Arcutis Biotherapeutics has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Administration for roflumilast cream 0.15% for the treatment of mild to moderate atopic dermatitis (AD) in adults and children aged 6 years and older.

Roflumilast cream 0.3% (Zoryve) is currently approved by the FDA for the topical treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age and older. Submission of the sNDA is based on positive results from the Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis (INTEGUMENT-1 and INTEGUMENT-2) trials; two identical Phase 3, vehicle-controlled trials in which roflumilast cream 0.15% or vehicle was applied once daily for 4 weeks to individuals 6 years of age and older with mild to moderate AD involving at least 3% body surface area. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor.

According to a press release from Arcutis, both studies met the primary endpoint of IGA Success, which was defined as a validated Investigator Global Assessment – Atopic Dermatitis (vIGA-AD) score of ‘clear’ or ‘almost clear’ plus a 2-grade improvement from baseline at week 4. In INTEGUMENT-1 this endpoint was achieved by 32.0% of subjects in the roflumilast cream group vs. 15.2% of those in the vehicle group (P < .0001). In INTEGUMENT-2, this endpoint was achieved by 28.9% of subjects in the roflumilast cream group vs. 12.0% of those in the vehicle group (P < .0001). The most common adverse reactions based on data from the combined trials were headache (2.9%), nausea (1.9%), application-site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

Arcutis Biotherapeutics has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Administration for roflumilast cream 0.15% for the treatment of mild to moderate atopic dermatitis (AD) in adults and children aged 6 years and older.

Roflumilast cream 0.3% (Zoryve) is currently approved by the FDA for the topical treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age and older. Submission of the sNDA is based on positive results from the Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis (INTEGUMENT-1 and INTEGUMENT-2) trials; two identical Phase 3, vehicle-controlled trials in which roflumilast cream 0.15% or vehicle was applied once daily for 4 weeks to individuals 6 years of age and older with mild to moderate AD involving at least 3% body surface area. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor.

According to a press release from Arcutis, both studies met the primary endpoint of IGA Success, which was defined as a validated Investigator Global Assessment – Atopic Dermatitis (vIGA-AD) score of ‘clear’ or ‘almost clear’ plus a 2-grade improvement from baseline at week 4. In INTEGUMENT-1 this endpoint was achieved by 32.0% of subjects in the roflumilast cream group vs. 15.2% of those in the vehicle group (P < .0001). In INTEGUMENT-2, this endpoint was achieved by 28.9% of subjects in the roflumilast cream group vs. 12.0% of those in the vehicle group (P < .0001). The most common adverse reactions based on data from the combined trials were headache (2.9%), nausea (1.9%), application-site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

Arcutis Biotherapeutics has submitted a supplemental New Drug Application (sNDA) to the Food and Drug Administration for roflumilast cream 0.15% for the treatment of mild to moderate atopic dermatitis (AD) in adults and children aged 6 years and older.

Roflumilast cream 0.3% (Zoryve) is currently approved by the FDA for the topical treatment of plaque psoriasis, including intertriginous areas, in patients 12 years of age and older. Submission of the sNDA is based on positive results from the Interventional Trial Evaluating Roflumilast Cream for the Treatment of Atopic Dermatitis (INTEGUMENT-1 and INTEGUMENT-2) trials; two identical Phase 3, vehicle-controlled trials in which roflumilast cream 0.15% or vehicle was applied once daily for 4 weeks to individuals 6 years of age and older with mild to moderate AD involving at least 3% body surface area. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor.

According to a press release from Arcutis, both studies met the primary endpoint of IGA Success, which was defined as a validated Investigator Global Assessment – Atopic Dermatitis (vIGA-AD) score of ‘clear’ or ‘almost clear’ plus a 2-grade improvement from baseline at week 4. In INTEGUMENT-1 this endpoint was achieved by 32.0% of subjects in the roflumilast cream group vs. 15.2% of those in the vehicle group (P < .0001). In INTEGUMENT-2, this endpoint was achieved by 28.9% of subjects in the roflumilast cream group vs. 12.0% of those in the vehicle group (P < .0001). The most common adverse reactions based on data from the combined trials were headache (2.9%), nausea (1.9%), application-site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

A very good thing happened this summer for patients with anxiety and the psychiatrists, psychologists, and other mental health professionals who provide treatment for them. The U.S. Preventive Services Task Force recommended anxiety screening for all adults younger than 65.

On the surface, this is a great recommendation for recognition and caring for those who deal with and suffer from an anxiety disorder or multiple anxiety disorders. Although the USPSTF recommendations are independent of the U.S. government and are not an official position of the Department of Health & Human Services, they are a wonderful start at recognizing the importance of mental health care.

Robert T. London

After all, anxiety disorders are the most commonly experienced and diagnosed mental disorders, according to the DSM-5.

