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Challenges in developing effective treatments for idiopathic pulmonary fibrosis: Lessons from the ISABELA trials
Diffuse Lung Disease & Lung Transplant Network
Interstitial Lung Disease Section
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease that affects an estimated 100,000 people in the United States alone. Despite the availability of two approved antifibrotic drugs, nintedanib and pirfenidone, there is still a need for effective treatments to improve patient outcomes.
The ISABELA 1 and 2 trials were two Phase III clinical trials designed to evaluate ziritaxestat, a novel autotaxin inhibitor, in patients with IPF. Unfortunately, both trials were terminated early after an interim analysis revealed a lack of efficacy and safety concerns. Specifically, neither dose of ziritaxestat showed any benefit on the rate of decline for FVC over 52 weeks. Moreover, the treatment with ziritaxestat showed no benefit on the reported secondary outcomes. Patients in the ziritaxestat groups experienced worse outcomes in terms of time to first respiratory- related hospitalization, respiratory- related mortality, and first acute IPF exacerbation. Pooled data for both trials showed higher all-cause mortality for the ziritaxestat groups in relation to placebo (Maher T, et al. JAMA. 2023;329[18]:1567).
These disappointing results highlight the challenges of developing effective treatments for IPF. The complexity of IPF as a disease, with multiple pathways contributing to its pathogenesis, makes it difficult to identify effective therapeutic targets. In addition, clinical trials for new treatments must also account for the availability of approved antifibrotic therapies, which creates an added challenge for clinical trial design.
Matthew Huang, MD
Section Fellow-in-Training
Brad Bemiss, MD
Section Member-at-Large
Diffuse Lung Disease & Lung Transplant Network
Interstitial Lung Disease Section
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease that affects an estimated 100,000 people in the United States alone. Despite the availability of two approved antifibrotic drugs, nintedanib and pirfenidone, there is still a need for effective treatments to improve patient outcomes.
The ISABELA 1 and 2 trials were two Phase III clinical trials designed to evaluate ziritaxestat, a novel autotaxin inhibitor, in patients with IPF. Unfortunately, both trials were terminated early after an interim analysis revealed a lack of efficacy and safety concerns. Specifically, neither dose of ziritaxestat showed any benefit on the rate of decline for FVC over 52 weeks. Moreover, the treatment with ziritaxestat showed no benefit on the reported secondary outcomes. Patients in the ziritaxestat groups experienced worse outcomes in terms of time to first respiratory- related hospitalization, respiratory- related mortality, and first acute IPF exacerbation. Pooled data for both trials showed higher all-cause mortality for the ziritaxestat groups in relation to placebo (Maher T, et al. JAMA. 2023;329[18]:1567).
These disappointing results highlight the challenges of developing effective treatments for IPF. The complexity of IPF as a disease, with multiple pathways contributing to its pathogenesis, makes it difficult to identify effective therapeutic targets. In addition, clinical trials for new treatments must also account for the availability of approved antifibrotic therapies, which creates an added challenge for clinical trial design.
Matthew Huang, MD
Section Fellow-in-Training
Brad Bemiss, MD
Section Member-at-Large
Diffuse Lung Disease & Lung Transplant Network
Interstitial Lung Disease Section
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease that affects an estimated 100,000 people in the United States alone. Despite the availability of two approved antifibrotic drugs, nintedanib and pirfenidone, there is still a need for effective treatments to improve patient outcomes.
The ISABELA 1 and 2 trials were two Phase III clinical trials designed to evaluate ziritaxestat, a novel autotaxin inhibitor, in patients with IPF. Unfortunately, both trials were terminated early after an interim analysis revealed a lack of efficacy and safety concerns. Specifically, neither dose of ziritaxestat showed any benefit on the rate of decline for FVC over 52 weeks. Moreover, the treatment with ziritaxestat showed no benefit on the reported secondary outcomes. Patients in the ziritaxestat groups experienced worse outcomes in terms of time to first respiratory- related hospitalization, respiratory- related mortality, and first acute IPF exacerbation. Pooled data for both trials showed higher all-cause mortality for the ziritaxestat groups in relation to placebo (Maher T, et al. JAMA. 2023;329[18]:1567).
These disappointing results highlight the challenges of developing effective treatments for IPF. The complexity of IPF as a disease, with multiple pathways contributing to its pathogenesis, makes it difficult to identify effective therapeutic targets. In addition, clinical trials for new treatments must also account for the availability of approved antifibrotic therapies, which creates an added challenge for clinical trial design.
Matthew Huang, MD
Section Fellow-in-Training
Brad Bemiss, MD
Section Member-at-Large
Transitioning from pediatric to adult care
Airways Disorders Network
Pediatric Chest Medicine Section
For young adults with chronic health conditions, the process of transitioning to adult health care is complicated, resulting in frustration for patients and families, and clinicians, as well as increased morbidity and mortality (Varty et al. J Pediatr Nurs. 2020;55:201). As such, there have been efforts to determine practices that can minimize risk and improve satisfaction with the transition process.
The National Alliance to Advance Adolescent Health developed the “Got Transition” program with input from pediatric and adult clinicians, as well as patient advocates (White, et al. Six Core Elements of Health Care Transition™ 3.0. Washington, DC: Got Transition, The National Alliance to Advance Adolescent Health, July 2020). CF R.I.S.E is a similar program aimed specifically at improving the transition to adult care among patients with cystic fibrosis (www.cfrise.com). Got Transition provides the following recommendations pertinent to both pediatric and adult providers.
