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.

This month we are following up on our previous piece on anxiety disorders. We wrote about how these disorders are common, amenable to treatment, and often curable, but are often missed as many children suffer silently or their symptoms are mistaken for signs of other problems. We reviewed the screening instruments that can help you to catch these “quiet” illnesses. Now, we are going to offer some detail about the effective treatments for the most common anxiety disorders and how to approach getting treatment started when a screen has turned up positive. If you are interested in a deeper dive, the American Academy of Child and Adolescent Psychiatry has detailed practice parameters for the disorders discussed below.

Anxiety disorders in young children

Separation anxiety disorder, specific phobia, generalized anxiety disorder, and social phobia are the anxiety disorders that most commonly affect the youngest children. Separation anxiety disorder is the most common childhood anxiety disorder and has an average age of onset of 6 years, whereas specific phobia peaks between 5 and 8 years of age, generalized anxiety disorder peaks at 8 years old and social phobia (or social anxiety disorder) has a peak age of onset of 13 years. The first-line treatment for each disorder is cognitive-behavioral therapy (CBT), and specifically a variant called exposure and response prevention. This treatment essentially helps patients to “learn” to have a different response, not anxiety, to the triggering thought or stimulus. CBT can be very effective, curative even, but these disorders can be difficult to treat when a child’s level of anxiety exceeds their ability to engage in treatment. In these cases, treatment can be facilitated by the addition of an SSRI, which is recommended by the American Academy of Child and Adolescent Psychiatry as a second-line treatment in children aged 6-18 years. Given the anxious child’s sensitivity to some side effects (such as GI distress) starting at a low dose and titrating up slowly is the recommendation, and effective dose ranges are higher than for the treatment of mood disorders. Without treatment, these disorders may become learned over years and predict complicating anxiety, mood, and substance use disorders in adolescence and adulthood. Any treatment can be helped by the addition of parent guidance, in which parents learn how to be emotionally supportive to their anxious children without accommodating to their demands or asking them to avoid of the source of anxiety.
 

Obsessive-compulsive disorder

Mild obsessive-compulsive disorder (OCD) describes what many of us do, like double-checking we have locked our door or put our work into our briefcase. OCD as a diagnosis with substantial dysfunction has a peak onset at age 10 and again at the age of 21. Over 50% of childhood-onset OCD will have a comorbid anxiety, attention, eating, or tic disorder. Without treatment, OCD is likely to become chronic, and the symptoms (intrusive thoughts, obsessive rumination, and compulsive behaviors) interfere with social and academic function. The behavioral accommodations and avoidance of distress that mark untreated OCD interfere with the healthy development of normal stress management skills that are a critical part of early and later adolescence. First-line treatment is CBT (with exposure and response prevention) with a therapist experienced in the treatment of OCD. A detailed symptom inventory (the Children’s Yale-Brown Obsessive Compulsive Scale) is relatively simple to complete, will confirm a suspected OCD diagnosis, and will create a valuable baseline by which treatment efficacy can be assessed. For those children with moderate to severe OCD, addition of an SSRI to augment and facilitate CBT therapy is recommended. Sertraline, fluvoxamine, fluoxetine, and paroxetine have all been studied and demonstrated efficacy. Clomipramine has well-established efficacy, but its more serious side effects and poorer tolerability make SSRIs the first choice. As with other anxiety disorders, starting at very low doses and titrating upward gradually is recommended. The efficacy of medication treatments is lower in those patients who have other psychiatric illnesses occurring with OCD. Again, parent guidance can be invaluable in supporting the child and improving family well-being.

PTSD

Studies have suggested that between 15% and 45% of children and adolescents in the United States experience a traumatic event, but of those children less than 15% of girls and 6% of boys will develop PTSD in the months that follow. It is important to consider other mood and anxiety disorders in assessing youth with a trauma history who present with symptoms of anxiety and impaired function more than 1 month after the traumatic event. With a history of a traumatic event, it can be helpful to use a specific screening instrument for PTSD, such as the Child PTSD Symptoms Scale or the UCLA PTSD Reaction Index. The symptoms of other disorders (including ADHD) can mimic PTSD, and these disorders may be comorbid with mood, substance use, and eating disorders. Treatment is trauma-focused CBT, with careful use of medications to manage specific symptoms (such as nightmares). Evidence has shown that inclusion of parents in the CBT treatment results in greater reduction in both mood and behavioral symptoms than treating the children alone.

Special cases: School refusal

School refusal affects between 2% and 5% of children, and it is critical to address it promptly or else it can become entrenched and much more difficult to treat. It peaks at 6 and again at 14 years old and often comes to the attention of the pediatrician as children complain of somatic concerns that prove to have no clear cause. It is important to screen for trauma, mood, and anxiety disorders so that you might make reasonable treatment recommendations. But the critical intervention is a behavioral plan that supports the child’s prompt return to school. This requires communication with school personnel and parents to create a plan for the child’s return to school (using natural rewards like friends and trusted teachers) and staying at school (with detailed contingency planning). Parents may need help finding ways to “demagnetize” home and “remagnetize” school, such as turning off the Internet at home and not allowing a child to play sports or with friends when not attending school. Psychotherapy will be helpful for an underlying anxiety or mood disorder, and medications may also be helpful, but education and support for parents to understand how to manage the distress avoidance and rewards of school refusal are generally the critical components of an effective response to this serious problem.

Special cases: Adolescents with new anxiety symptoms

Most childhood anxiety disorders occur before puberty, but anxiety is a common symptom of mood and substance use disorders in teenagers, and often the symptom that drives help-seeking. It is important to screen teens who present with anxiety for underlying mood or substance use disorders. For example, panic disorder is relatively common in young adults, while in teenagers, panic attacks are a frequent symptom of depression or of withdrawal from regular cannabis use. If anxiety has been present and untreated since childhood, adolescents may present with complex comorbid mood and anxiety disorders and struggle with distress tolerance, social difficulties, and perfectionism. Anxiety itself is a very regular developmental feature of adolescence as this is a time of navigating peer relationships, identity, gradual separation from family, and transition to college or work. Every teen would likely benefit from advice about their sleep, exercise, use of any substances, and screen time habits.

For all of your patients with anxiety (and their parents), recognize that anxiety about being liked, making a varsity team, competing for college entrance, and becoming a young adult is expected: uncomfortable, but part of life. It’s adaptive. It helps people to stay safe, get their homework done, and avoid accidents. When people have high levels of anxiety, they can learn to identify their feelings, distinguish between facts and feelings, and learn to manage the anxiety adaptively. If anxiety causes dysfunction in major areas (school, family, friends, activities, and mood), prompt attention is required.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

This month we are following up on our previous piece on anxiety disorders. We wrote about how these disorders are common, amenable to treatment, and often curable, but are often missed as many children suffer silently or their symptoms are mistaken for signs of other problems. We reviewed the screening instruments that can help you to catch these “quiet” illnesses. Now, we are going to offer some detail about the effective treatments for the most common anxiety disorders and how to approach getting treatment started when a screen has turned up positive. If you are interested in a deeper dive, the American Academy of Child and Adolescent Psychiatry has detailed practice parameters for the disorders discussed below.

Anxiety disorders in young children

Separation anxiety disorder, specific phobia, generalized anxiety disorder, and social phobia are the anxiety disorders that most commonly affect the youngest children. Separation anxiety disorder is the most common childhood anxiety disorder and has an average age of onset of 6 years, whereas specific phobia peaks between 5 and 8 years of age, generalized anxiety disorder peaks at 8 years old and social phobia (or social anxiety disorder) has a peak age of onset of 13 years. The first-line treatment for each disorder is cognitive-behavioral therapy (CBT), and specifically a variant called exposure and response prevention. This treatment essentially helps patients to “learn” to have a different response, not anxiety, to the triggering thought or stimulus. CBT can be very effective, curative even, but these disorders can be difficult to treat when a child’s level of anxiety exceeds their ability to engage in treatment. In these cases, treatment can be facilitated by the addition of an SSRI, which is recommended by the American Academy of Child and Adolescent Psychiatry as a second-line treatment in children aged 6-18 years. Given the anxious child’s sensitivity to some side effects (such as GI distress) starting at a low dose and titrating up slowly is the recommendation, and effective dose ranges are higher than for the treatment of mood disorders. Without treatment, these disorders may become learned over years and predict complicating anxiety, mood, and substance use disorders in adolescence and adulthood. Any treatment can be helped by the addition of parent guidance, in which parents learn how to be emotionally supportive to their anxious children without accommodating to their demands or asking them to avoid of the source of anxiety.
 

Obsessive-compulsive disorder

Mild obsessive-compulsive disorder (OCD) describes what many of us do, like double-checking we have locked our door or put our work into our briefcase. OCD as a diagnosis with substantial dysfunction has a peak onset at age 10 and again at the age of 21. Over 50% of childhood-onset OCD will have a comorbid anxiety, attention, eating, or tic disorder. Without treatment, OCD is likely to become chronic, and the symptoms (intrusive thoughts, obsessive rumination, and compulsive behaviors) interfere with social and academic function. The behavioral accommodations and avoidance of distress that mark untreated OCD interfere with the healthy development of normal stress management skills that are a critical part of early and later adolescence. First-line treatment is CBT (with exposure and response prevention) with a therapist experienced in the treatment of OCD. A detailed symptom inventory (the Children’s Yale-Brown Obsessive Compulsive Scale) is relatively simple to complete, will confirm a suspected OCD diagnosis, and will create a valuable baseline by which treatment efficacy can be assessed. For those children with moderate to severe OCD, addition of an SSRI to augment and facilitate CBT therapy is recommended. Sertraline, fluvoxamine, fluoxetine, and paroxetine have all been studied and demonstrated efficacy. Clomipramine has well-established efficacy, but its more serious side effects and poorer tolerability make SSRIs the first choice. As with other anxiety disorders, starting at very low doses and titrating upward gradually is recommended. The efficacy of medication treatments is lower in those patients who have other psychiatric illnesses occurring with OCD. Again, parent guidance can be invaluable in supporting the child and improving family well-being.

PTSD

Studies have suggested that between 15% and 45% of children and adolescents in the United States experience a traumatic event, but of those children less than 15% of girls and 6% of boys will develop PTSD in the months that follow. It is important to consider other mood and anxiety disorders in assessing youth with a trauma history who present with symptoms of anxiety and impaired function more than 1 month after the traumatic event. With a history of a traumatic event, it can be helpful to use a specific screening instrument for PTSD, such as the Child PTSD Symptoms Scale or the UCLA PTSD Reaction Index. The symptoms of other disorders (including ADHD) can mimic PTSD, and these disorders may be comorbid with mood, substance use, and eating disorders. Treatment is trauma-focused CBT, with careful use of medications to manage specific symptoms (such as nightmares). Evidence has shown that inclusion of parents in the CBT treatment results in greater reduction in both mood and behavioral symptoms than treating the children alone.

Special cases: School refusal

School refusal affects between 2% and 5% of children, and it is critical to address it promptly or else it can become entrenched and much more difficult to treat. It peaks at 6 and again at 14 years old and often comes to the attention of the pediatrician as children complain of somatic concerns that prove to have no clear cause. It is important to screen for trauma, mood, and anxiety disorders so that you might make reasonable treatment recommendations. But the critical intervention is a behavioral plan that supports the child’s prompt return to school. This requires communication with school personnel and parents to create a plan for the child’s return to school (using natural rewards like friends and trusted teachers) and staying at school (with detailed contingency planning). Parents may need help finding ways to “demagnetize” home and “remagnetize” school, such as turning off the Internet at home and not allowing a child to play sports or with friends when not attending school. Psychotherapy will be helpful for an underlying anxiety or mood disorder, and medications may also be helpful, but education and support for parents to understand how to manage the distress avoidance and rewards of school refusal are generally the critical components of an effective response to this serious problem.

Special cases: Adolescents with new anxiety symptoms

Most childhood anxiety disorders occur before puberty, but anxiety is a common symptom of mood and substance use disorders in teenagers, and often the symptom that drives help-seeking. It is important to screen teens who present with anxiety for underlying mood or substance use disorders. For example, panic disorder is relatively common in young adults, while in teenagers, panic attacks are a frequent symptom of depression or of withdrawal from regular cannabis use. If anxiety has been present and untreated since childhood, adolescents may present with complex comorbid mood and anxiety disorders and struggle with distress tolerance, social difficulties, and perfectionism. Anxiety itself is a very regular developmental feature of adolescence as this is a time of navigating peer relationships, identity, gradual separation from family, and transition to college or work. Every teen would likely benefit from advice about their sleep, exercise, use of any substances, and screen time habits.