They range mainly from generalized anxiety disorder (GAD), to panic attacks and panic disorder, separation anxiety, specific type phobias (bridges, tunnels, insects, snakes, and the list goes on), to other phobias, including agoraphobia, social phobia, and of course, anxiety caused by medical conditions. GAD alone occurs in, at least, more than 3% of the population.

Those of us who have been treating anxiety disorders for decades recognize them as an issue affecting both mental and physical well-being, not only because of the emotional causes but the physical distress and illnesses that anxiety may precipitate or worsen.

For example, blood pressure– and heart-related issues, GI disorders, and musculoskeletal issues are just a few examples of how our bodies and organ systems are affected by anxiety. Just the momentary physical symptoms of tachycardia or the “runs” before an exam are fine examples of how anxiety may affect patients physically, and an ongoing, consistent anxiety is potentially more harmful.

In fact, a first panic attack or episode of generalized anxiety may be so serious that an emergency department or physician visit is necessary to rule out a heart attack, asthma, or breathing issues – even a hormone or thyroid emergency, or a cardiac arrhythmia. Panic attacks alone create a high number of ED visits.

Treatments mainly include medication management and a variety of psychotherapy techniques. Currently, the most preferred, first-choice medications are the SSRI antidepressants, which are Food and Drug Administration approved for anxiety as well. These include Zoloft (sertraline), Prozac/Sarafem (fluoxetine), Celexa (citalopram), and Lexapro (escitalopram).

For many years, benzodiazepines (that is, tranquillizers) such as Valium (diazepam), Ativan (lorazepam), and Klonopin/Rivotril (clonazepam) to name a few, were the mainstay of anxiety treatment, but they have proven addictive and may affect cognition and memory. As the current opioid epidemic has shown, when combined with opioids, benzodiazepines are a potentially lethal combination and when used, they need to be for shorter-term care and monitored very judiciously.

It should be noted that after ongoing long-term use of an SSRI for anxiety or depression, it should not be stopped abruptly, as a variety of physical symptoms (for example, flu-like symptoms) may occur.
 

Benefits of nonmedicinal therapies

There are a variety of talk therapies, from dynamic psychotherapies to cognitive-behavioral therapies (CBT), plus relaxation techniques and guided imagery that have all had a good amount of success in treating generalized anxiety, panic disorder, as well as various types of phobias.

When medications are stopped, the anxiety symptoms may well return. But when using nonmedicinal therapies, clinicians have discovered that when patients develop a new perspective on the anxiety problem or have a new technique to treat anxiety, it may well be long lasting.

For me, using CBT, relaxation techniques, hypnosis, and guided imagery has been very successful in treating anxiety disorders with long-lasting results. Once a person learns to relax, whether it’s from deep breathing exercises, hypnosis (which is not sleep), mindfulness, or meditation, a strategy of guided imagery can be taught, which allows a person to practice as well as control their anxiety as a lifetime process. For example, I like imagining a large movie screen to desensitize and project anxieties.

In many instances, a combination of a medication and a talk therapy approach works best, but there are an equal number of instances in which just medication or just talk therapy is needed. Once again, knowledge, clinical judgment, and the art of care are required to make these assessments.

In other words, recognizing and treating anxiety requires highly specialized training, which is why I thought the USPSTF recommendations raise a few critical questions.
 

Questions and concerns

One issue, of course, is the exclusion of those patients over age 65 because of a lack of “data.” Why such an exclusion? Does this mean that data are lacking for this age group?

The concept of using solely evidenced-based data in psychiatry is itself an interesting concept because our profession, like many other medical specialties, requires practitioners to use a combination of art and science. And much can be said either way about the clarity of accuracy in the diversity of issues that arise when treating emotional disorders.

When looking at the over-65 population, has anyone thought of clinical knowledge, judgment, experience, observation, and, of course, common sense?

Just consider the worry (a cardinal feature of anxiety) that besets people over 65 when it comes to issues such as retirement, financial security, “empty nesting,” physical health issues, decreased socialization that resulted from the COVID-19 pandemic, and the perpetual loss of relatives and friends.

In addition, as we age, anxiety can come simply from the loss of identity as active lifestyles decrease and the reality of nearing life’s end becomes more of a reality. It would seem that this population would benefit enormously from anxiety screening and possible treatment.

Another major concern is that the screening and potential treatment of patients is aimed at primary care physicians. Putting the sole responsibility of providing mental health care on these overworked PCPs defies common sense unless we’re okay with 1- to 2-minute assessments of mental health issues and no doubt, a pharmacology-only approach.

If this follows the same route as well-intentioned PCPs treating depression, where 5-minute medication management is far too common, the only proper diagnostic course – the in-depth interview necessary to make a proper diagnosis – is often missing.