Pediatric clinics should start to assess transition readiness in early adolescence, and provide training pertinent to any skill gaps identified. This may include knowledge about condition-specific self-care skills, as well as navigation of the health care system. An individualized plan can then be developed, including timing of transition and identification of an appropriate adult provider.
The transfer should include communication between the pediatric and adult care providers prior to and, if needed, after the patient’s first appointment with the adult provider. Adult clinics can enhance the transition process by establishing a method to welcome transitioning young adult patients and orient them to the practice, addressing patient concerns regarding the transition, and assessing the patients’ self-management skills with resources provided, as needed.
Both pediatric and adult providers have a role in helping patients transition safely and smoothly from pediatric to adult care.
Sarah Cohen, MD
Section Fellow-in-Training
Airways Disorders Network
Pediatric Chest Medicine Section
For young adults with chronic health conditions, the process of transitioning to adult health care is complicated, resulting in frustration for patients and families, and clinicians, as well as increased morbidity and mortality (Varty et al. J Pediatr Nurs. 2020;55:201). As such, there have been efforts to determine practices that can minimize risk and improve satisfaction with the transition process.
The National Alliance to Advance Adolescent Health developed the “Got Transition” program with input from pediatric and adult clinicians, as well as patient advocates (White, et al. Six Core Elements of Health Care Transition™ 3.0. Washington, DC: Got Transition, The National Alliance to Advance Adolescent Health, July 2020). CF R.I.S.E is a similar program aimed specifically at improving the transition to adult care among patients with cystic fibrosis (www.cfrise.com). Got Transition provides the following recommendations pertinent to both pediatric and adult providers.
Pediatric clinics should start to assess transition readiness in early adolescence, and provide training pertinent to any skill gaps identified. This may include knowledge about condition-specific self-care skills, as well as navigation of the health care system. An individualized plan can then be developed, including timing of transition and identification of an appropriate adult provider.
The transfer should include communication between the pediatric and adult care providers prior to and, if needed, after the patient’s first appointment with the adult provider. Adult clinics can enhance the transition process by establishing a method to welcome transitioning young adult patients and orient them to the practice, addressing patient concerns regarding the transition, and assessing the patients’ self-management skills with resources provided, as needed.
Both pediatric and adult providers have a role in helping patients transition safely and smoothly from pediatric to adult care.
Sarah Cohen, MD
Section Fellow-in-Training
Airways Disorders Network
Pediatric Chest Medicine Section
For young adults with chronic health conditions, the process of transitioning to adult health care is complicated, resulting in frustration for patients and families, and clinicians, as well as increased morbidity and mortality (Varty et al. J Pediatr Nurs. 2020;55:201). As such, there have been efforts to determine practices that can minimize risk and improve satisfaction with the transition process.
The National Alliance to Advance Adolescent Health developed the “Got Transition” program with input from pediatric and adult clinicians, as well as patient advocates (White, et al. Six Core Elements of Health Care Transition™ 3.0. Washington, DC: Got Transition, The National Alliance to Advance Adolescent Health, July 2020). CF R.I.S.E is a similar program aimed specifically at improving the transition to adult care among patients with cystic fibrosis (www.cfrise.com). Got Transition provides the following recommendations pertinent to both pediatric and adult providers.
Pediatric clinics should start to assess transition readiness in early adolescence, and provide training pertinent to any skill gaps identified. This may include knowledge about condition-specific self-care skills, as well as navigation of the health care system. An individualized plan can then be developed, including timing of transition and identification of an appropriate adult provider.
The transfer should include communication between the pediatric and adult care providers prior to and, if needed, after the patient’s first appointment with the adult provider. Adult clinics can enhance the transition process by establishing a method to welcome transitioning young adult patients and orient them to the practice, addressing patient concerns regarding the transition, and assessing the patients’ self-management skills with resources provided, as needed.
Both pediatric and adult providers have a role in helping patients transition safely and smoothly from pediatric to adult care.
Sarah Cohen, MD
Section Fellow-in-Training
CHEST journal CME program designed to reinforce key points in research
If you’re a regular reader of the journal CHEST®, you may have noticed an exciting new initiative for clinicians looking to enhance their understanding of the latest advances in research, improve their clinical knowledge, and earn credits toward certification: the opportunity to earn continuing medical education (CME) credits from monthly journal issues. Launched in late 2022, this new initiative was inspired by the desire to complement the excellent clinical work already being done by readers of the journal.
“Essentially, the idea was that CHEST journal readers are doing the work to keep themselves current and stay excellent doctors, and they should get credit for that work,” said Amy Morris, MD, FCCP, Chair of the CHEST Journal CME Editorial Board. “We all have to do CME, so why not get some credit for the reading that we do on a regular basis to stay current, and add some additional value for journal readers?”
But the initiative isn’t just an opportunity to offer free credits.
“We try to rotate topics month to month, but more than that, we look for articles that either have a broad impact on current clinical practice for a lot of providers, or convey some particular new interest – a way for our readers to learn about something new and interesting,” she said. “We avoid trivia, essentially “gotcha” questions that simply ensure you read the article, but rather focus on questions that reinforce key points in the article.”
To ensure the content covers a wide breadth of topics, the CME Editorial Board – comprising leaders from pulmonary, critical care, and sleep medicine to ensure the process meets a high clinical standard – reviews articles that are slated for publication monthly and selects one or more manuscripts with impactful findings. Once the articles are selected, they are sent to a cohort of experienced question writers sourced from the Network specialty areas within CHEST to draft clinically relevant questions. The final questions and answers then are returned to the Board for a careful review of their accuracy, quality, and relevancy.
Readers can visit chestnet.org/journalcme every month to see a new selection of CME-eligible articles and access questions from past issues – an offering that will only grow more robust as the initiative progresses.