For all of your patients with anxiety (and their parents), recognize that anxiety about being liked, making a varsity team, competing for college entrance, and becoming a young adult is expected: uncomfortable, but part of life. It’s adaptive. It helps people to stay safe, get their homework done, and avoid accidents. When people have high levels of anxiety, they can learn to identify their feelings, distinguish between facts and feelings, and learn to manage the anxiety adaptively. If anxiety causes dysfunction in major areas (school, family, friends, activities, and mood), prompt attention is required.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

This month we are following up on our previous piece on anxiety disorders. We wrote about how these disorders are common, amenable to treatment, and often curable, but are often missed as many children suffer silently or their symptoms are mistaken for signs of other problems. We reviewed the screening instruments that can help you to catch these “quiet” illnesses. Now, we are going to offer some detail about the effective treatments for the most common anxiety disorders and how to approach getting treatment started when a screen has turned up positive. If you are interested in a deeper dive, the American Academy of Child and Adolescent Psychiatry has detailed practice parameters for the disorders discussed below.

Anxiety disorders in young children

Separation anxiety disorder, specific phobia, generalized anxiety disorder, and social phobia are the anxiety disorders that most commonly affect the youngest children. Separation anxiety disorder is the most common childhood anxiety disorder and has an average age of onset of 6 years, whereas specific phobia peaks between 5 and 8 years of age, generalized anxiety disorder peaks at 8 years old and social phobia (or social anxiety disorder) has a peak age of onset of 13 years. The first-line treatment for each disorder is cognitive-behavioral therapy (CBT), and specifically a variant called exposure and response prevention. This treatment essentially helps patients to “learn” to have a different response, not anxiety, to the triggering thought or stimulus. CBT can be very effective, curative even, but these disorders can be difficult to treat when a child’s level of anxiety exceeds their ability to engage in treatment. In these cases, treatment can be facilitated by the addition of an SSRI, which is recommended by the American Academy of Child and Adolescent Psychiatry as a second-line treatment in children aged 6-18 years. Given the anxious child’s sensitivity to some side effects (such as GI distress) starting at a low dose and titrating up slowly is the recommendation, and effective dose ranges are higher than for the treatment of mood disorders. Without treatment, these disorders may become learned over years and predict complicating anxiety, mood, and substance use disorders in adolescence and adulthood. Any treatment can be helped by the addition of parent guidance, in which parents learn how to be emotionally supportive to their anxious children without accommodating to their demands or asking them to avoid of the source of anxiety.
 

Obsessive-compulsive disorder

Mild obsessive-compulsive disorder (OCD) describes what many of us do, like double-checking we have locked our door or put our work into our briefcase. OCD as a diagnosis with substantial dysfunction has a peak onset at age 10 and again at the age of 21. Over 50% of childhood-onset OCD will have a comorbid anxiety, attention, eating, or tic disorder. Without treatment, OCD is likely to become chronic, and the symptoms (intrusive thoughts, obsessive rumination, and compulsive behaviors) interfere with social and academic function. The behavioral accommodations and avoidance of distress that mark untreated OCD interfere with the healthy development of normal stress management skills that are a critical part of early and later adolescence. First-line treatment is CBT (with exposure and response prevention) with a therapist experienced in the treatment of OCD. A detailed symptom inventory (the Children’s Yale-Brown Obsessive Compulsive Scale) is relatively simple to complete, will confirm a suspected OCD diagnosis, and will create a valuable baseline by which treatment efficacy can be assessed. For those children with moderate to severe OCD, addition of an SSRI to augment and facilitate CBT therapy is recommended. Sertraline, fluvoxamine, fluoxetine, and paroxetine have all been studied and demonstrated efficacy. Clomipramine has well-established efficacy, but its more serious side effects and poorer tolerability make SSRIs the first choice. As with other anxiety disorders, starting at very low doses and titrating upward gradually is recommended. The efficacy of medication treatments is lower in those patients who have other psychiatric illnesses occurring with OCD. Again, parent guidance can be invaluable in supporting the child and improving family well-being.

PTSD

Studies have suggested that between 15% and 45% of children and adolescents in the United States experience a traumatic event, but of those children less than 15% of girls and 6% of boys will develop PTSD in the months that follow. It is important to consider other mood and anxiety disorders in assessing youth with a trauma history who present with symptoms of anxiety and impaired function more than 1 month after the traumatic event. With a history of a traumatic event, it can be helpful to use a specific screening instrument for PTSD, such as the Child PTSD Symptoms Scale or the UCLA PTSD Reaction Index. The symptoms of other disorders (including ADHD) can mimic PTSD, and these disorders may be comorbid with mood, substance use, and eating disorders. Treatment is trauma-focused CBT, with careful use of medications to manage specific symptoms (such as nightmares). Evidence has shown that inclusion of parents in the CBT treatment results in greater reduction in both mood and behavioral symptoms than treating the children alone.

Special cases: School refusal

School refusal affects between 2% and 5% of children, and it is critical to address it promptly or else it can become entrenched and much more difficult to treat. It peaks at 6 and again at 14 years old and often comes to the attention of the pediatrician as children complain of somatic concerns that prove to have no clear cause. It is important to screen for trauma, mood, and anxiety disorders so that you might make reasonable treatment recommendations. But the critical intervention is a behavioral plan that supports the child’s prompt return to school. This requires communication with school personnel and parents to create a plan for the child’s return to school (using natural rewards like friends and trusted teachers) and staying at school (with detailed contingency planning). Parents may need help finding ways to “demagnetize” home and “remagnetize” school, such as turning off the Internet at home and not allowing a child to play sports or with friends when not attending school. Psychotherapy will be helpful for an underlying anxiety or mood disorder, and medications may also be helpful, but education and support for parents to understand how to manage the distress avoidance and rewards of school refusal are generally the critical components of an effective response to this serious problem.

Special cases: Adolescents with new anxiety symptoms

Most childhood anxiety disorders occur before puberty, but anxiety is a common symptom of mood and substance use disorders in teenagers, and often the symptom that drives help-seeking. It is important to screen teens who present with anxiety for underlying mood or substance use disorders. For example, panic disorder is relatively common in young adults, while in teenagers, panic attacks are a frequent symptom of depression or of withdrawal from regular cannabis use. If anxiety has been present and untreated since childhood, adolescents may present with complex comorbid mood and anxiety disorders and struggle with distress tolerance, social difficulties, and perfectionism. Anxiety itself is a very regular developmental feature of adolescence as this is a time of navigating peer relationships, identity, gradual separation from family, and transition to college or work. Every teen would likely benefit from advice about their sleep, exercise, use of any substances, and screen time habits.

For all of your patients with anxiety (and their parents), recognize that anxiety about being liked, making a varsity team, competing for college entrance, and becoming a young adult is expected: uncomfortable, but part of life. It’s adaptive. It helps people to stay safe, get their homework done, and avoid accidents. When people have high levels of anxiety, they can learn to identify their feelings, distinguish between facts and feelings, and learn to manage the anxiety adaptively. If anxiety causes dysfunction in major areas (school, family, friends, activities, and mood), prompt attention is required.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.

However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.

“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.

He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.

“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, the bottom line is that there is no compelling reason to stop these medications in the hospital,” he added.

The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.

Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.

“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.

“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.

Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.

“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.

The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.

“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.

“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.

In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.

SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.

To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.

Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.

By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.

Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.

The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.

The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.

The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.

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

A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.

However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.

“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.

He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.

“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, the bottom line is that there is no compelling reason to stop these medications in the hospital,” he added.

The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.

Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.

“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.

“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.

Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.

“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.

The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.

“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.

“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.

In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.

SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.

To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.

Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.

By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.

Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.

The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.

The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.

The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.

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

A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.

However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.

“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.

He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.

“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, the bottom line is that there is no compelling reason to stop these medications in the hospital,” he added.

The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.

Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.

“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.

“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.

Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.

“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.

The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.

“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.

“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.

In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.

SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.

To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.

Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.

By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.

Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.

The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.

The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.

The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.

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

A new study published in Annals of Internal Medicine found atypical antipsychotics were not safer than haloperidol when it comes to treating postoperative delirium in older patients.

Dae Hyun Kim, MD, ScD, associate professor of medicine at Harvard Medical School, in Boston, who is the lead author of the study, said the findings were especially relevant, as the use of atypical antipsychotics, such as quetiapine, olanzapine, and risperidone, has increased while use of haloperidol has fallen.

A separate but related study led by Dr. Kim, which was recently published in the Journal of the American Geriatrics Society, showed that between 2008 and 2018, use of haloperidol and benzodiazepines in community hospitals and academic medical centers decreased while use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine rose (P < .01).

“Clinicians should not think atypical antipsychotics are the safer option to haloperidol,” Dr. Kim said. “We should focus on reducing prescriptions.”
 

Postoperative delirium

Postoperative delirium is the among the most common complications of surgery in older adults, affecting between 15% and 50% of those patients who undergo major operations. Postoperative delirium is associated with longer hospital stays, poor functional recovery, institutionalization, dementia, and death.

According to research from Harvard Medical School, postoperative delirium is linked to a 40% faster rate of cognitive decline among patients who develop the condition, compared with those who do not experience the complication.

While older patients often feel tired or a bit off after surgery, marked changes in mental function, such as confusion, disorientation, agitation, aggression, hallucinations, or persistent sleepiness, could indicate postoperative delirium.

“Antipsychotic medications are most commonly used off label for managing those symptoms of delirium,” Dr. Kim said. “What we’ve done is look at the comparative safety of two other drugs.”
 

Results

In the retrospective cohort study, researchers analyzed data from 17,115 patients aged 65 years and older who were without psychiatric disorders and who received oral antipsychotics after major surgery requiring general anesthesia.

“These results don’t apply to people in emergent situations where there is severe behavior that threatens their safety and others,” Dr. Kim noted.

There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%), olanzapine (2.8%; relative risk, 0.74; 95% confidence interval, 0.42-1.27), quetiapine (2.6%; RR, 0.70; 95% CI, 0.47-1.04), or risperidone (3.3%; RR, 0.90; CI, 0.53-1.41).

The study also found statistically insignificant differences in the risk for nonfatal clinical events. Those risks ranged from 2% to 2.6% for a cardiac arrhythmia, from 4.2% to 4.6% for pneumonia, and from 0.6% to 1.2% for strokes or transient ischemic attacks.

Esther Oh, MD, PhD, an associate professor at Johns Hopkins University, Baltimore, said that caring for patients who experience acute changes in mental status or behaviors during hospitalization can be difficult.

“Although there is a lot of evidence in the literature that nonpharmacological methods to address these problems are effective, staff shortages of recent years have made it even more difficult for the care team to institute these methods,” Dr. Oh said in an interview.
 

Prevention

Dr. Oh and Dr. Kim agreed that nonpharmacologic strategies, such as ensuring good nutrition and hydration, daily walking, cognitive-stimulating activities, and good sleep hygiene, are effective and safe in preventing postoperative delirium.

“These are common sense interventions, but they require a lot of staffing and training,” Dr. Kim said. “It’s a resource-intensive intervention that requires really changing the way hospital staff interacts with older patients in the hospital.”

Second-generation antipsychotic medications often are thought to be safer than haloperidol in terms of side effects, Dr. Oh said, but the new findings challenge that assumption.

“Based on the findings from this study and on prior studies of antipsychotic use for older adults, use of all antipsychotics, both first and second generation, should be reviewed carefully to ensure they are being administered at the lowest effective dose for the shortest duration possible,” she said.

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Kim and Dr. Oh disclosed no relevant financial relationships.

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

A new study published in Annals of Internal Medicine found atypical antipsychotics were not safer than haloperidol when it comes to treating postoperative delirium in older patients.

Dae Hyun Kim, MD, ScD, associate professor of medicine at Harvard Medical School, in Boston, who is the lead author of the study, said the findings were especially relevant, as the use of atypical antipsychotics, such as quetiapine, olanzapine, and risperidone, has increased while use of haloperidol has fallen.

