CHEST Physician

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

Taking a patient’s blood pressure while the patient is lying down may yield more information about their cardiovascular risk than taking the reading while the patient is sitting upright, new preliminary research suggests.

An analysis of data from a long-running Atherosclerosis Risk in Communities (ARIC) study of more than 11,000 adults showed that those who had hypertension while supine were at elevated risk for cardiovascular disease (CVD) independently of their having hypertension while seated.

“If blood pressure is only measured while people are seated upright, cardiovascular disease risk may be missed if not measured also while they are lying supine on their backs,” lead investigator Duc M. Giao, a researcher and a fourth-year medical student at Harvard Medical School, Boston, said in a news release.

Mr. Giao presented the findings at the Hypertension Scientific Sessions.
 

Take seated and supine BP in clinic?

Hypertension while asleep is strongly associated with CVD and death, but whether hypertension detected in clinic while the patient is lying flat is a risk factor for CVD independently of the patient’s BP while seated remains unclear.

To investigate, Mr. Giao and colleagues reviewed health data for 11,369 adults (mean age, 54 years; 56% women; 25% Black persons) from the longitudinal ARIC study. None had a history of coronary heart disease (CHD), heart failure (HF), or stroke at baseline.

As part of the study, data on supine and seated BP were obtained during the enrollment period at ARIC visit 1, which took place between 1987 and 1989. Both seated and supine hypertension were defined as systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

The data revealed that 16% of those without seated hypertension had supine hypertension, while 74% of those with seated hypertension had supine hypertension.

Despite adjusting for seated hypertension, during a median follow-up of 25-28 years, supine hypertension was associated with an increased risk for incident CHD (adjusted hazard ratio, 1.60; 95% confidence interval, 1.45-1.76), HF (aHR, 1.83; 95% CI, 1.68-2.01), stroke (aHR, 1.86; 95% CI, 1.63-2.13), fatal CHD (aHR, 2.18; 95% CI, 1.84-2.59), and all-cause mortality (aHR, 1.43; 95% CI, 1.35-1.52).

The results did not differ by antihypertensive medication use (P > .05).

For patients who had hypertension while supine but not while seated, elevations in risk were similar to those of peers who had hypertension while both seated and supine.

“Our findings suggest people with known risk factors for heart disease and stroke may benefit from having their blood pressure checked while lying flat on their backs,” Mr. Giao said in the conference news release.

“Efforts to manage blood pressure during daily life may help lower blood pressure while sleeping. Future research should compare supine blood pressure measurements in the clinic with overnight measurements,” Mr. Giao added.
 

Busy clinical practice

In a comment, Wanpen Vongpatanasin, MD, clinical chair for the conference, sponsored by the American Heart Association, said, “This finding highlights the importance of sustained control of BP in all body positions.”

She noted that many population-based studies have shown that nighttime BP independently predicts CV outcomes. “It’s unclear whether the timing of BP measurement (night vs. day) or the position (as most people sleep in supine position at night) explains this phenomenon.”

The study by Mr. Giao and colleagues suggests that “supine BP may be one explanation, as it has as much impact on long-term CV outcome as seated BP,” said Dr. Vongpatanasin, professor of internal medicine and director of the hypertension section, cardiology division, UT Southwestern Medical Center in Dallas.

However, “in busy clinical practice, it is impossible to do both seated and supine, as well as standing BP,” said Dr. Vongpatanasin.

“Additional studies are needed to determine what is considered to be the cutoff for normal supine BP and how to incorporate it in management of hypertension,” she added.

The study had no commercial funding. Mr. Giao and Dr. Vongpatanasin have disclosed no relevant financial relationships.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

MILAN – Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the annual congress of the European Respiratory Society, held in Milan, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.

The STELLAR trial: A milestone in PAH research

PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.

Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the department of respiratory medicine at Hannover Medical School, Hannover, Germany.  

Dr. Hoeper commented on results published in the New England Journal of Medicine during a session titled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
 

Disease modification in PAH

In his initial address, Dr. Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”

“Sotatercept is probably going to be a game changer in our field,” Dr. Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Dr. Hoeper went through the list of characteristics that a disease-modifying agent should have.

“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
 

Unmasking hemodynamic impact

Dr. Hoeper’s second presentation focused on a post hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:

• A small increase in systemic blood pressure and systemic vascular resistance.
• No changes in systolic and diastolic volumes of the left ventricle (lv).
• A small but significant reduction in lv ejection fraction.
• A great reduction in the mean pulmonary artery pressure (mPAP).
• No change in cardiac output.
• An improvement in pulmonary artery compliance.
• A reduction in the right ventricle work and in right atrial pressure.
• An improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation.

“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Dr. Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
 

A new course in PAH treatment?

Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Dr. Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told this news organization.

Dr. Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.

“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Dr. Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
 

Further insights into sotatercept

The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events (TEAEs) were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, four serious TEAEs (1% of patients) led to death, but only five patients (1.2%) discontinued sotatercept because of TEAE.

Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office,” Dr. Preston said.

A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Arbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and four lung/heart-lung transplantations per 1,000 patients. “Real-world data are needed to confirm these findings,” cautioned Dr. McLaughlin.

Dr. Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Dr. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD. Dr. Preston disclosed speaking and consulting fees from Janssen and United Therapeutics, and grant/research support from Janssen and Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics. Dr. McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.

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

The remarkable story of cystic fibrosis (CF) – from gene discovery in 1989 to highly effective precision-medicine therapies today – inspires Christine Kim Garcia, MD, PhD, as she searches for rare mutations in genes linked to inherited forms of lung fibrosis, termed familial pulmonary fibrosis (FPF).

“Cystic fibrosis has provided a framework for approaching the genetics of lung fibrosis,” said Dr. Garcia, Frode Jensen Professor of Medicine and chief of the pulmonology, allergy, and critical care medicine division at Columbia University, and director of the Columbia Precision Medicine Initiative, both in New York.

Pulmonary fibrosis is more complicated than CF. “Mutations in more than 10 different genes can lead to the increased heritable risk of pulmonary fibrosis that we find in families. Different mutations exist for each gene. Sometimes the mutations are so rare that they are only found in a single family,” she said. “In addition, different subtypes of fibrotic interstitial lung disease can be linked to the same mutation and found in the same family.”

Despite these complexities, genetic discoveries in PF have illuminated pathophysiologic pathways and are driving the research that Dr. Garcia and other experts hope will lead to helpful prognostic tools and to precision therapies. And already, at institutions like Columbia, genetic discoveries are changing clinical care, driving treatment decisions and spurring family screening.

Thomas Ferkol, MD, whose research focuses on genetic factors that contribute to suppurative airway diseases such as CF and primary ciliary dyskinesia (PCD), similarly regards CF as a road map for genetics research and genetic testing in practice.

“The treatments we’re doing now for CF are increasingly based on the genetics of the individual,” said Dr. Ferkol, professor and division chief for pediatric pulmonology at the University of North Carolina at Chapel Hill, where the UNC Children’s Hospital hosts a rare and genetic lung disease program. For PCD, genetic testing has become a front-line diagnostic tool. But in the future, he hopes, it will also become a determinant for personalized treatment for children with PCD.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was the first lung disease gene to be discovered using gene-mapping techniques. Since then, and especially in the last 15-20 years, “there’s been a lot of progress in the identification of genes for which mutations and variations cause specific forms of pulmonary disease, many of which can now establish a firm diagnosis, and some of which lead to very directed changes in management. There has also been great progress in the availability of genetic testing,” said Benjamin A. Raby, MD, MPH, director of the Pulmonary Genetics Center at Brigham and Women’s Hospital, Boston, which sees patients with a host of cystic lung diseases, bronchiectasic lung diseases, fibrotic lung diseases, and other conditions, including pulmonary fibrosis and PCD.

Pulmonary fibrosis in adults and PCD in children are two examples of lung diseases for which genetic discoveries have exploded in recent years, with important implications for care now and in the future.
 

Leveraging genetic testing in PF

FPF describes families with two or more members with PF within three degrees of relationship; it is a designation believed to affect 20%-25% of people with PF and occurs predominantly later in the adult years (after 50 years of age), most commonly in autosomal dominant fashion, and amidst a stew of genetic risks, environmental exposures, and other insults.

Dr. Garcia and other researchers have uncovered two main types of genes in which rare variants can give rise to a heritable risk of FP: Genes that contribute to the maintenance of telomere length, and genes involved in surfactant metabolism. [Last year, Dr. Garcia and colleagues reported their discovery of both rare and common variants in a “spindle gene,” KIF15, in patients with IPF, suggesting an additional pathogenic pathway. The gene controls dynamics of cell division. (Am J Respir Crit Care Med. 2022;206[1]:p 56-69.)]

Detection of telomere pathway involvement – most commonly involving the TERT gene – is consequential because patients with telomere-associated gene mutations “tend to progress faster and have a more aggressive disease course than patients without these mutations … regardless of how their scans or biopsies look,” as do patients who have short age-adjusted telomere length, said Dr. Chad Newton, MD, who directs the Interstitial Lung Disease program at the University of Texas Southwestern and researches the genetics of ILD.

Dr. Newton and Dr. Garcia advise patients with PF and a positive family history to undergo panel-based genetic sequencing, along with telomere length measurement. They also advise that undiagnosed first-degree relatives consider what’s called “cascade testing” – genetic sequencing for any pathogenic or likely pathogenic rare variants found in the patient’s investigation. (Dr. Garcia, who cochairs a National Institutes of Health–funded interstitial lung disease curation panel, said she finds evidence of a pathogenic or likely pathogenic variant in about 25% of patients with a family history of PF.)

“We can use this genetic information to consider starting early [antifibrotic] treatment to try to delay progression … just as we would with other forms of pulmonary fibrosis,” Dr. Newton said, “and to expand our reach to others not sitting in our clinics who have the same rare condition or are at risk.”

After cascade testing, Dr. Garcia said, she invites family members with positive results to have baseline CT scans and pulmonary function testing. “And if there’s anything abnormal, we’re inviting them to have regular follow-up testing,” she said, “because we advise starting antifibrotic treatment at the very first sign of disease worsening.”

Such an approach to genetic testing for patients and relatives is described in a statement commissioned by the Pulmonary Fibrosis Foundation and published last year in the journal Chest (2022:162[2]:394-405). The statement, for which Dr. Newton and Dr. Garcia were among the authors, also lists clinical features within patients and families suggestive of a possible genetic pathway, and describes the potential yield for identifying a variant in different clinical scenarios.

Pathogenic variants in telomere genes as well as findings of short telomere length are associated with various extrapulmonary manifestations such as liver dysfunction, bone marrow dysfunction, and head and neck cancers, Dr. Newton said, making surveillance and referrals important. (Rare variants and short telomere length are associated with disease progression across several non-IPF diagnoses as well.)

Moreover, short telomeres may signal the need to avoid long-term immunosuppression. Research published in 2019 from multiple cohorts, and led by Dr. Newton and Dr. Garcia, showed that short telomere length is associated with worse outcomes (faster time to composite death, transplant, FVC decline, and hospitalization) in patients with IPF who received immunosuppression. These adverse outcomes were not found in IPF patients with normal telomere lengths who received similar immunosuppression (Am J Respir Crit Care Med. 2019;200(3):336-347).

Gene sequencing and telomere length measurement are described in the 2020 Chest statement on the role of genetic testing in PF as yielding “different yet complementary information.” Short age-adjusted telomere length (less than the 10th percentile) is common in those with pathogenic variants in telomere genes, but it can also occur in the absence of identifiable rare telomere-related variants, the statement says. Telomere length testing can be helpful, it notes, in determining the significance of a “variant of unknown significance (VUS)” if gene sequencing identifies one.
 

The future of genetic screening for PF

Future genetic screening approaches for PF may cast an even wider net while better stratifying risk for family members. At Brigham and Women’s Hospital, where family screening was a major impetus for the 2008 founding of the Pulmonary Genetics Center, research published several years ago by Dr. Raby and his colleagues found that 31% of 107 asymptomatic first-degree relatives of patients with PF had interstitial lung abnormalities on chest CTs – whether or not a family history was reported – and 18% had clear radiographic or physiological manifestations of fibrosis (Am J Respir Crit Care Med. 2020;201[10]:1240-8).

“That’s more than 10-fold higher than what we thought we’d see, based on prior literature. … And the numbers were pretty much the same whether or not there was a family history of fibrosis reported by the patient,” said Dr. Raby, also the Leila and Irving Perlmutter professor of pediatrics at Harvard Medical School, Boston, and chief of the division of pulmonary medicine at Boston Children’s Hospital. “We used to think we only needed to worry about genetic risk when there was a family history. But now we see that sporadic cases are also driven by genetics.”

Their study also included a 2-year follow-up chest CT, in which the majority of the screened relatives participated. Of those, 65% who had interstitial changes at baseline showed progression. Four percent of those without interstitial abnormalities at baseline developed abnormalities (Am J Respir Crit Care Med. 2023;207[2]:211-4). “The fact that 65% progressed suggests that in the majority of patients what we’re finding is something that’s real and is going to be clinically meaningful for patients,” he said.
 

Genetic signatures

A next phase of research at Brigham & Women’s and Boston Children’s, he said, will address PF’s “complex genetic signature” and test polygenic risk scores for idiopathic PF that take into account not only rare genetic variants that can be solidly linked to disease but many common genetic variants being detected in genome-wide association studies. [By definition, common variants, otherwise known as single-nucleotide polymorphisms (SNPs) occur with greater frequency in the general population (> 5%), generally reside within noncoding regions, and may contribute to disease risk but alone do not cause disease.]

“As technologies and genetic studies improve, we’re seeing we can estimate much better the likelihood of disease than we could 10 years ago,” he said. A “potent” common variant called the MUC5B promoter polymorphism has been shown to confer a 3-fold to 20-fold increased risk for PF, he noted. (Polygenic risk scores are also being developed, he said, for asthma and chronic obstructive pulmonary disease.)

“Every time one sees a patient with PF that is thought to be idiopathic one should start thinking about their at-risk family members, particularly their siblings,” Dr. Raby said. But in doing so, “wouldn’t it be wonderful if we could use polygenic risk scores to assure some [family members] that they’re in the lowest tier of risk and might need pulmonary function studies every 5 years, for example, versus someone we’d want to see more frequently, versus someone [for whom] we’d want to start preventive therapy at the earlier signs of declining lung function?”

Moving forward, he and the others said, the field needs more research to determine how genetic risk factors predict disease progression and prospective clinical trials to test whether long-term outcomes are indeed improved by early institution of antifibrotic therapy and other genetics-driven management decisions. “The data we’re using to inform prognosis and treatment decisions are compelling, but a lot of it is based on cohort studies and retrospective research,” Dr. Newton said.

Multi-institutional transomics studies and other research projects are underway, meanwhile, to build upon gene identifications and learn more about the pathobiology of PF. “We know about two big genetic pathways … but we need to sort it all out,” he said. For instance, “are there intermediate pathways? And where does it actually start? What kind of cell?”
 

Genetics’ impact on PCD

About 20 years ago, only two genes were linked to PCD, a largely autosomal recessive disorder that results from abnormalities in the cilia and subsequently improper airway clearance. Today, said Dr. Ferkol, there are over 50 known genes that, if defective, can lead to PCD.

“Based on our latest estimates, I’d say we can diagnose people using genetics about 70%, maybe 80%, of the time,” Dr. Ferkol said. Genetic testing has become a first-line diagnostic tool for PCD in North America – a significant development given that a definitive diagnosis has long been challenging, he said.

A genetics-based diagnosis of PCD is sometimes challenged by the finding of variants of unknown significance (VUSs) on genetic testing (often missense mutations) “because some of the genes involved are huge,” noted Dr. Ferkol, who coleads the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium. “But many times, it’s straightforward.”

Children with PCD have repeated or persistent upper respiratory tract infections beginning early in life – like chronic rhinosinusitis or suppurative otitis media – and chronic bronchitis, leading to bronchiectasis. About half of patients have a spectrum of laterality defects, where organs are malpositioned in a mirror image of normal. Some individuals also have cardiac defects, and subfertility in both males and females can frequently occur.

Just as it has become increasingly clear that CF exists as a continuum, with milder and variant forms having been recognized since the advent of genetic testing, “we’re finding genotype-phenotype relationships in PCD,” Dr. Ferkol said. “Certain individuals have more rapid pulmonary decline, which is related in part to their genetics.”

With PCD, “I’m convinced this is a continuum. Some patients have unmistakable, clear-cut PCD, but I’m sure we’re going to find individuals who have milder variants in these PCD-associated genes that lead to milder disease,” he said.

There are no specific treatments that will correct cilia dysfunction, and current therapy options are borrowed from other diseases such as asthma and CF. However, newer treatments targeting specific genetic defects are in early clinical studies. Will the gene discoveries and more research open up new avenues for treating PCD, as happened in CF? Dr. Ferkol hopes so.

Approximately 2,000 genetic variants have been identified in the CFTR gene, though not all are pathogenic. “The newer, highly effective modulators used in CF target a particular CFTR mutation class, so some drugs will work for some people with the disease, but not all,” Dr. Ferkol said. “It’s personalized medicine.”

Modulator therapies designed to correct the malfunctioning proteins made by the CFTR gene have profoundly changed the lives of many with CF, improving lung function and everyday symptoms for patients, allowing them to lead near-normal lives. “It’s astonishing,” he said.

Dr. Garcia reported consulting for Rejuvenation Technologies and Rejuveron Telomere Therapeutics; in addition, her laboratory has received support from Boehringer Ingelheim and Astrazeneca for investigator-initiated research. Dr. Newton reported he has performed consulting for Boehringer Ingelheim. Dr. Ferkol reported involvement in a longitudinal study defining endpoints for future clinical PCD trials funded by ReCode Therapeutics and leadership of an international clinical trial for PCD supported by Parion Sciences. He has received honoraria from the Cystic Fibrosis Foundation and serves as a member of the ReCode Therapeutics PCD Clinical Steering Committee. Dr. Raby reported no relevant disclosures.

The remarkable story of cystic fibrosis (CF) – from gene discovery in 1989 to highly effective precision-medicine therapies today – inspires Christine Kim Garcia, MD, PhD, as she searches for rare mutations in genes linked to inherited forms of lung fibrosis, termed familial pulmonary fibrosis (FPF).

“Cystic fibrosis has provided a framework for approaching the genetics of lung fibrosis,” said Dr. Garcia, Frode Jensen Professor of Medicine and chief of the pulmonology, allergy, and critical care medicine division at Columbia University, and director of the Columbia Precision Medicine Initiative, both in New York.