“We have a regularly accumulating collection of questions such that folks who read the journal every month will always have questions to answer, and those who prefer to do some reading and CME acquisition in bulk can find a rich database of useful, interesting articles that maybe they didn’t have a chance to read when they first came out,” said Dr. Morris.
As the initiative evolves, so too will the content selected and the questions offered – a process readers will have an integral role in guiding. After answering the questions, readers will have the opportunity to provide feedback on whether the activity achieved its learning objectives, future topics to cover, and more.
Although the initiative will evolve with this feedback, said Dr. Morris, one thing remains constant: the commitment of the team developing these resources to their fellow clinicians. “We couldn’t do this without a dedicated team and a lot of volunteer time from individuals who really care about education and clinical practice, and making the literature relevant to clinical practice. It takes a lot of time and effort, and I so appreciate the work those individuals are doing.”
To access the latest CME-eligible research, and review past questions, visit chestnet.org/journalcme.
If you’re a regular reader of the journal CHEST®, you may have noticed an exciting new initiative for clinicians looking to enhance their understanding of the latest advances in research, improve their clinical knowledge, and earn credits toward certification: the opportunity to earn continuing medical education (CME) credits from monthly journal issues. Launched in late 2022, this new initiative was inspired by the desire to complement the excellent clinical work already being done by readers of the journal.
“Essentially, the idea was that CHEST journal readers are doing the work to keep themselves current and stay excellent doctors, and they should get credit for that work,” said Amy Morris, MD, FCCP, Chair of the CHEST Journal CME Editorial Board. “We all have to do CME, so why not get some credit for the reading that we do on a regular basis to stay current, and add some additional value for journal readers?”
But the initiative isn’t just an opportunity to offer free credits.
“We try to rotate topics month to month, but more than that, we look for articles that either have a broad impact on current clinical practice for a lot of providers, or convey some particular new interest – a way for our readers to learn about something new and interesting,” she said. “We avoid trivia, essentially “gotcha” questions that simply ensure you read the article, but rather focus on questions that reinforce key points in the article.”
To ensure the content covers a wide breadth of topics, the CME Editorial Board – comprising leaders from pulmonary, critical care, and sleep medicine to ensure the process meets a high clinical standard – reviews articles that are slated for publication monthly and selects one or more manuscripts with impactful findings. Once the articles are selected, they are sent to a cohort of experienced question writers sourced from the Network specialty areas within CHEST to draft clinically relevant questions. The final questions and answers then are returned to the Board for a careful review of their accuracy, quality, and relevancy.
Readers can visit chestnet.org/journalcme every month to see a new selection of CME-eligible articles and access questions from past issues – an offering that will only grow more robust as the initiative progresses.
“We have a regularly accumulating collection of questions such that folks who read the journal every month will always have questions to answer, and those who prefer to do some reading and CME acquisition in bulk can find a rich database of useful, interesting articles that maybe they didn’t have a chance to read when they first came out,” said Dr. Morris.
As the initiative evolves, so too will the content selected and the questions offered – a process readers will have an integral role in guiding. After answering the questions, readers will have the opportunity to provide feedback on whether the activity achieved its learning objectives, future topics to cover, and more.
Although the initiative will evolve with this feedback, said Dr. Morris, one thing remains constant: the commitment of the team developing these resources to their fellow clinicians. “We couldn’t do this without a dedicated team and a lot of volunteer time from individuals who really care about education and clinical practice, and making the literature relevant to clinical practice. It takes a lot of time and effort, and I so appreciate the work those individuals are doing.”
To access the latest CME-eligible research, and review past questions, visit chestnet.org/journalcme.
If you’re a regular reader of the journal CHEST®, you may have noticed an exciting new initiative for clinicians looking to enhance their understanding of the latest advances in research, improve their clinical knowledge, and earn credits toward certification: the opportunity to earn continuing medical education (CME) credits from monthly journal issues. Launched in late 2022, this new initiative was inspired by the desire to complement the excellent clinical work already being done by readers of the journal.
“Essentially, the idea was that CHEST journal readers are doing the work to keep themselves current and stay excellent doctors, and they should get credit for that work,” said Amy Morris, MD, FCCP, Chair of the CHEST Journal CME Editorial Board. “We all have to do CME, so why not get some credit for the reading that we do on a regular basis to stay current, and add some additional value for journal readers?”
But the initiative isn’t just an opportunity to offer free credits.
“We try to rotate topics month to month, but more than that, we look for articles that either have a broad impact on current clinical practice for a lot of providers, or convey some particular new interest – a way for our readers to learn about something new and interesting,” she said. “We avoid trivia, essentially “gotcha” questions that simply ensure you read the article, but rather focus on questions that reinforce key points in the article.”
To ensure the content covers a wide breadth of topics, the CME Editorial Board – comprising leaders from pulmonary, critical care, and sleep medicine to ensure the process meets a high clinical standard – reviews articles that are slated for publication monthly and selects one or more manuscripts with impactful findings. Once the articles are selected, they are sent to a cohort of experienced question writers sourced from the Network specialty areas within CHEST to draft clinically relevant questions. The final questions and answers then are returned to the Board for a careful review of their accuracy, quality, and relevancy.
Readers can visit chestnet.org/journalcme every month to see a new selection of CME-eligible articles and access questions from past issues – an offering that will only grow more robust as the initiative progresses.
“We have a regularly accumulating collection of questions such that folks who read the journal every month will always have questions to answer, and those who prefer to do some reading and CME acquisition in bulk can find a rich database of useful, interesting articles that maybe they didn’t have a chance to read when they first came out,” said Dr. Morris.