A separate but related study led by Dr. Kim, which was recently published in the Journal of the American Geriatrics Society, showed that between 2008 and 2018, use of haloperidol and benzodiazepines in community hospitals and academic medical centers decreased while use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine rose (P < .01).

“Clinicians should not think atypical antipsychotics are the safer option to haloperidol,” Dr. Kim said. “We should focus on reducing prescriptions.”
 

Postoperative delirium

Postoperative delirium is the among the most common complications of surgery in older adults, affecting between 15% and 50% of those patients who undergo major operations. Postoperative delirium is associated with longer hospital stays, poor functional recovery, institutionalization, dementia, and death.

According to research from Harvard Medical School, postoperative delirium is linked to a 40% faster rate of cognitive decline among patients who develop the condition, compared with those who do not experience the complication.

While older patients often feel tired or a bit off after surgery, marked changes in mental function, such as confusion, disorientation, agitation, aggression, hallucinations, or persistent sleepiness, could indicate postoperative delirium.

“Antipsychotic medications are most commonly used off label for managing those symptoms of delirium,” Dr. Kim said. “What we’ve done is look at the comparative safety of two other drugs.”
 

Results

In the retrospective cohort study, researchers analyzed data from 17,115 patients aged 65 years and older who were without psychiatric disorders and who received oral antipsychotics after major surgery requiring general anesthesia.

“These results don’t apply to people in emergent situations where there is severe behavior that threatens their safety and others,” Dr. Kim noted.

There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%), olanzapine (2.8%; relative risk, 0.74; 95% confidence interval, 0.42-1.27), quetiapine (2.6%; RR, 0.70; 95% CI, 0.47-1.04), or risperidone (3.3%; RR, 0.90; CI, 0.53-1.41).

The study also found statistically insignificant differences in the risk for nonfatal clinical events. Those risks ranged from 2% to 2.6% for a cardiac arrhythmia, from 4.2% to 4.6% for pneumonia, and from 0.6% to 1.2% for strokes or transient ischemic attacks.

Esther Oh, MD, PhD, an associate professor at Johns Hopkins University, Baltimore, said that caring for patients who experience acute changes in mental status or behaviors during hospitalization can be difficult.

“Although there is a lot of evidence in the literature that nonpharmacological methods to address these problems are effective, staff shortages of recent years have made it even more difficult for the care team to institute these methods,” Dr. Oh said in an interview.
 

Prevention

Dr. Oh and Dr. Kim agreed that nonpharmacologic strategies, such as ensuring good nutrition and hydration, daily walking, cognitive-stimulating activities, and good sleep hygiene, are effective and safe in preventing postoperative delirium.

“These are common sense interventions, but they require a lot of staffing and training,” Dr. Kim said. “It’s a resource-intensive intervention that requires really changing the way hospital staff interacts with older patients in the hospital.”

Second-generation antipsychotic medications often are thought to be safer than haloperidol in terms of side effects, Dr. Oh said, but the new findings challenge that assumption.

“Based on the findings from this study and on prior studies of antipsychotic use for older adults, use of all antipsychotics, both first and second generation, should be reviewed carefully to ensure they are being administered at the lowest effective dose for the shortest duration possible,” she said.

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Kim and Dr. Oh disclosed no relevant financial relationships.

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

A new study published in Annals of Internal Medicine found atypical antipsychotics were not safer than haloperidol when it comes to treating postoperative delirium in older patients.

Dae Hyun Kim, MD, ScD, associate professor of medicine at Harvard Medical School, in Boston, who is the lead author of the study, said the findings were especially relevant, as the use of atypical antipsychotics, such as quetiapine, olanzapine, and risperidone, has increased while use of haloperidol has fallen.

A separate but related study led by Dr. Kim, which was recently published in the Journal of the American Geriatrics Society, showed that between 2008 and 2018, use of haloperidol and benzodiazepines in community hospitals and academic medical centers decreased while use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine rose (P < .01).

“Clinicians should not think atypical antipsychotics are the safer option to haloperidol,” Dr. Kim said. “We should focus on reducing prescriptions.”
 

Postoperative delirium

Postoperative delirium is the among the most common complications of surgery in older adults, affecting between 15% and 50% of those patients who undergo major operations. Postoperative delirium is associated with longer hospital stays, poor functional recovery, institutionalization, dementia, and death.

According to research from Harvard Medical School, postoperative delirium is linked to a 40% faster rate of cognitive decline among patients who develop the condition, compared with those who do not experience the complication.

While older patients often feel tired or a bit off after surgery, marked changes in mental function, such as confusion, disorientation, agitation, aggression, hallucinations, or persistent sleepiness, could indicate postoperative delirium.

“Antipsychotic medications are most commonly used off label for managing those symptoms of delirium,” Dr. Kim said. “What we’ve done is look at the comparative safety of two other drugs.”
 

Results

In the retrospective cohort study, researchers analyzed data from 17,115 patients aged 65 years and older who were without psychiatric disorders and who received oral antipsychotics after major surgery requiring general anesthesia.

“These results don’t apply to people in emergent situations where there is severe behavior that threatens their safety and others,” Dr. Kim noted.

There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%), olanzapine (2.8%; relative risk, 0.74; 95% confidence interval, 0.42-1.27), quetiapine (2.6%; RR, 0.70; 95% CI, 0.47-1.04), or risperidone (3.3%; RR, 0.90; CI, 0.53-1.41).

The study also found statistically insignificant differences in the risk for nonfatal clinical events. Those risks ranged from 2% to 2.6% for a cardiac arrhythmia, from 4.2% to 4.6% for pneumonia, and from 0.6% to 1.2% for strokes or transient ischemic attacks.

Esther Oh, MD, PhD, an associate professor at Johns Hopkins University, Baltimore, said that caring for patients who experience acute changes in mental status or behaviors during hospitalization can be difficult.

“Although there is a lot of evidence in the literature that nonpharmacological methods to address these problems are effective, staff shortages of recent years have made it even more difficult for the care team to institute these methods,” Dr. Oh said in an interview.
 

Prevention

Dr. Oh and Dr. Kim agreed that nonpharmacologic strategies, such as ensuring good nutrition and hydration, daily walking, cognitive-stimulating activities, and good sleep hygiene, are effective and safe in preventing postoperative delirium.

“These are common sense interventions, but they require a lot of staffing and training,” Dr. Kim said. “It’s a resource-intensive intervention that requires really changing the way hospital staff interacts with older patients in the hospital.”

Second-generation antipsychotic medications often are thought to be safer than haloperidol in terms of side effects, Dr. Oh said, but the new findings challenge that assumption.

“Based on the findings from this study and on prior studies of antipsychotic use for older adults, use of all antipsychotics, both first and second generation, should be reviewed carefully to ensure they are being administered at the lowest effective dose for the shortest duration possible,” she said.

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Kim and Dr. Oh disclosed no relevant financial relationships.

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

A routine role for intravascular imaging (IVI) guidance for percutaneous coronary intervention (PCI) has long been favored by many of the technology’s researchers and enthusiasts. Now evidence from large, randomized trials may be catching up with such aspirations, though not without caveats.

Recently unveiled studies collectively suggest that such IVI guidance, at least for PCI of more challenging lesions, can improve the effectiveness of coronary stent delivery in ways that directly lead to better outcomes.

One way IVI guidance may achieve that, the research suggests, albeit more speculatively, is by cutting risk for stent thrombosis, compared with the risk associated with angiography-only PCI.

The new studies, two large randomized IVI trials plus a meta-analysis of 20 such studies, were presented at the annual congress of the European Society of Cardiology.

In one, called ILUMIEN-4, PCI guided by optical coherence tomography (OCT) was associated with fewer procedural complications and better acute results – that is, larger post-PCI minimum stent area (MSA) – than in angiography-only procedures (P < .001). Poststenting MSA, an established predictor of clinical outcomes, was the primary imaging endpoint of the trial with almost 2,500 patients.

Yet the OCT group’s greater post-PCI MSA did not translate to reduced risk for the primary clinical endpoint of 2-year target-vessel failure. Among secondary endpoints, however, stent thrombosis at some point during the follow-up was 64% less likely (P = .02) with OCT guidance than angiography-only PCI.

ILUMIEN-4, despite its neutral clinical result, still “strongly advocates” for PCI guidance by OCT, at least among patients like those in the trial, said principal investigator Ziad Ali, MD, DPhil. He based that largely on the strategy’s greater postprocedure lumen areas in the trials, which are among “the strongest independent predictors for long term outcomes,” said Dr. Ali, of St. Francis Hospital & Heart Center, Roslyn, N.Y., at a press conference on IVI trials during the ESC Congress.
 

Selected complex lesion type

In contrast, the OCTOBER trial, presented at the sessions back to back with ILUMIEN-4, saw OCT guidance lead to better clinical outcomes than angiography alone after PCI of bifurcation lesions, which normally can be a special challenge for operators.

In the trial, which entered about 1,200 patients with such complex lesions, the 2-year risk for major adverse cardiac events (MACE) fell 60% after OCT-guided PCI, compared with angiography-only procedures (P = .035).

The finding is novel for showing that OCT guidance in bifurcation PCI can make a significant clinical difference, said OCTOBER investigator Niels R. Holm, MD, at the same media presentation on IVI trials.

“Multiple studies have shown that OCT allows for optimization of bifurcation PCI, and our results confirm that such optimization may improve the patient’s prognosis,” said Dr. Holm of Aarhus (Denmark) University Hospital.

ILUMIEN-4 and OCTOBER, both of which prespecified the Xience (Abbott) everolimus-eluting stent for the procedures, were published in the New England Journal of Medicine in tandem with their respective presentations at the ESC sessions.
 

Covering the spectrum

A meta-analysis presented at the same ESC session compared IVI using either OCT or intravascular ultrasound (IVUS) with angiography-only PCI across 20 randomized trials with a total of more than 12,000 patients.

Significant outcomes for IVI guidance versus angiography alone included a 31% drop in risk for target-lesion failure, the primary endpoint. And this study, as well, showed a steep 52% reduction in risk for in-stent thrombosis with the IVI-guided approach.

And “for the first time” in IVI studies, “we demonstrated reductions in all-myocardial-infarction and all-cause death, the latter by 25%,” Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in presenting the meta-analysis. Dr. Stone is also the ILUMIEN-4 study chairperson.

“The routine use of OCT or IVUS to guide most PCI procedures will substantially improve patient event-free survival,” he predicted, “enhancing both the long-term safety and effectiveness of the procedure.”

Dr. Stone said that IVI guidance “should be standard of care, if not in all patients, then in most patients.” Part of the rationale: PCI is unlikely to be improved much further by incremental gains in drug-eluting stent design. “That technology has almost plateaued.” But there’s yet room for “substantially improved outcomes” from adjunctive treatments and techniques such as IVI guidance.

The 20 studies in the meta-analysis encompassed an array of patients and lesions both complex and noncomplex, Dr. Stone observed, including bifurcation lesions, chronic total occlusions, left-main coronary stenoses, and MI culprit lesions.

“They really covered the spectrum of PCI,” he said. “I’m not recommending that intravascular imaging be used in every single case. But I do think it should be used in the majority of patients” and be standard of care for PCI in left-main lesions and “complex coronary disease, high-risk patients, and high-risk lesions.”
 

Unique advantage

The IVI-guidance groups in both ILUMIEN-4 and the meta-analysis showed a significant drop in risk for stent thrombosis – that is, abrupt thrombotic vessel closure, which typically occurs in 1% or fewer PCI cases but can trigger an MI and pose a mortality risk up to 45%.

Those risk reductions are consistent with a unique IVI advantage: the ability to guide optimization of stent deployments. When formally presenting ILUMIEN-4 at the ESC sessions, Ali observed that IVUS and OCT imaging allows operators to identify and often correct less-than-ideal results of an initial stent delivery – such as residual gaps between stent struts and vessel wall – that may encroach on the lumen, with possible clinical consequences.

Such imaging, said Dr. Ali, “lets you identify tissue protrusions, malappositions, dissections, and untreated reference-segment disease” that may potentially trigger thrombosis. That makes a strong argument for giving IVI guidance a more common, perhaps even routine role in PCI procedures.
 