For example, in depression alone, it takes psychiatric experience and time to differentiate a major depressive disorder from a bipolar depression and to provide the appropriate medication and treatment plan with careful follow-up. In my experience, this usually does not happen in the exceedingly overworked, time-driven day of a PCP.

Anxiety disorders and depression can prove debilitating, and if a PCP wants the responsibility of treatment, a mandated mental health program should be followed – just as here in New York, prescribers are mandated to take a pain control, opioid, and infection control CME course to keep our licenses up to date.

Short of mandating a mental health program for PCPs, it should be part of training and CME courses that whenever PCPs diagnose a mental illness, a proper referral to a psychiatrist or psychologist should be made – whether for a consultation or for shared care. Psychiatry is a super specialty, much like orthopedics and ophthalmology, and primary care physicians should never hesitate to make referrals to the specialist.

The big picture for me, and I hope for us all, is that the USPSTF has started things rolling by making it clear that PCPs and other health care clinicians need to screen for anxiety as a disabling disorder that is quite treatable.

This approach will help to advance the destigmatization of mental health disorders. But as result, with more patients diagnosed, there will be a need for more psychiatrists – and psychologists with PhDs or PsyDs – to fill the gaps in mental health care.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

A very good thing happened this summer for patients with anxiety and the psychiatrists, psychologists, and other mental health professionals who provide treatment for them. The U.S. Preventive Services Task Force recommended anxiety screening for all adults younger than 65.

On the surface, this is a great recommendation for recognition and caring for those who deal with and suffer from an anxiety disorder or multiple anxiety disorders. Although the USPSTF recommendations are independent of the U.S. government and are not an official position of the Department of Health & Human Services, they are a wonderful start at recognizing the importance of mental health care.

Robert T. London

After all, anxiety disorders are the most commonly experienced and diagnosed mental disorders, according to the DSM-5.

They range mainly from generalized anxiety disorder (GAD), to panic attacks and panic disorder, separation anxiety, specific type phobias (bridges, tunnels, insects, snakes, and the list goes on), to other phobias, including agoraphobia, social phobia, and of course, anxiety caused by medical conditions. GAD alone occurs in, at least, more than 3% of the population.

Those of us who have been treating anxiety disorders for decades recognize them as an issue affecting both mental and physical well-being, not only because of the emotional causes but the physical distress and illnesses that anxiety may precipitate or worsen.

For example, blood pressure– and heart-related issues, GI disorders, and musculoskeletal issues are just a few examples of how our bodies and organ systems are affected by anxiety. Just the momentary physical symptoms of tachycardia or the “runs” before an exam are fine examples of how anxiety may affect patients physically, and an ongoing, consistent anxiety is potentially more harmful.

In fact, a first panic attack or episode of generalized anxiety may be so serious that an emergency department or physician visit is necessary to rule out a heart attack, asthma, or breathing issues – even a hormone or thyroid emergency, or a cardiac arrhythmia. Panic attacks alone create a high number of ED visits.

Treatments mainly include medication management and a variety of psychotherapy techniques. Currently, the most preferred, first-choice medications are the SSRI antidepressants, which are Food and Drug Administration approved for anxiety as well. These include Zoloft (sertraline), Prozac/Sarafem (fluoxetine), Celexa (citalopram), and Lexapro (escitalopram).

For many years, benzodiazepines (that is, tranquillizers) such as Valium (diazepam), Ativan (lorazepam), and Klonopin/Rivotril (clonazepam) to name a few, were the mainstay of anxiety treatment, but they have proven addictive and may affect cognition and memory. As the current opioid epidemic has shown, when combined with opioids, benzodiazepines are a potentially lethal combination and when used, they need to be for shorter-term care and monitored very judiciously.

It should be noted that after ongoing long-term use of an SSRI for anxiety or depression, it should not be stopped abruptly, as a variety of physical symptoms (for example, flu-like symptoms) may occur.
 

Benefits of nonmedicinal therapies

There are a variety of talk therapies, from dynamic psychotherapies to cognitive-behavioral therapies (CBT), plus relaxation techniques and guided imagery that have all had a good amount of success in treating generalized anxiety, panic disorder, as well as various types of phobias.

When medications are stopped, the anxiety symptoms may well return. But when using nonmedicinal therapies, clinicians have discovered that when patients develop a new perspective on the anxiety problem or have a new technique to treat anxiety, it may well be long lasting.

For me, using CBT, relaxation techniques, hypnosis, and guided imagery has been very successful in treating anxiety disorders with long-lasting results. Once a person learns to relax, whether it’s from deep breathing exercises, hypnosis (which is not sleep), mindfulness, or meditation, a strategy of guided imagery can be taught, which allows a person to practice as well as control their anxiety as a lifetime process. For example, I like imagining a large movie screen to desensitize and project anxieties.