As the initiative evolves, so too will the content selected and the questions offered – a process readers will have an integral role in guiding. After answering the questions, readers will have the opportunity to provide feedback on whether the activity achieved its learning objectives, future topics to cover, and more.
Although the initiative will evolve with this feedback, said Dr. Morris, one thing remains constant: the commitment of the team developing these resources to their fellow clinicians. “We couldn’t do this without a dedicated team and a lot of volunteer time from individuals who really care about education and clinical practice, and making the literature relevant to clinical practice. It takes a lot of time and effort, and I so appreciate the work those individuals are doing.”
To access the latest CME-eligible research, and review past questions, visit chestnet.org/journalcme.
CHEST 2023 Master Classes offer advanced learning from big names in chest medicine
Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.
Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.
“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.
These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.
“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.
She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.
“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”
Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
October 7 (held in Honolulu on O’ahu)
How I Do It – Challenging Cases in Sleep Medicine
Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.
Interstitial Lung Disease
Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.
Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot
Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.
Pulmonary Hypertension – Expert Didactics and Discussion
Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.
October 12-13 (held in Wailea on Maui)
2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology
Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.
Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care
Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.
CHEST 2023 hands-on and interactive learning opportunities
By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.
Simulation sessions
Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.
Problem-based learning sessions
Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.
Meet the Professor sessions
Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.
Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.
Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.
“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.
These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.
“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.
She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.
“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”
Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
October 7 (held in Honolulu on O’ahu)
How I Do It – Challenging Cases in Sleep Medicine
Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.
Interstitial Lung Disease
Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.
Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot
Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.
Pulmonary Hypertension – Expert Didactics and Discussion
Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.
October 12-13 (held in Wailea on Maui)
2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology
Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.
Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care
Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.
CHEST 2023 hands-on and interactive learning opportunities
By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.
Simulation sessions
Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.
Problem-based learning sessions
Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.
Meet the Professor sessions
Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.
Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.
Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.
“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.
These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.
“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.
She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.
“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”
Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
October 7 (held in Honolulu on O’ahu)
How I Do It – Challenging Cases in Sleep Medicine
Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.
Interstitial Lung Disease
Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.
Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot
Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.
Pulmonary Hypertension – Expert Didactics and Discussion
Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.
October 12-13 (held in Wailea on Maui)
2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology
Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.
Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care
Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.
CHEST 2023 hands-on and interactive learning opportunities
By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.
Simulation sessions
Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.
Problem-based learning sessions
Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.
Meet the Professor sessions
Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.
Take this chance to be a mentor at CHEST 2023
When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.
I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.
I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.
To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.
The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)
I genuinely believe our community would say yes to anyone looking for guidance.
To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.
Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.
Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.
While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.
Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.
Until next time,
Doreen J. Addrizzo- Harris, MD, FCCP
When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.
I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.
I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.
To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.
The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)
I genuinely believe our community would say yes to anyone looking for guidance.
To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.
Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.
Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.
While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.
Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.
Until next time,
Doreen J. Addrizzo- Harris, MD, FCCP
When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.
I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.
I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.
To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.
The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)
I genuinely believe our community would say yes to anyone looking for guidance.
To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.
Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.
Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.
While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.
Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.
Until next time,
Doreen J. Addrizzo- Harris, MD, FCCP
CPAP for OSA: What is the verdict?
Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.
Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).
But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.
Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al. N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.
These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).
What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).
Another, distinct reason for these negative results is that the AHI – our main metric for quantifying OSA severity for several decades – fails to capture the disorder’s heterogeneity. Identifying different phenotypes of OSA may enable more personalized approaches to prognostication as well as treatment. For example, one study identified four symptom clusters of OSA – patients with disturbed sleep, minimally symptomatic, excessively sleepy, and moderately sleepy – who may exhibit different responses to CPAP treatment. Further work is needed to discern whether these clusters reliably predict outcomes in a manner that can be useful clinically (Zinchuk A, et al. Sleep Med Rev. 2017;35:113).
So, what is the verdict for CPAP? Sleepy patients with even mild OSA warrant treatment, as is common practice, and these patients are more likely to adhere to therapy. Patients with other symptoms potentially related to untreated OSA should be offered treatment as well. But in asymptomatic patients, it is difficult to make a compelling case to start CPAP on the basis of the AHI alone. It is our hope that novel ways of classifying OSA severity and phenotype will allow better prediction of which patients will experience a protective effect from CPAP. For example, certain subsets of patients may realize greater benefits from CPAP, including those with a high hypoxic burden (Trzepizur W, et al. Am J Respir Crit Care Med. 2022;205[1]:108).
For now though, we can allow the evidence that has accumulated in recent years to guide our collaborative decision-making with patients about whether to try CPAP. Depending on how exuberantly we sang CPAP’s praises, we may need to temper our song – at least with regards to cardiovascular risk reduction. In the sleep world, patients are educated not only by sleep providers but also by respiratory therapists who help patients with initial CPAP setups. Consistent, evidence-based messaging by the entire health care team is key. We cannot say that “using CPAP prevents heart attacks” but rather “we’re still not quite sure.”
As in other areas of medicine, sleep medicine may see a shift in focus toward symptoms and patient-oriented outcomes as opposed to the presence of comorbidities. In fact, the recently revised International Classification of Sleep Disorders (ICSD-3-TR) released this year eliminated comorbidity criteria from the definition of Obstructive Sleep Apnea in adults. If adopted by Centers for Medicare & Medicaid Services and other insurers, patients with mild OSA by sleep testing (AHI≥5 but <15) who lack symptoms will no longer qualify for CPAP on the basis of having hypertension, a mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type 2 diabetes mellitus. How will this major revision impact the sleep medicine world? Practically speaking, it is likely that fewer patients who present without symptoms and are found to have only mild OSA will end up on PAP.
