”

Sharon Hunt, MD, professor emerita, Stanford (Calif.) University Medical Center, and past president of the International Society for Heart Lung Transplantation, said it’s not the technical aspects, but the biology of xenotransplantation that’s really daunting.

“It’s not the physical act of doing it, like they needed a bigger heart or a smaller heart. Those are technical problems but they’ll manage them,” she said. “The big problem is biological – and the bottom line is we don’t really know. We may have overcome hyperacute rejection, which is great, but the rest remains to be seen.”

Dr. Hunt, who worked with heart transplantation pioneer Norman Shumway, MD, and spent decades caring for patients after transplantation, said most families will consent to 24 or 48 hours or even a week of experimentation on a brain-dead loved one, but what the transplant community wants to know is whether this is workable for many months.

“So the fact that the xenotransplant works for 72 hours, yeah, that’s groovy. But, you know, the answer is kind of ‘so what,’ ” she said. “I’d like to see this go for months, like they were trying to do in the human in Maryland.”

For phase 1 trials, even longer-term survival with or without rejection or with rejection that’s treatable is needed, Dr. Hunt suggested.

“We haven’t seen that yet. The Maryland people were very valiant but they lost the cause,” she said. “There’s just so much more to do before we have a viable model to start anything like a phase 1 trial. I’d love it if that happens in my lifetime, but I’m not sure it’s going to.”

Dr. Russell and Dr. Hunt reported no relevant financial relationships. Dr. Caplan reported serving as a director, officer, partner, employee, advisor, consultant, or trustee for Johnson & Johnson’s Panel for Compassionate Drug Use (unpaid position) and is a contributing author and adviser for Medscape.

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