In many instances, a combination of a medication and a talk therapy approach works best, but there are an equal number of instances in which just medication or just talk therapy is needed. Once again, knowledge, clinical judgment, and the art of care are required to make these assessments.

In other words, recognizing and treating anxiety requires highly specialized training, which is why I thought the USPSTF recommendations raise a few critical questions.
 

Questions and concerns

One issue, of course, is the exclusion of those patients over age 65 because of a lack of “data.” Why such an exclusion? Does this mean that data are lacking for this age group?

The concept of using solely evidenced-based data in psychiatry is itself an interesting concept because our profession, like many other medical specialties, requires practitioners to use a combination of art and science. And much can be said either way about the clarity of accuracy in the diversity of issues that arise when treating emotional disorders.

When looking at the over-65 population, has anyone thought of clinical knowledge, judgment, experience, observation, and, of course, common sense?

Just consider the worry (a cardinal feature of anxiety) that besets people over 65 when it comes to issues such as retirement, financial security, “empty nesting,” physical health issues, decreased socialization that resulted from the COVID-19 pandemic, and the perpetual loss of relatives and friends.

In addition, as we age, anxiety can come simply from the loss of identity as active lifestyles decrease and the reality of nearing life’s end becomes more of a reality. It would seem that this population would benefit enormously from anxiety screening and possible treatment.

Another major concern is that the screening and potential treatment of patients is aimed at primary care physicians. Putting the sole responsibility of providing mental health care on these overworked PCPs defies common sense unless we’re okay with 1- to 2-minute assessments of mental health issues and no doubt, a pharmacology-only approach.

If this follows the same route as well-intentioned PCPs treating depression, where 5-minute medication management is far too common, the only proper diagnostic course – the in-depth interview necessary to make a proper diagnosis – is often missing.

For example, in depression alone, it takes psychiatric experience and time to differentiate a major depressive disorder from a bipolar depression and to provide the appropriate medication and treatment plan with careful follow-up. In my experience, this usually does not happen in the exceedingly overworked, time-driven day of a PCP.

Anxiety disorders and depression can prove debilitating, and if a PCP wants the responsibility of treatment, a mandated mental health program should be followed – just as here in New York, prescribers are mandated to take a pain control, opioid, and infection control CME course to keep our licenses up to date.

Short of mandating a mental health program for PCPs, it should be part of training and CME courses that whenever PCPs diagnose a mental illness, a proper referral to a psychiatrist or psychologist should be made – whether for a consultation or for shared care. Psychiatry is a super specialty, much like orthopedics and ophthalmology, and primary care physicians should never hesitate to make referrals to the specialist.

The big picture for me, and I hope for us all, is that the USPSTF has started things rolling by making it clear that PCPs and other health care clinicians need to screen for anxiety as a disabling disorder that is quite treatable.

This approach will help to advance the destigmatization of mental health disorders. But as result, with more patients diagnosed, there will be a need for more psychiatrists – and psychologists with PhDs or PsyDs – to fill the gaps in mental health care.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

A very good thing happened this summer for patients with anxiety and the psychiatrists, psychologists, and other mental health professionals who provide treatment for them. The U.S. Preventive Services Task Force recommended anxiety screening for all adults younger than 65.

On the surface, this is a great recommendation for recognition and caring for those who deal with and suffer from an anxiety disorder or multiple anxiety disorders. Although the USPSTF recommendations are independent of the U.S. government and are not an official position of the Department of Health & Human Services, they are a wonderful start at recognizing the importance of mental health care.

Robert T. London

After all, anxiety disorders are the most commonly experienced and diagnosed mental disorders, according to the DSM-5.

They range mainly from generalized anxiety disorder (GAD), to panic attacks and panic disorder, separation anxiety, specific type phobias (bridges, tunnels, insects, snakes, and the list goes on), to other phobias, including agoraphobia, social phobia, and of course, anxiety caused by medical conditions. GAD alone occurs in, at least, more than 3% of the population.

Those of us who have been treating anxiety disorders for decades recognize them as an issue affecting both mental and physical well-being, not only because of the emotional causes but the physical distress and illnesses that anxiety may precipitate or worsen.

For example, blood pressure– and heart-related issues, GI disorders, and musculoskeletal issues are just a few examples of how our bodies and organ systems are affected by anxiety. Just the momentary physical symptoms of tachycardia or the “runs” before an exam are fine examples of how anxiety may affect patients physically, and an ongoing, consistent anxiety is potentially more harmful.

In fact, a first panic attack or episode of generalized anxiety may be so serious that an emergency department or physician visit is necessary to rule out a heart attack, asthma, or breathing issues – even a hormone or thyroid emergency, or a cardiac arrhythmia. Panic attacks alone create a high number of ED visits.