There will undoubtedly be frustration related to these greater restrictions on who qualifies for PAP. On the other hand, perhaps our energy is better focused on procuring PAP not for asymptomatic patients but rather promoting access and adherence in those who are symptomatic. Differential access to CPAP remains a major problem that very likely contributes to health disparities. In fact, a recent international committee acknowledged that the current CMS criteria for PAP coverage create disproportionate difficulties for non-white patients and those of low socioeconomic background to meet adherence criteria. Their specific recommendations to reduce this disparity in PAP access included eradication of requirements for repeat polysomnography and eliminating the 4-hour rule.
We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.
Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.
Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).
But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.
Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al. N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.
These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).
What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).
Another, distinct reason for these negative results is that the AHI – our main metric for quantifying OSA severity for several decades – fails to capture the disorder’s heterogeneity. Identifying different phenotypes of OSA may enable more personalized approaches to prognostication as well as treatment. For example, one study identified four symptom clusters of OSA – patients with disturbed sleep, minimally symptomatic, excessively sleepy, and moderately sleepy – who may exhibit different responses to CPAP treatment. Further work is needed to discern whether these clusters reliably predict outcomes in a manner that can be useful clinically (Zinchuk A, et al. Sleep Med Rev. 2017;35:113).
So, what is the verdict for CPAP? Sleepy patients with even mild OSA warrant treatment, as is common practice, and these patients are more likely to adhere to therapy. Patients with other symptoms potentially related to untreated OSA should be offered treatment as well. But in asymptomatic patients, it is difficult to make a compelling case to start CPAP on the basis of the AHI alone. It is our hope that novel ways of classifying OSA severity and phenotype will allow better prediction of which patients will experience a protective effect from CPAP. For example, certain subsets of patients may realize greater benefits from CPAP, including those with a high hypoxic burden (Trzepizur W, et al. Am J Respir Crit Care Med. 2022;205[1]:108).
For now though, we can allow the evidence that has accumulated in recent years to guide our collaborative decision-making with patients about whether to try CPAP. Depending on how exuberantly we sang CPAP’s praises, we may need to temper our song – at least with regards to cardiovascular risk reduction. In the sleep world, patients are educated not only by sleep providers but also by respiratory therapists who help patients with initial CPAP setups. Consistent, evidence-based messaging by the entire health care team is key. We cannot say that “using CPAP prevents heart attacks” but rather “we’re still not quite sure.”
As in other areas of medicine, sleep medicine may see a shift in focus toward symptoms and patient-oriented outcomes as opposed to the presence of comorbidities. In fact, the recently revised International Classification of Sleep Disorders (ICSD-3-TR) released this year eliminated comorbidity criteria from the definition of Obstructive Sleep Apnea in adults. If adopted by Centers for Medicare & Medicaid Services and other insurers, patients with mild OSA by sleep testing (AHI≥5 but <15) who lack symptoms will no longer qualify for CPAP on the basis of having hypertension, a mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type 2 diabetes mellitus. How will this major revision impact the sleep medicine world? Practically speaking, it is likely that fewer patients who present without symptoms and are found to have only mild OSA will end up on PAP.
There will undoubtedly be frustration related to these greater restrictions on who qualifies for PAP. On the other hand, perhaps our energy is better focused on procuring PAP not for asymptomatic patients but rather promoting access and adherence in those who are symptomatic. Differential access to CPAP remains a major problem that very likely contributes to health disparities. In fact, a recent international committee acknowledged that the current CMS criteria for PAP coverage create disproportionate difficulties for non-white patients and those of low socioeconomic background to meet adherence criteria. Their specific recommendations to reduce this disparity in PAP access included eradication of requirements for repeat polysomnography and eliminating the 4-hour rule.
We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.
Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.
Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).
But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.
Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al. N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.
These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).
What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).
Another, distinct reason for these negative results is that the AHI – our main metric for quantifying OSA severity for several decades – fails to capture the disorder’s heterogeneity. Identifying different phenotypes of OSA may enable more personalized approaches to prognostication as well as treatment. For example, one study identified four symptom clusters of OSA – patients with disturbed sleep, minimally symptomatic, excessively sleepy, and moderately sleepy – who may exhibit different responses to CPAP treatment. Further work is needed to discern whether these clusters reliably predict outcomes in a manner that can be useful clinically (Zinchuk A, et al. Sleep Med Rev. 2017;35:113).
So, what is the verdict for CPAP? Sleepy patients with even mild OSA warrant treatment, as is common practice, and these patients are more likely to adhere to therapy. Patients with other symptoms potentially related to untreated OSA should be offered treatment as well. But in asymptomatic patients, it is difficult to make a compelling case to start CPAP on the basis of the AHI alone. It is our hope that novel ways of classifying OSA severity and phenotype will allow better prediction of which patients will experience a protective effect from CPAP. For example, certain subsets of patients may realize greater benefits from CPAP, including those with a high hypoxic burden (Trzepizur W, et al. Am J Respir Crit Care Med. 2022;205[1]:108).
For now though, we can allow the evidence that has accumulated in recent years to guide our collaborative decision-making with patients about whether to try CPAP. Depending on how exuberantly we sang CPAP’s praises, we may need to temper our song – at least with regards to cardiovascular risk reduction. In the sleep world, patients are educated not only by sleep providers but also by respiratory therapists who help patients with initial CPAP setups. Consistent, evidence-based messaging by the entire health care team is key. We cannot say that “using CPAP prevents heart attacks” but rather “we’re still not quite sure.”