Pulmonary fibrosis is more complicated than CF. “Mutations in more than 10 different genes can lead to the increased heritable risk of pulmonary fibrosis that we find in families. Different mutations exist for each gene. Sometimes the mutations are so rare that they are only found in a single family,” she said. “In addition, different subtypes of fibrotic interstitial lung disease can be linked to the same mutation and found in the same family.”

Despite these complexities, genetic discoveries in PF have illuminated pathophysiologic pathways and are driving the research that Dr. Garcia and other experts hope will lead to helpful prognostic tools and to precision therapies. And already, at institutions like Columbia, genetic discoveries are changing clinical care, driving treatment decisions and spurring family screening.

Thomas Ferkol, MD, whose research focuses on genetic factors that contribute to suppurative airway diseases such as CF and primary ciliary dyskinesia (PCD), similarly regards CF as a road map for genetics research and genetic testing in practice.

“The treatments we’re doing now for CF are increasingly based on the genetics of the individual,” said Dr. Ferkol, professor and division chief for pediatric pulmonology at the University of North Carolina at Chapel Hill, where the UNC Children’s Hospital hosts a rare and genetic lung disease program. For PCD, genetic testing has become a front-line diagnostic tool. But in the future, he hopes, it will also become a determinant for personalized treatment for children with PCD.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was the first lung disease gene to be discovered using gene-mapping techniques. Since then, and especially in the last 15-20 years, “there’s been a lot of progress in the identification of genes for which mutations and variations cause specific forms of pulmonary disease, many of which can now establish a firm diagnosis, and some of which lead to very directed changes in management. There has also been great progress in the availability of genetic testing,” said Benjamin A. Raby, MD, MPH, director of the Pulmonary Genetics Center at Brigham and Women’s Hospital, Boston, which sees patients with a host of cystic lung diseases, bronchiectasic lung diseases, fibrotic lung diseases, and other conditions, including pulmonary fibrosis and PCD.

Pulmonary fibrosis in adults and PCD in children are two examples of lung diseases for which genetic discoveries have exploded in recent years, with important implications for care now and in the future.
 

Leveraging genetic testing in PF

FPF describes families with two or more members with PF within three degrees of relationship; it is a designation believed to affect 20%-25% of people with PF and occurs predominantly later in the adult years (after 50 years of age), most commonly in autosomal dominant fashion, and amidst a stew of genetic risks, environmental exposures, and other insults.

Dr. Garcia and other researchers have uncovered two main types of genes in which rare variants can give rise to a heritable risk of FP: Genes that contribute to the maintenance of telomere length, and genes involved in surfactant metabolism. [Last year, Dr. Garcia and colleagues reported their discovery of both rare and common variants in a “spindle gene,” KIF15, in patients with IPF, suggesting an additional pathogenic pathway. The gene controls dynamics of cell division. (Am J Respir Crit Care Med. 2022;206[1]:p 56-69.)]

Detection of telomere pathway involvement – most commonly involving the TERT gene – is consequential because patients with telomere-associated gene mutations “tend to progress faster and have a more aggressive disease course than patients without these mutations … regardless of how their scans or biopsies look,” as do patients who have short age-adjusted telomere length, said Dr. Chad Newton, MD, who directs the Interstitial Lung Disease program at the University of Texas Southwestern and researches the genetics of ILD.

Dr. Newton and Dr. Garcia advise patients with PF and a positive family history to undergo panel-based genetic sequencing, along with telomere length measurement. They also advise that undiagnosed first-degree relatives consider what’s called “cascade testing” – genetic sequencing for any pathogenic or likely pathogenic rare variants found in the patient’s investigation. (Dr. Garcia, who cochairs a National Institutes of Health–funded interstitial lung disease curation panel, said she finds evidence of a pathogenic or likely pathogenic variant in about 25% of patients with a family history of PF.)

“We can use this genetic information to consider starting early [antifibrotic] treatment to try to delay progression … just as we would with other forms of pulmonary fibrosis,” Dr. Newton said, “and to expand our reach to others not sitting in our clinics who have the same rare condition or are at risk.”

After cascade testing, Dr. Garcia said, she invites family members with positive results to have baseline CT scans and pulmonary function testing. “And if there’s anything abnormal, we’re inviting them to have regular follow-up testing,” she said, “because we advise starting antifibrotic treatment at the very first sign of disease worsening.”

Such an approach to genetic testing for patients and relatives is described in a statement commissioned by the Pulmonary Fibrosis Foundation and published last year in the journal Chest (2022:162[2]:394-405). The statement, for which Dr. Newton and Dr. Garcia were among the authors, also lists clinical features within patients and families suggestive of a possible genetic pathway, and describes the potential yield for identifying a variant in different clinical scenarios.

Pathogenic variants in telomere genes as well as findings of short telomere length are associated with various extrapulmonary manifestations such as liver dysfunction, bone marrow dysfunction, and head and neck cancers, Dr. Newton said, making surveillance and referrals important. (Rare variants and short telomere length are associated with disease progression across several non-IPF diagnoses as well.)

Moreover, short telomeres may signal the need to avoid long-term immunosuppression. Research published in 2019 from multiple cohorts, and led by Dr. Newton and Dr. Garcia, showed that short telomere length is associated with worse outcomes (faster time to composite death, transplant, FVC decline, and hospitalization) in patients with IPF who received immunosuppression. These adverse outcomes were not found in IPF patients with normal telomere lengths who received similar immunosuppression (Am J Respir Crit Care Med. 2019;200(3):336-347).

Gene sequencing and telomere length measurement are described in the 2020 Chest statement on the role of genetic testing in PF as yielding “different yet complementary information.” Short age-adjusted telomere length (less than the 10th percentile) is common in those with pathogenic variants in telomere genes, but it can also occur in the absence of identifiable rare telomere-related variants, the statement says. Telomere length testing can be helpful, it notes, in determining the significance of a “variant of unknown significance (VUS)” if gene sequencing identifies one.
 

The future of genetic screening for PF

Future genetic screening approaches for PF may cast an even wider net while better stratifying risk for family members. At Brigham and Women’s Hospital, where family screening was a major impetus for the 2008 founding of the Pulmonary Genetics Center, research published several years ago by Dr. Raby and his colleagues found that 31% of 107 asymptomatic first-degree relatives of patients with PF had interstitial lung abnormalities on chest CTs – whether or not a family history was reported – and 18% had clear radiographic or physiological manifestations of fibrosis (Am J Respir Crit Care Med. 2020;201[10]:1240-8).

“That’s more than 10-fold higher than what we thought we’d see, based on prior literature. … And the numbers were pretty much the same whether or not there was a family history of fibrosis reported by the patient,” said Dr. Raby, also the Leila and Irving Perlmutter professor of pediatrics at Harvard Medical School, Boston, and chief of the division of pulmonary medicine at Boston Children’s Hospital. “We used to think we only needed to worry about genetic risk when there was a family history. But now we see that sporadic cases are also driven by genetics.”

Their study also included a 2-year follow-up chest CT, in which the majority of the screened relatives participated. Of those, 65% who had interstitial changes at baseline showed progression. Four percent of those without interstitial abnormalities at baseline developed abnormalities (Am J Respir Crit Care Med. 2023;207[2]:211-4). “The fact that 65% progressed suggests that in the majority of patients what we’re finding is something that’s real and is going to be clinically meaningful for patients,” he said.
 

Genetic signatures

A next phase of research at Brigham & Women’s and Boston Children’s, he said, will address PF’s “complex genetic signature” and test polygenic risk scores for idiopathic PF that take into account not only rare genetic variants that can be solidly linked to disease but many common genetic variants being detected in genome-wide association studies. [By definition, common variants, otherwise known as single-nucleotide polymorphisms (SNPs) occur with greater frequency in the general population (> 5%), generally reside within noncoding regions, and may contribute to disease risk but alone do not cause disease.]

“As technologies and genetic studies improve, we’re seeing we can estimate much better the likelihood of disease than we could 10 years ago,” he said. A “potent” common variant called the MUC5B promoter polymorphism has been shown to confer a 3-fold to 20-fold increased risk for PF, he noted. (Polygenic risk scores are also being developed, he said, for asthma and chronic obstructive pulmonary disease.)

“Every time one sees a patient with PF that is thought to be idiopathic one should start thinking about their at-risk family members, particularly their siblings,” Dr. Raby said. But in doing so, “wouldn’t it be wonderful if we could use polygenic risk scores to assure some [family members] that they’re in the lowest tier of risk and might need pulmonary function studies every 5 years, for example, versus someone we’d want to see more frequently, versus someone [for whom] we’d want to start preventive therapy at the earlier signs of declining lung function?”

Moving forward, he and the others said, the field needs more research to determine how genetic risk factors predict disease progression and prospective clinical trials to test whether long-term outcomes are indeed improved by early institution of antifibrotic therapy and other genetics-driven management decisions. “The data we’re using to inform prognosis and treatment decisions are compelling, but a lot of it is based on cohort studies and retrospective research,” Dr. Newton said.

Multi-institutional transomics studies and other research projects are underway, meanwhile, to build upon gene identifications and learn more about the pathobiology of PF. “We know about two big genetic pathways … but we need to sort it all out,” he said. For instance, “are there intermediate pathways? And where does it actually start? What kind of cell?”
 

Genetics’ impact on PCD

About 20 years ago, only two genes were linked to PCD, a largely autosomal recessive disorder that results from abnormalities in the cilia and subsequently improper airway clearance. Today, said Dr. Ferkol, there are over 50 known genes that, if defective, can lead to PCD.

“Based on our latest estimates, I’d say we can diagnose people using genetics about 70%, maybe 80%, of the time,” Dr. Ferkol said. Genetic testing has become a first-line diagnostic tool for PCD in North America – a significant development given that a definitive diagnosis has long been challenging, he said.

A genetics-based diagnosis of PCD is sometimes challenged by the finding of variants of unknown significance (VUSs) on genetic testing (often missense mutations) “because some of the genes involved are huge,” noted Dr. Ferkol, who coleads the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium. “But many times, it’s straightforward.”

Children with PCD have repeated or persistent upper respiratory tract infections beginning early in life – like chronic rhinosinusitis or suppurative otitis media – and chronic bronchitis, leading to bronchiectasis. About half of patients have a spectrum of laterality defects, where organs are malpositioned in a mirror image of normal. Some individuals also have cardiac defects, and subfertility in both males and females can frequently occur.

Just as it has become increasingly clear that CF exists as a continuum, with milder and variant forms having been recognized since the advent of genetic testing, “we’re finding genotype-phenotype relationships in PCD,” Dr. Ferkol said. “Certain individuals have more rapid pulmonary decline, which is related in part to their genetics.”

With PCD, “I’m convinced this is a continuum. Some patients have unmistakable, clear-cut PCD, but I’m sure we’re going to find individuals who have milder variants in these PCD-associated genes that lead to milder disease,” he said.

There are no specific treatments that will correct cilia dysfunction, and current therapy options are borrowed from other diseases such as asthma and CF. However, newer treatments targeting specific genetic defects are in early clinical studies. Will the gene discoveries and more research open up new avenues for treating PCD, as happened in CF? Dr. Ferkol hopes so.

Approximately 2,000 genetic variants have been identified in the CFTR gene, though not all are pathogenic. “The newer, highly effective modulators used in CF target a particular CFTR mutation class, so some drugs will work for some people with the disease, but not all,” Dr. Ferkol said. “It’s personalized medicine.”

Modulator therapies designed to correct the malfunctioning proteins made by the CFTR gene have profoundly changed the lives of many with CF, improving lung function and everyday symptoms for patients, allowing them to lead near-normal lives. “It’s astonishing,” he said.

Dr. Garcia reported consulting for Rejuvenation Technologies and Rejuveron Telomere Therapeutics; in addition, her laboratory has received support from Boehringer Ingelheim and Astrazeneca for investigator-initiated research. Dr. Newton reported he has performed consulting for Boehringer Ingelheim. Dr. Ferkol reported involvement in a longitudinal study defining endpoints for future clinical PCD trials funded by ReCode Therapeutics and leadership of an international clinical trial for PCD supported by Parion Sciences. He has received honoraria from the Cystic Fibrosis Foundation and serves as a member of the ReCode Therapeutics PCD Clinical Steering Committee. Dr. Raby reported no relevant disclosures.

The remarkable story of cystic fibrosis (CF) – from gene discovery in 1989 to highly effective precision-medicine therapies today – inspires Christine Kim Garcia, MD, PhD, as she searches for rare mutations in genes linked to inherited forms of lung fibrosis, termed familial pulmonary fibrosis (FPF).

“Cystic fibrosis has provided a framework for approaching the genetics of lung fibrosis,” said Dr. Garcia, Frode Jensen Professor of Medicine and chief of the pulmonology, allergy, and critical care medicine division at Columbia University, and director of the Columbia Precision Medicine Initiative, both in New York.

Pulmonary fibrosis is more complicated than CF. “Mutations in more than 10 different genes can lead to the increased heritable risk of pulmonary fibrosis that we find in families. Different mutations exist for each gene. Sometimes the mutations are so rare that they are only found in a single family,” she said. “In addition, different subtypes of fibrotic interstitial lung disease can be linked to the same mutation and found in the same family.”

Despite these complexities, genetic discoveries in PF have illuminated pathophysiologic pathways and are driving the research that Dr. Garcia and other experts hope will lead to helpful prognostic tools and to precision therapies. And already, at institutions like Columbia, genetic discoveries are changing clinical care, driving treatment decisions and spurring family screening.

Thomas Ferkol, MD, whose research focuses on genetic factors that contribute to suppurative airway diseases such as CF and primary ciliary dyskinesia (PCD), similarly regards CF as a road map for genetics research and genetic testing in practice.

“The treatments we’re doing now for CF are increasingly based on the genetics of the individual,” said Dr. Ferkol, professor and division chief for pediatric pulmonology at the University of North Carolina at Chapel Hill, where the UNC Children’s Hospital hosts a rare and genetic lung disease program. For PCD, genetic testing has become a front-line diagnostic tool. But in the future, he hopes, it will also become a determinant for personalized treatment for children with PCD.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was the first lung disease gene to be discovered using gene-mapping techniques. Since then, and especially in the last 15-20 years, “there’s been a lot of progress in the identification of genes for which mutations and variations cause specific forms of pulmonary disease, many of which can now establish a firm diagnosis, and some of which lead to very directed changes in management. There has also been great progress in the availability of genetic testing,” said Benjamin A. Raby, MD, MPH, director of the Pulmonary Genetics Center at Brigham and Women’s Hospital, Boston, which sees patients with a host of cystic lung diseases, bronchiectasic lung diseases, fibrotic lung diseases, and other conditions, including pulmonary fibrosis and PCD.

Pulmonary fibrosis in adults and PCD in children are two examples of lung diseases for which genetic discoveries have exploded in recent years, with important implications for care now and in the future.
 

Leveraging genetic testing in PF

FPF describes families with two or more members with PF within three degrees of relationship; it is a designation believed to affect 20%-25% of people with PF and occurs predominantly later in the adult years (after 50 years of age), most commonly in autosomal dominant fashion, and amidst a stew of genetic risks, environmental exposures, and other insults.

Dr. Garcia and other researchers have uncovered two main types of genes in which rare variants can give rise to a heritable risk of FP: Genes that contribute to the maintenance of telomere length, and genes involved in surfactant metabolism. [Last year, Dr. Garcia and colleagues reported their discovery of both rare and common variants in a “spindle gene,” KIF15, in patients with IPF, suggesting an additional pathogenic pathway. The gene controls dynamics of cell division. (Am J Respir Crit Care Med. 2022;206[1]:p 56-69.)]

Detection of telomere pathway involvement – most commonly involving the TERT gene – is consequential because patients with telomere-associated gene mutations “tend to progress faster and have a more aggressive disease course than patients without these mutations … regardless of how their scans or biopsies look,” as do patients who have short age-adjusted telomere length, said Dr. Chad Newton, MD, who directs the Interstitial Lung Disease program at the University of Texas Southwestern and researches the genetics of ILD.

Dr. Newton and Dr. Garcia advise patients with PF and a positive family history to undergo panel-based genetic sequencing, along with telomere length measurement. They also advise that undiagnosed first-degree relatives consider what’s called “cascade testing” – genetic sequencing for any pathogenic or likely pathogenic rare variants found in the patient’s investigation. (Dr. Garcia, who cochairs a National Institutes of Health–funded interstitial lung disease curation panel, said she finds evidence of a pathogenic or likely pathogenic variant in about 25% of patients with a family history of PF.)

“We can use this genetic information to consider starting early [antifibrotic] treatment to try to delay progression … just as we would with other forms of pulmonary fibrosis,” Dr. Newton said, “and to expand our reach to others not sitting in our clinics who have the same rare condition or are at risk.”

After cascade testing, Dr. Garcia said, she invites family members with positive results to have baseline CT scans and pulmonary function testing. “And if there’s anything abnormal, we’re inviting them to have regular follow-up testing,” she said, “because we advise starting antifibrotic treatment at the very first sign of disease worsening.”

Such an approach to genetic testing for patients and relatives is described in a statement commissioned by the Pulmonary Fibrosis Foundation and published last year in the journal Chest (2022:162[2]:394-405). The statement, for which Dr. Newton and Dr. Garcia were among the authors, also lists clinical features within patients and families suggestive of a possible genetic pathway, and describes the potential yield for identifying a variant in different clinical scenarios.

Pathogenic variants in telomere genes as well as findings of short telomere length are associated with various extrapulmonary manifestations such as liver dysfunction, bone marrow dysfunction, and head and neck cancers, Dr. Newton said, making surveillance and referrals important. (Rare variants and short telomere length are associated with disease progression across several non-IPF diagnoses as well.)

Moreover, short telomeres may signal the need to avoid long-term immunosuppression. Research published in 2019 from multiple cohorts, and led by Dr. Newton and Dr. Garcia, showed that short telomere length is associated with worse outcomes (faster time to composite death, transplant, FVC decline, and hospitalization) in patients with IPF who received immunosuppression. These adverse outcomes were not found in IPF patients with normal telomere lengths who received similar immunosuppression (Am J Respir Crit Care Med. 2019;200(3):336-347).

Gene sequencing and telomere length measurement are described in the 2020 Chest statement on the role of genetic testing in PF as yielding “different yet complementary information.” Short age-adjusted telomere length (less than the 10th percentile) is common in those with pathogenic variants in telomere genes, but it can also occur in the absence of identifiable rare telomere-related variants, the statement says. Telomere length testing can be helpful, it notes, in determining the significance of a “variant of unknown significance (VUS)” if gene sequencing identifies one.
 