Treatments mainly include medication management and a variety of psychotherapy techniques. Currently, the most preferred, first-choice medications are the SSRI antidepressants, which are Food and Drug Administration approved for anxiety as well. These include Zoloft (sertraline), Prozac/Sarafem (fluoxetine), Celexa (citalopram), and Lexapro (escitalopram).

For many years, benzodiazepines (that is, tranquillizers) such as Valium (diazepam), Ativan (lorazepam), and Klonopin/Rivotril (clonazepam) to name a few, were the mainstay of anxiety treatment, but they have proven addictive and may affect cognition and memory. As the current opioid epidemic has shown, when combined with opioids, benzodiazepines are a potentially lethal combination and when used, they need to be for shorter-term care and monitored very judiciously.

It should be noted that after ongoing long-term use of an SSRI for anxiety or depression, it should not be stopped abruptly, as a variety of physical symptoms (for example, flu-like symptoms) may occur.
 

Benefits of nonmedicinal therapies

There are a variety of talk therapies, from dynamic psychotherapies to cognitive-behavioral therapies (CBT), plus relaxation techniques and guided imagery that have all had a good amount of success in treating generalized anxiety, panic disorder, as well as various types of phobias.

When medications are stopped, the anxiety symptoms may well return. But when using nonmedicinal therapies, clinicians have discovered that when patients develop a new perspective on the anxiety problem or have a new technique to treat anxiety, it may well be long lasting.

For me, using CBT, relaxation techniques, hypnosis, and guided imagery has been very successful in treating anxiety disorders with long-lasting results. Once a person learns to relax, whether it’s from deep breathing exercises, hypnosis (which is not sleep), mindfulness, or meditation, a strategy of guided imagery can be taught, which allows a person to practice as well as control their anxiety as a lifetime process. For example, I like imagining a large movie screen to desensitize and project anxieties.

In many instances, a combination of a medication and a talk therapy approach works best, but there are an equal number of instances in which just medication or just talk therapy is needed. Once again, knowledge, clinical judgment, and the art of care are required to make these assessments.

In other words, recognizing and treating anxiety requires highly specialized training, which is why I thought the USPSTF recommendations raise a few critical questions.
 

Questions and concerns

One issue, of course, is the exclusion of those patients over age 65 because of a lack of “data.” Why such an exclusion? Does this mean that data are lacking for this age group?

The concept of using solely evidenced-based data in psychiatry is itself an interesting concept because our profession, like many other medical specialties, requires practitioners to use a combination of art and science. And much can be said either way about the clarity of accuracy in the diversity of issues that arise when treating emotional disorders.

When looking at the over-65 population, has anyone thought of clinical knowledge, judgment, experience, observation, and, of course, common sense?

Just consider the worry (a cardinal feature of anxiety) that besets people over 65 when it comes to issues such as retirement, financial security, “empty nesting,” physical health issues, decreased socialization that resulted from the COVID-19 pandemic, and the perpetual loss of relatives and friends.

In addition, as we age, anxiety can come simply from the loss of identity as active lifestyles decrease and the reality of nearing life’s end becomes more of a reality. It would seem that this population would benefit enormously from anxiety screening and possible treatment.

Another major concern is that the screening and potential treatment of patients is aimed at primary care physicians. Putting the sole responsibility of providing mental health care on these overworked PCPs defies common sense unless we’re okay with 1- to 2-minute assessments of mental health issues and no doubt, a pharmacology-only approach.

If this follows the same route as well-intentioned PCPs treating depression, where 5-minute medication management is far too common, the only proper diagnostic course – the in-depth interview necessary to make a proper diagnosis – is often missing.

For example, in depression alone, it takes psychiatric experience and time to differentiate a major depressive disorder from a bipolar depression and to provide the appropriate medication and treatment plan with careful follow-up. In my experience, this usually does not happen in the exceedingly overworked, time-driven day of a PCP.

Anxiety disorders and depression can prove debilitating, and if a PCP wants the responsibility of treatment, a mandated mental health program should be followed – just as here in New York, prescribers are mandated to take a pain control, opioid, and infection control CME course to keep our licenses up to date.

Short of mandating a mental health program for PCPs, it should be part of training and CME courses that whenever PCPs diagnose a mental illness, a proper referral to a psychiatrist or psychologist should be made – whether for a consultation or for shared care. Psychiatry is a super specialty, much like orthopedics and ophthalmology, and primary care physicians should never hesitate to make referrals to the specialist.

The big picture for me, and I hope for us all, is that the USPSTF has started things rolling by making it clear that PCPs and other health care clinicians need to screen for anxiety as a disabling disorder that is quite treatable.

This approach will help to advance the destigmatization of mental health disorders. But as result, with more patients diagnosed, there will be a need for more psychiatrists – and psychologists with PhDs or PsyDs – to fill the gaps in mental health care.

Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.

Erythema chronicum migrans (ECM) is the classical dermatologic manifestation of Lyme disease, a condition caused by Borrelia burgdorferi, a bacterial spirochete. Lyme disease is the most commonly transmitted tick-borne illness in the United States. This infection is typically transmitted through a bite by the Ixodes tick commonly found in the Midwest, Northeast, and mid-Atlantic regions; however, the geographical distribution continues to expand over time in the United States. Ticks must be attached for 24-48 hours to transmit the pathogen. There are three general stages of the disease: early localized, early disseminated, and late disseminated.

The most common presentation is the early localized disease, which manifests between 3 and 30 days after an infected tick bite. Approximately 70%-80% of cases feature a targetlike lesion that expands centrifugally at the site of the bite. Most commonly, lesions appear on the abdomen, groin, axilla, and popliteal fossa. The diagnosis of ECM requires lesions at least 5 cm in size. Lesions may be asymptomatic, although burning may occur in half of patients. Atypical presentations include bullous, vesicular, hemorrhagic, or necrotic lesions. Up to half of patients may develop multiple ECM lesions. Palms and soles are spared. Differential diagnoses include arthropod reactions, pyoderma gangrenosum, cellulitis, herpes simplex virus and varicella zoster virus, contact dermatitis, or granuloma annulare. The rash is often accompanied by systemic symptoms including fatigue, myalgia, headache, and fever.

The next two stages include early and late disseminated infection. Early disseminated infection often occurs 3-12 weeks after infection and is characterized by muscle pain, dizziness, headache, and cardiac symptoms. CNS involvement occurs in about 20% of patients. Joint involvement may include the knee, ankle, and wrist. If symptoms are only in one joint, septic arthritis is part of the differential diagnosis, so clinical correlation and labs must be considered. Late disseminated infection occurs months or years after initial infection and includes neurologic and rheumatologic symptoms including meningitis, Bell’s palsy, arthritis, and dysesthesia. Knee arthritis is a key feature of this stage. Patients commonly have radicular pain and fibromyalgia-type pain. More severe disease processes include encephalomyelitis, arrhythmias, and heart block.

ECM is often a clinical diagnosis because serologic testing may not be positive during the first 2 weeks of infection. The screening serologic test is the ELISA, and a Western blot confirms the results. Skin histopathology for Lyme disease is often nonspecific and reveals a perivascular infiltrate of histiocytes, plasma cells, and lymphocytes. Silver stain or antibody testing may be used to identify the spirochete. In acrodermatitis chronica atrophicans, late Lyme disease presenting on the distal extremities, lymphocytic and plasma cell infiltrates are present. In borrelial lymphocytoma, a dense dermal lymphocytic infiltrate is present.

The standard for treatment of early localized disease is oral doxycycline in adults. Alternatives may be used if a patient is allergic or for children under 9. Disseminated disease may be treated with IV ceftriaxone and topical steroids are used if ocular symptoms are involved. Early treatment is often curative.

This patient’s antibodies were negative initially, but became positive after 6 weeks. He was treated empirically at the time of his office visit with doxycycline for 1 month.

This case and the photo were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Susannah Berke, MD, Three Rivers Dermatology, Coraopolis, Pa. The column was edited by Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at MDedge.com/Dermatology. To submit a case for possible publication, send an email to [email protected].

References
 

Carriveau A et al. Nurs Clin North Am. 2019 Jun;54(2):261-75.

Skar GL and Simonsen KA. Lyme Disease. [Updated 2023 May 31]. In: “StatPearls” [Internet]. Treasure Island, Fla.: StatPearls Publishing; 2023 Jan.

Tiger JB et al. J Am Acad Dermatol. 2014 Oct;71(4):e133-4.

Erythema chronicum migrans (ECM) is the classical dermatologic manifestation of Lyme disease, a condition caused by Borrelia burgdorferi, a bacterial spirochete. Lyme disease is the most commonly transmitted tick-borne illness in the United States. This infection is typically transmitted through a bite by the Ixodes tick commonly found in the Midwest, Northeast, and mid-Atlantic regions; however, the geographical distribution continues to expand over time in the United States. Ticks must be attached for 24-48 hours to transmit the pathogen. There are three general stages of the disease: early localized, early disseminated, and late disseminated.

The most common presentation is the early localized disease, which manifests between 3 and 30 days after an infected tick bite. Approximately 70%-80% of cases feature a targetlike lesion that expands centrifugally at the site of the bite. Most commonly, lesions appear on the abdomen, groin, axilla, and popliteal fossa. The diagnosis of ECM requires lesions at least 5 cm in size. Lesions may be asymptomatic, although burning may occur in half of patients. Atypical presentations include bullous, vesicular, hemorrhagic, or necrotic lesions. Up to half of patients may develop multiple ECM lesions. Palms and soles are spared. Differential diagnoses include arthropod reactions, pyoderma gangrenosum, cellulitis, herpes simplex virus and varicella zoster virus, contact dermatitis, or granuloma annulare. The rash is often accompanied by systemic symptoms including fatigue, myalgia, headache, and fever.