Selling routine IVI-guided PCI in practice

“I think the study results are quite clear,” said Deepak L. Bhatt, MD, MPH, as session comoderator following the OCTOBER presentation. “The challenge, though, will be convincing the average interventional cardiologist worldwide that it was specifically the imaging and not the extra care that the patient getting OCT also inherently receives.”

Did OCT’s better trial outcomes stem from IVI itself or from greater operator attentiveness to procedural results – such as, for example, more high-pressure expansions to optimize stent placement, “the sort of thing that tends to occur when invasive imaging is added on to just plain old angiography?” Dr. Bhatt asked of Lene N. Andreasen, MD, who had just presented the OCTOBER trial. “There’s no way of uncoupling the two things.”

What can be said, “at this point, to convince interventional cardiologists that the extra time, energy, expense, is truly indicated,” that the data are “sufficient to change global practice?” asked Dr. Bhatt, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai.

That remains an open question,” acknowledged Dr. Andreasen of Aarhus University Hospital. The best argument in favor of selective IVI-guided PCI is that “we actually see a clinical benefit” in the trials. “But of course, it comes with a cost. It comes with longer procedures and more contrast.” How clinical practice responds to the new data remains to be seen, she proposed.
 

ILUMIEN-4 and OCTOBER in detail

Conducted at 80 centers in 18 countries, ILUMIEN-4 randomly assigned patients with diabetes or complex coronary lesions to undergo PCI guided by OCT or using standard angiography only, 1,233 and 1,254 patients, respectively.

Post-PCI MSA averaged 5.72 mm² with OCT guidance and 5.36 mm² in the angiography-only group (P < .001).

Their rates of target-vessel failure at 2 years were not significantly different at 7.4% and 8.2%, respectively. The 2-year composite endpoint included cardiac death, target vessel–related MI, or ischemia-driven target-vessel revascularization.

Definite or probable stent thrombosis was observed over 2 years in 0.5% of the OCT group and 1.4% of those with angiography-only PCI (hazard ratio, 0.36; 95% confidence interval, 0.14-0.91; P = .02) favoring OCT.

The OCTOBER trial, conducted at 38 centers in Europe, entered 1201 patients with stable angina or acute coronary syndromes and angiographically identified complex bifurcation lesions. They involved the left-main coronary artery in about one-fifth of cases.

Patients were randomly assigned to bifurcation PCI guided by OCT or under standard angiography, 600 and 601 patients, respectively. Rates for procedure-related complications were similar at 6.8% and 5.7%, respectively.

Over a median of 2 years, 10.1% of the OCT group and 14.1% of angiography-only patients developed a MACE event, including cardiac death, target-lesion MI, or ischemia-driven target-lesion revascularization. The adjusted HR was 0.71 (95% CI, 0.51-0.98; P = .035) in favor of OCT.
 

Meta-analysis, trials to date

The meta-analysis presented by Dr. Stone included ILUMIEN-4, OCTOBER, and 18 earlier outcomes trials comparing PCI guided by IVI, either OCT or IVUS, and angiography-only PCI. It covered 12,428 patients with chronic or acute coronary disease and followed them a mean of 26 months; the longest follow-up was 5 years. They were assigned to IVI-guided or angiography-only PCI, 7,038 and 5,390 patients, respectively.

Dr. Stone and colleagues conducted a network meta-analysis of the 20 studies, that is, a combined analysis that allowed both direct and indirect comparisons of standard angiography-only procedures to each of the other studied comparator interventions including OCT, IVUS, and either OCT or IVUS. They then derived network-estimate odds ratios for IVI-guided PCI vs angiography-only procedures.

“Hopefully, this will impact the guidelines,” Dr. Stone said of the meta-analysis. Procedures guided by IVI might become more common in clinical practice if they were to garner a Class-I guideline recommendation, the strongest recommendation category.

“That would make a difference, but we’d also need to work to remove impediments to increasing intravascular imaging guidance” for most patients undergoing PCI, he said, referring to challenges in obtaining reimbursement for IVI-guided PCI and training enough operators to handle the projected demand.

ILUMIEN-4 was funded by Abbott. OCTOBER was supported by grants from Abbott Vascular, St. Jude Medical, and Aarhus University. The network meta-analysis received statistical support from Abbott. Dr. Ali disclosed institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems, Medtronic, the National Institutes of Health, Opsens Medical, Philips, and Teleflex; consulting fees from Astra Zeneca, Philips, Shockwave; and holding equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr. Holm and Dr. Bhatt reported numerous conflicts of interest. Dr. Andreasen disclosed no relevant financial relationships.

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

A routine role for intravascular imaging (IVI) guidance for percutaneous coronary intervention (PCI) has long been favored by many of the technology’s researchers and enthusiasts. Now evidence from large, randomized trials may be catching up with such aspirations, though not without caveats.

Recently unveiled studies collectively suggest that such IVI guidance, at least for PCI of more challenging lesions, can improve the effectiveness of coronary stent delivery in ways that directly lead to better outcomes.

One way IVI guidance may achieve that, the research suggests, albeit more speculatively, is by cutting risk for stent thrombosis, compared with the risk associated with angiography-only PCI.

The new studies, two large randomized IVI trials plus a meta-analysis of 20 such studies, were presented at the annual congress of the European Society of Cardiology.

In one, called ILUMIEN-4, PCI guided by optical coherence tomography (OCT) was associated with fewer procedural complications and better acute results – that is, larger post-PCI minimum stent area (MSA) – than in angiography-only procedures (P < .001). Poststenting MSA, an established predictor of clinical outcomes, was the primary imaging endpoint of the trial with almost 2,500 patients.

Yet the OCT group’s greater post-PCI MSA did not translate to reduced risk for the primary clinical endpoint of 2-year target-vessel failure. Among secondary endpoints, however, stent thrombosis at some point during the follow-up was 64% less likely (P = .02) with OCT guidance than angiography-only PCI.

ILUMIEN-4, despite its neutral clinical result, still “strongly advocates” for PCI guidance by OCT, at least among patients like those in the trial, said principal investigator Ziad Ali, MD, DPhil. He based that largely on the strategy’s greater postprocedure lumen areas in the trials, which are among “the strongest independent predictors for long term outcomes,” said Dr. Ali, of St. Francis Hospital & Heart Center, Roslyn, N.Y., at a press conference on IVI trials during the ESC Congress.
 

Selected complex lesion type

In contrast, the OCTOBER trial, presented at the sessions back to back with ILUMIEN-4, saw OCT guidance lead to better clinical outcomes than angiography alone after PCI of bifurcation lesions, which normally can be a special challenge for operators.

In the trial, which entered about 1,200 patients with such complex lesions, the 2-year risk for major adverse cardiac events (MACE) fell 60% after OCT-guided PCI, compared with angiography-only procedures (P = .035).

The finding is novel for showing that OCT guidance in bifurcation PCI can make a significant clinical difference, said OCTOBER investigator Niels R. Holm, MD, at the same media presentation on IVI trials.

“Multiple studies have shown that OCT allows for optimization of bifurcation PCI, and our results confirm that such optimization may improve the patient’s prognosis,” said Dr. Holm of Aarhus (Denmark) University Hospital.

ILUMIEN-4 and OCTOBER, both of which prespecified the Xience (Abbott) everolimus-eluting stent for the procedures, were published in the New England Journal of Medicine in tandem with their respective presentations at the ESC sessions.
 

Covering the spectrum

A meta-analysis presented at the same ESC session compared IVI using either OCT or intravascular ultrasound (IVUS) with angiography-only PCI across 20 randomized trials with a total of more than 12,000 patients.

Significant outcomes for IVI guidance versus angiography alone included a 31% drop in risk for target-lesion failure, the primary endpoint. And this study, as well, showed a steep 52% reduction in risk for in-stent thrombosis with the IVI-guided approach.

And “for the first time” in IVI studies, “we demonstrated reductions in all-myocardial-infarction and all-cause death, the latter by 25%,” Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in presenting the meta-analysis. Dr. Stone is also the ILUMIEN-4 study chairperson.

“The routine use of OCT or IVUS to guide most PCI procedures will substantially improve patient event-free survival,” he predicted, “enhancing both the long-term safety and effectiveness of the procedure.”

Dr. Stone said that IVI guidance “should be standard of care, if not in all patients, then in most patients.” Part of the rationale: PCI is unlikely to be improved much further by incremental gains in drug-eluting stent design. “That technology has almost plateaued.” But there’s yet room for “substantially improved outcomes” from adjunctive treatments and techniques such as IVI guidance.

The 20 studies in the meta-analysis encompassed an array of patients and lesions both complex and noncomplex, Dr. Stone observed, including bifurcation lesions, chronic total occlusions, left-main coronary stenoses, and MI culprit lesions.

“They really covered the spectrum of PCI,” he said. “I’m not recommending that intravascular imaging be used in every single case. But I do think it should be used in the majority of patients” and be standard of care for PCI in left-main lesions and “complex coronary disease, high-risk patients, and high-risk lesions.”
 

Unique advantage

The IVI-guidance groups in both ILUMIEN-4 and the meta-analysis showed a significant drop in risk for stent thrombosis – that is, abrupt thrombotic vessel closure, which typically occurs in 1% or fewer PCI cases but can trigger an MI and pose a mortality risk up to 45%.

Those risk reductions are consistent with a unique IVI advantage: the ability to guide optimization of stent deployments. When formally presenting ILUMIEN-4 at the ESC sessions, Ali observed that IVUS and OCT imaging allows operators to identify and often correct less-than-ideal results of an initial stent delivery – such as residual gaps between stent struts and vessel wall – that may encroach on the lumen, with possible clinical consequences.

Such imaging, said Dr. Ali, “lets you identify tissue protrusions, malappositions, dissections, and untreated reference-segment disease” that may potentially trigger thrombosis. That makes a strong argument for giving IVI guidance a more common, perhaps even routine role in PCI procedures.
 

Selling routine IVI-guided PCI in practice

“I think the study results are quite clear,” said Deepak L. Bhatt, MD, MPH, as session comoderator following the OCTOBER presentation. “The challenge, though, will be convincing the average interventional cardiologist worldwide that it was specifically the imaging and not the extra care that the patient getting OCT also inherently receives.”

Did OCT’s better trial outcomes stem from IVI itself or from greater operator attentiveness to procedural results – such as, for example, more high-pressure expansions to optimize stent placement, “the sort of thing that tends to occur when invasive imaging is added on to just plain old angiography?” Dr. Bhatt asked of Lene N. Andreasen, MD, who had just presented the OCTOBER trial. “There’s no way of uncoupling the two things.”

What can be said, “at this point, to convince interventional cardiologists that the extra time, energy, expense, is truly indicated,” that the data are “sufficient to change global practice?” asked Dr. Bhatt, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai.

That remains an open question,” acknowledged Dr. Andreasen of Aarhus University Hospital. The best argument in favor of selective IVI-guided PCI is that “we actually see a clinical benefit” in the trials. “But of course, it comes with a cost. It comes with longer procedures and more contrast.” How clinical practice responds to the new data remains to be seen, she proposed.
 

ILUMIEN-4 and OCTOBER in detail

Conducted at 80 centers in 18 countries, ILUMIEN-4 randomly assigned patients with diabetes or complex coronary lesions to undergo PCI guided by OCT or using standard angiography only, 1,233 and 1,254 patients, respectively.

Post-PCI MSA averaged 5.72 mm² with OCT guidance and 5.36 mm² in the angiography-only group (P < .001).

Their rates of target-vessel failure at 2 years were not significantly different at 7.4% and 8.2%, respectively. The 2-year composite endpoint included cardiac death, target vessel–related MI, or ischemia-driven target-vessel revascularization.

Definite or probable stent thrombosis was observed over 2 years in 0.5% of the OCT group and 1.4% of those with angiography-only PCI (hazard ratio, 0.36; 95% confidence interval, 0.14-0.91; P = .02) favoring OCT.

The OCTOBER trial, conducted at 38 centers in Europe, entered 1201 patients with stable angina or acute coronary syndromes and angiographically identified complex bifurcation lesions. They involved the left-main coronary artery in about one-fifth of cases.

Patients were randomly assigned to bifurcation PCI guided by OCT or under standard angiography, 600 and 601 patients, respectively. Rates for procedure-related complications were similar at 6.8% and 5.7%, respectively.