The future of genetic screening for PF

Future genetic screening approaches for PF may cast an even wider net while better stratifying risk for family members. At Brigham and Women’s Hospital, where family screening was a major impetus for the 2008 founding of the Pulmonary Genetics Center, research published several years ago by Dr. Raby and his colleagues found that 31% of 107 asymptomatic first-degree relatives of patients with PF had interstitial lung abnormalities on chest CTs – whether or not a family history was reported – and 18% had clear radiographic or physiological manifestations of fibrosis (Am J Respir Crit Care Med. 2020;201[10]:1240-8).

“That’s more than 10-fold higher than what we thought we’d see, based on prior literature. … And the numbers were pretty much the same whether or not there was a family history of fibrosis reported by the patient,” said Dr. Raby, also the Leila and Irving Perlmutter professor of pediatrics at Harvard Medical School, Boston, and chief of the division of pulmonary medicine at Boston Children’s Hospital. “We used to think we only needed to worry about genetic risk when there was a family history. But now we see that sporadic cases are also driven by genetics.”

Their study also included a 2-year follow-up chest CT, in which the majority of the screened relatives participated. Of those, 65% who had interstitial changes at baseline showed progression. Four percent of those without interstitial abnormalities at baseline developed abnormalities (Am J Respir Crit Care Med. 2023;207[2]:211-4). “The fact that 65% progressed suggests that in the majority of patients what we’re finding is something that’s real and is going to be clinically meaningful for patients,” he said.
 

Genetic signatures

A next phase of research at Brigham & Women’s and Boston Children’s, he said, will address PF’s “complex genetic signature” and test polygenic risk scores for idiopathic PF that take into account not only rare genetic variants that can be solidly linked to disease but many common genetic variants being detected in genome-wide association studies. [By definition, common variants, otherwise known as single-nucleotide polymorphisms (SNPs) occur with greater frequency in the general population (> 5%), generally reside within noncoding regions, and may contribute to disease risk but alone do not cause disease.]

“As technologies and genetic studies improve, we’re seeing we can estimate much better the likelihood of disease than we could 10 years ago,” he said. A “potent” common variant called the MUC5B promoter polymorphism has been shown to confer a 3-fold to 20-fold increased risk for PF, he noted. (Polygenic risk scores are also being developed, he said, for asthma and chronic obstructive pulmonary disease.)

“Every time one sees a patient with PF that is thought to be idiopathic one should start thinking about their at-risk family members, particularly their siblings,” Dr. Raby said. But in doing so, “wouldn’t it be wonderful if we could use polygenic risk scores to assure some [family members] that they’re in the lowest tier of risk and might need pulmonary function studies every 5 years, for example, versus someone we’d want to see more frequently, versus someone [for whom] we’d want to start preventive therapy at the earlier signs of declining lung function?”

Moving forward, he and the others said, the field needs more research to determine how genetic risk factors predict disease progression and prospective clinical trials to test whether long-term outcomes are indeed improved by early institution of antifibrotic therapy and other genetics-driven management decisions. “The data we’re using to inform prognosis and treatment decisions are compelling, but a lot of it is based on cohort studies and retrospective research,” Dr. Newton said.

Multi-institutional transomics studies and other research projects are underway, meanwhile, to build upon gene identifications and learn more about the pathobiology of PF. “We know about two big genetic pathways … but we need to sort it all out,” he said. For instance, “are there intermediate pathways? And where does it actually start? What kind of cell?”
 

Genetics’ impact on PCD

About 20 years ago, only two genes were linked to PCD, a largely autosomal recessive disorder that results from abnormalities in the cilia and subsequently improper airway clearance. Today, said Dr. Ferkol, there are over 50 known genes that, if defective, can lead to PCD.

“Based on our latest estimates, I’d say we can diagnose people using genetics about 70%, maybe 80%, of the time,” Dr. Ferkol said. Genetic testing has become a first-line diagnostic tool for PCD in North America – a significant development given that a definitive diagnosis has long been challenging, he said.

A genetics-based diagnosis of PCD is sometimes challenged by the finding of variants of unknown significance (VUSs) on genetic testing (often missense mutations) “because some of the genes involved are huge,” noted Dr. Ferkol, who coleads the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium. “But many times, it’s straightforward.”

Children with PCD have repeated or persistent upper respiratory tract infections beginning early in life – like chronic rhinosinusitis or suppurative otitis media – and chronic bronchitis, leading to bronchiectasis. About half of patients have a spectrum of laterality defects, where organs are malpositioned in a mirror image of normal. Some individuals also have cardiac defects, and subfertility in both males and females can frequently occur.

Just as it has become increasingly clear that CF exists as a continuum, with milder and variant forms having been recognized since the advent of genetic testing, “we’re finding genotype-phenotype relationships in PCD,” Dr. Ferkol said. “Certain individuals have more rapid pulmonary decline, which is related in part to their genetics.”

With PCD, “I’m convinced this is a continuum. Some patients have unmistakable, clear-cut PCD, but I’m sure we’re going to find individuals who have milder variants in these PCD-associated genes that lead to milder disease,” he said.

There are no specific treatments that will correct cilia dysfunction, and current therapy options are borrowed from other diseases such as asthma and CF. However, newer treatments targeting specific genetic defects are in early clinical studies. Will the gene discoveries and more research open up new avenues for treating PCD, as happened in CF? Dr. Ferkol hopes so.

Approximately 2,000 genetic variants have been identified in the CFTR gene, though not all are pathogenic. “The newer, highly effective modulators used in CF target a particular CFTR mutation class, so some drugs will work for some people with the disease, but not all,” Dr. Ferkol said. “It’s personalized medicine.”

Modulator therapies designed to correct the malfunctioning proteins made by the CFTR gene have profoundly changed the lives of many with CF, improving lung function and everyday symptoms for patients, allowing them to lead near-normal lives. “It’s astonishing,” he said.

Dr. Garcia reported consulting for Rejuvenation Technologies and Rejuveron Telomere Therapeutics; in addition, her laboratory has received support from Boehringer Ingelheim and Astrazeneca for investigator-initiated research. Dr. Newton reported he has performed consulting for Boehringer Ingelheim. Dr. Ferkol reported involvement in a longitudinal study defining endpoints for future clinical PCD trials funded by ReCode Therapeutics and leadership of an international clinical trial for PCD supported by Parion Sciences. He has received honoraria from the Cystic Fibrosis Foundation and serves as a member of the ReCode Therapeutics PCD Clinical Steering Committee. Dr. Raby reported no relevant disclosures.

Obstructive sleep apnea (OSA) remains a significantly underdiagnosed condition, despite its high prevalence. Primary care physicians play a pivotal role in identifying patients afflicted by this condition. To effectively diagnose OSA in primary care, increasing awareness and enhancing communication are imperative. Fortunately, several straightforward diagnostic tools are readily available, and even more sophisticated ones, driven by artificial intelligence, are on the horizon.

Recognize the problem

At the annual congress of the European Respiratory Society, Cláudia Sofia De Almeida Vicente Ferreira, MD, a family physician from Coimbra, Portugal, and coordinator of the Respiratory Diseases Interest Group of the Portuguese Association of General and Family Medicine, highlighted the challenges of diagnosing OSA.

“Sleep apnea is underdiagnosed because the most common symptoms, like excessive daytime sleepiness or snoring, are undervalued by patients. People do not come to the doctor and complain about it. Sometimes you catch it in the middle of other things,” she said in an interview.

Moreover, physicians’ busy schedules and limited appointment times often lead to a focus on the symptoms reported by patients, and insufficient attention is paid to the quality of sleep. This may be compounded by a tendency among medical professionals to underestimate the risks associated with OSA, as it is not directly linked to mortality, despite its clear connection to cardiovascular risks.

Identifying and recognizing risk factors can facilitate OSA suspicion during patient evaluations. These factors encompass both structural (for example, craniofacial and upper airway anomalies) and nonstructural elements (for example, smoking, alcohol use, or sedative consumption). While men are at higher risk, postmenopausal women who are not receiving hormone replacement therapy face similar risks. Certain medical conditions, such as hypothyroidism, acromegaly, amyloidosis, Cushing syndrome, and Down syndrome, have also been associated with OSA. A comprehensive physical examination can provide additional clues. Factors might include obesity, neck circumference, Mallampati score, and nasal and pharyngeal problems.
 

Inquire actively

Once the possibility of OSA is considered, the next step is to ask patients about their symptoms. Questionnaires are simple yet valuable tools for this purpose. The STOP questionnaire comprises four key questions:

• Do you SNORE loudly (louder than talking or loud enough to be heard through closed doors)?
• Do you often feel TIRED, fatigued, or sleepy during daytime?
• Has anyone OBSERVED you stop breathing during your sleep?
• Do you have or are you being treated for high blood PRESSURE?

The STOP-BANG questionnaire adds four clinical attributes: obesity (body mass index > 35 kg/m²), age (> 50 years), neck size (> 40 cm, or 16 inches), and sex.

Patients are classified as being at low, intermediate, or high risk for OSA.

The Epworth Sleepiness Scale, which is self-administered, is also useful: patients rate the likelihood of falling asleep in various daytime contexts. These questionnaires can be seamlessly integrated into routine patient appointments.
 

Comorbidities and occupation

Primary care physicians should carefully assess comorbidities, especially those linked to cardiovascular risk. Patients with resistant hypertension, pulmonary hypertension, and recurrent atrial fibrillation following cardioversion/ablation should be prioritized for diagnostic testing for OSA. Patients with other conditions, such as coronary artery disease or cerebrovascular disease, should also be referred to a sleep center if OSA is suspected on the basis of comprehensive sleep assessment. OSA has also been associated with type 2 diabetes, metabolic syndrome, and asthma.

Gaining access to sleep study services and subsequent therapy, such as continuous positive airway pressure (CPAP), can be challenging. Primary care physicians should prioritize patients on the basis of their risk levels. Occupation plays a significant role in this prioritization, as sleep fragmentation and daytime sleepiness can lead to workplace and vehicular accidents.

“You should include the occupation in the patient’s profile. What is he doing? Is he sitting at a desk, or is he working at height, driving, or operating machines? These workers are high-risk patients,” continued Dr. De Almeida Vicente Ferreira.

“I think that the family physician has a key role in the follow-up. Nobody else will look for CPAP compliance and will verify if CPAP is working or not. If the patient is not using it or if it is not effective, still there is someone paying for the machine (the national health care system or an insurance company). More importantly, if CPAP is not working, we are not improving our patient’s life in terms of reducing cardiovascular risk and ameliorating the quality of life.”
 

Is home testing a viable option?

Diagnosing OSA typically relies on overnight polysomnography in specialized sleep clinics, which is often associated with long waiting lists. Researchers are actively working on innovative sensors and digital solutions for home-based sleep testing, but according to Dr. De Almeida Vicente Ferreira, they are not yet ready for prime time: “Home-based studies with fewer evaluation parameters (such as pulse and oxygen levels) are not so secure or sensitive to establish a correct and complete diagnosis. Actually, the architecture of sleep is very complex. The test must be performed and read by a specialized team.”

Still, according to Renaud Tamisier, MD, PhD, professor of clinical physiology at the Université Grenoble Alpes in La Tronche, France, simplified sleep testing could be very useful. “There are many patients that still are not diagnosed despite having severe sleep apnea, with symptoms and comorbidities. These patients usually are not aware of their disease but complain about changes in their quality of life with excessive tiredness and sleepiness. Also, they are not connected to the healthcare system, for different reasons, including no time for consulting a sleep physician and performing a polysomnography, health cost, negligence. Therefore, providing through primary care a simple diagnostic approach deserves efforts and research,” he said in an interview.

New technologies could enable diagnostic sleep tests to be conducted at home, with the added benefit of multiple-night recordings to overcome the challenges of night-to-night variability in the apnea-hypopnea index. These novel testing methods should be cost effective, easy to install, and user friendly. Dr. Tamisier continued: “The issue about sleep diagnosis is that up to now, there was no such devices available. Many physicians use type III sleep recording that are dedicated to highly trained sleep scorers, but they use automatic analysis which in many cases is unsuccessful. For a trained sleep physician, it is easy to see that the result is inaccurate. New devices are being built for automatic analysis using artificial intelligence algorithms. Because by design they are automatic, the rate of success is very high, and if used with the right purpose, they could be highly effective and quick.”

In conclusion, the diagnosis of sleep apnea in primary care is becoming more feasible with advancements in diagnostic tools and technology. However, it is crucial for primary care physicians to exercise caution in cases in which the clinical presentation is not straightforward or when OSA is associated with comorbidities. Care management and clear boundaries are vital to ensure effective treatment and improve patient outcomes.

Dr. De Almeida Vicente Ferreira and Dr. Tamisier disclosed no relevant financial relationships.

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

Obstructive sleep apnea (OSA) remains a significantly underdiagnosed condition, despite its high prevalence. Primary care physicians play a pivotal role in identifying patients afflicted by this condition. To effectively diagnose OSA in primary care, increasing awareness and enhancing communication are imperative. Fortunately, several straightforward diagnostic tools are readily available, and even more sophisticated ones, driven by artificial intelligence, are on the horizon.

Recognize the problem

At the annual congress of the European Respiratory Society, Cláudia Sofia De Almeida Vicente Ferreira, MD, a family physician from Coimbra, Portugal, and coordinator of the Respiratory Diseases Interest Group of the Portuguese Association of General and Family Medicine, highlighted the challenges of diagnosing OSA.

“Sleep apnea is underdiagnosed because the most common symptoms, like excessive daytime sleepiness or snoring, are undervalued by patients. People do not come to the doctor and complain about it. Sometimes you catch it in the middle of other things,” she said in an interview.

Moreover, physicians’ busy schedules and limited appointment times often lead to a focus on the symptoms reported by patients, and insufficient attention is paid to the quality of sleep. This may be compounded by a tendency among medical professionals to underestimate the risks associated with OSA, as it is not directly linked to mortality, despite its clear connection to cardiovascular risks.

Identifying and recognizing risk factors can facilitate OSA suspicion during patient evaluations. These factors encompass both structural (for example, craniofacial and upper airway anomalies) and nonstructural elements (for example, smoking, alcohol use, or sedative consumption). While men are at higher risk, postmenopausal women who are not receiving hormone replacement therapy face similar risks. Certain medical conditions, such as hypothyroidism, acromegaly, amyloidosis, Cushing syndrome, and Down syndrome, have also been associated with OSA. A comprehensive physical examination can provide additional clues. Factors might include obesity, neck circumference, Mallampati score, and nasal and pharyngeal problems.
 

Inquire actively

Once the possibility of OSA is considered, the next step is to ask patients about their symptoms. Questionnaires are simple yet valuable tools for this purpose. The STOP questionnaire comprises four key questions:

• Do you SNORE loudly (louder than talking or loud enough to be heard through closed doors)?
• Do you often feel TIRED, fatigued, or sleepy during daytime?
• Has anyone OBSERVED you stop breathing during your sleep?
• Do you have or are you being treated for high blood PRESSURE?

The STOP-BANG questionnaire adds four clinical attributes: obesity (body mass index > 35 kg/m²), age (> 50 years), neck size (> 40 cm, or 16 inches), and sex.

Patients are classified as being at low, intermediate, or high risk for OSA.

The Epworth Sleepiness Scale, which is self-administered, is also useful: patients rate the likelihood of falling asleep in various daytime contexts. These questionnaires can be seamlessly integrated into routine patient appointments.
 

Comorbidities and occupation

Primary care physicians should carefully assess comorbidities, especially those linked to cardiovascular risk. Patients with resistant hypertension, pulmonary hypertension, and recurrent atrial fibrillation following cardioversion/ablation should be prioritized for diagnostic testing for OSA. Patients with other conditions, such as coronary artery disease or cerebrovascular disease, should also be referred to a sleep center if OSA is suspected on the basis of comprehensive sleep assessment. OSA has also been associated with type 2 diabetes, metabolic syndrome, and asthma.

Gaining access to sleep study services and subsequent therapy, such as continuous positive airway pressure (CPAP), can be challenging. Primary care physicians should prioritize patients on the basis of their risk levels. Occupation plays a significant role in this prioritization, as sleep fragmentation and daytime sleepiness can lead to workplace and vehicular accidents.

“You should include the occupation in the patient’s profile. What is he doing? Is he sitting at a desk, or is he working at height, driving, or operating machines? These workers are high-risk patients,” continued Dr. De Almeida Vicente Ferreira.

“I think that the family physician has a key role in the follow-up. Nobody else will look for CPAP compliance and will verify if CPAP is working or not. If the patient is not using it or if it is not effective, still there is someone paying for the machine (the national health care system or an insurance company). More importantly, if CPAP is not working, we are not improving our patient’s life in terms of reducing cardiovascular risk and ameliorating the quality of life.”
 

Is home testing a viable option?

Diagnosing OSA typically relies on overnight polysomnography in specialized sleep clinics, which is often associated with long waiting lists. Researchers are actively working on innovative sensors and digital solutions for home-based sleep testing, but according to Dr. De Almeida Vicente Ferreira, they are not yet ready for prime time: “Home-based studies with fewer evaluation parameters (such as pulse and oxygen levels) are not so secure or sensitive to establish a correct and complete diagnosis. Actually, the architecture of sleep is very complex. The test must be performed and read by a specialized team.”

Still, according to Renaud Tamisier, MD, PhD, professor of clinical physiology at the Université Grenoble Alpes in La Tronche, France, simplified sleep testing could be very useful. “There are many patients that still are not diagnosed despite having severe sleep apnea, with symptoms and comorbidities. These patients usually are not aware of their disease but complain about changes in their quality of life with excessive tiredness and sleepiness. Also, they are not connected to the healthcare system, for different reasons, including no time for consulting a sleep physician and performing a polysomnography, health cost, negligence. Therefore, providing through primary care a simple diagnostic approach deserves efforts and research,” he said in an interview.

New technologies could enable diagnostic sleep tests to be conducted at home, with the added benefit of multiple-night recordings to overcome the challenges of night-to-night variability in the apnea-hypopnea index. These novel testing methods should be cost effective, easy to install, and user friendly. Dr. Tamisier continued: “The issue about sleep diagnosis is that up to now, there was no such devices available. Many physicians use type III sleep recording that are dedicated to highly trained sleep scorers, but they use automatic analysis which in many cases is unsuccessful. For a trained sleep physician, it is easy to see that the result is inaccurate. New devices are being built for automatic analysis using artificial intelligence algorithms. Because by design they are automatic, the rate of success is very high, and if used with the right purpose, they could be highly effective and quick.”