The next two stages include early and late disseminated infection. Early disseminated infection often occurs 3-12 weeks after infection and is characterized by muscle pain, dizziness, headache, and cardiac symptoms. CNS involvement occurs in about 20% of patients. Joint involvement may include the knee, ankle, and wrist. If symptoms are only in one joint, septic arthritis is part of the differential diagnosis, so clinical correlation and labs must be considered. Late disseminated infection occurs months or years after initial infection and includes neurologic and rheumatologic symptoms including meningitis, Bell’s palsy, arthritis, and dysesthesia. Knee arthritis is a key feature of this stage. Patients commonly have radicular pain and fibromyalgia-type pain. More severe disease processes include encephalomyelitis, arrhythmias, and heart block.

ECM is often a clinical diagnosis because serologic testing may not be positive during the first 2 weeks of infection. The screening serologic test is the ELISA, and a Western blot confirms the results. Skin histopathology for Lyme disease is often nonspecific and reveals a perivascular infiltrate of histiocytes, plasma cells, and lymphocytes. Silver stain or antibody testing may be used to identify the spirochete. In acrodermatitis chronica atrophicans, late Lyme disease presenting on the distal extremities, lymphocytic and plasma cell infiltrates are present. In borrelial lymphocytoma, a dense dermal lymphocytic infiltrate is present.

The standard for treatment of early localized disease is oral doxycycline in adults. Alternatives may be used if a patient is allergic or for children under 9. Disseminated disease may be treated with IV ceftriaxone and topical steroids are used if ocular symptoms are involved. Early treatment is often curative.

This patient’s antibodies were negative initially, but became positive after 6 weeks. He was treated empirically at the time of his office visit with doxycycline for 1 month.

This case and the photo were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Susannah Berke, MD, Three Rivers Dermatology, Coraopolis, Pa. The column was edited by Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at MDedge.com/Dermatology. To submit a case for possible publication, send an email to [email protected].

References
 

Carriveau A et al. Nurs Clin North Am. 2019 Jun;54(2):261-75.

Skar GL and Simonsen KA. Lyme Disease. [Updated 2023 May 31]. In: “StatPearls” [Internet]. Treasure Island, Fla.: StatPearls Publishing; 2023 Jan.

Tiger JB et al. J Am Acad Dermatol. 2014 Oct;71(4):e133-4.

Erythema chronicum migrans (ECM) is the classical dermatologic manifestation of Lyme disease, a condition caused by Borrelia burgdorferi, a bacterial spirochete. Lyme disease is the most commonly transmitted tick-borne illness in the United States. This infection is typically transmitted through a bite by the Ixodes tick commonly found in the Midwest, Northeast, and mid-Atlantic regions; however, the geographical distribution continues to expand over time in the United States. Ticks must be attached for 24-48 hours to transmit the pathogen. There are three general stages of the disease: early localized, early disseminated, and late disseminated.

The most common presentation is the early localized disease, which manifests between 3 and 30 days after an infected tick bite. Approximately 70%-80% of cases feature a targetlike lesion that expands centrifugally at the site of the bite. Most commonly, lesions appear on the abdomen, groin, axilla, and popliteal fossa. The diagnosis of ECM requires lesions at least 5 cm in size. Lesions may be asymptomatic, although burning may occur in half of patients. Atypical presentations include bullous, vesicular, hemorrhagic, or necrotic lesions. Up to half of patients may develop multiple ECM lesions. Palms and soles are spared. Differential diagnoses include arthropod reactions, pyoderma gangrenosum, cellulitis, herpes simplex virus and varicella zoster virus, contact dermatitis, or granuloma annulare. The rash is often accompanied by systemic symptoms including fatigue, myalgia, headache, and fever.

The next two stages include early and late disseminated infection. Early disseminated infection often occurs 3-12 weeks after infection and is characterized by muscle pain, dizziness, headache, and cardiac symptoms. CNS involvement occurs in about 20% of patients. Joint involvement may include the knee, ankle, and wrist. If symptoms are only in one joint, septic arthritis is part of the differential diagnosis, so clinical correlation and labs must be considered. Late disseminated infection occurs months or years after initial infection and includes neurologic and rheumatologic symptoms including meningitis, Bell’s palsy, arthritis, and dysesthesia. Knee arthritis is a key feature of this stage. Patients commonly have radicular pain and fibromyalgia-type pain. More severe disease processes include encephalomyelitis, arrhythmias, and heart block.