Over a median of 2 years, 10.1% of the OCT group and 14.1% of angiography-only patients developed a MACE event, including cardiac death, target-lesion MI, or ischemia-driven target-lesion revascularization. The adjusted HR was 0.71 (95% CI, 0.51-0.98; P = .035) in favor of OCT.
 

Meta-analysis, trials to date

The meta-analysis presented by Dr. Stone included ILUMIEN-4, OCTOBER, and 18 earlier outcomes trials comparing PCI guided by IVI, either OCT or IVUS, and angiography-only PCI. It covered 12,428 patients with chronic or acute coronary disease and followed them a mean of 26 months; the longest follow-up was 5 years. They were assigned to IVI-guided or angiography-only PCI, 7,038 and 5,390 patients, respectively.

Dr. Stone and colleagues conducted a network meta-analysis of the 20 studies, that is, a combined analysis that allowed both direct and indirect comparisons of standard angiography-only procedures to each of the other studied comparator interventions including OCT, IVUS, and either OCT or IVUS. They then derived network-estimate odds ratios for IVI-guided PCI vs angiography-only procedures.

“Hopefully, this will impact the guidelines,” Dr. Stone said of the meta-analysis. Procedures guided by IVI might become more common in clinical practice if they were to garner a Class-I guideline recommendation, the strongest recommendation category.

“That would make a difference, but we’d also need to work to remove impediments to increasing intravascular imaging guidance” for most patients undergoing PCI, he said, referring to challenges in obtaining reimbursement for IVI-guided PCI and training enough operators to handle the projected demand.

ILUMIEN-4 was funded by Abbott. OCTOBER was supported by grants from Abbott Vascular, St. Jude Medical, and Aarhus University. The network meta-analysis received statistical support from Abbott. Dr. Ali disclosed institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems, Medtronic, the National Institutes of Health, Opsens Medical, Philips, and Teleflex; consulting fees from Astra Zeneca, Philips, Shockwave; and holding equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr. Holm and Dr. Bhatt reported numerous conflicts of interest. Dr. Andreasen disclosed no relevant financial relationships.

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

A routine role for intravascular imaging (IVI) guidance for percutaneous coronary intervention (PCI) has long been favored by many of the technology’s researchers and enthusiasts. Now evidence from large, randomized trials may be catching up with such aspirations, though not without caveats.

Recently unveiled studies collectively suggest that such IVI guidance, at least for PCI of more challenging lesions, can improve the effectiveness of coronary stent delivery in ways that directly lead to better outcomes.

One way IVI guidance may achieve that, the research suggests, albeit more speculatively, is by cutting risk for stent thrombosis, compared with the risk associated with angiography-only PCI.

The new studies, two large randomized IVI trials plus a meta-analysis of 20 such studies, were presented at the annual congress of the European Society of Cardiology.

In one, called ILUMIEN-4, PCI guided by optical coherence tomography (OCT) was associated with fewer procedural complications and better acute results – that is, larger post-PCI minimum stent area (MSA) – than in angiography-only procedures (P < .001). Poststenting MSA, an established predictor of clinical outcomes, was the primary imaging endpoint of the trial with almost 2,500 patients.

Yet the OCT group’s greater post-PCI MSA did not translate to reduced risk for the primary clinical endpoint of 2-year target-vessel failure. Among secondary endpoints, however, stent thrombosis at some point during the follow-up was 64% less likely (P = .02) with OCT guidance than angiography-only PCI.

ILUMIEN-4, despite its neutral clinical result, still “strongly advocates” for PCI guidance by OCT, at least among patients like those in the trial, said principal investigator Ziad Ali, MD, DPhil. He based that largely on the strategy’s greater postprocedure lumen areas in the trials, which are among “the strongest independent predictors for long term outcomes,” said Dr. Ali, of St. Francis Hospital & Heart Center, Roslyn, N.Y., at a press conference on IVI trials during the ESC Congress.
 

Selected complex lesion type

In contrast, the OCTOBER trial, presented at the sessions back to back with ILUMIEN-4, saw OCT guidance lead to better clinical outcomes than angiography alone after PCI of bifurcation lesions, which normally can be a special challenge for operators.

In the trial, which entered about 1,200 patients with such complex lesions, the 2-year risk for major adverse cardiac events (MACE) fell 60% after OCT-guided PCI, compared with angiography-only procedures (P = .035).

The finding is novel for showing that OCT guidance in bifurcation PCI can make a significant clinical difference, said OCTOBER investigator Niels R. Holm, MD, at the same media presentation on IVI trials.

“Multiple studies have shown that OCT allows for optimization of bifurcation PCI, and our results confirm that such optimization may improve the patient’s prognosis,” said Dr. Holm of Aarhus (Denmark) University Hospital.

ILUMIEN-4 and OCTOBER, both of which prespecified the Xience (Abbott) everolimus-eluting stent for the procedures, were published in the New England Journal of Medicine in tandem with their respective presentations at the ESC sessions.
 

Covering the spectrum

A meta-analysis presented at the same ESC session compared IVI using either OCT or intravascular ultrasound (IVUS) with angiography-only PCI across 20 randomized trials with a total of more than 12,000 patients.

Significant outcomes for IVI guidance versus angiography alone included a 31% drop in risk for target-lesion failure, the primary endpoint. And this study, as well, showed a steep 52% reduction in risk for in-stent thrombosis with the IVI-guided approach.

And “for the first time” in IVI studies, “we demonstrated reductions in all-myocardial-infarction and all-cause death, the latter by 25%,” Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said in presenting the meta-analysis. Dr. Stone is also the ILUMIEN-4 study chairperson.

“The routine use of OCT or IVUS to guide most PCI procedures will substantially improve patient event-free survival,” he predicted, “enhancing both the long-term safety and effectiveness of the procedure.”

Dr. Stone said that IVI guidance “should be standard of care, if not in all patients, then in most patients.” Part of the rationale: PCI is unlikely to be improved much further by incremental gains in drug-eluting stent design. “That technology has almost plateaued.” But there’s yet room for “substantially improved outcomes” from adjunctive treatments and techniques such as IVI guidance.

The 20 studies in the meta-analysis encompassed an array of patients and lesions both complex and noncomplex, Dr. Stone observed, including bifurcation lesions, chronic total occlusions, left-main coronary stenoses, and MI culprit lesions.

“They really covered the spectrum of PCI,” he said. “I’m not recommending that intravascular imaging be used in every single case. But I do think it should be used in the majority of patients” and be standard of care for PCI in left-main lesions and “complex coronary disease, high-risk patients, and high-risk lesions.”
 

Unique advantage

The IVI-guidance groups in both ILUMIEN-4 and the meta-analysis showed a significant drop in risk for stent thrombosis – that is, abrupt thrombotic vessel closure, which typically occurs in 1% or fewer PCI cases but can trigger an MI and pose a mortality risk up to 45%.

Those risk reductions are consistent with a unique IVI advantage: the ability to guide optimization of stent deployments. When formally presenting ILUMIEN-4 at the ESC sessions, Ali observed that IVUS and OCT imaging allows operators to identify and often correct less-than-ideal results of an initial stent delivery – such as residual gaps between stent struts and vessel wall – that may encroach on the lumen, with possible clinical consequences.

Such imaging, said Dr. Ali, “lets you identify tissue protrusions, malappositions, dissections, and untreated reference-segment disease” that may potentially trigger thrombosis. That makes a strong argument for giving IVI guidance a more common, perhaps even routine role in PCI procedures.
 

Selling routine IVI-guided PCI in practice

“I think the study results are quite clear,” said Deepak L. Bhatt, MD, MPH, as session comoderator following the OCTOBER presentation. “The challenge, though, will be convincing the average interventional cardiologist worldwide that it was specifically the imaging and not the extra care that the patient getting OCT also inherently receives.”

Did OCT’s better trial outcomes stem from IVI itself or from greater operator attentiveness to procedural results – such as, for example, more high-pressure expansions to optimize stent placement, “the sort of thing that tends to occur when invasive imaging is added on to just plain old angiography?” Dr. Bhatt asked of Lene N. Andreasen, MD, who had just presented the OCTOBER trial. “There’s no way of uncoupling the two things.”

What can be said, “at this point, to convince interventional cardiologists that the extra time, energy, expense, is truly indicated,” that the data are “sufficient to change global practice?” asked Dr. Bhatt, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai.

That remains an open question,” acknowledged Dr. Andreasen of Aarhus University Hospital. The best argument in favor of selective IVI-guided PCI is that “we actually see a clinical benefit” in the trials. “But of course, it comes with a cost. It comes with longer procedures and more contrast.” How clinical practice responds to the new data remains to be seen, she proposed.
 

ILUMIEN-4 and OCTOBER in detail

Conducted at 80 centers in 18 countries, ILUMIEN-4 randomly assigned patients with diabetes or complex coronary lesions to undergo PCI guided by OCT or using standard angiography only, 1,233 and 1,254 patients, respectively.

Post-PCI MSA averaged 5.72 mm² with OCT guidance and 5.36 mm² in the angiography-only group (P < .001).

Their rates of target-vessel failure at 2 years were not significantly different at 7.4% and 8.2%, respectively. The 2-year composite endpoint included cardiac death, target vessel–related MI, or ischemia-driven target-vessel revascularization.

Definite or probable stent thrombosis was observed over 2 years in 0.5% of the OCT group and 1.4% of those with angiography-only PCI (hazard ratio, 0.36; 95% confidence interval, 0.14-0.91; P = .02) favoring OCT.

The OCTOBER trial, conducted at 38 centers in Europe, entered 1201 patients with stable angina or acute coronary syndromes and angiographically identified complex bifurcation lesions. They involved the left-main coronary artery in about one-fifth of cases.

Patients were randomly assigned to bifurcation PCI guided by OCT or under standard angiography, 600 and 601 patients, respectively. Rates for procedure-related complications were similar at 6.8% and 5.7%, respectively.

Over a median of 2 years, 10.1% of the OCT group and 14.1% of angiography-only patients developed a MACE event, including cardiac death, target-lesion MI, or ischemia-driven target-lesion revascularization. The adjusted HR was 0.71 (95% CI, 0.51-0.98; P = .035) in favor of OCT.
 

Meta-analysis, trials to date

The meta-analysis presented by Dr. Stone included ILUMIEN-4, OCTOBER, and 18 earlier outcomes trials comparing PCI guided by IVI, either OCT or IVUS, and angiography-only PCI. It covered 12,428 patients with chronic or acute coronary disease and followed them a mean of 26 months; the longest follow-up was 5 years. They were assigned to IVI-guided or angiography-only PCI, 7,038 and 5,390 patients, respectively.

Dr. Stone and colleagues conducted a network meta-analysis of the 20 studies, that is, a combined analysis that allowed both direct and indirect comparisons of standard angiography-only procedures to each of the other studied comparator interventions including OCT, IVUS, and either OCT or IVUS. They then derived network-estimate odds ratios for IVI-guided PCI vs angiography-only procedures.

“Hopefully, this will impact the guidelines,” Dr. Stone said of the meta-analysis. Procedures guided by IVI might become more common in clinical practice if they were to garner a Class-I guideline recommendation, the strongest recommendation category.

“That would make a difference, but we’d also need to work to remove impediments to increasing intravascular imaging guidance” for most patients undergoing PCI, he said, referring to challenges in obtaining reimbursement for IVI-guided PCI and training enough operators to handle the projected demand.

ILUMIEN-4 was funded by Abbott. OCTOBER was supported by grants from Abbott Vascular, St. Jude Medical, and Aarhus University. The network meta-analysis received statistical support from Abbott. Dr. Ali disclosed institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems, Medtronic, the National Institutes of Health, Opsens Medical, Philips, and Teleflex; consulting fees from Astra Zeneca, Philips, Shockwave; and holding equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr. Holm and Dr. Bhatt reported numerous conflicts of interest. Dr. Andreasen disclosed no relevant financial relationships.

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

Two years is a long time in the world of heart failure (HF) management, enough to see publication of more than a dozen studies with insights that would supplant and expand key sections of a far-reaching European Society of Cardiology (ESC) clinical practice guideline on HF unveiled in 2021.