As in other areas of medicine, sleep medicine may see a shift in focus toward symptoms and patient-oriented outcomes as opposed to the presence of comorbidities. In fact, the recently revised International Classification of Sleep Disorders (ICSD-3-TR) released this year eliminated comorbidity criteria from the definition of Obstructive Sleep Apnea in adults. If adopted by Centers for Medicare & Medicaid Services and other insurers, patients with mild OSA by sleep testing (AHI≥5 but <15) who lack symptoms will no longer qualify for CPAP on the basis of having hypertension, a mood disorder, cognitive dysfunction, coronary artery disease, stroke, congestive heart failure, atrial fibrillation, or type 2 diabetes mellitus. How will this major revision impact the sleep medicine world? Practically speaking, it is likely that fewer patients who present without symptoms and are found to have only mild OSA will end up on PAP.
There will undoubtedly be frustration related to these greater restrictions on who qualifies for PAP. On the other hand, perhaps our energy is better focused on procuring PAP not for asymptomatic patients but rather promoting access and adherence in those who are symptomatic. Differential access to CPAP remains a major problem that very likely contributes to health disparities. In fact, a recent international committee acknowledged that the current CMS criteria for PAP coverage create disproportionate difficulties for non-white patients and those of low socioeconomic background to meet adherence criteria. Their specific recommendations to reduce this disparity in PAP access included eradication of requirements for repeat polysomnography and eliminating the 4-hour rule.
We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.
AGA Research Scholar Awards advance the GI field
AGA’s flagship award is the Research Scholar Award (RSA), which provides career development support for young investigators in gastroenterology and hepatology research.
The AGA Research Awards program has a significant impact on digestive disease research.
- More than $58 million has been awarded in research grants.
- More than 1,000 scientists have been awarded grants.
- Over the first 30 years of the Research Scholar Awards program, 57% of RSA recipients subsequently received at least one NIH R01 award, with 5 years on average between the RSA and first R01. Collectively, this group of investigators has secured 280 distinct R01 or equivalent awards.
Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits patients.
“In order to produce truly innovative work at the forefront of current discoveries, donations to research in GI are essential and cannot be replaced by other funding sources,” states Kathleen Curtius, PhD, MS, 2022 AGA Foundation Research Scholar Award recipient.
Join others in supporting the AGA Research Foundation. You will ensure that young researchers have opportunities to continue their lifesaving work. Your tax-deductible contribution supports the Foundation’s research award program, including the RSA, which ensures that studies are funded, discoveries are made, and patients are treated.
To learn more or to make a contribution, visit www.foundation.gastro.org.
AGA’s flagship award is the Research Scholar Award (RSA), which provides career development support for young investigators in gastroenterology and hepatology research.
The AGA Research Awards program has a significant impact on digestive disease research.
- More than $58 million has been awarded in research grants.
- More than 1,000 scientists have been awarded grants.
- Over the first 30 years of the Research Scholar Awards program, 57% of RSA recipients subsequently received at least one NIH R01 award, with 5 years on average between the RSA and first R01. Collectively, this group of investigators has secured 280 distinct R01 or equivalent awards.
Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits patients.
“In order to produce truly innovative work at the forefront of current discoveries, donations to research in GI are essential and cannot be replaced by other funding sources,” states Kathleen Curtius, PhD, MS, 2022 AGA Foundation Research Scholar Award recipient.
Join others in supporting the AGA Research Foundation. You will ensure that young researchers have opportunities to continue their lifesaving work. Your tax-deductible contribution supports the Foundation’s research award program, including the RSA, which ensures that studies are funded, discoveries are made, and patients are treated.
To learn more or to make a contribution, visit www.foundation.gastro.org.
AGA’s flagship award is the Research Scholar Award (RSA), which provides career development support for young investigators in gastroenterology and hepatology research.
The AGA Research Awards program has a significant impact on digestive disease research.
- More than $58 million has been awarded in research grants.
- More than 1,000 scientists have been awarded grants.
- Over the first 30 years of the Research Scholar Awards program, 57% of RSA recipients subsequently received at least one NIH R01 award, with 5 years on average between the RSA and first R01. Collectively, this group of investigators has secured 280 distinct R01 or equivalent awards.
Funded by the generosity of donors, the AGA Research Foundation’s research award program ensures that we are building a community of researchers whose work serves the greater community and benefits patients.
“In order to produce truly innovative work at the forefront of current discoveries, donations to research in GI are essential and cannot be replaced by other funding sources,” states Kathleen Curtius, PhD, MS, 2022 AGA Foundation Research Scholar Award recipient.
Join others in supporting the AGA Research Foundation. You will ensure that young researchers have opportunities to continue their lifesaving work. Your tax-deductible contribution supports the Foundation’s research award program, including the RSA, which ensures that studies are funded, discoveries are made, and patients are treated.
To learn more or to make a contribution, visit www.foundation.gastro.org.
Lobar vs. sublobar resection in stage 1 lung cancer
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
Lobectomy with intrathoracic nodal dissection remains the standard of care for early stage (tumor size ≤ 3.0 cm) peripheral non–small cell lung cancer (NSCLC). This practice is primarily influenced by data from the mid-1990s associating limited resection (segmentectomy or wedge resection) with increased recurrence rate and mortality compared with lobectomy (Ginsberg et al. Ann Thorac Surg. 1995;60:615). Recent advances in video and robot-assisted thoracic surgery, as well as the implementation of lung cancer screening, improvement in minimally invasive diagnostic modalities, and neoadjuvant therapies have driven the medical community to revisit the role of sublobar lung resection.