In conclusion, the diagnosis of sleep apnea in primary care is becoming more feasible with advancements in diagnostic tools and technology. However, it is crucial for primary care physicians to exercise caution in cases in which the clinical presentation is not straightforward or when OSA is associated with comorbidities. Care management and clear boundaries are vital to ensure effective treatment and improve patient outcomes.

Dr. De Almeida Vicente Ferreira and Dr. Tamisier disclosed no relevant financial relationships.

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

Obstructive sleep apnea (OSA) remains a significantly underdiagnosed condition, despite its high prevalence. Primary care physicians play a pivotal role in identifying patients afflicted by this condition. To effectively diagnose OSA in primary care, increasing awareness and enhancing communication are imperative. Fortunately, several straightforward diagnostic tools are readily available, and even more sophisticated ones, driven by artificial intelligence, are on the horizon.

Recognize the problem

At the annual congress of the European Respiratory Society, Cláudia Sofia De Almeida Vicente Ferreira, MD, a family physician from Coimbra, Portugal, and coordinator of the Respiratory Diseases Interest Group of the Portuguese Association of General and Family Medicine, highlighted the challenges of diagnosing OSA.

“Sleep apnea is underdiagnosed because the most common symptoms, like excessive daytime sleepiness or snoring, are undervalued by patients. People do not come to the doctor and complain about it. Sometimes you catch it in the middle of other things,” she said in an interview.

Moreover, physicians’ busy schedules and limited appointment times often lead to a focus on the symptoms reported by patients, and insufficient attention is paid to the quality of sleep. This may be compounded by a tendency among medical professionals to underestimate the risks associated with OSA, as it is not directly linked to mortality, despite its clear connection to cardiovascular risks.

Identifying and recognizing risk factors can facilitate OSA suspicion during patient evaluations. These factors encompass both structural (for example, craniofacial and upper airway anomalies) and nonstructural elements (for example, smoking, alcohol use, or sedative consumption). While men are at higher risk, postmenopausal women who are not receiving hormone replacement therapy face similar risks. Certain medical conditions, such as hypothyroidism, acromegaly, amyloidosis, Cushing syndrome, and Down syndrome, have also been associated with OSA. A comprehensive physical examination can provide additional clues. Factors might include obesity, neck circumference, Mallampati score, and nasal and pharyngeal problems.
 

Inquire actively

Once the possibility of OSA is considered, the next step is to ask patients about their symptoms. Questionnaires are simple yet valuable tools for this purpose. The STOP questionnaire comprises four key questions:

• Do you SNORE loudly (louder than talking or loud enough to be heard through closed doors)?
• Do you often feel TIRED, fatigued, or sleepy during daytime?
• Has anyone OBSERVED you stop breathing during your sleep?
• Do you have or are you being treated for high blood PRESSURE?

The STOP-BANG questionnaire adds four clinical attributes: obesity (body mass index > 35 kg/m²), age (> 50 years), neck size (> 40 cm, or 16 inches), and sex.

Patients are classified as being at low, intermediate, or high risk for OSA.

The Epworth Sleepiness Scale, which is self-administered, is also useful: patients rate the likelihood of falling asleep in various daytime contexts. These questionnaires can be seamlessly integrated into routine patient appointments.
 

Comorbidities and occupation

Primary care physicians should carefully assess comorbidities, especially those linked to cardiovascular risk. Patients with resistant hypertension, pulmonary hypertension, and recurrent atrial fibrillation following cardioversion/ablation should be prioritized for diagnostic testing for OSA. Patients with other conditions, such as coronary artery disease or cerebrovascular disease, should also be referred to a sleep center if OSA is suspected on the basis of comprehensive sleep assessment. OSA has also been associated with type 2 diabetes, metabolic syndrome, and asthma.

Gaining access to sleep study services and subsequent therapy, such as continuous positive airway pressure (CPAP), can be challenging. Primary care physicians should prioritize patients on the basis of their risk levels. Occupation plays a significant role in this prioritization, as sleep fragmentation and daytime sleepiness can lead to workplace and vehicular accidents.

“You should include the occupation in the patient’s profile. What is he doing? Is he sitting at a desk, or is he working at height, driving, or operating machines? These workers are high-risk patients,” continued Dr. De Almeida Vicente Ferreira.

“I think that the family physician has a key role in the follow-up. Nobody else will look for CPAP compliance and will verify if CPAP is working or not. If the patient is not using it or if it is not effective, still there is someone paying for the machine (the national health care system or an insurance company). More importantly, if CPAP is not working, we are not improving our patient’s life in terms of reducing cardiovascular risk and ameliorating the quality of life.”
 

Is home testing a viable option?

Diagnosing OSA typically relies on overnight polysomnography in specialized sleep clinics, which is often associated with long waiting lists. Researchers are actively working on innovative sensors and digital solutions for home-based sleep testing, but according to Dr. De Almeida Vicente Ferreira, they are not yet ready for prime time: “Home-based studies with fewer evaluation parameters (such as pulse and oxygen levels) are not so secure or sensitive to establish a correct and complete diagnosis. Actually, the architecture of sleep is very complex. The test must be performed and read by a specialized team.”

Still, according to Renaud Tamisier, MD, PhD, professor of clinical physiology at the Université Grenoble Alpes in La Tronche, France, simplified sleep testing could be very useful. “There are many patients that still are not diagnosed despite having severe sleep apnea, with symptoms and comorbidities. These patients usually are not aware of their disease but complain about changes in their quality of life with excessive tiredness and sleepiness. Also, they are not connected to the healthcare system, for different reasons, including no time for consulting a sleep physician and performing a polysomnography, health cost, negligence. Therefore, providing through primary care a simple diagnostic approach deserves efforts and research,” he said in an interview.

New technologies could enable diagnostic sleep tests to be conducted at home, with the added benefit of multiple-night recordings to overcome the challenges of night-to-night variability in the apnea-hypopnea index. These novel testing methods should be cost effective, easy to install, and user friendly. Dr. Tamisier continued: “The issue about sleep diagnosis is that up to now, there was no such devices available. Many physicians use type III sleep recording that are dedicated to highly trained sleep scorers, but they use automatic analysis which in many cases is unsuccessful. For a trained sleep physician, it is easy to see that the result is inaccurate. New devices are being built for automatic analysis using artificial intelligence algorithms. Because by design they are automatic, the rate of success is very high, and if used with the right purpose, they could be highly effective and quick.”

In conclusion, the diagnosis of sleep apnea in primary care is becoming more feasible with advancements in diagnostic tools and technology. However, it is crucial for primary care physicians to exercise caution in cases in which the clinical presentation is not straightforward or when OSA is associated with comorbidities. Care management and clear boundaries are vital to ensure effective treatment and improve patient outcomes.

Dr. De Almeida Vicente Ferreira and Dr. Tamisier disclosed no relevant financial relationships.

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

MILAN – The European Respiratory Society Congress 2023 dedicated an entire session to the multifaceted challenges and ongoing debates surrounding progressive pulmonary fibrosis (PPF). Renowned medical professionals and experts congregated in Milan to explore the current landscape and future prospects of diagnosing PPF, with a particular focus on expediting the diagnostic process.

Anna Podolanczuk, MD, assistant professor of medicine at Weill Cornell Medicine, New York, dissected the diagnostic intricacies of PPF, addressing not only the existing challenges but also the opportunities to streamline diagnosis.

As the session’s cochair, Michael Kreuter, MD, director of the Lung Center at University Hospital, Mainz, Germany, emphasized the importance of patients’ voices in understanding and addressing diseases. Joining him as a cochair was Marlies S. Wijsenbeek, a pulmonary physician and the head of the Interstitial Lung Disease Centre at Erasmus University Medical Centre in Rotterdam, the Netherlands.

The session commenced with a powerful testament from Elisabeth Robertson, a PPF patient representative from the United Kingdom. Diagnosed with PPF in 2011, her journey to diagnosis was far from straightforward, and she spoke in a video about the frustrations she encountered due to the lack of accessible information. Ms. Robertson called for a clearer diagnostic pathway.
 

Timely diagnosis: Key to better outcomes

Despite advancements in PPF diagnosis, considerable challenges persist in the diagnostic odyssey of this recently defined phenotype. Dr. Podolanczuk underscored the significance of early diagnosis, citing Ms. Robertson’s personal experience as a poignant example. An early diagnosis not only alleviates patients’ uncertainties and anxieties about their future but also enables the utilization of available treatments, such as antifibrotic therapies, which can slow the decline in forced vital capacity (FVC) in patients with progressive fibrotic interstitial lung diseases.

Data gleaned from the INBUILD trial was presented, revealing that patients in the placebo group experienced a nearly 200 mL decline in lung function over 52 weeks. Dr. Podolanczuk stressed that initiating antifibrotic therapies sooner could lead to better outcomes, as baseline conditions are likely to worsen over time.

“General practitioners can have a role in diagnosing and managing PPF. They are the frontline. We need to increase awareness, because they are generally not aware of this disease, and they usually think about COPD, asthma, or cardiovascular diseases whenever a patient presents with such symptoms,” Dr. Podolanczuk told this news organization.
 

Defining the challenge

The foundation of any diagnosis lies in a clear definition and established diagnostic criteria. During the session, it became apparent that different criteria could be employed for PPF diagnosis, leading to the identification of distinct patient populations.

In 2022, the Official ATS/ERS/JRS/ALAT Clinical Practice Guideline provided the first comprehensive definition of the PPF phenotype. According to this guideline, PPF is defined by the presence of at least two of three criteria: worsening symptoms, radiological progression, or physiologic progression defined as a ≥ 5% absolute decline in FVC or ≥ 10% absolute decline in diffusion lung CO (DLCO) within the past year in a patient with interstitial lung disease (ILD) and lung scarring other than idiopathic pulmonary fibrosis (IPF), with no alternative explanation.

“Definitions from the guidelines were based on the available trials at that moment. Registry data suggest that using different criteria will probably lead to the identification of different, but always progressive, populations,” Dr. Wijsenbeek commented to this news organization. “I think we should not worry too much about the details of the criteria and it is good that we have a multimodality assessment: We ask the patient, we look at the pictures, and we measure the lung function. Combining those data, you can have a robust indication of progression.”
 

The current landscape

Currently, PPF diagnosis hinges on a combination of CT scans, patient narratives, and, in some cases, histological examination. Dr. Wijsenbeek stressed the need to transition to novel diagnostic modalities, including tools that can be readily employed by GPs in their practices.

“GPs have to care about a lot of different diseases, and it makes it more complicated to be aware of conditions like PPF: Symptoms are in fact extremely unspecific” Dr. Kreuter told this news organization. “My suggestion to GPs is to pay attention to the so-called inspiratory crackles because they represent a very early and specific sign of lung fibrosis. This sound does not resemble any other sound that you can hear with your stethoscope: It is like the sound you make walking on fresh snow,” he added, recommending a referral to the pulmonologist in case of identification of inspiratory crackles.

Additionally, several biomarkers can contribute to early PPF diagnosis, including the identification of the usual interstitial pneumonia (UIP) pattern through biopsy or imaging. “We know that this pattern predicts poor outcomes regardless of ILD type,” Dr. Podolanczuk explained, underlining the possibility of using a molecular classifier to identify a UIP pattern on transbronchial lung biopsy. “This is an already existing technology used to identify a gene expression pattern that is strongly predictive of a UIP pattern,” she said.

Furthermore, blood biomarkers, such as high peripheral blood monocyte count and telomere length, hold promise for early PPF detection and prognosis assessment.
 

The road ahead

The diagnostic landscape for PPF is evolving rapidly, with various emerging biomarkers and tools showing promise. Proteomics, alongside home spirometry as a digital biomarker for frequent FVC monitoring, have demonstrated potential for identifying patients who may benefit from early treatment. A 2022 study defined a 12-proteomic biomarkers signature of progressive fibrosing ILD that can identify patients who may benefit from early treatment and is predictive of outcomes regardless of the underlying CT pattern.

The integration of artificial intelligence into the interpretation of CT and x-ray images represents another avenue of advancement in PPF diagnosis. Dr. Podolanczuk highlighted the role of AI and quantitative CTs in enhancing diagnostic accuracy. She also mentioned innovative imaging methods, such as hyperpolarized gas MRI and endobronchial optical coherence tomography (EB-OCT), which offer new insights into disease progression and treatment response.

Beyond imaging and AI, various research tools are entering the diagnostic arena, including real-time breath analysis for distinguishing between different respiratory conditions. These tools collectively promise to shorten the time from symptom presentation to PPF diagnosis, a vital step in improving patient outcomes. In the words of Dr. Podolanczuk, “How early is too early to identify these patients? Let me say that there’s no such thing as ‘too early’ in the diagnosis of PPF!”

Dr. Podolanczuk disclosed grant funding from NHLBI, ALA, and Three Lakes Foundation; consulting fees from Regeneron, Roche, Imvaria, Boehringer Ingelheim, Veracyte, United Therapeutics, and Eisai; and honoraria from NACE and EBSCO/DynaMed. Ms. Robertson disclosed having no conflict.

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

MILAN – The European Respiratory Society Congress 2023 dedicated an entire session to the multifaceted challenges and ongoing debates surrounding progressive pulmonary fibrosis (PPF). Renowned medical professionals and experts congregated in Milan to explore the current landscape and future prospects of diagnosing PPF, with a particular focus on expediting the diagnostic process.

Anna Podolanczuk, MD, assistant professor of medicine at Weill Cornell Medicine, New York, dissected the diagnostic intricacies of PPF, addressing not only the existing challenges but also the opportunities to streamline diagnosis.

As the session’s cochair, Michael Kreuter, MD, director of the Lung Center at University Hospital, Mainz, Germany, emphasized the importance of patients’ voices in understanding and addressing diseases. Joining him as a cochair was Marlies S. Wijsenbeek, a pulmonary physician and the head of the Interstitial Lung Disease Centre at Erasmus University Medical Centre in Rotterdam, the Netherlands.

The session commenced with a powerful testament from Elisabeth Robertson, a PPF patient representative from the United Kingdom. Diagnosed with PPF in 2011, her journey to diagnosis was far from straightforward, and she spoke in a video about the frustrations she encountered due to the lack of accessible information. Ms. Robertson called for a clearer diagnostic pathway.
 

Timely diagnosis: Key to better outcomes

Despite advancements in PPF diagnosis, considerable challenges persist in the diagnostic odyssey of this recently defined phenotype. Dr. Podolanczuk underscored the significance of early diagnosis, citing Ms. Robertson’s personal experience as a poignant example. An early diagnosis not only alleviates patients’ uncertainties and anxieties about their future but also enables the utilization of available treatments, such as antifibrotic therapies, which can slow the decline in forced vital capacity (FVC) in patients with progressive fibrotic interstitial lung diseases.

Data gleaned from the INBUILD trial was presented, revealing that patients in the placebo group experienced a nearly 200 mL decline in lung function over 52 weeks. Dr. Podolanczuk stressed that initiating antifibrotic therapies sooner could lead to better outcomes, as baseline conditions are likely to worsen over time.

“General practitioners can have a role in diagnosing and managing PPF. They are the frontline. We need to increase awareness, because they are generally not aware of this disease, and they usually think about COPD, asthma, or cardiovascular diseases whenever a patient presents with such symptoms,” Dr. Podolanczuk told this news organization.
 

Defining the challenge

The foundation of any diagnosis lies in a clear definition and established diagnostic criteria. During the session, it became apparent that different criteria could be employed for PPF diagnosis, leading to the identification of distinct patient populations.

In 2022, the Official ATS/ERS/JRS/ALAT Clinical Practice Guideline provided the first comprehensive definition of the PPF phenotype. According to this guideline, PPF is defined by the presence of at least two of three criteria: worsening symptoms, radiological progression, or physiologic progression defined as a ≥ 5% absolute decline in FVC or ≥ 10% absolute decline in diffusion lung CO (DLCO) within the past year in a patient with interstitial lung disease (ILD) and lung scarring other than idiopathic pulmonary fibrosis (IPF), with no alternative explanation.

“Definitions from the guidelines were based on the available trials at that moment. Registry data suggest that using different criteria will probably lead to the identification of different, but always progressive, populations,” Dr. Wijsenbeek commented to this news organization. “I think we should not worry too much about the details of the criteria and it is good that we have a multimodality assessment: We ask the patient, we look at the pictures, and we measure the lung function. Combining those data, you can have a robust indication of progression.”
 

The current landscape

Currently, PPF diagnosis hinges on a combination of CT scans, patient narratives, and, in some cases, histological examination. Dr. Wijsenbeek stressed the need to transition to novel diagnostic modalities, including tools that can be readily employed by GPs in their practices.

“GPs have to care about a lot of different diseases, and it makes it more complicated to be aware of conditions like PPF: Symptoms are in fact extremely unspecific” Dr. Kreuter told this news organization. “My suggestion to GPs is to pay attention to the so-called inspiratory crackles because they represent a very early and specific sign of lung fibrosis. This sound does not resemble any other sound that you can hear with your stethoscope: It is like the sound you make walking on fresh snow,” he added, recommending a referral to the pulmonologist in case of identification of inspiratory crackles.

Additionally, several biomarkers can contribute to early PPF diagnosis, including the identification of the usual interstitial pneumonia (UIP) pattern through biopsy or imaging. “We know that this pattern predicts poor outcomes regardless of ILD type,” Dr. Podolanczuk explained, underlining the possibility of using a molecular classifier to identify a UIP pattern on transbronchial lung biopsy. “This is an already existing technology used to identify a gene expression pattern that is strongly predictive of a UIP pattern,” she said.

Furthermore, blood biomarkers, such as high peripheral blood monocyte count and telomere length, hold promise for early PPF detection and prognosis assessment.
 

The road ahead

The diagnostic landscape for PPF is evolving rapidly, with various emerging biomarkers and tools showing promise. Proteomics, alongside home spirometry as a digital biomarker for frequent FVC monitoring, have demonstrated potential for identifying patients who may benefit from early treatment. A 2022 study defined a 12-proteomic biomarkers signature of progressive fibrosing ILD that can identify patients who may benefit from early treatment and is predictive of outcomes regardless of the underlying CT pattern.