“Back in 2021, we had three and a half decades of data to consider,” but recent years have seen “an amazing amount of progress” that has necessitated some adjustments and key additions, including several Class I recommendations, observed Roy S. Gardner, MBChB, MD, Golden Jubilee National Hospital, Clydebank, United Kingdom.

Much of that recent progress, driven by trials like EMPEROR-Preserved, DELIVER, STRONG-HF, and IRONMAN, has been crystalized into the “2023 Focused Update of the 2021 ESC Guidelines” on HF management, which Dr. Gardner helped unveil over several days at the annual congress of the European Society of Cardiology, held in Amsterdam.

The new document was also published in the European Heart Journal during the ESC sessions. Dr. Gardner is a co-author on both the 2021 and 2023 documents.

The task force that was charged with the focused update’s development “considered a large number of trials across the spectrum of acute chronic heart failure and the comorbidities associated with it,” Ultimately, it considered only those with “results that would lead to new or changed Class I or Class IIa recommendations,” noted Theresa A. McDonagh, MD, during the ESC sessions.

Dr. McDonagh, of King’s College Hospital, London, chaired the task force and led the document’s list of authors along with Marco Metra, MD, University of Brescia (Italy).
 

Chronic HF management

The 2021 document’s “beautiful algorithm” on managing HF with reduced ejection fraction, that is HF with an LVEF less than 40%, had helped enshrine the expeditious uptitration of the “four pillars” of drug therapy as a top management goal. That remains unchanged in the focused update, Dr. Gardner noted.

But the new document gives a boost to recommendations for HF with mildly reduced ejection fraction (HFmrEF), characterized by an LVEF greater than 40% to less than 50%. For that, the 2021 document recommended three of the four pillars of HF medical therapy: beta blockers, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system (RAS) inhibitors.

The focused update, however, adds the fourth pillar – SGLT2 inhibitors – to core therapy for both HFmrEF and HF with preserved ejection fraction (HFpEF), the latter defined by an LVEF greater than 50%. Publication of trials supporting those new recommendations had narrowly missed availability for the 2021 document.

EMPEROR-Preserved, for example, was published during the same ESC 2021 sessions that introduced the 2021 guidelines. Its patients with HFpEF (which at the time included patients meeting the current definition of HFmrEF) assigned to the SGLT2 inhibitor empagliflozin (Jardiance) showed a 21% reduction in risk for a composite primary endpoint that was driven by the HF-hospitalization component.

“This wasn’t a fluke finding,” Dr. Gardner said, as the following year saw publication of the DELIVER trial, which resembled EMPEROR-Preserved in design and outcomes using the SGLT2 inhibitor dapagliflozin (Farxiga).

The two trials, backed up by meta-analyses that also included DAPA-HF and other studies, suggested as well that the two SGLT2 inhibitors “work across the spectrum of ejection fraction,” Dr. Gardner said.

The 2023 focused update indicates an SGLT2 inhibitor, either empagliflozin or dapagliflozin, for patients with either HFmrEF or HFpEF to reduce the risk of HF hospitalization or cardiovascular death. Both recommendations are of Class I, level of evidence A.

The new indications make SGLT2 inhibitors and diuretics (as needed for fluid retention) the only drugs for HFmrEF or HFpEF with a Class I recommendation. Previously established “rather weaker” Class IIb recommendation for RAS inhibitors, MRAs, and beta blockers that had been “based on subgroup analyses of neutral trials” remained unchanged in the focused update, Dr. McDonagh noted.
 

Patients hospitalized with HF

The 2021 guidelines had recommended that patients hospitalized with acute HF be started on evidence-based meds before discharge and that they return for evaluation 1 to 2 weeks after discharge. But the recommendation was unsupported by randomized trials.

That changed with the 2022 publication of STRONG-HF, in which a strategy of early and rapid uptitration of guideline-directed meds, initiated predischarge regardless of LVEF, led to a one-third reduced 6-month risk for death or HF readmission.

Based primarily on STRONG-HF, the focused update recommends “an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks after hospitalization” to reduce readmission and mortality: Class I, level of evidence B.

“There was a large consensus around this recommendation,” said STRONG-HF principal investigator Alexandre Mebazaa, MD, PhD, a co-author of both the 2021 and 2023 documents. Conducted before the advent of the four pillars of drug therapy, sometimes called quartet therapy, the trial’s requirement for evidence-based meds didn’t include SGLT2 inhibitors.

The new focused update considers the new status of those agents, especially with regard to their benefits independent of LVEF. So, it completed the quartet by adding empagliflozin or dapagliflozin to the agents that should be initiated predischarge, observed Dr. Mebazaa, University Hospitals Saint Louis‐Lariboisière, Paris, at the focused-update’s ESC 2023 sessions.

The new document also follows STRONG-HF with its emphasis on “frequent and careful follow-up” by recommending certain clinical and laboratory evaluations known to be prognostic in HF. They include congestion status, blood pressure, heart rate, natriuretic peptide (NT-proBNP) and potassium levels and estimated glomerular filtration rate.

Dr. Mebazaa stressed the importance of monitoring NT-proBNP after discharge. “What we saw in STRONG-HF is that sometimes the clinical signs do not necessarily tell you that the patient is still congested.”

After discharge, he said, NT-proBNP levels “should only go down.” So, knowing whether NT-proBNP levels “are stable or increasing” during the med optimization process can help guide diuretic dosing.
 

HF with comorbidities

The new document includes two new Class I recommendations for patients with HF and both type 2 diabetes and chronic kidney disease based on several recent randomized trials and meta-analyses.

The focused update recommends SGLT2 inhibitors as well as the selective, non-steroidal MRA finerenone (Kerendia) in HF patients with CKD and type-2 diabetes. Both Class I recommendations are supported by a level of evidence A.

The SGLT2 indication is based on DAPA-CKD and EMPA-KIDNEY plus meta-analyses that included those trials along with others. The recommendation for finerenone derives from the FIDELIO-DKD and FIGARO-DKD trials and a pooled analysis of the two studies.

The 2023 focused update also accounts for new clinical-trial insights for patients with HF and iron deficiency. The 2021 document featured recommendations for the diagnosis and iron-repletion therapy in such cases, but only as Class IIa or at lower low levels of evidence. The focused update considers more recent studies, especially IRONMAN and some meta-analyses.

The 2023 document indicates intravenous iron supplementation for symptomatic patients with iron deficiency and either HFrEF or HFmrEF to improve symptoms and quality of life (Class I, level of evidence A), and says it should be considered (Class IIa, level of evidence A) to reduce risk for HF hospitalization.

When the task force assembled to plan the 2023 focused update, Dr. Gardner observed, “the first thing we thought about was the nomenclature around the phenotyping of heart failure.”

Although the 2021 guidelines relied fundamentally on the distinctions between HFrEF, HFmrEF, and HFpEF, it had become apparent to some in the field that some meds, especially the SGLT2 inhibitors, were obscuring their LVEF-based boundaries, at least with respect to drug therapy.

The 2023 document’s developers, Dr. Gardner said, seriously considered changing the three categories to two, that is HFrEF and – to account for all other heart failure – HF with normal ejection fraction (HFnEF).

That didn’t happen, although the proposal was popular within the task force. Any changes to the 2021 document would require a 75% consensus on the matter, Dr. Gardner explained. When the task force took a vote on whether to change the nomenclature, he said, 71% favored the proposal.

Disclosures for members of the task force can be found in a supplement to the published 2023 Focused Update.

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

Two years is a long time in the world of heart failure (HF) management, enough to see publication of more than a dozen studies with insights that would supplant and expand key sections of a far-reaching European Society of Cardiology (ESC) clinical practice guideline on HF unveiled in 2021.

“Back in 2021, we had three and a half decades of data to consider,” but recent years have seen “an amazing amount of progress” that has necessitated some adjustments and key additions, including several Class I recommendations, observed Roy S. Gardner, MBChB, MD, Golden Jubilee National Hospital, Clydebank, United Kingdom.

Much of that recent progress, driven by trials like EMPEROR-Preserved, DELIVER, STRONG-HF, and IRONMAN, has been crystalized into the “2023 Focused Update of the 2021 ESC Guidelines” on HF management, which Dr. Gardner helped unveil over several days at the annual congress of the European Society of Cardiology, held in Amsterdam.

The new document was also published in the European Heart Journal during the ESC sessions. Dr. Gardner is a co-author on both the 2021 and 2023 documents.

The task force that was charged with the focused update’s development “considered a large number of trials across the spectrum of acute chronic heart failure and the comorbidities associated with it,” Ultimately, it considered only those with “results that would lead to new or changed Class I or Class IIa recommendations,” noted Theresa A. McDonagh, MD, during the ESC sessions.

Dr. McDonagh, of King’s College Hospital, London, chaired the task force and led the document’s list of authors along with Marco Metra, MD, University of Brescia (Italy).
 

Chronic HF management

The 2021 document’s “beautiful algorithm” on managing HF with reduced ejection fraction, that is HF with an LVEF less than 40%, had helped enshrine the expeditious uptitration of the “four pillars” of drug therapy as a top management goal. That remains unchanged in the focused update, Dr. Gardner noted.

But the new document gives a boost to recommendations for HF with mildly reduced ejection fraction (HFmrEF), characterized by an LVEF greater than 40% to less than 50%. For that, the 2021 document recommended three of the four pillars of HF medical therapy: beta blockers, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system (RAS) inhibitors.

The focused update, however, adds the fourth pillar – SGLT2 inhibitors – to core therapy for both HFmrEF and HF with preserved ejection fraction (HFpEF), the latter defined by an LVEF greater than 50%. Publication of trials supporting those new recommendations had narrowly missed availability for the 2021 document.

EMPEROR-Preserved, for example, was published during the same ESC 2021 sessions that introduced the 2021 guidelines. Its patients with HFpEF (which at the time included patients meeting the current definition of HFmrEF) assigned to the SGLT2 inhibitor empagliflozin (Jardiance) showed a 21% reduction in risk for a composite primary endpoint that was driven by the HF-hospitalization component.

“This wasn’t a fluke finding,” Dr. Gardner said, as the following year saw publication of the DELIVER trial, which resembled EMPEROR-Preserved in design and outcomes using the SGLT2 inhibitor dapagliflozin (Farxiga).

The two trials, backed up by meta-analyses that also included DAPA-HF and other studies, suggested as well that the two SGLT2 inhibitors “work across the spectrum of ejection fraction,” Dr. Gardner said.

The 2023 focused update indicates an SGLT2 inhibitor, either empagliflozin or dapagliflozin, for patients with either HFmrEF or HFpEF to reduce the risk of HF hospitalization or cardiovascular death. Both recommendations are of Class I, level of evidence A.

The new indications make SGLT2 inhibitors and diuretics (as needed for fluid retention) the only drugs for HFmrEF or HFpEF with a Class I recommendation. Previously established “rather weaker” Class IIb recommendation for RAS inhibitors, MRAs, and beta blockers that had been “based on subgroup analyses of neutral trials” remained unchanged in the focused update, Dr. McDonagh noted.
 

Patients hospitalized with HF

The 2021 guidelines had recommended that patients hospitalized with acute HF be started on evidence-based meds before discharge and that they return for evaluation 1 to 2 weeks after discharge. But the recommendation was unsupported by randomized trials.

That changed with the 2022 publication of STRONG-HF, in which a strategy of early and rapid uptitration of guideline-directed meds, initiated predischarge regardless of LVEF, led to a one-third reduced 6-month risk for death or HF readmission.

Based primarily on STRONG-HF, the focused update recommends “an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks after hospitalization” to reduce readmission and mortality: Class I, level of evidence B.

“There was a large consensus around this recommendation,” said STRONG-HF principal investigator Alexandre Mebazaa, MD, PhD, a co-author of both the 2021 and 2023 documents. Conducted before the advent of the four pillars of drug therapy, sometimes called quartet therapy, the trial’s requirement for evidence-based meds didn’t include SGLT2 inhibitors.

The new focused update considers the new status of those agents, especially with regard to their benefits independent of LVEF. So, it completed the quartet by adding empagliflozin or dapagliflozin to the agents that should be initiated predischarge, observed Dr. Mebazaa, University Hospitals Saint Louis‐Lariboisière, Paris, at the focused-update’s ESC 2023 sessions.