Two newly published large randomized control multicenter multinational trials (Saji et al. Lancet. 2022;399:1670 and Altorki et al. N Engl J Med. 2023;388:489) have challenged our well-established practices. They compared overall and disease-free survival sublobar to lobar resection of early stage NSCLC (tumor size ≤ 2.0 cm and negative intraoperative nodal disease) and demonstrated noninferiority of sublobar resection with respect to overall survival and disease-free survival. While the sublobar resection in the Saji et al. trial consisted strictly of segmentectomy, the majority of sublobar resections in the Altorki et al. trial were wedge resections. Interestingly, both trials chose lower cut-offs for tumor size (≤ 2.0 cm) compared with the Ginsberg trial (≤ 3.0 cm), which could arguably have accounted for this difference in outcomes.
Christopher Yurosko, DO – Section Fellow-in-Training
Melissa Rosas, MD – Section Member-at-Large
Labib Debiane, MD - Section Member-at-Large
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
Lobectomy with intrathoracic nodal dissection remains the standard of care for early stage (tumor size ≤ 3.0 cm) peripheral non–small cell lung cancer (NSCLC). This practice is primarily influenced by data from the mid-1990s associating limited resection (segmentectomy or wedge resection) with increased recurrence rate and mortality compared with lobectomy (Ginsberg et al. Ann Thorac Surg. 1995;60:615). Recent advances in video and robot-assisted thoracic surgery, as well as the implementation of lung cancer screening, improvement in minimally invasive diagnostic modalities, and neoadjuvant therapies have driven the medical community to revisit the role of sublobar lung resection.
Two newly published large randomized control multicenter multinational trials (Saji et al. Lancet. 2022;399:1670 and Altorki et al. N Engl J Med. 2023;388:489) have challenged our well-established practices. They compared overall and disease-free survival sublobar to lobar resection of early stage NSCLC (tumor size ≤ 2.0 cm and negative intraoperative nodal disease) and demonstrated noninferiority of sublobar resection with respect to overall survival and disease-free survival. While the sublobar resection in the Saji et al. trial consisted strictly of segmentectomy, the majority of sublobar resections in the Altorki et al. trial were wedge resections. Interestingly, both trials chose lower cut-offs for tumor size (≤ 2.0 cm) compared with the Ginsberg trial (≤ 3.0 cm), which could arguably have accounted for this difference in outcomes.
Christopher Yurosko, DO – Section Fellow-in-Training
Melissa Rosas, MD – Section Member-at-Large
Labib Debiane, MD - Section Member-at-Large
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
Lobectomy with intrathoracic nodal dissection remains the standard of care for early stage (tumor size ≤ 3.0 cm) peripheral non–small cell lung cancer (NSCLC). This practice is primarily influenced by data from the mid-1990s associating limited resection (segmentectomy or wedge resection) with increased recurrence rate and mortality compared with lobectomy (Ginsberg et al. Ann Thorac Surg. 1995;60:615). Recent advances in video and robot-assisted thoracic surgery, as well as the implementation of lung cancer screening, improvement in minimally invasive diagnostic modalities, and neoadjuvant therapies have driven the medical community to revisit the role of sublobar lung resection.
Two newly published large randomized control multicenter multinational trials (Saji et al. Lancet. 2022;399:1670 and Altorki et al. N Engl J Med. 2023;388:489) have challenged our well-established practices. They compared overall and disease-free survival sublobar to lobar resection of early stage NSCLC (tumor size ≤ 2.0 cm and negative intraoperative nodal disease) and demonstrated noninferiority of sublobar resection with respect to overall survival and disease-free survival. While the sublobar resection in the Saji et al. trial consisted strictly of segmentectomy, the majority of sublobar resections in the Altorki et al. trial were wedge resections. Interestingly, both trials chose lower cut-offs for tumor size (≤ 2.0 cm) compared with the Ginsberg trial (≤ 3.0 cm), which could arguably have accounted for this difference in outcomes.
Christopher Yurosko, DO – Section Fellow-in-Training
Melissa Rosas, MD – Section Member-at-Large
Labib Debiane, MD - Section Member-at-Large
Beating jet lag at CHEST 2023
Sleep Medicine Network
Non-Respiratory Sleep Section
Want to feel your best when enjoying CHEST 2023 sessions, games, vendors, networking events, and much more on the island paradise of Hawai’i? It’s time to start making plans to align your circadian rhythm with Hawai’i Standard Time (HST).
Dr. Sabra Abbott, a circadian rhythm expert and the Director of the Circadian Medicine Clinic at Northwestern University, recommends “to best adapt to the time zone change, you can take advantage of the time-of-day specific phase shifting properties of light and melatonin.”
Luckily, afternoon/early evening light exposure is encouraged, which will help get some extra hours on the beach! Don’t forget your sunglasses to help with blocking light in the morning.
Once the meeting has concluded, attendees from mainland USA will need to advance their internal clocks earlier as they travel east back home. This can be achieved by taking melatonin 0.5 mg around bedtime and seeking bright-light during the mid-to-late morning.
To develop a personalized sleep prescription based on your time zone and preferred sleep times, you can use an online jet lag calculator, such as Jet Lag Rooster (jetlag.sleepopolis.com; no affiliations with authors or Dr. Abbott).
To learn more about circadian rhythm alignment when working and traveling, we’ll see you at the CHEST 2023 session “Shifting to Hawai’i – Jet Lag, Shift Workers, and Sleep for Health Care Providers” (10/8/2023 at 0815-HST). If you haven't registered for the meeting, make sure to do so soon! You'll find the full schedule, pricing, and more at the CHEST 2023 website.