The integration of artificial intelligence into the interpretation of CT and x-ray images represents another avenue of advancement in PPF diagnosis. Dr. Podolanczuk highlighted the role of AI and quantitative CTs in enhancing diagnostic accuracy. She also mentioned innovative imaging methods, such as hyperpolarized gas MRI and endobronchial optical coherence tomography (EB-OCT), which offer new insights into disease progression and treatment response.

Beyond imaging and AI, various research tools are entering the diagnostic arena, including real-time breath analysis for distinguishing between different respiratory conditions. These tools collectively promise to shorten the time from symptom presentation to PPF diagnosis, a vital step in improving patient outcomes. In the words of Dr. Podolanczuk, “How early is too early to identify these patients? Let me say that there’s no such thing as ‘too early’ in the diagnosis of PPF!”

Dr. Podolanczuk disclosed grant funding from NHLBI, ALA, and Three Lakes Foundation; consulting fees from Regeneron, Roche, Imvaria, Boehringer Ingelheim, Veracyte, United Therapeutics, and Eisai; and honoraria from NACE and EBSCO/DynaMed. Ms. Robertson disclosed having no conflict.

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

MILAN – The European Respiratory Society Congress 2023 dedicated an entire session to the multifaceted challenges and ongoing debates surrounding progressive pulmonary fibrosis (PPF). Renowned medical professionals and experts congregated in Milan to explore the current landscape and future prospects of diagnosing PPF, with a particular focus on expediting the diagnostic process.

Anna Podolanczuk, MD, assistant professor of medicine at Weill Cornell Medicine, New York, dissected the diagnostic intricacies of PPF, addressing not only the existing challenges but also the opportunities to streamline diagnosis.

As the session’s cochair, Michael Kreuter, MD, director of the Lung Center at University Hospital, Mainz, Germany, emphasized the importance of patients’ voices in understanding and addressing diseases. Joining him as a cochair was Marlies S. Wijsenbeek, a pulmonary physician and the head of the Interstitial Lung Disease Centre at Erasmus University Medical Centre in Rotterdam, the Netherlands.

The session commenced with a powerful testament from Elisabeth Robertson, a PPF patient representative from the United Kingdom. Diagnosed with PPF in 2011, her journey to diagnosis was far from straightforward, and she spoke in a video about the frustrations she encountered due to the lack of accessible information. Ms. Robertson called for a clearer diagnostic pathway.
 

Timely diagnosis: Key to better outcomes

Despite advancements in PPF diagnosis, considerable challenges persist in the diagnostic odyssey of this recently defined phenotype. Dr. Podolanczuk underscored the significance of early diagnosis, citing Ms. Robertson’s personal experience as a poignant example. An early diagnosis not only alleviates patients’ uncertainties and anxieties about their future but also enables the utilization of available treatments, such as antifibrotic therapies, which can slow the decline in forced vital capacity (FVC) in patients with progressive fibrotic interstitial lung diseases.

Data gleaned from the INBUILD trial was presented, revealing that patients in the placebo group experienced a nearly 200 mL decline in lung function over 52 weeks. Dr. Podolanczuk stressed that initiating antifibrotic therapies sooner could lead to better outcomes, as baseline conditions are likely to worsen over time.

“General practitioners can have a role in diagnosing and managing PPF. They are the frontline. We need to increase awareness, because they are generally not aware of this disease, and they usually think about COPD, asthma, or cardiovascular diseases whenever a patient presents with such symptoms,” Dr. Podolanczuk told this news organization.
 

Defining the challenge

The foundation of any diagnosis lies in a clear definition and established diagnostic criteria. During the session, it became apparent that different criteria could be employed for PPF diagnosis, leading to the identification of distinct patient populations.

In 2022, the Official ATS/ERS/JRS/ALAT Clinical Practice Guideline provided the first comprehensive definition of the PPF phenotype. According to this guideline, PPF is defined by the presence of at least two of three criteria: worsening symptoms, radiological progression, or physiologic progression defined as a ≥ 5% absolute decline in FVC or ≥ 10% absolute decline in diffusion lung CO (DLCO) within the past year in a patient with interstitial lung disease (ILD) and lung scarring other than idiopathic pulmonary fibrosis (IPF), with no alternative explanation.

“Definitions from the guidelines were based on the available trials at that moment. Registry data suggest that using different criteria will probably lead to the identification of different, but always progressive, populations,” Dr. Wijsenbeek commented to this news organization. “I think we should not worry too much about the details of the criteria and it is good that we have a multimodality assessment: We ask the patient, we look at the pictures, and we measure the lung function. Combining those data, you can have a robust indication of progression.”
 

The current landscape

Currently, PPF diagnosis hinges on a combination of CT scans, patient narratives, and, in some cases, histological examination. Dr. Wijsenbeek stressed the need to transition to novel diagnostic modalities, including tools that can be readily employed by GPs in their practices.

“GPs have to care about a lot of different diseases, and it makes it more complicated to be aware of conditions like PPF: Symptoms are in fact extremely unspecific” Dr. Kreuter told this news organization. “My suggestion to GPs is to pay attention to the so-called inspiratory crackles because they represent a very early and specific sign of lung fibrosis. This sound does not resemble any other sound that you can hear with your stethoscope: It is like the sound you make walking on fresh snow,” he added, recommending a referral to the pulmonologist in case of identification of inspiratory crackles.

Additionally, several biomarkers can contribute to early PPF diagnosis, including the identification of the usual interstitial pneumonia (UIP) pattern through biopsy or imaging. “We know that this pattern predicts poor outcomes regardless of ILD type,” Dr. Podolanczuk explained, underlining the possibility of using a molecular classifier to identify a UIP pattern on transbronchial lung biopsy. “This is an already existing technology used to identify a gene expression pattern that is strongly predictive of a UIP pattern,” she said.

Furthermore, blood biomarkers, such as high peripheral blood monocyte count and telomere length, hold promise for early PPF detection and prognosis assessment.
 

The road ahead

The diagnostic landscape for PPF is evolving rapidly, with various emerging biomarkers and tools showing promise. Proteomics, alongside home spirometry as a digital biomarker for frequent FVC monitoring, have demonstrated potential for identifying patients who may benefit from early treatment. A 2022 study defined a 12-proteomic biomarkers signature of progressive fibrosing ILD that can identify patients who may benefit from early treatment and is predictive of outcomes regardless of the underlying CT pattern.

The integration of artificial intelligence into the interpretation of CT and x-ray images represents another avenue of advancement in PPF diagnosis. Dr. Podolanczuk highlighted the role of AI and quantitative CTs in enhancing diagnostic accuracy. She also mentioned innovative imaging methods, such as hyperpolarized gas MRI and endobronchial optical coherence tomography (EB-OCT), which offer new insights into disease progression and treatment response.

Beyond imaging and AI, various research tools are entering the diagnostic arena, including real-time breath analysis for distinguishing between different respiratory conditions. These tools collectively promise to shorten the time from symptom presentation to PPF diagnosis, a vital step in improving patient outcomes. In the words of Dr. Podolanczuk, “How early is too early to identify these patients? Let me say that there’s no such thing as ‘too early’ in the diagnosis of PPF!”

Dr. Podolanczuk disclosed grant funding from NHLBI, ALA, and Three Lakes Foundation; consulting fees from Regeneron, Roche, Imvaria, Boehringer Ingelheim, Veracyte, United Therapeutics, and Eisai; and honoraria from NACE and EBSCO/DynaMed. Ms. Robertson disclosed having no conflict.

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

A physician in your office is hot-tempered, critical, and upsets both the physicians and staff. Two of your partners are arguing over a software vendor and refuse to compromise. One doctor’s spouse is the office manager and snipes at everyone; the lead partner micromanages and second-guesses other doctors’ treatment plans, and no one will stand up to her.

If your practice has similar scenarios, you’re likely dealing with your own anger, irritation, and dread at work. You’re struggling with a toxic practice atmosphere, and you must make changes – fast.

However, this isn’t easy, given that what goes on in a doctor’s office is “high consequence,” says Leonard J. Marcus, PhD, founding director of the program for health care negotiation and conflict resolution at the Harvard School of Public Health in Boston.

The two things that tend to plague medical practices most: A culture of fear and someone who is letting ego run the day-to-day, he says.

“Fear overwhelms any chance for good morale among colleagues,” says Dr. Marcus, who is also the coauthor of “Renegotiating Health Care: Resolving Conflict to Build Collaboration.” “In a work environment where the fear is overwhelming, the ego can take over, and someone at the practice becomes overly concerned about getting credit, taking control, ordering other people around, and deciding who is on top and who is on the bottom.”

Tension, stress, back-biting, and rudeness are also symptoms of a more significant problem, says Jes Montgomery, MD, a psychiatrist and medical director of APN Dallas, a mental health–focused practice.

“If you don’t get toxicity under control, it will blow the office apart,” Dr. Montgomery says.

Here are five tips to turn around a toxic practice culture.
 

1. Recognize the signs

Part of the problem with a toxic medical practice is that, culturally, we don’t treat mental health and burnout as real illnesses. “A physician who is depressed is not going to be melancholy or bursting into tears with patients,” Dr. Montgomery says. “They’ll get behind on paperwork, skip meals, or find that it’s difficult to sleep at night. Next, they’ll yell at the partners and staff, always be in a foul mood, and gripe about inconsequential things. Their behavior affects everyone.”

Dr. Montgomery says that physicians aren’t taught to ask for help, making it difficult to see what’s really going on when someone displays toxic behavior in the practice. If it’s a partner, take time to ask what’s going on. If it’s yourself, step back and see if you can ask someone for the help you need.
 

2. Have difficult conversations

This is tough for most of us, says Jeremy Pollack, PhD, CEO and founder of Pollack Peacebuilding Systems, a conflict resolution consulting firm. If a team member is hot-tempered, disrespectful, or talking to patients in an unproductive manner, see if you can have an effective conversation with that person. The tricky part is critiquing in a way that doesn’t make them feel defensive – and wanting to push back.

For a micromanaging office manager, for example, you could say something like,”You’re doing a great job with the inventory, but I need you to let the staff have some autonomy and not hover over every supply they use in the break room, so that people won’t feel resentful toward us.” Make it clear you’re a team, and this is a team challenge. “However, if a doctor feels like they’ve tried to communicate to that colleague and are still walking on eggshells, it’s time to try to get help from someone – perhaps a practice management organization,” says Dr. Pollack.
 

3. Open lines of communication

It’s critical to create a comfortable space to speak with your colleagues, says Marisa Garshick, MD, a dermatologist in private practice in New York. “Creating an environment where there is an open line of communication, whether it’s directly to somebody in charge or having a system where you can give feedback more privately or anonymously, is important so that tension doesn’t build.”

“Being a doctor is a social enterprise,” Dr. Marcus says. “The science of medicine is critically important, but patients and the other health care workers on your team are also critically important. In the long run, the most successful physicians pay attention to both. It’s a full package.”
 

4. Emphasize the positive

Instead of discussing things only when they go wrong, try optimism, Dr. Garshick said. When positive things happen, whether it’s an excellent patient encounter or the office did something really well together, highlight it so everyone has a sense of accomplishment. If a patient compliments a medical assistant or raves about a nurse, share those compliments with the employees so that not every encounter you have calls out problems and staff missteps.

Suppose partners have a conflict with one another or are arguing over something. In that case, you may need to mediate or invest in a meaningful intervention so people can reflect on the narrative they’re contributing to the culture.
 

5. Practice self-care

Finally, the work of a physician is exhausting, so it’s crucial to practice personal TLC. That may mean taking micro breaks, getting adequate sleep, maintaining a healthy diet, and exercising well and managing stress to maintain energy levels and patience.

“Sometimes, when I’m fed up with the office, I need to get away,” Dr. Montgomery says. “I’ll take a day to go fishing, golfing, and not think about the office.” Just a small break can shift the lens that you see through when you return to the office and put problems in perspective.

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

A physician in your office is hot-tempered, critical, and upsets both the physicians and staff. Two of your partners are arguing over a software vendor and refuse to compromise. One doctor’s spouse is the office manager and snipes at everyone; the lead partner micromanages and second-guesses other doctors’ treatment plans, and no one will stand up to her.

If your practice has similar scenarios, you’re likely dealing with your own anger, irritation, and dread at work. You’re struggling with a toxic practice atmosphere, and you must make changes – fast.

However, this isn’t easy, given that what goes on in a doctor’s office is “high consequence,” says Leonard J. Marcus, PhD, founding director of the program for health care negotiation and conflict resolution at the Harvard School of Public Health in Boston.

The two things that tend to plague medical practices most: A culture of fear and someone who is letting ego run the day-to-day, he says.

“Fear overwhelms any chance for good morale among colleagues,” says Dr. Marcus, who is also the coauthor of “Renegotiating Health Care: Resolving Conflict to Build Collaboration.” “In a work environment where the fear is overwhelming, the ego can take over, and someone at the practice becomes overly concerned about getting credit, taking control, ordering other people around, and deciding who is on top and who is on the bottom.”

Tension, stress, back-biting, and rudeness are also symptoms of a more significant problem, says Jes Montgomery, MD, a psychiatrist and medical director of APN Dallas, a mental health–focused practice.

“If you don’t get toxicity under control, it will blow the office apart,” Dr. Montgomery says.

Here are five tips to turn around a toxic practice culture.
 

1. Recognize the signs

Part of the problem with a toxic medical practice is that, culturally, we don’t treat mental health and burnout as real illnesses. “A physician who is depressed is not going to be melancholy or bursting into tears with patients,” Dr. Montgomery says. “They’ll get behind on paperwork, skip meals, or find that it’s difficult to sleep at night. Next, they’ll yell at the partners and staff, always be in a foul mood, and gripe about inconsequential things. Their behavior affects everyone.”

Dr. Montgomery says that physicians aren’t taught to ask for help, making it difficult to see what’s really going on when someone displays toxic behavior in the practice. If it’s a partner, take time to ask what’s going on. If it’s yourself, step back and see if you can ask someone for the help you need.
 

2. Have difficult conversations

This is tough for most of us, says Jeremy Pollack, PhD, CEO and founder of Pollack Peacebuilding Systems, a conflict resolution consulting firm. If a team member is hot-tempered, disrespectful, or talking to patients in an unproductive manner, see if you can have an effective conversation with that person. The tricky part is critiquing in a way that doesn’t make them feel defensive – and wanting to push back.

For a micromanaging office manager, for example, you could say something like,”You’re doing a great job with the inventory, but I need you to let the staff have some autonomy and not hover over every supply they use in the break room, so that people won’t feel resentful toward us.” Make it clear you’re a team, and this is a team challenge. “However, if a doctor feels like they’ve tried to communicate to that colleague and are still walking on eggshells, it’s time to try to get help from someone – perhaps a practice management organization,” says Dr. Pollack.
 

3. Open lines of communication

It’s critical to create a comfortable space to speak with your colleagues, says Marisa Garshick, MD, a dermatologist in private practice in New York. “Creating an environment where there is an open line of communication, whether it’s directly to somebody in charge or having a system where you can give feedback more privately or anonymously, is important so that tension doesn’t build.”

“Being a doctor is a social enterprise,” Dr. Marcus says. “The science of medicine is critically important, but patients and the other health care workers on your team are also critically important. In the long run, the most successful physicians pay attention to both. It’s a full package.”
 

4. Emphasize the positive

Instead of discussing things only when they go wrong, try optimism, Dr. Garshick said. When positive things happen, whether it’s an excellent patient encounter or the office did something really well together, highlight it so everyone has a sense of accomplishment. If a patient compliments a medical assistant or raves about a nurse, share those compliments with the employees so that not every encounter you have calls out problems and staff missteps.

Suppose partners have a conflict with one another or are arguing over something. In that case, you may need to mediate or invest in a meaningful intervention so people can reflect on the narrative they’re contributing to the culture.
 

5. Practice self-care

Finally, the work of a physician is exhausting, so it’s crucial to practice personal TLC. That may mean taking micro breaks, getting adequate sleep, maintaining a healthy diet, and exercising well and managing stress to maintain energy levels and patience.

“Sometimes, when I’m fed up with the office, I need to get away,” Dr. Montgomery says. “I’ll take a day to go fishing, golfing, and not think about the office.” Just a small break can shift the lens that you see through when you return to the office and put problems in perspective.

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

A physician in your office is hot-tempered, critical, and upsets both the physicians and staff. Two of your partners are arguing over a software vendor and refuse to compromise. One doctor’s spouse is the office manager and snipes at everyone; the lead partner micromanages and second-guesses other doctors’ treatment plans, and no one will stand up to her.

If your practice has similar scenarios, you’re likely dealing with your own anger, irritation, and dread at work. You’re struggling with a toxic practice atmosphere, and you must make changes – fast.

However, this isn’t easy, given that what goes on in a doctor’s office is “high consequence,” says Leonard J. Marcus, PhD, founding director of the program for health care negotiation and conflict resolution at the Harvard School of Public Health in Boston.

The two things that tend to plague medical practices most: A culture of fear and someone who is letting ego run the day-to-day, he says.

“Fear overwhelms any chance for good morale among colleagues,” says Dr. Marcus, who is also the coauthor of “Renegotiating Health Care: Resolving Conflict to Build Collaboration.” “In a work environment where the fear is overwhelming, the ego can take over, and someone at the practice becomes overly concerned about getting credit, taking control, ordering other people around, and deciding who is on top and who is on the bottom.”

Tension, stress, back-biting, and rudeness are also symptoms of a more significant problem, says Jes Montgomery, MD, a psychiatrist and medical director of APN Dallas, a mental health–focused practice.

“If you don’t get toxicity under control, it will blow the office apart,” Dr. Montgomery says.

Here are five tips to turn around a toxic practice culture.
 

1. Recognize the signs

Part of the problem with a toxic medical practice is that, culturally, we don’t treat mental health and burnout as real illnesses. “A physician who is depressed is not going to be melancholy or bursting into tears with patients,” Dr. Montgomery says. “They’ll get behind on paperwork, skip meals, or find that it’s difficult to sleep at night. Next, they’ll yell at the partners and staff, always be in a foul mood, and gripe about inconsequential things. Their behavior affects everyone.”

Dr. Montgomery says that physicians aren’t taught to ask for help, making it difficult to see what’s really going on when someone displays toxic behavior in the practice. If it’s a partner, take time to ask what’s going on. If it’s yourself, step back and see if you can ask someone for the help you need.
 

2. Have difficult conversations

This is tough for most of us, says Jeremy Pollack, PhD, CEO and founder of Pollack Peacebuilding Systems, a conflict resolution consulting firm. If a team member is hot-tempered, disrespectful, or talking to patients in an unproductive manner, see if you can have an effective conversation with that person. The tricky part is critiquing in a way that doesn’t make them feel defensive – and wanting to push back.