The new document also follows STRONG-HF with its emphasis on “frequent and careful follow-up” by recommending certain clinical and laboratory evaluations known to be prognostic in HF. They include congestion status, blood pressure, heart rate, natriuretic peptide (NT-proBNP) and potassium levels and estimated glomerular filtration rate.

Dr. Mebazaa stressed the importance of monitoring NT-proBNP after discharge. “What we saw in STRONG-HF is that sometimes the clinical signs do not necessarily tell you that the patient is still congested.”

After discharge, he said, NT-proBNP levels “should only go down.” So, knowing whether NT-proBNP levels “are stable or increasing” during the med optimization process can help guide diuretic dosing.
 

HF with comorbidities

The new document includes two new Class I recommendations for patients with HF and both type 2 diabetes and chronic kidney disease based on several recent randomized trials and meta-analyses.

The focused update recommends SGLT2 inhibitors as well as the selective, non-steroidal MRA finerenone (Kerendia) in HF patients with CKD and type-2 diabetes. Both Class I recommendations are supported by a level of evidence A.

The SGLT2 indication is based on DAPA-CKD and EMPA-KIDNEY plus meta-analyses that included those trials along with others. The recommendation for finerenone derives from the FIDELIO-DKD and FIGARO-DKD trials and a pooled analysis of the two studies.

The 2023 focused update also accounts for new clinical-trial insights for patients with HF and iron deficiency. The 2021 document featured recommendations for the diagnosis and iron-repletion therapy in such cases, but only as Class IIa or at lower low levels of evidence. The focused update considers more recent studies, especially IRONMAN and some meta-analyses.

The 2023 document indicates intravenous iron supplementation for symptomatic patients with iron deficiency and either HFrEF or HFmrEF to improve symptoms and quality of life (Class I, level of evidence A), and says it should be considered (Class IIa, level of evidence A) to reduce risk for HF hospitalization.

When the task force assembled to plan the 2023 focused update, Dr. Gardner observed, “the first thing we thought about was the nomenclature around the phenotyping of heart failure.”

Although the 2021 guidelines relied fundamentally on the distinctions between HFrEF, HFmrEF, and HFpEF, it had become apparent to some in the field that some meds, especially the SGLT2 inhibitors, were obscuring their LVEF-based boundaries, at least with respect to drug therapy.

The 2023 document’s developers, Dr. Gardner said, seriously considered changing the three categories to two, that is HFrEF and – to account for all other heart failure – HF with normal ejection fraction (HFnEF).

That didn’t happen, although the proposal was popular within the task force. Any changes to the 2021 document would require a 75% consensus on the matter, Dr. Gardner explained. When the task force took a vote on whether to change the nomenclature, he said, 71% favored the proposal.

Disclosures for members of the task force can be found in a supplement to the published 2023 Focused Update.

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

Two years is a long time in the world of heart failure (HF) management, enough to see publication of more than a dozen studies with insights that would supplant and expand key sections of a far-reaching European Society of Cardiology (ESC) clinical practice guideline on HF unveiled in 2021.

“Back in 2021, we had three and a half decades of data to consider,” but recent years have seen “an amazing amount of progress” that has necessitated some adjustments and key additions, including several Class I recommendations, observed Roy S. Gardner, MBChB, MD, Golden Jubilee National Hospital, Clydebank, United Kingdom.

Much of that recent progress, driven by trials like EMPEROR-Preserved, DELIVER, STRONG-HF, and IRONMAN, has been crystalized into the “2023 Focused Update of the 2021 ESC Guidelines” on HF management, which Dr. Gardner helped unveil over several days at the annual congress of the European Society of Cardiology, held in Amsterdam.

The new document was also published in the European Heart Journal during the ESC sessions. Dr. Gardner is a co-author on both the 2021 and 2023 documents.

The task force that was charged with the focused update’s development “considered a large number of trials across the spectrum of acute chronic heart failure and the comorbidities associated with it,” Ultimately, it considered only those with “results that would lead to new or changed Class I or Class IIa recommendations,” noted Theresa A. McDonagh, MD, during the ESC sessions.

Dr. McDonagh, of King’s College Hospital, London, chaired the task force and led the document’s list of authors along with Marco Metra, MD, University of Brescia (Italy).
 

Chronic HF management

The 2021 document’s “beautiful algorithm” on managing HF with reduced ejection fraction, that is HF with an LVEF less than 40%, had helped enshrine the expeditious uptitration of the “four pillars” of drug therapy as a top management goal. That remains unchanged in the focused update, Dr. Gardner noted.

But the new document gives a boost to recommendations for HF with mildly reduced ejection fraction (HFmrEF), characterized by an LVEF greater than 40% to less than 50%. For that, the 2021 document recommended three of the four pillars of HF medical therapy: beta blockers, mineralocorticoid receptor antagonists (MRA), renin-angiotensin system (RAS) inhibitors.

The focused update, however, adds the fourth pillar – SGLT2 inhibitors – to core therapy for both HFmrEF and HF with preserved ejection fraction (HFpEF), the latter defined by an LVEF greater than 50%. Publication of trials supporting those new recommendations had narrowly missed availability for the 2021 document.

EMPEROR-Preserved, for example, was published during the same ESC 2021 sessions that introduced the 2021 guidelines. Its patients with HFpEF (which at the time included patients meeting the current definition of HFmrEF) assigned to the SGLT2 inhibitor empagliflozin (Jardiance) showed a 21% reduction in risk for a composite primary endpoint that was driven by the HF-hospitalization component.

“This wasn’t a fluke finding,” Dr. Gardner said, as the following year saw publication of the DELIVER trial, which resembled EMPEROR-Preserved in design and outcomes using the SGLT2 inhibitor dapagliflozin (Farxiga).

The two trials, backed up by meta-analyses that also included DAPA-HF and other studies, suggested as well that the two SGLT2 inhibitors “work across the spectrum of ejection fraction,” Dr. Gardner said.

The 2023 focused update indicates an SGLT2 inhibitor, either empagliflozin or dapagliflozin, for patients with either HFmrEF or HFpEF to reduce the risk of HF hospitalization or cardiovascular death. Both recommendations are of Class I, level of evidence A.

The new indications make SGLT2 inhibitors and diuretics (as needed for fluid retention) the only drugs for HFmrEF or HFpEF with a Class I recommendation. Previously established “rather weaker” Class IIb recommendation for RAS inhibitors, MRAs, and beta blockers that had been “based on subgroup analyses of neutral trials” remained unchanged in the focused update, Dr. McDonagh noted.
 

Patients hospitalized with HF

The 2021 guidelines had recommended that patients hospitalized with acute HF be started on evidence-based meds before discharge and that they return for evaluation 1 to 2 weeks after discharge. But the recommendation was unsupported by randomized trials.

That changed with the 2022 publication of STRONG-HF, in which a strategy of early and rapid uptitration of guideline-directed meds, initiated predischarge regardless of LVEF, led to a one-third reduced 6-month risk for death or HF readmission.

Based primarily on STRONG-HF, the focused update recommends “an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge and during frequent and careful follow-up visits in the first 6 weeks after hospitalization” to reduce readmission and mortality: Class I, level of evidence B.

“There was a large consensus around this recommendation,” said STRONG-HF principal investigator Alexandre Mebazaa, MD, PhD, a co-author of both the 2021 and 2023 documents. Conducted before the advent of the four pillars of drug therapy, sometimes called quartet therapy, the trial’s requirement for evidence-based meds didn’t include SGLT2 inhibitors.

The new focused update considers the new status of those agents, especially with regard to their benefits independent of LVEF. So, it completed the quartet by adding empagliflozin or dapagliflozin to the agents that should be initiated predischarge, observed Dr. Mebazaa, University Hospitals Saint Louis‐Lariboisière, Paris, at the focused-update’s ESC 2023 sessions.

The new document also follows STRONG-HF with its emphasis on “frequent and careful follow-up” by recommending certain clinical and laboratory evaluations known to be prognostic in HF. They include congestion status, blood pressure, heart rate, natriuretic peptide (NT-proBNP) and potassium levels and estimated glomerular filtration rate.

Dr. Mebazaa stressed the importance of monitoring NT-proBNP after discharge. “What we saw in STRONG-HF is that sometimes the clinical signs do not necessarily tell you that the patient is still congested.”

After discharge, he said, NT-proBNP levels “should only go down.” So, knowing whether NT-proBNP levels “are stable or increasing” during the med optimization process can help guide diuretic dosing.
 

HF with comorbidities

The new document includes two new Class I recommendations for patients with HF and both type 2 diabetes and chronic kidney disease based on several recent randomized trials and meta-analyses.

The focused update recommends SGLT2 inhibitors as well as the selective, non-steroidal MRA finerenone (Kerendia) in HF patients with CKD and type-2 diabetes. Both Class I recommendations are supported by a level of evidence A.

The SGLT2 indication is based on DAPA-CKD and EMPA-KIDNEY plus meta-analyses that included those trials along with others. The recommendation for finerenone derives from the FIDELIO-DKD and FIGARO-DKD trials and a pooled analysis of the two studies.

The 2023 focused update also accounts for new clinical-trial insights for patients with HF and iron deficiency. The 2021 document featured recommendations for the diagnosis and iron-repletion therapy in such cases, but only as Class IIa or at lower low levels of evidence. The focused update considers more recent studies, especially IRONMAN and some meta-analyses.

The 2023 document indicates intravenous iron supplementation for symptomatic patients with iron deficiency and either HFrEF or HFmrEF to improve symptoms and quality of life (Class I, level of evidence A), and says it should be considered (Class IIa, level of evidence A) to reduce risk for HF hospitalization.

When the task force assembled to plan the 2023 focused update, Dr. Gardner observed, “the first thing we thought about was the nomenclature around the phenotyping of heart failure.”

Although the 2021 guidelines relied fundamentally on the distinctions between HFrEF, HFmrEF, and HFpEF, it had become apparent to some in the field that some meds, especially the SGLT2 inhibitors, were obscuring their LVEF-based boundaries, at least with respect to drug therapy.

The 2023 document’s developers, Dr. Gardner said, seriously considered changing the three categories to two, that is HFrEF and – to account for all other heart failure – HF with normal ejection fraction (HFnEF).

That didn’t happen, although the proposal was popular within the task force. Any changes to the 2021 document would require a 75% consensus on the matter, Dr. Gardner explained. When the task force took a vote on whether to change the nomenclature, he said, 71% favored the proposal.

Disclosures for members of the task force can be found in a supplement to the published 2023 Focused Update.

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

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

INTRODUCTION

Lymphadenopathy in Chronic Lymphocytic Leukemia (CLL) is a very common feature. However, sudden increase in lymphadenopathy or other symptoms like weight loss should be evaluated for possible metastatic malignancy. We describe a CLL patient with diffuse mediastinal lymphadenopathy who was diagnosed with metastatic bladder cancer without a primary bladder tumor mass on imaging.

CASE DESCRIPTION

A 60-year-old man with a 60 pack-year smoking history, alcoholic cirrhosis, and a 5-year history of stage 1 CLL presented with 3 months of progressive shortness of breath; persistent cough; chills; hemoptysis; and a steady weight loss of 35 lbs. Notably, he had no bladder symptoms. Initial labs showed leukocytosis of 35.8k with a lymphocytic predominance. Screening low-dose chest CT was positive for diffuse mediastinal lymphadenopathy. Subsequent PET/CT revealed numerous hypermetabolic lymph nodes in the neck, mediastinum, left hilum, and right periaortic abdominal region. CT Chest, Abdomen, Pelvis revealed progressive lymphadenopathy as seen in prior imaging, stable pulmonary nodules up to 4 mm in size, and splenomegaly. No distant primary sites, including of the bladder, were identified. Mediastinal lymph node biopsy confirmed metastatic poorly differentiated carcinoma with immunohistochemical staining negative for p40, p63, CK20, TTF-1, Napsin A, CDX2, CA19- 9, Calretinin, and D2-40 and positive for CK7, GATA3, Ber-EP4, and Uroplakin, supporting bladder as primary origin. Urology deferred a cystoscopy given his lack of urinary symptoms and positive biopsy and was started on Carboplatin/Gemcitabine for his metastatic disease. He was ineligible for Cisplatin given his cirrhosis and hearing impairment.