Paul Chung, DO – Section Fellow-in-Training
Sleep Medicine Network
Non-Respiratory Sleep Section
Want to feel your best when enjoying CHEST 2023 sessions, games, vendors, networking events, and much more on the island paradise of Hawai’i? It’s time to start making plans to align your circadian rhythm with Hawai’i Standard Time (HST).
Dr. Sabra Abbott, a circadian rhythm expert and the Director of the Circadian Medicine Clinic at Northwestern University, recommends “to best adapt to the time zone change, you can take advantage of the time-of-day specific phase shifting properties of light and melatonin.”
Luckily, afternoon/early evening light exposure is encouraged, which will help get some extra hours on the beach! Don’t forget your sunglasses to help with blocking light in the morning.
Once the meeting has concluded, attendees from mainland USA will need to advance their internal clocks earlier as they travel east back home. This can be achieved by taking melatonin 0.5 mg around bedtime and seeking bright-light during the mid-to-late morning.
To develop a personalized sleep prescription based on your time zone and preferred sleep times, you can use an online jet lag calculator, such as Jet Lag Rooster (jetlag.sleepopolis.com; no affiliations with authors or Dr. Abbott).
To learn more about circadian rhythm alignment when working and traveling, we’ll see you at the CHEST 2023 session “Shifting to Hawai’i – Jet Lag, Shift Workers, and Sleep for Health Care Providers” (10/8/2023 at 0815-HST). If you haven't registered for the meeting, make sure to do so soon! You'll find the full schedule, pricing, and more at the CHEST 2023 website.
Paul Chung, DO – Section Fellow-in-Training
Sleep Medicine Network
Non-Respiratory Sleep Section
Want to feel your best when enjoying CHEST 2023 sessions, games, vendors, networking events, and much more on the island paradise of Hawai’i? It’s time to start making plans to align your circadian rhythm with Hawai’i Standard Time (HST).
Dr. Sabra Abbott, a circadian rhythm expert and the Director of the Circadian Medicine Clinic at Northwestern University, recommends “to best adapt to the time zone change, you can take advantage of the time-of-day specific phase shifting properties of light and melatonin.”
Luckily, afternoon/early evening light exposure is encouraged, which will help get some extra hours on the beach! Don’t forget your sunglasses to help with blocking light in the morning.
Once the meeting has concluded, attendees from mainland USA will need to advance their internal clocks earlier as they travel east back home. This can be achieved by taking melatonin 0.5 mg around bedtime and seeking bright-light during the mid-to-late morning.
To develop a personalized sleep prescription based on your time zone and preferred sleep times, you can use an online jet lag calculator, such as Jet Lag Rooster (jetlag.sleepopolis.com; no affiliations with authors or Dr. Abbott).
To learn more about circadian rhythm alignment when working and traveling, we’ll see you at the CHEST 2023 session “Shifting to Hawai’i – Jet Lag, Shift Workers, and Sleep for Health Care Providers” (10/8/2023 at 0815-HST). If you haven't registered for the meeting, make sure to do so soon! You'll find the full schedule, pricing, and more at the CHEST 2023 website.
Paul Chung, DO – Section Fellow-in-Training
The STELLAR Travel to BMPR2-based therapies for pulmonary arterial hypertension
Pulmonary Vascular & Cardiovascular Network
Pulmonary Vascular Disease Section
The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).
including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.
The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).
The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?
Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large
Pulmonary Vascular & Cardiovascular Network
Pulmonary Vascular Disease Section
The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).
including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.
The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).
The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?
Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large
Pulmonary Vascular & Cardiovascular Network
Pulmonary Vascular Disease Section
The recently published STELLAR trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study designed to evaluate patients with PAH receiving stable vasodilator therapy after treatment with sotatercept, a first-in-class recombinant fusion protein with parts of the activin receptor type IIA, a member of the BMPR2/TGF-beta superfamily of receptors and ligands (Hoeper. N Engl J Med. 2023;388:1478).
including changes in PVR, NT-ProBNP levels, functional class, French risk score, and time-to-clinical worsening when compared with placebo. However, many questions remain about the mechanisms whereby sotatercept achieved its clinical endpoints, the answers to which may lie within its basic molecular biology.
The focus on BMPR2/TGF-beta cell signaling pathways originated from the identification of loss-of-function mutations in the BMPR2 gene in patients with heritable and idiopathic PAH (Morrell, NW. Eur Respir J. 2019;53[3]: 1900078). An imbalance in BMPR2/TGF-beta signaling (low BMPR2/high TGF-beta function) has been proposed as a central mechanism in the development of PAH. Specifically, researchers have shown increased levels of Activin A, one of 33 ligands that can bind either BMPR2 or TGF-beta receptors, within vascular lesions in the lungs of patients with PAH. It has been thus hypothesized that reducing the amount of circulating Activin A could treat PAH by rebalancing BMPR2/TGF-beta signaling in lung vascular cells. In preclinical experimental models of PAH with elevated Activin A levels, sotatercept has been shown to reduce distal small vessel medial thickness/muscularization and increase the number of patent small vessels (Yung, LM. Sci Transl Med. 2020;12).
The exact mechanism by which sotatercept improves hemodynamics and outcomes remains unclear. Indeed, whether de-remodeling of the lung vasculature or new vessel formation occurs in humans is unknown. The results from STELLAR mark a new era in the development of potential “disease-modifying agents” for PAH; however, the question is: what exactly are we modifying?
Jose Gomez-Arroyo, MD, PhD – Section Fellow-in-Training
Dana Kay, DO – Section Member-at-Large