For a micromanaging office manager, for example, you could say something like,”You’re doing a great job with the inventory, but I need you to let the staff have some autonomy and not hover over every supply they use in the break room, so that people won’t feel resentful toward us.” Make it clear you’re a team, and this is a team challenge. “However, if a doctor feels like they’ve tried to communicate to that colleague and are still walking on eggshells, it’s time to try to get help from someone – perhaps a practice management organization,” says Dr. Pollack.
 

3. Open lines of communication

It’s critical to create a comfortable space to speak with your colleagues, says Marisa Garshick, MD, a dermatologist in private practice in New York. “Creating an environment where there is an open line of communication, whether it’s directly to somebody in charge or having a system where you can give feedback more privately or anonymously, is important so that tension doesn’t build.”

“Being a doctor is a social enterprise,” Dr. Marcus says. “The science of medicine is critically important, but patients and the other health care workers on your team are also critically important. In the long run, the most successful physicians pay attention to both. It’s a full package.”
 

4. Emphasize the positive

Instead of discussing things only when they go wrong, try optimism, Dr. Garshick said. When positive things happen, whether it’s an excellent patient encounter or the office did something really well together, highlight it so everyone has a sense of accomplishment. If a patient compliments a medical assistant or raves about a nurse, share those compliments with the employees so that not every encounter you have calls out problems and staff missteps.

Suppose partners have a conflict with one another or are arguing over something. In that case, you may need to mediate or invest in a meaningful intervention so people can reflect on the narrative they’re contributing to the culture.
 

5. Practice self-care

Finally, the work of a physician is exhausting, so it’s crucial to practice personal TLC. That may mean taking micro breaks, getting adequate sleep, maintaining a healthy diet, and exercising well and managing stress to maintain energy levels and patience.

“Sometimes, when I’m fed up with the office, I need to get away,” Dr. Montgomery says. “I’ll take a day to go fishing, golfing, and not think about the office.” Just a small break can shift the lens that you see through when you return to the office and put problems in perspective.

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

Whether you’ve decided to retire, relocate, or work for your local hospital, unwinding your practice will take time. Physicians can avoid mistakes by planning ahead and making a checklist for what to do and when to do it.

“Doctors shouldn’t assume everything takes care of itself. Many don’t think about compliance issues, patient abandonment, or accounts receivable that they need to keep open to collect from billing, which can occur months after the dates of service,” said David Zetter, president of Zetter HealthCare management consultants in Pennsylvania.

Debra Phairas, president of Practice and Liability Consultants, LLC, in California, suggests doctors start planning for the closing of their practice at least 90-120 days from their closing date.

“Many people and entities need to be notified,” said Ms. Phairas. The list includes patients, payers, vendors, employees, licensing boards, and federal and state agencies.

Medical societies may have specific bylaws that apply; malpractice carriers have rules about how long you should retain medical records; and some state laws require that you communicate that you’re closing in a newspaper, Mr. Zetter added.

Ms. Phairas recommends that physicians decide first whether they will sell their practice or if they’ll just shut it down. If they sell and the buyer is a doctor, they may want to provide transition assistance such as introducing patients and staff, she said. Otherwise, doctors may need to terminate their staff.

After doctors make that decision, Mr. Zetter and Ms. Phairas recommend taking these 12 steps to ensure that the process goes smoothly.
 

What to do 60-90 days out

1. Check your insurance contracts. The Centers for Medicare & Medicaid Services requires physicians to notify them 90 days after deciding to retire or withdraw from Medicare or Medicaid. Other payers may also require 90 days’ notice to terminate their contracts.

You’ll also need to provide payers with a forwarding address for sending payments after the office closes, and notify your malpractice insurance carrier and any other contracted insurance carriers such as workers’ compensation or employee benefit plans.

2. Buy “tail” coverage. Doctors can be sued for malpractice years after they close their practice so this provides coverage against claims reported after the liability policy expires.

3. Check your hospital contracts. Most hospitals where you have privileges require 90 days’ notice that you are closing the practice.

4. Arrange for safe storage of medical records. If you are selling your practice to another physician, that doctor can take charge of them, as long as you obtain a patient’s consent to transfer the medical records, said Ms. Phairas. Otherwise, the practice is required to make someone the guardian of the records after the practice closes, said Mr. Zetter. This allows patients at a later date to obtain copies of their records at a cost.

“This usually means printing all the records to PDF to be retained; otherwise, doctors have to continue to pay the license fee for the EMR software to access the records, and no practice is going to continue to pay this indefinitely,” said Mr. Zetter.

Check with your malpractice insurance carrier for how long they require medical records to be retained, which may vary for adult and pediatric records.

Ms. Phairas also advises doctors to keep their original records. “The biggest mistake doctors can make is to give patients all their records. Your chart is your best defense weapon in a liability claim.”
 

What to do 30-60 days out

5. Tell your staff. They should not hear that you’re retiring or leaving the practice from other people, said Ms. Phairas. But timing is important. “If you notify them too soon, they may look for another job. I recommend telling them about 45 days out and just before you notify patients, although you may want to tell the office manager sooner.”

Doctors may need help closing the practice and should consider offering the employees a severance bonus to stay until the end, said Ms. Phairas. If they do leave sooner, then you can hire temporary staff.

6. Notify patients to avoid any claims of abandonment. You should notify all active patients, which, depending on your state, can be any patient the physician has treated sometime in the past 12-36 months.

Some state laws require the notice to be published as an advertisement in the local newspaper and will say how far in advance it needs to be published and how long the ad needs to run. Notification also should be posted throughout the practice, and patients who call or visit should be given oral reminders.

“Your biggest expense will be mailing a letter to all patients,” said Mr. Zetter. The letter should include:

• The date of closing.
• The name(s) of the physicians taking over the practice (if applicable).
• Local physicians who would be willing to accept new patients.
• Instructions for how patients can obtain or transfer medical records (with a deadline for submitting record requests).
• How to contact the practice if patients and families have any concerns about the closing.

7. Notify your professional associations. These include your state medical board, credentialing organizations, and professional memberships. It’s critical to renew your license even if you plan to practice in other states. He recalled that one doctor let his license lapse and the medical board notified Medicaid that he was no longer licensed. “CMS went after him because he didn’t notify them that he was no longer operating in Washington. CMS shut him down in every state/territory. This interventional radiologist spent 3 years with two attorneys to get it resolved,” said Mr. Zetter.

8. Terminate any leases with landlords or try to negotiate renting the office space on a month-to-month basis until you close or sell, suggests Ms. Phairas. If the practice owns the space, the partners will need to decide if the space will be sold or leased to a new business.
 

What to do 30 days out

9. Notify referring physicians of when you plan to close your practice so they don’t send new patients after that date.

10. Send a letter to the Drug Enforcement Agency to deactivate your license if you plan not to write another prescription and after you have safely disposed of prescription drugs following the federal guidelines. Destroy all prescription pads and contact drug representatives to determine what to do with unused samples, if needed.

11. Notify all vendors. Inform medical suppliers, office suppliers, collection agencies, laundry services, housekeeping services, hazardous waste disposal services, and any other vendors. Make sure to request a final statement from them so you can close out your accounts.

12. Process your accounts receivable to collect money owed to you. Consider employing a collection agency or staff member to reconcile accounts after the practice has closed.

Mr. Zetter also suggested retaining a certified accountant to handle the expenses for shutting down the business and to handle your future tax returns. “If you shut down the practice in 2023, you will still have to file a tax return for that year in 2024,” he said.

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

Whether you’ve decided to retire, relocate, or work for your local hospital, unwinding your practice will take time. Physicians can avoid mistakes by planning ahead and making a checklist for what to do and when to do it.

“Doctors shouldn’t assume everything takes care of itself. Many don’t think about compliance issues, patient abandonment, or accounts receivable that they need to keep open to collect from billing, which can occur months after the dates of service,” said David Zetter, president of Zetter HealthCare management consultants in Pennsylvania.

Debra Phairas, president of Practice and Liability Consultants, LLC, in California, suggests doctors start planning for the closing of their practice at least 90-120 days from their closing date.

“Many people and entities need to be notified,” said Ms. Phairas. The list includes patients, payers, vendors, employees, licensing boards, and federal and state agencies.

Medical societies may have specific bylaws that apply; malpractice carriers have rules about how long you should retain medical records; and some state laws require that you communicate that you’re closing in a newspaper, Mr. Zetter added.

Ms. Phairas recommends that physicians decide first whether they will sell their practice or if they’ll just shut it down. If they sell and the buyer is a doctor, they may want to provide transition assistance such as introducing patients and staff, she said. Otherwise, doctors may need to terminate their staff.

After doctors make that decision, Mr. Zetter and Ms. Phairas recommend taking these 12 steps to ensure that the process goes smoothly.
 

What to do 60-90 days out

1. Check your insurance contracts. The Centers for Medicare & Medicaid Services requires physicians to notify them 90 days after deciding to retire or withdraw from Medicare or Medicaid. Other payers may also require 90 days’ notice to terminate their contracts.

You’ll also need to provide payers with a forwarding address for sending payments after the office closes, and notify your malpractice insurance carrier and any other contracted insurance carriers such as workers’ compensation or employee benefit plans.

2. Buy “tail” coverage. Doctors can be sued for malpractice years after they close their practice so this provides coverage against claims reported after the liability policy expires.

3. Check your hospital contracts. Most hospitals where you have privileges require 90 days’ notice that you are closing the practice.

4. Arrange for safe storage of medical records. If you are selling your practice to another physician, that doctor can take charge of them, as long as you obtain a patient’s consent to transfer the medical records, said Ms. Phairas. Otherwise, the practice is required to make someone the guardian of the records after the practice closes, said Mr. Zetter. This allows patients at a later date to obtain copies of their records at a cost.

“This usually means printing all the records to PDF to be retained; otherwise, doctors have to continue to pay the license fee for the EMR software to access the records, and no practice is going to continue to pay this indefinitely,” said Mr. Zetter.

Check with your malpractice insurance carrier for how long they require medical records to be retained, which may vary for adult and pediatric records.

Ms. Phairas also advises doctors to keep their original records. “The biggest mistake doctors can make is to give patients all their records. Your chart is your best defense weapon in a liability claim.”
 

What to do 30-60 days out

5. Tell your staff. They should not hear that you’re retiring or leaving the practice from other people, said Ms. Phairas. But timing is important. “If you notify them too soon, they may look for another job. I recommend telling them about 45 days out and just before you notify patients, although you may want to tell the office manager sooner.”

Doctors may need help closing the practice and should consider offering the employees a severance bonus to stay until the end, said Ms. Phairas. If they do leave sooner, then you can hire temporary staff.

6. Notify patients to avoid any claims of abandonment. You should notify all active patients, which, depending on your state, can be any patient the physician has treated sometime in the past 12-36 months.

Some state laws require the notice to be published as an advertisement in the local newspaper and will say how far in advance it needs to be published and how long the ad needs to run. Notification also should be posted throughout the practice, and patients who call or visit should be given oral reminders.

“Your biggest expense will be mailing a letter to all patients,” said Mr. Zetter. The letter should include:

• The date of closing.
• The name(s) of the physicians taking over the practice (if applicable).
• Local physicians who would be willing to accept new patients.
• Instructions for how patients can obtain or transfer medical records (with a deadline for submitting record requests).
• How to contact the practice if patients and families have any concerns about the closing.

7. Notify your professional associations. These include your state medical board, credentialing organizations, and professional memberships. It’s critical to renew your license even if you plan to practice in other states. He recalled that one doctor let his license lapse and the medical board notified Medicaid that he was no longer licensed. “CMS went after him because he didn’t notify them that he was no longer operating in Washington. CMS shut him down in every state/territory. This interventional radiologist spent 3 years with two attorneys to get it resolved,” said Mr. Zetter.

8. Terminate any leases with landlords or try to negotiate renting the office space on a month-to-month basis until you close or sell, suggests Ms. Phairas. If the practice owns the space, the partners will need to decide if the space will be sold or leased to a new business.
 

What to do 30 days out

9. Notify referring physicians of when you plan to close your practice so they don’t send new patients after that date.

10. Send a letter to the Drug Enforcement Agency to deactivate your license if you plan not to write another prescription and after you have safely disposed of prescription drugs following the federal guidelines. Destroy all prescription pads and contact drug representatives to determine what to do with unused samples, if needed.

11. Notify all vendors. Inform medical suppliers, office suppliers, collection agencies, laundry services, housekeeping services, hazardous waste disposal services, and any other vendors. Make sure to request a final statement from them so you can close out your accounts.

12. Process your accounts receivable to collect money owed to you. Consider employing a collection agency or staff member to reconcile accounts after the practice has closed.

Mr. Zetter also suggested retaining a certified accountant to handle the expenses for shutting down the business and to handle your future tax returns. “If you shut down the practice in 2023, you will still have to file a tax return for that year in 2024,” he said.

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

Whether you’ve decided to retire, relocate, or work for your local hospital, unwinding your practice will take time. Physicians can avoid mistakes by planning ahead and making a checklist for what to do and when to do it.

“Doctors shouldn’t assume everything takes care of itself. Many don’t think about compliance issues, patient abandonment, or accounts receivable that they need to keep open to collect from billing, which can occur months after the dates of service,” said David Zetter, president of Zetter HealthCare management consultants in Pennsylvania.

Debra Phairas, president of Practice and Liability Consultants, LLC, in California, suggests doctors start planning for the closing of their practice at least 90-120 days from their closing date.

“Many people and entities need to be notified,” said Ms. Phairas. The list includes patients, payers, vendors, employees, licensing boards, and federal and state agencies.

Medical societies may have specific bylaws that apply; malpractice carriers have rules about how long you should retain medical records; and some state laws require that you communicate that you’re closing in a newspaper, Mr. Zetter added.

Ms. Phairas recommends that physicians decide first whether they will sell their practice or if they’ll just shut it down. If they sell and the buyer is a doctor, they may want to provide transition assistance such as introducing patients and staff, she said. Otherwise, doctors may need to terminate their staff.

After doctors make that decision, Mr. Zetter and Ms. Phairas recommend taking these 12 steps to ensure that the process goes smoothly.
 

What to do 60-90 days out

1. Check your insurance contracts. The Centers for Medicare & Medicaid Services requires physicians to notify them 90 days after deciding to retire or withdraw from Medicare or Medicaid. Other payers may also require 90 days’ notice to terminate their contracts.

You’ll also need to provide payers with a forwarding address for sending payments after the office closes, and notify your malpractice insurance carrier and any other contracted insurance carriers such as workers’ compensation or employee benefit plans.

2. Buy “tail” coverage. Doctors can be sued for malpractice years after they close their practice so this provides coverage against claims reported after the liability policy expires.

3. Check your hospital contracts. Most hospitals where you have privileges require 90 days’ notice that you are closing the practice.

4. Arrange for safe storage of medical records. If you are selling your practice to another physician, that doctor can take charge of them, as long as you obtain a patient’s consent to transfer the medical records, said Ms. Phairas. Otherwise, the practice is required to make someone the guardian of the records after the practice closes, said Mr. Zetter. This allows patients at a later date to obtain copies of their records at a cost.

“This usually means printing all the records to PDF to be retained; otherwise, doctors have to continue to pay the license fee for the EMR software to access the records, and no practice is going to continue to pay this indefinitely,” said Mr. Zetter.

Check with your malpractice insurance carrier for how long they require medical records to be retained, which may vary for adult and pediatric records.

Ms. Phairas also advises doctors to keep their original records. “The biggest mistake doctors can make is to give patients all their records. Your chart is your best defense weapon in a liability claim.”
 

What to do 30-60 days out

5. Tell your staff. They should not hear that you’re retiring or leaving the practice from other people, said Ms. Phairas. But timing is important. “If you notify them too soon, they may look for another job. I recommend telling them about 45 days out and just before you notify patients, although you may want to tell the office manager sooner.”

Doctors may need help closing the practice and should consider offering the employees a severance bonus to stay until the end, said Ms. Phairas. If they do leave sooner, then you can hire temporary staff.

6. Notify patients to avoid any claims of abandonment. You should notify all active patients, which, depending on your state, can be any patient the physician has treated sometime in the past 12-36 months.

Some state laws require the notice to be published as an advertisement in the local newspaper and will say how far in advance it needs to be published and how long the ad needs to run. Notification also should be posted throughout the practice, and patients who call or visit should be given oral reminders.

“Your biggest expense will be mailing a letter to all patients,” said Mr. Zetter. The letter should include:

• The date of closing.
• The name(s) of the physicians taking over the practice (if applicable).
• Local physicians who would be willing to accept new patients.
• Instructions for how patients can obtain or transfer medical records (with a deadline for submitting record requests).
• How to contact the practice if patients and families have any concerns about the closing.

7. Notify your professional associations. These include your state medical board, credentialing organizations, and professional memberships. It’s critical to renew your license even if you plan to practice in other states. He recalled that one doctor let his license lapse and the medical board notified Medicaid that he was no longer licensed. “CMS went after him because he didn’t notify them that he was no longer operating in Washington. CMS shut him down in every state/territory. This interventional radiologist spent 3 years with two attorneys to get it resolved,” said Mr. Zetter.

8. Terminate any leases with landlords or try to negotiate renting the office space on a month-to-month basis until you close or sell, suggests Ms. Phairas. If the practice owns the space, the partners will need to decide if the space will be sold or leased to a new business.
 

What to do 30 days out

9. Notify referring physicians of when you plan to close your practice so they don’t send new patients after that date.

10. Send a letter to the Drug Enforcement Agency to deactivate your license if you plan not to write another prescription and after you have safely disposed of prescription drugs following the federal guidelines. Destroy all prescription pads and contact drug representatives to determine what to do with unused samples, if needed.

11. Notify all vendors. Inform medical suppliers, office suppliers, collection agencies, laundry services, housekeeping services, hazardous waste disposal services, and any other vendors. Make sure to request a final statement from them so you can close out your accounts.

12. Process your accounts receivable to collect money owed to you. Consider employing a collection agency or staff member to reconcile accounts after the practice has closed.

Mr. Zetter also suggested retaining a certified accountant to handle the expenses for shutting down the business and to handle your future tax returns. “If you shut down the practice in 2023, you will still have to file a tax return for that year in 2024,” he said.

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

America’s most popular oral nasal decongestant, phenylephrine, was deemed ineffective by a Food and Drug Administration panel in a unanimous vote on Sept. 12.