DISCUSSION

In patients with CLL, new onset mediastinal lymphadenopathy is concerning for disease progression and possible transformation to a diffuse b-cell lymphoma. However, this symptom has a broad differential, including primary lung carcinomas, sarcomas, and metastatic disease. While our patient’s PET/CT and pan-CT failed to identify a distant primary site, maintaining a low clinical suspicion for metastatic disease and doing a thorough work-up was paramount. Only through immunohistochemical staining were we able to diagnosis this patient with urothelial carcinoma.

CONCLUSIONS

Biopsy with immunohistochemical staining and maintaining a low suspicion for worsening lymphadenopathy can identify unusually presenting urothelial carcinomas in CLL patients.

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

FROM SOHO 2023

It may be possible for patients with Hodgkin lymphoma to safely skip their interim PET-CT scan (PET2) following two cycles of frontline brentuximab vedotin (Adcetris), according to research presented at the annual meeting of the Society of Hematologic Oncology in Houston.

Data from four recent studies indicate that adding frontline brentuximab vedotin to AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) improves outcomes for patients, regardless of PET2 scan results, according to lead investigator Ravand Samaeekia, MD, MSc, from Loma Linda (Calif.) University Medical Center.

These studies, including one conducted by Dr. Samaeekia’s team, provide “evidence for the safe omission of PET2 in treatment regimens that contain brentuximab vedotin,” Dr. Samaeekia, who presented the data, concluded.

Performing an interim PET-CT scan after two cycles of chemotherapy can help oncologists adapt treatment protocols for patients with Hodgkin lymphoma and has become the standard of care for these patients.

However, “there are obviously challenges associated with implementing a PET-guided approach,” said Dr. Samaeekia. Additional PET-CT scans can be costly, time consuming, and increase patients’ risk for toxicities when treatment is escalated based on the scan results.

Given these caveats, Dr. Samaeekia reviewed data exploring whether PET2 has predictive value for patients who receive the anti-CD30 antibody-drug conjugate, brentuximab vedotin, as part of first-line treatment alongside AVD chemotherapy.

Dr. Samaeekia’s team analyzed findings from three trials – ECHELON-1, AHOD1331, and BREACH – which assessed frontline standard of care chemotherapy with or without brentuximab. The team found that incorporating brentuximab into frontline treatment resulted in superior efficacy, and PET2 scans results generally did not change how patients were managed.

In ECHELON-1, 6-year overall survival favored patients with advanced Hodgkin lymphoma who received brentuximab and were PET2 negative (94.9% vs. 90.6%; hazard ratio for death, 0.54) as well as those who were PET2 positive (95% vs. 77%; HR, 0.16). Overall, just over 2% of patients who received the brentuximab regimen switched to an alternative chemotherapy and even fewer did so based on PET2 results.

In AHOD1331, 3-year event-free survival was significantly higher among adolescents and children with Hodgkin lymphoma who received brentuximab – 90.7% for those who had slow-responding lesions and 92.3% for those with rapid-responding lesions. Based on these results, the authors concluded that adding brentuximab “eliminated the predictive value of the interim PET assessment.” The BREACH trial echoed the findings from ECHELON-1 and AHOD1331.

Finally, in a retrospective study of 40 patients treated at Loma Linda with brentuximab vedotin plus AVD, Dr. Samaeekia and colleagues found that 24 were PET2 negative and 12 were PET2 positive. All patients who were PET2 negative remained negative on the end-of-treatment PET, indicating no cancer progression. Of the 12 PET2-positive patients, four (33%) remained PET positive at the end of treatment. Only one patient overall changed regimens following PET2.

Dr. Samaeekia’s team concluded that PET2 scan results “did not have any meaningful impact” on patient management or outcomes.

During the Q&A, Martin Hutchings, MD, PhD, challenged the idea that PET2 can be omitted. Dr. Hutchings, from the Rigshospitalet in Copenhagen, pointed out that 4 of the 12 PET2-positive patients treated at Loma Linda were still PET positive at the end of treatment.

Even so, Dr. Samaeekia explained, PET2 findings did not alter treatment for most patients, noting that doing a PET2 scan may make “us feel better,” but it ultimately doesn’t “make any difference in our management.”

In the AHOD1331 study, “the findings on the interim PET scan were not helpful in the ultimate outcome, whether it was either positive or negative,” added session comoderator Jonathan W. Friedberg, MD, MMSc, director of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.) Medical Center.

The study by Dr. Samaeekia and colleagues was internally funded. Dr. Samaeekia reports no relevant financial relationships. Dr. Hutchings has previously reported consultancy and research funding from numerous companies. Dr. Friedberg reports no relevant financial relationships.

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

FROM SOHO 2023

It may be possible for patients with Hodgkin lymphoma to safely skip their interim PET-CT scan (PET2) following two cycles of frontline brentuximab vedotin (Adcetris), according to research presented at the annual meeting of the Society of Hematologic Oncology in Houston.

Data from four recent studies indicate that adding frontline brentuximab vedotin to AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) improves outcomes for patients, regardless of PET2 scan results, according to lead investigator Ravand Samaeekia, MD, MSc, from Loma Linda (Calif.) University Medical Center.

These studies, including one conducted by Dr. Samaeekia’s team, provide “evidence for the safe omission of PET2 in treatment regimens that contain brentuximab vedotin,” Dr. Samaeekia, who presented the data, concluded.

Performing an interim PET-CT scan after two cycles of chemotherapy can help oncologists adapt treatment protocols for patients with Hodgkin lymphoma and has become the standard of care for these patients.

However, “there are obviously challenges associated with implementing a PET-guided approach,” said Dr. Samaeekia. Additional PET-CT scans can be costly, time consuming, and increase patients’ risk for toxicities when treatment is escalated based on the scan results.

Given these caveats, Dr. Samaeekia reviewed data exploring whether PET2 has predictive value for patients who receive the anti-CD30 antibody-drug conjugate, brentuximab vedotin, as part of first-line treatment alongside AVD chemotherapy.

Dr. Samaeekia’s team analyzed findings from three trials – ECHELON-1, AHOD1331, and BREACH – which assessed frontline standard of care chemotherapy with or without brentuximab. The team found that incorporating brentuximab into frontline treatment resulted in superior efficacy, and PET2 scans results generally did not change how patients were managed.

In ECHELON-1, 6-year overall survival favored patients with advanced Hodgkin lymphoma who received brentuximab and were PET2 negative (94.9% vs. 90.6%; hazard ratio for death, 0.54) as well as those who were PET2 positive (95% vs. 77%; HR, 0.16). Overall, just over 2% of patients who received the brentuximab regimen switched to an alternative chemotherapy and even fewer did so based on PET2 results.

In AHOD1331, 3-year event-free survival was significantly higher among adolescents and children with Hodgkin lymphoma who received brentuximab – 90.7% for those who had slow-responding lesions and 92.3% for those with rapid-responding lesions. Based on these results, the authors concluded that adding brentuximab “eliminated the predictive value of the interim PET assessment.” The BREACH trial echoed the findings from ECHELON-1 and AHOD1331.

Finally, in a retrospective study of 40 patients treated at Loma Linda with brentuximab vedotin plus AVD, Dr. Samaeekia and colleagues found that 24 were PET2 negative and 12 were PET2 positive. All patients who were PET2 negative remained negative on the end-of-treatment PET, indicating no cancer progression. Of the 12 PET2-positive patients, four (33%) remained PET positive at the end of treatment. Only one patient overall changed regimens following PET2.

Dr. Samaeekia’s team concluded that PET2 scan results “did not have any meaningful impact” on patient management or outcomes.

During the Q&A, Martin Hutchings, MD, PhD, challenged the idea that PET2 can be omitted. Dr. Hutchings, from the Rigshospitalet in Copenhagen, pointed out that 4 of the 12 PET2-positive patients treated at Loma Linda were still PET positive at the end of treatment.

Even so, Dr. Samaeekia explained, PET2 findings did not alter treatment for most patients, noting that doing a PET2 scan may make “us feel better,” but it ultimately doesn’t “make any difference in our management.”

In the AHOD1331 study, “the findings on the interim PET scan were not helpful in the ultimate outcome, whether it was either positive or negative,” added session comoderator Jonathan W. Friedberg, MD, MMSc, director of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.) Medical Center.

The study by Dr. Samaeekia and colleagues was internally funded. Dr. Samaeekia reports no relevant financial relationships. Dr. Hutchings has previously reported consultancy and research funding from numerous companies. Dr. Friedberg reports no relevant financial relationships.

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

FROM SOHO 2023

It may be possible for patients with Hodgkin lymphoma to safely skip their interim PET-CT scan (PET2) following two cycles of frontline brentuximab vedotin (Adcetris), according to research presented at the annual meeting of the Society of Hematologic Oncology in Houston.

Data from four recent studies indicate that adding frontline brentuximab vedotin to AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) improves outcomes for patients, regardless of PET2 scan results, according to lead investigator Ravand Samaeekia, MD, MSc, from Loma Linda (Calif.) University Medical Center.

These studies, including one conducted by Dr. Samaeekia’s team, provide “evidence for the safe omission of PET2 in treatment regimens that contain brentuximab vedotin,” Dr. Samaeekia, who presented the data, concluded.

Performing an interim PET-CT scan after two cycles of chemotherapy can help oncologists adapt treatment protocols for patients with Hodgkin lymphoma and has become the standard of care for these patients.

However, “there are obviously challenges associated with implementing a PET-guided approach,” said Dr. Samaeekia. Additional PET-CT scans can be costly, time consuming, and increase patients’ risk for toxicities when treatment is escalated based on the scan results.

Given these caveats, Dr. Samaeekia reviewed data exploring whether PET2 has predictive value for patients who receive the anti-CD30 antibody-drug conjugate, brentuximab vedotin, as part of first-line treatment alongside AVD chemotherapy.

Dr. Samaeekia’s team analyzed findings from three trials – ECHELON-1, AHOD1331, and BREACH – which assessed frontline standard of care chemotherapy with or without brentuximab. The team found that incorporating brentuximab into frontline treatment resulted in superior efficacy, and PET2 scans results generally did not change how patients were managed.

In ECHELON-1, 6-year overall survival favored patients with advanced Hodgkin lymphoma who received brentuximab and were PET2 negative (94.9% vs. 90.6%; hazard ratio for death, 0.54) as well as those who were PET2 positive (95% vs. 77%; HR, 0.16). Overall, just over 2% of patients who received the brentuximab regimen switched to an alternative chemotherapy and even fewer did so based on PET2 results.

In AHOD1331, 3-year event-free survival was significantly higher among adolescents and children with Hodgkin lymphoma who received brentuximab – 90.7% for those who had slow-responding lesions and 92.3% for those with rapid-responding lesions. Based on these results, the authors concluded that adding brentuximab “eliminated the predictive value of the interim PET assessment.” The BREACH trial echoed the findings from ECHELON-1 and AHOD1331.

Finally, in a retrospective study of 40 patients treated at Loma Linda with brentuximab vedotin plus AVD, Dr. Samaeekia and colleagues found that 24 were PET2 negative and 12 were PET2 positive. All patients who were PET2 negative remained negative on the end-of-treatment PET, indicating no cancer progression. Of the 12 PET2-positive patients, four (33%) remained PET positive at the end of treatment. Only one patient overall changed regimens following PET2.

Dr. Samaeekia’s team concluded that PET2 scan results “did not have any meaningful impact” on patient management or outcomes.

During the Q&A, Martin Hutchings, MD, PhD, challenged the idea that PET2 can be omitted. Dr. Hutchings, from the Rigshospitalet in Copenhagen, pointed out that 4 of the 12 PET2-positive patients treated at Loma Linda were still PET positive at the end of treatment.

Even so, Dr. Samaeekia explained, PET2 findings did not alter treatment for most patients, noting that doing a PET2 scan may make “us feel better,” but it ultimately doesn’t “make any difference in our management.”

In the AHOD1331 study, “the findings on the interim PET scan were not helpful in the ultimate outcome, whether it was either positive or negative,” added session comoderator Jonathan W. Friedberg, MD, MMSc, director of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.) Medical Center.

The study by Dr. Samaeekia and colleagues was internally funded. Dr. Samaeekia reports no relevant financial relationships. Dr. Hutchings has previously reported consultancy and research funding from numerous companies. Dr. Friedberg reports no relevant financial relationships.

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