The Nonprescription Drug Advisory Committee discussed the efficacy and pharmacokinetic data for phenylephrine. The committee’s next move is to determine if the drug’s status as Generally Recognized as Safe and Effective should be revoked. This would mean manufacturers would have to come up with new formulations, or products containing the drug would be removed from store shelves. NDAC did not disclose a timeline for assessing GRASE status.

A version of this article appeared on Medscape.com.

America’s most popular oral nasal decongestant, phenylephrine, was deemed ineffective by a Food and Drug Administration panel in a unanimous vote on Sept. 12.

The Nonprescription Drug Advisory Committee discussed the efficacy and pharmacokinetic data for phenylephrine. The committee’s next move is to determine if the drug’s status as Generally Recognized as Safe and Effective should be revoked. This would mean manufacturers would have to come up with new formulations, or products containing the drug would be removed from store shelves. NDAC did not disclose a timeline for assessing GRASE status.

A version of this article appeared on Medscape.com.

America’s most popular oral nasal decongestant, phenylephrine, was deemed ineffective by a Food and Drug Administration panel in a unanimous vote on Sept. 12.

The Nonprescription Drug Advisory Committee discussed the efficacy and pharmacokinetic data for phenylephrine. The committee’s next move is to determine if the drug’s status as Generally Recognized as Safe and Effective should be revoked. This would mean manufacturers would have to come up with new formulations, or products containing the drug would be removed from store shelves. NDAC did not disclose a timeline for assessing GRASE status.

A version of this article appeared on Medscape.com.

Recorded Aug. 28, 2023. This transcript has been edited for clarity.
 

John M. Mandrola, MD: I’m here at the European Society of Cardiology meeting, and I’m very excited to have two colleagues whom I met at the Western Atrial Fibrillation Symposium (Western AFib) and who presented the CASTLE-HTx study. This is Christian Sohns and Philipp Sommer, and the CASTLE-HTx study is very exciting.

Before I get into that, I really want to introduce the concept of atrial fibrillation in heart failure. I like to say that there are two big populations of patients with atrial fibrillation, and the vast majority can be treated slowly with reassurance and education. There is a group of patients who have heart failure who, when they develop atrial fibrillation, can degenerate rapidly. The CASTLE-HTx study looked at catheter ablation versus medical therapy in patients with advanced heart failure.

Christian, why don’t you tell us the top-line results and what you found.
 

CASTLE-HTx key findings

Christian Sohns, MD, PhD: Thanks, first of all, for mentioning this special cohort of patients in end-stage heart failure, which is very important. The endpoint of the study was a composite of death from any cause or left ventricular assist device (LVAD) implantation and heart transplantation. These are very hard, strong clinical endpoints, not the rate of rehospitalization or something like that.

Catheter ablation was superior to medical therapy alone in terms of this composite endpoint. That was driven by cardiovascular death and all-cause mortality, which highlights the fact that you should always consider atrial fibrillation ablation in the end-stage heart failure cohort. The findings were driven by the fact that we saw left ventricular reverse remodeling and the reduction of atrial fibrillation in these patients.

Dr. Mandrola: Tell me about how it came about. It was conducted at your center. Who were these patients?

Philipp Sommer, MD: As one of the biggest centers for heart transplantations all over Europe, with roughly 100 transplants per year, we had many patients being referred to our center with the questions of whether those patients are eligible for a heart transplantation. Not all of the patients in our study were listed for a transplant, but all of them were admitted in that end-stage heart failure status to evaluate their eligibility for transplant.

If we look at the baseline data of those patients, they had an ejection fraction of 29%. They had a 6-minute walk test as a functional capacity parameter of around 300 m. Approximately two thirds of them were New York Heart Association class III and IV, which is significantly worse than what we saw in the previous studies dealing with heart failure patients.

I think overall, if you also look at NT-proBNP levels, this is a really sick patient population where some people might doubt if they should admit and refer those patients for an ablation procedure. Therefore, it’s really interesting and fascinating to see the results.

Dr. Mandrola: I did read in the manuscript, and I heard from you, that these were recruited as outpatients. So they were stable outpatients who were referred to the center for consideration of an LVAD or transplant?

Dr. Sohns: The definition of stability is very difficult in these patients because they have hospital stays, they have a history of drug therapy, and they have a history of interventions also behind them – not atrial fibrillation ablation, but others. I think these patients are referred because the referring physicians are done with the case. They can no longer offer any option to the patients other than surgical treatment, assist device, pump implantation, or transplantation.

If you look at the guidelines, they do not comment on atrial fibrillation ablation in this cohort of patients. Also, they have different recommendations between the American societies and the European societies regarding what is end-stage heart failure and how to treat these patients. Therefore, it was a big benefit of CASTLE-HTx that we randomized a cohort of patients with advanced end-stage heart failure.
 

How can AFib ablation have such big, early effects?

Dr. Mandrola: These are very clinically significant findings, with large effect sizes and very early separation of the Kaplan-Meier curves. How do you explain how dramatic an effect that is, and how early of an effect?

Dr. Sommer: That’s one of the key questions at the end of the day. I think our job basically was to provide the data and to ensure that the data are clean and that it’s all perfectly done. The interpretation of these data is really kind of difficult, although we do not have the 100% perfect and obvious explanation why the curves separated so early. Our view on that is that we are talking about a pretty fragile patient population, so little differences like having a tachyarrhythmia of 110 day in, day out or being in sinus rhythm of 60 can make a huge difference. That’s obviously pretty early.

The one that remains in tachyarrhythmia will deteriorate and will require an LVAD after a couple of months, and the one that you may keep in sinus rhythm, even with reduced atrial fibrillation burden – not zero, but reduced atrial fibrillation burden – and improved LV function, all of a sudden this patient will still remain on a low level of being stable, but he or she will remain stable and will not require any surgical interventions for the next 1.5-2 years. If we can manage to do this, just postponing the natural cause of the disease, I think that is a great benefit for the patient.

Dr. Mandrola: One of the things that comes up in our center is that I look at some of these patients and think, there’s no way I can put this patient under general anesthetic and do all of this. Your ablation procedure wasn’t that extensive, was it?

Dr. Sohns: On the one hand, no. On the other hand, yes. You need to take into consideration that it has been performed by experienced physicians with experience in heart failure treatment and atrial fibrillation in heart transplantation centers, though it›s not sure that we can transfer these results one-to-one to all other centers in the world.

It is very clear that we have almost no major complications in these patients. We were able to do these ablation procedures without general anesthesia. We have 60% of patients who had pulmonary vein isolation only and 40% of patients who have PVI and additional therapy. We have a procedure duration of almost 90 minutes during radiofrequency ablation.

We have different categories. When you talk about the different patient cohorts, we also see different stages of myocardial tissue damage, which will be part of another publication for sure. It is, in part, surprising how normal some of the atria were despite having a volume of 180 mL, but they had no fibrosis. That was very interesting.

Dr. Mandrola: How did the persistent vs paroxysmal atrial fibrillation sort out? Were these mostly patients with persistent atrial fibrillation?

Dr. Sommer: Two-thirds were persistent. It would be expected in this patient population that you would not find so many paroxysmal cases. I think it›s very important what Christian was just mentioning that when we discussed the trial design, we were anticipating problems with the sedation, for example. With the follow-up of those procedures, would they decompensate because of the fluid that you have to deliver during such a procedure.

We were quite surprised at the end of the day that the procedures were quite straightforward. Fortunately, we had no major complications. I think there were four complications in the 100 ablated patients. I think we were really positive about how the procedures turned out.

I should mention that one of the exclusion criteria was a left atrial diameter of about 60 mm. The huge ones may be very diseased, and maybe the hopeless ones were excluded from the study. Below 60 mm, we did the ablation.
 

Rhythm control

Dr. Mandrola: One of my colleagues, who is even more skeptical than me, wanted me to ask you, why wouldn’t you take a patient with persistent atrial fibrillation who had heart failure and just cardiovert and use amiodarone and try and maintain sinus rhythm that way?

Dr. Sohns: It is important to mention that 50% of the patients have already had amiodarone before they were randomized and enrolled for the trial. It might bring you a couple of minutes or a couple of hours [of relief], but the patients would get recurrence.

It was very interesting also, and this is in line with the data from Jason Andrade, who demonstrated that we were able to reduce the percentage of patients with persistent atrial fibrillation to paroxysmal. We did a down-staging of the underlying disease. This is not possible with cardioversion or drugs, for example.

Dr. Sommer: What I really like about that question and that comment is the idea that rhythm control in this subset of patients obviously has a role and an importance. It may be a cardioversion initially, giving amiodarone if they didn’t have that before, and you can keep the patient in sinus rhythm with this therapy, I think we’re reaching the same goal.

I think the critical point to get into the mind of physicians who treat heart failure is that sinus rhythm is beneficial, however you get there. Ablation, of course, as in other studies, is the most powerful tool to get there. Cardioversion can be a really good thing to do; you just have to think about it and consider it.

Dr. Mandrola: I do want to say to everybody that there is a tension sometimes between the heart failure community and the electrophysiology community. I think the ideal situation is that we work together, because I think that we can help with the maintenance of sinus rhythm. The control group mortality at 1 year was 20%, and I’ve heard people say that that’s not advanced heart failure. Advanced heart failure patients have much higher mortality than that. My colleague who is a heart failure specialist was criticizing a selection bias in picking the best patients. How would you answer that?

Dr. Sohns: There are data available from Eurotransplant, for example, that the waiting list mortality is 18%, so I think we are almost in line with this 20% mortality in this conservative group. You cannot generalize it. All these patients have different histories. We have 60% dilated cardiomyopathy and 40% ischemic cardiomyopathy. I think it is a very representative group in contrast to your friend who suggests that it is not.

Dr. Sommer: What I like about the discussion is that some approach us to say that the mortality in the control group is much too high – like, what are you doing with those patients that you create so many endpoints? Then others say that it’s not high enough because that is not end-stage heart failure. Come on! We have a patient cohort that is very well described and very well characterized.

If the label is end-stage heart failure, advanced heart failure, or whatever, they are sicker than the patients that we had in earlier trials. The patients that we treated were mostly excluded from all other trials. We opened the door. We found a clear result. I think everyone can see whatever you like to see.

Dr. Mandrola: What would your take-home message be after having done this trial design, the trial was conducted in your single center, and you come up with these amazing results? What would your message be to the whole community?

Dr. Sohns: Taking into consideration how severely sick these patients are, I can just repeat it: They are one step away from death, more or less, or from surgical intervention that can prolong their life. You should also consider that there are options like atrial fibrillation ablation that can buy time, postpone the natural course, or even in some patients replace the destination therapy. Therefore, in my opinion the next guidelines should recommend that every patient should carefully be checked for sinus rhythm before bringing these patients into the environment of transplantation.

Dr. Sommer: My interpretation is that we have to try to bring into physicians’ minds that besides a well-established and well-documented effect of drug therapy with the fabulous four, we may now have the fabulous five, including an ablation option for patients with atrial fibrillation.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. Dr. Sohns is deputy director of the Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany. Dr. Sommer is professor of cardiology at the Heart and Diabetes Center NRW. Dr. Mandrola reported no conflicts of interest. Dr. Sohns reported receiving research funding from Else Kröner–Fresenius–Stiftung. Dr. Sommer reported consulting with Abbott, Biosense Webster, Boston Scientific, and Medtronic USA.


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

Recorded Aug. 28, 2023. This transcript has been edited for clarity.
 

John M. Mandrola, MD: I’m here at the European Society of Cardiology meeting, and I’m very excited to have two colleagues whom I met at the Western Atrial Fibrillation Symposium (Western AFib) and who presented the CASTLE-HTx study. This is Christian Sohns and Philipp Sommer, and the CASTLE-HTx study is very exciting.

Before I get into that, I really want to introduce the concept of atrial fibrillation in heart failure. I like to say that there are two big populations of patients with atrial fibrillation, and the vast majority can be treated slowly with reassurance and education. There is a group of patients who have heart failure who, when they develop atrial fibrillation, can degenerate rapidly. The CASTLE-HTx study looked at catheter ablation versus medical therapy in patients with advanced heart failure.

Christian, why don’t you tell us the top-line results and what you found.
 

CASTLE-HTx key findings

Christian Sohns, MD, PhD: Thanks, first of all, for mentioning this special cohort of patients in end-stage heart failure, which is very important. The endpoint of the study was a composite of death from any cause or left ventricular assist device (LVAD) implantation and heart transplantation. These are very hard, strong clinical endpoints, not the rate of rehospitalization or something like that.

Catheter ablation was superior to medical therapy alone in terms of this composite endpoint. That was driven by cardiovascular death and all-cause mortality, which highlights the fact that you should always consider atrial fibrillation ablation in the end-stage heart failure cohort. The findings were driven by the fact that we saw left ventricular reverse remodeling and the reduction of atrial fibrillation in these patients.

Dr. Mandrola: Tell me about how it came about. It was conducted at your center. Who were these patients?

Philipp Sommer, MD: As one of the biggest centers for heart transplantations all over Europe, with roughly 100 transplants per year, we had many patients being referred to our center with the questions of whether those patients are eligible for a heart transplantation. Not all of the patients in our study were listed for a transplant, but all of them were admitted in that end-stage heart failure status to evaluate their eligibility for transplant.

If we look at the baseline data of those patients, they had an ejection fraction of 29%. They had a 6-minute walk test as a functional capacity parameter of around 300 m. Approximately two thirds of them were New York Heart Association class III and IV, which is significantly worse than what we saw in the previous studies dealing with heart failure patients.

I think overall, if you also look at NT-proBNP levels, this is a really sick patient population where some people might doubt if they should admit and refer those patients for an ablation procedure. Therefore, it’s really interesting and fascinating to see the results.

Dr. Mandrola: I did read in the manuscript, and I heard from you, that these were recruited as outpatients. So they were stable outpatients who were referred to the center for consideration of an LVAD or transplant?

Dr. Sohns: The definition of stability is very difficult in these patients because they have hospital stays, they have a history of drug therapy, and they have a history of interventions also behind them – not atrial fibrillation ablation, but others. I think these patients are referred because the referring physicians are done with the case. They can no longer offer any option to the patients other than surgical treatment, assist device, pump implantation, or transplantation.

If you look at the guidelines, they do not comment on atrial fibrillation ablation in this cohort of patients. Also, they have different recommendations between the American societies and the European societies regarding what is end-stage heart failure and how to treat these patients. Therefore, it was a big benefit of CASTLE-HTx that we randomized a cohort of patients with advanced end-stage heart failure.
 

How can AFib ablation have such big, early effects?

Dr. Mandrola: These are very clinically significant findings, with large effect sizes and very early separation of the Kaplan-Meier curves. How do you explain how dramatic an effect that is, and how early of an effect?

Dr. Sommer: That’s one of the key questions at the end of the day. I think our job basically was to provide the data and to ensure that the data are clean and that it’s all perfectly done. The interpretation of these data is really kind of difficult, although we do not have the 100% perfect and obvious explanation why the curves separated so early. Our view on that is that we are talking about a pretty fragile patient population, so little differences like having a tachyarrhythmia of 110 day in, day out or being in sinus rhythm of 60 can make a huge difference. That’s obviously pretty early.

The one that remains in tachyarrhythmia will deteriorate and will require an LVAD after a couple of months, and the one that you may keep in sinus rhythm, even with reduced atrial fibrillation burden – not zero, but reduced atrial fibrillation burden – and improved LV function, all of a sudden this patient will still remain on a low level of being stable, but he or she will remain stable and will not require any surgical interventions for the next 1.5-2 years. If we can manage to do this, just postponing the natural cause of the disease, I think that is a great benefit for the patient.

Dr. Mandrola: One of the things that comes up in our center is that I look at some of these patients and think, there’s no way I can put this patient under general anesthetic and do all of this. Your ablation procedure wasn’t that extensive, was it?

Dr. Sohns: On the one hand, no. On the other hand, yes. You need to take into consideration that it has been performed by experienced physicians with experience in heart failure treatment and atrial fibrillation in heart transplantation centers, though it›s not sure that we can transfer these results one-to-one to all other centers in the world.

It is very clear that we have almost no major complications in these patients. We were able to do these ablation procedures without general anesthesia. We have 60% of patients who had pulmonary vein isolation only and 40% of patients who have PVI and additional therapy. We have a procedure duration of almost 90 minutes during radiofrequency ablation.

We have different categories. When you talk about the different patient cohorts, we also see different stages of myocardial tissue damage, which will be part of another publication for sure. It is, in part, surprising how normal some of the atria were despite having a volume of 180 mL, but they had no fibrosis. That was very interesting.

Dr. Mandrola: How did the persistent vs paroxysmal atrial fibrillation sort out? Were these mostly patients with persistent atrial fibrillation?

Dr. Sommer: Two-thirds were persistent. It would be expected in this patient population that you would not find so many paroxysmal cases. I think it›s very important what Christian was just mentioning that when we discussed the trial design, we were anticipating problems with the sedation, for example. With the follow-up of those procedures, would they decompensate because of the fluid that you have to deliver during such a procedure.

We were quite surprised at the end of the day that the procedures were quite straightforward. Fortunately, we had no major complications. I think there were four complications in the 100 ablated patients. I think we were really positive about how the procedures turned out.

I should mention that one of the exclusion criteria was a left atrial diameter of about 60 mm. The huge ones may be very diseased, and maybe the hopeless ones were excluded from the study. Below 60 mm, we did the ablation.
 

Rhythm control

Dr. Mandrola: One of my colleagues, who is even more skeptical than me, wanted me to ask you, why wouldn’t you take a patient with persistent atrial fibrillation who had heart failure and just cardiovert and use amiodarone and try and maintain sinus rhythm that way?

Dr. Sohns: It is important to mention that 50% of the patients have already had amiodarone before they were randomized and enrolled for the trial. It might bring you a couple of minutes or a couple of hours [of relief], but the patients would get recurrence.

It was very interesting also, and this is in line with the data from Jason Andrade, who demonstrated that we were able to reduce the percentage of patients with persistent atrial fibrillation to paroxysmal. We did a down-staging of the underlying disease. This is not possible with cardioversion or drugs, for example.

Dr. Sommer: What I really like about that question and that comment is the idea that rhythm control in this subset of patients obviously has a role and an importance. It may be a cardioversion initially, giving amiodarone if they didn’t have that before, and you can keep the patient in sinus rhythm with this therapy, I think we’re reaching the same goal.

I think the critical point to get into the mind of physicians who treat heart failure is that sinus rhythm is beneficial, however you get there. Ablation, of course, as in other studies, is the most powerful tool to get there. Cardioversion can be a really good thing to do; you just have to think about it and consider it.

Dr. Mandrola: I do want to say to everybody that there is a tension sometimes between the heart failure community and the electrophysiology community. I think the ideal situation is that we work together, because I think that we can help with the maintenance of sinus rhythm. The control group mortality at 1 year was 20%, and I’ve heard people say that that’s not advanced heart failure. Advanced heart failure patients have much higher mortality than that. My colleague who is a heart failure specialist was criticizing a selection bias in picking the best patients. How would you answer that?

Dr. Sohns: There are data available from Eurotransplant, for example, that the waiting list mortality is 18%, so I think we are almost in line with this 20% mortality in this conservative group. You cannot generalize it. All these patients have different histories. We have 60% dilated cardiomyopathy and 40% ischemic cardiomyopathy. I think it is a very representative group in contrast to your friend who suggests that it is not.

Dr. Sommer: What I like about the discussion is that some approach us to say that the mortality in the control group is much too high – like, what are you doing with those patients that you create so many endpoints? Then others say that it’s not high enough because that is not end-stage heart failure. Come on! We have a patient cohort that is very well described and very well characterized.

If the label is end-stage heart failure, advanced heart failure, or whatever, they are sicker than the patients that we had in earlier trials. The patients that we treated were mostly excluded from all other trials. We opened the door. We found a clear result. I think everyone can see whatever you like to see.

Dr. Mandrola: What would your take-home message be after having done this trial design, the trial was conducted in your single center, and you come up with these amazing results? What would your message be to the whole community?

Dr. Sohns: Taking into consideration how severely sick these patients are, I can just repeat it: They are one step away from death, more or less, or from surgical intervention that can prolong their life. You should also consider that there are options like atrial fibrillation ablation that can buy time, postpone the natural course, or even in some patients replace the destination therapy. Therefore, in my opinion the next guidelines should recommend that every patient should carefully be checked for sinus rhythm before bringing these patients into the environment of transplantation.

Dr. Sommer: My interpretation is that we have to try to bring into physicians’ minds that besides a well-established and well-documented effect of drug therapy with the fabulous four, we may now have the fabulous five, including an ablation option for patients with atrial fibrillation.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. Dr. Sohns is deputy director of the Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany. Dr. Sommer is professor of cardiology at the Heart and Diabetes Center NRW. Dr. Mandrola reported no conflicts of interest. Dr. Sohns reported receiving research funding from Else Kröner–Fresenius–Stiftung. Dr. Sommer reported consulting with Abbott, Biosense Webster, Boston Scientific, and Medtronic USA.


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

Recorded Aug. 28, 2023. This transcript has been edited for clarity.
 

John M. Mandrola, MD: I’m here at the European Society of Cardiology meeting, and I’m very excited to have two colleagues whom I met at the Western Atrial Fibrillation Symposium (Western AFib) and who presented the CASTLE-HTx study. This is Christian Sohns and Philipp Sommer, and the CASTLE-HTx study is very exciting.

Before I get into that, I really want to introduce the concept of atrial fibrillation in heart failure. I like to say that there are two big populations of patients with atrial fibrillation, and the vast majority can be treated slowly with reassurance and education. There is a group of patients who have heart failure who, when they develop atrial fibrillation, can degenerate rapidly. The CASTLE-HTx study looked at catheter ablation versus medical therapy in patients with advanced heart failure.

Christian, why don’t you tell us the top-line results and what you found.
 

CASTLE-HTx key findings

Christian Sohns, MD, PhD: Thanks, first of all, for mentioning this special cohort of patients in end-stage heart failure, which is very important. The endpoint of the study was a composite of death from any cause or left ventricular assist device (LVAD) implantation and heart transplantation. These are very hard, strong clinical endpoints, not the rate of rehospitalization or something like that.

Catheter ablation was superior to medical therapy alone in terms of this composite endpoint. That was driven by cardiovascular death and all-cause mortality, which highlights the fact that you should always consider atrial fibrillation ablation in the end-stage heart failure cohort. The findings were driven by the fact that we saw left ventricular reverse remodeling and the reduction of atrial fibrillation in these patients.

Dr. Mandrola: Tell me about how it came about. It was conducted at your center. Who were these patients?

Philipp Sommer, MD: As one of the biggest centers for heart transplantations all over Europe, with roughly 100 transplants per year, we had many patients being referred to our center with the questions of whether those patients are eligible for a heart transplantation. Not all of the patients in our study were listed for a transplant, but all of them were admitted in that end-stage heart failure status to evaluate their eligibility for transplant.

If we look at the baseline data of those patients, they had an ejection fraction of 29%. They had a 6-minute walk test as a functional capacity parameter of around 300 m. Approximately two thirds of them were New York Heart Association class III and IV, which is significantly worse than what we saw in the previous studies dealing with heart failure patients.

I think overall, if you also look at NT-proBNP levels, this is a really sick patient population where some people might doubt if they should admit and refer those patients for an ablation procedure. Therefore, it’s really interesting and fascinating to see the results.

Dr. Mandrola: I did read in the manuscript, and I heard from you, that these were recruited as outpatients. So they were stable outpatients who were referred to the center for consideration of an LVAD or transplant?

Dr. Sohns: The definition of stability is very difficult in these patients because they have hospital stays, they have a history of drug therapy, and they have a history of interventions also behind them – not atrial fibrillation ablation, but others. I think these patients are referred because the referring physicians are done with the case. They can no longer offer any option to the patients other than surgical treatment, assist device, pump implantation, or transplantation.

If you look at the guidelines, they do not comment on atrial fibrillation ablation in this cohort of patients. Also, they have different recommendations between the American societies and the European societies regarding what is end-stage heart failure and how to treat these patients. Therefore, it was a big benefit of CASTLE-HTx that we randomized a cohort of patients with advanced end-stage heart failure.
 

How can AFib ablation have such big, early effects?

Dr. Mandrola: These are very clinically significant findings, with large effect sizes and very early separation of the Kaplan-Meier curves. How do you explain how dramatic an effect that is, and how early of an effect?

Dr. Sommer: That’s one of the key questions at the end of the day. I think our job basically was to provide the data and to ensure that the data are clean and that it’s all perfectly done. The interpretation of these data is really kind of difficult, although we do not have the 100% perfect and obvious explanation why the curves separated so early. Our view on that is that we are talking about a pretty fragile patient population, so little differences like having a tachyarrhythmia of 110 day in, day out or being in sinus rhythm of 60 can make a huge difference. That’s obviously pretty early.

The one that remains in tachyarrhythmia will deteriorate and will require an LVAD after a couple of months, and the one that you may keep in sinus rhythm, even with reduced atrial fibrillation burden – not zero, but reduced atrial fibrillation burden – and improved LV function, all of a sudden this patient will still remain on a low level of being stable, but he or she will remain stable and will not require any surgical interventions for the next 1.5-2 years. If we can manage to do this, just postponing the natural cause of the disease, I think that is a great benefit for the patient.

Dr. Mandrola: One of the things that comes up in our center is that I look at some of these patients and think, there’s no way I can put this patient under general anesthetic and do all of this. Your ablation procedure wasn’t that extensive, was it?

Dr. Sohns: On the one hand, no. On the other hand, yes. You need to take into consideration that it has been performed by experienced physicians with experience in heart failure treatment and atrial fibrillation in heart transplantation centers, though it›s not sure that we can transfer these results one-to-one to all other centers in the world.

It is very clear that we have almost no major complications in these patients. We were able to do these ablation procedures without general anesthesia. We have 60% of patients who had pulmonary vein isolation only and 40% of patients who have PVI and additional therapy. We have a procedure duration of almost 90 minutes during radiofrequency ablation.

We have different categories. When you talk about the different patient cohorts, we also see different stages of myocardial tissue damage, which will be part of another publication for sure. It is, in part, surprising how normal some of the atria were despite having a volume of 180 mL, but they had no fibrosis. That was very interesting.

Dr. Mandrola: How did the persistent vs paroxysmal atrial fibrillation sort out? Were these mostly patients with persistent atrial fibrillation?

Dr. Sommer: Two-thirds were persistent. It would be expected in this patient population that you would not find so many paroxysmal cases. I think it›s very important what Christian was just mentioning that when we discussed the trial design, we were anticipating problems with the sedation, for example. With the follow-up of those procedures, would they decompensate because of the fluid that you have to deliver during such a procedure.

We were quite surprised at the end of the day that the procedures were quite straightforward. Fortunately, we had no major complications. I think there were four complications in the 100 ablated patients. I think we were really positive about how the procedures turned out.

I should mention that one of the exclusion criteria was a left atrial diameter of about 60 mm. The huge ones may be very diseased, and maybe the hopeless ones were excluded from the study. Below 60 mm, we did the ablation.
 

Rhythm control

Dr. Mandrola: One of my colleagues, who is even more skeptical than me, wanted me to ask you, why wouldn’t you take a patient with persistent atrial fibrillation who had heart failure and just cardiovert and use amiodarone and try and maintain sinus rhythm that way?

Dr. Sohns: It is important to mention that 50% of the patients have already had amiodarone before they were randomized and enrolled for the trial. It might bring you a couple of minutes or a couple of hours [of relief], but the patients would get recurrence.

It was very interesting also, and this is in line with the data from Jason Andrade, who demonstrated that we were able to reduce the percentage of patients with persistent atrial fibrillation to paroxysmal. We did a down-staging of the underlying disease. This is not possible with cardioversion or drugs, for example.

Dr. Sommer: What I really like about that question and that comment is the idea that rhythm control in this subset of patients obviously has a role and an importance. It may be a cardioversion initially, giving amiodarone if they didn’t have that before, and you can keep the patient in sinus rhythm with this therapy, I think we’re reaching the same goal.

I think the critical point to get into the mind of physicians who treat heart failure is that sinus rhythm is beneficial, however you get there. Ablation, of course, as in other studies, is the most powerful tool to get there. Cardioversion can be a really good thing to do; you just have to think about it and consider it.

Dr. Mandrola: I do want to say to everybody that there is a tension sometimes between the heart failure community and the electrophysiology community. I think the ideal situation is that we work together, because I think that we can help with the maintenance of sinus rhythm. The control group mortality at 1 year was 20%, and I’ve heard people say that that’s not advanced heart failure. Advanced heart failure patients have much higher mortality than that. My colleague who is a heart failure specialist was criticizing a selection bias in picking the best patients. How would you answer that?

Dr. Sohns: There are data available from Eurotransplant, for example, that the waiting list mortality is 18%, so I think we are almost in line with this 20% mortality in this conservative group. You cannot generalize it. All these patients have different histories. We have 60% dilated cardiomyopathy and 40% ischemic cardiomyopathy. I think it is a very representative group in contrast to your friend who suggests that it is not.

Dr. Sommer: What I like about the discussion is that some approach us to say that the mortality in the control group is much too high – like, what are you doing with those patients that you create so many endpoints? Then others say that it’s not high enough because that is not end-stage heart failure. Come on! We have a patient cohort that is very well described and very well characterized.

If the label is end-stage heart failure, advanced heart failure, or whatever, they are sicker than the patients that we had in earlier trials. The patients that we treated were mostly excluded from all other trials. We opened the door. We found a clear result. I think everyone can see whatever you like to see.

Dr. Mandrola: What would your take-home message be after having done this trial design, the trial was conducted in your single center, and you come up with these amazing results? What would your message be to the whole community?

Dr. Sohns: Taking into consideration how severely sick these patients are, I can just repeat it: They are one step away from death, more or less, or from surgical intervention that can prolong their life. You should also consider that there are options like atrial fibrillation ablation that can buy time, postpone the natural course, or even in some patients replace the destination therapy. Therefore, in my opinion the next guidelines should recommend that every patient should carefully be checked for sinus rhythm before bringing these patients into the environment of transplantation.

Dr. Sommer: My interpretation is that we have to try to bring into physicians’ minds that besides a well-established and well-documented effect of drug therapy with the fabulous four, we may now have the fabulous five, including an ablation option for patients with atrial fibrillation.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. Dr. Sohns is deputy director of the Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany. Dr. Sommer is professor of cardiology at the Heart and Diabetes Center NRW. Dr. Mandrola reported no conflicts of interest. Dr. Sohns reported receiving research funding from Else Kröner–Fresenius–Stiftung. Dr. Sommer reported consulting with Abbott, Biosense Webster, Boston Scientific, and Medtronic USA.


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

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

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

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

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

This transcript has been edited for clarity.

Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue reporting for Medscape. Joining me today is Dr. Sahil Parikh, who’s a cardiologist and an interventionalist at Columbia University. He’s an associate professor of medicine.

We’ll be discussing two interesting trials that were presented at the ESC Congress here in Amsterdam. They do have the potential to be very practice-changing, so I think it’s worth talking about.
 

The FIRE trial

The first trial we’ll be talking about is the FIRE trial. Perhaps setting the stage, Sahil, I’d love to get your thoughts. We’ve had data in this space to suggest that, for patients with STEMI [ST-segment elevation myocardial infarction], a strategy of complete revascularization – and not only treating the culprit lesion but also treating additional lesions – may be of benefit. Where does that lead us in terms of what we didn’t know?

Sahil A. Parikh, MD: I think that the practice has moved, at least in the United States, over the past two decades, from staging percutaneous coronary interventions over 30 days from index to intervention to now trying to do patients in the same hospitalization whenever possible to achieve complete revascularization.

I think these data support not only that complete revascularization is compulsory now in these patients, but also doing it sooner rather than later, and that the benefit applies to most of the patients that we see in clinical practice. In the earlier data, the patients were relatively youthful – under Medicare age, less than 65 – and now this dataset has a median age of 80. This is more like the real-world clinical practice that most of us are encountering, and it extends the benefit, perhaps, greater than we’ve ever seen before.

O’Donoghue: The FIRE trial is interesting. As you say, it enrolled patients who were over the age of 75, where I think that some proceduralists are probably a little bit hesitant to think about complete revascularization due to concerns about any additional contrast load on their kidneys and other types of comorbidities. Of course, for any trial, there’s going to be some patient selection.

I think it’s very reassuring that even in this older patient group, a strategy of treating all the lesions – and not only in STEMI but also in non-STEMI patients – reduced cardiovascular events and mortality. I was really quite impressed by the mortality benefit.

Parikh: The mortality curve is almost surprising to me. On the other hand, it emboldens us now that we can treat these patients more completely and earlier in their clinical presentation. Certainly, we worried about contrast exposure and the duration of procedures in this older population, but it seems that the benefit that’s derived, which we saw in younger patients where we had a natural inclination to be more aggressive, extends also to this older population.
 

MULTISTARS AMI

O’Donoghue: To the question of timing, as you mentioned, prior to this, we had a study presented earlier this year, the BIOVASC trial, which also was suggestive that maybe earlier complete revascularization was better. But it wasn’t a significant difference, at least for the primary outcome. Now we have MULTISTARS AMI, which is very supportive of what we saw earlier this year, suggesting that complete revascularization really at the time that you’re treating the culprit may be the way to go.

Parikh: All of us, as interventionalists, are circumspect about what we might do in the middle of the night versus what we would do in the light of day. Certainly it seems clear, particularly if it’s straightforward anatomy, that taking care of it in the index procedure is not only saving contrast and fluoroscopy time, but it’s also providing a clinical benefit to the patients. That’s something that will also impact how clinicians interpret these data. Previously, there was always a question about whether we should just do it in the same hospitalization or do it at the same time. I think now, increasingly, we’re emboldened to do more in the index procedure.

O’Donoghue: When you’re thinking about nonculprit lesions and which ones to treat, do you always make that determination based on physiologic guidance of some kind? Are you using instantaneous wave-free ratio? What’s your practice?

Parikh: In the acute setting, imaging is superior for at least the assessment of which is a culprit. If you see a ruptured atherothrombotic situation on optical coherence tomography, for example, that’s fairly convincing and definitive. In the absence of that physiology, we are taught to avoid in the infarct-related artery because of potential spuriously false-negative findings.

In this situation, certainly, an imaging subgroup probably would be helpful because some of the benefit is almost certainly derived from identifying the infarct-related artery by accident – in other words, doing what you thought was the nonculprit artery, which is, in fact, the culprit. I think that probably is part of this. As somebody who uses imaging in the overwhelming number of my cases, I think that imaging would be an important surrogate to this.
 

Index procedure versus staged

O’Donoghue: For the operator who is coming in to do their STEMI case at 2:00 in the morning, would these data now push you toward doing complete revascularization at that time of night, or do you think that there is wiggle room in terms of interpreting these results regarding timing, where as long as you were doing it before hospital discharge and not, let’s say, 30 days out, that you may be able to derive the same benefit? What are some of the pros and cons?

Parikh: There’s definitely a fatigue factor in the middle of the night if it’s a particularly arduous intervention for the index infarct-related artery. I think there’s a human element where it may make sense just to stop and then bring the patient back in the same hospitalization. It’s clear, though, that doing complete revascularization is better and doing it sooner is better. How soon one actually does it is a judgment call, as ever.

In our practice, we’ve been pushing ourselves to get most of the patients done in their index hospitalization. If you have a left-sided culprit, the left anterior descending artery, for example, and there’s a high-grade stenosis in the circumflex, it may make sense to take care of that in the same index procedure. If, on the other hand, it’s in the right coronary artery where you have to put a new guide in and spend more time, that may be a patient whom you stage. I think those nuances will come up as interventionalists look at the subgroup analysis data more carefully.

O’Donoghue: Those are great points, and I think they also underscore that we always need to think about what type of patient was enrolled in these studies. Certainly, if you have somebody with renal dysfunction, there might be more concern about giving them a large contrast load all in one sitting, albeit hard to know whether they do or not. But spacing that out by just a couple of days would really have a big impact.

Parikh: Very often in the STEMI patient, you don’t have the benefit of knowing the creatinine. The patient will come in immediately, if not directly from the ambulance to the cath lab, and there are no laboratories at all to work with. If the patient has never been seen in the system before, you won’t know. Again, in those situations, one may have pause, particularly if it’s an older patient. I think what’s reassuring, though, is that the data are supportive of being more aggressive earlier, and certainly this is the dataset that we were looking for.

O’Donoghue: To summarize, the two key takeaways are that, one, we now have more data to support a complete revascularization strategy and even extending that now to non-STEMI patients. Two, sooner appears to be better, so ideally, all done at the time of the index procedure. I think this is very interesting science and we’ll see how it changes practice.

Thanks for joining me today. Signing off for Medscape, this is Dr. Michelle O’Donoghue.

Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group.

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