ECM is often a clinical diagnosis because serologic testing may not be positive during the first 2 weeks of infection. The screening serologic test is the ELISA, and a Western blot confirms the results. Skin histopathology for Lyme disease is often nonspecific and reveals a perivascular infiltrate of histiocytes, plasma cells, and lymphocytes. Silver stain or antibody testing may be used to identify the spirochete. In acrodermatitis chronica atrophicans, late Lyme disease presenting on the distal extremities, lymphocytic and plasma cell infiltrates are present. In borrelial lymphocytoma, a dense dermal lymphocytic infiltrate is present.

The standard for treatment of early localized disease is oral doxycycline in adults. Alternatives may be used if a patient is allergic or for children under 9. Disseminated disease may be treated with IV ceftriaxone and topical steroids are used if ocular symptoms are involved. Early treatment is often curative.

This patient’s antibodies were negative initially, but became positive after 6 weeks. He was treated empirically at the time of his office visit with doxycycline for 1 month.

This case and the photo were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Susannah Berke, MD, Three Rivers Dermatology, Coraopolis, Pa. The column was edited by Donna Bilu Martin, MD.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at MDedge.com/Dermatology. To submit a case for possible publication, send an email to [email protected].

References
 

Carriveau A et al. Nurs Clin North Am. 2019 Jun;54(2):261-75.

Skar GL and Simonsen KA. Lyme Disease. [Updated 2023 May 31]. In: “StatPearls” [Internet]. Treasure Island, Fla.: StatPearls Publishing; 2023 Jan.

Tiger JB et al. J Am Acad Dermatol. 2014 Oct;71(4):e133-4.

TOPLINE:

In an online survey of 605 people with diabetes who use insulin and continuous glucose monitors (CGMs), a majority expressed satisfaction with many aspects of the devices’ performance. However, significant proportions also reported concerns about accuracy under certain circumstances and about skin problems.

METHODOLOGY:

Researchers did an online survey of 504 people with type 1 diabetes from the T1D Exchange and 101 with type 2 diabetes from the Dynata database.

TAKEAWAY:

• The Dexcom G6 device was used by 60.7% of all current CGM users, including 69% of those with type 1 diabetes vs. 12% with type 2 diabetes.
• People with type 2 diabetes were more likely to use older Dexcom versions (G4/G5) (32%) or Abbott’s FreeStyle Libre systems (35%).
• Overall, 90% agreed that most sensors were accurate, but just 79% and 78%, respectively, were satisfied with sensor performance on the first and last day of wear.
• Moreover, 42% suspected variations in accuracy from sensor to sensor, and 32% continue to perform finger-stick monitoring more than six times a week.
• Individuals with type 2 diabetes were more likely than those with type 1 diabetes to be concerned about poor sensor performance affecting confidence in making diabetes management decisions (52% vs. 19%).
• Over half reported skin reactions and/or pain with the sensors (53.7% and 55.4%, respectively).
• Concerns about medications affecting sensor accuracy were more common among those with type 2 vs. type 1 diabetes (65% vs. 29%).
• Among overall concerns about substances or situations affecting sensor accuracy, the top choice (47%) was dehydration (despite a lack of supportive published literature), followed by pain medications (43%), cold/flu medications (32%), and coffee (24%).
• Inaccurate/false alarms negatively affected daily life for 36% of participants and diabetes management for 34%.

IN PRACTICE:

“CGM is a game-changing technology and has evolved in the past decade to overcome many technical and usability obstacles. Our survey suggests that there remain areas for further improvement ... Mistrust in CGM performance was more common than expected.”

SOURCE:

The study was done by Elizabeth Holt, of LifeScan, and colleagues. It was published in Clinical Diabetes.

LIMITATIONS:

• The databases used to recruit study participants may not be representative of the entire respective patient populations.
• Exercise wasn’t given as an option for affecting CGM accuracy, which might partly explain the dehydration finding.

DISCLOSURES:

Funding for this study and preparation of the manuscript were provided by LifeScan Inc. Two authors are LifeScan employees, and two others currently work for the T1D Exchange.

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

TOPLINE:

In an online survey of 605 people with diabetes who use insulin and continuous glucose monitors (CGMs), a majority expressed satisfaction with many aspects of the devices’ performance. However, significant proportions also reported concerns about accuracy under certain circumstances and about skin problems.

METHODOLOGY:

Researchers did an online survey of 504 people with type 1 diabetes from the T1D Exchange and 101 with type 2 diabetes from the Dynata database.

TAKEAWAY:

• The Dexcom G6 device was used by 60.7% of all current CGM users, including 69% of those with type 1 diabetes vs. 12% with type 2 diabetes.
• People with type 2 diabetes were more likely to use older Dexcom versions (G4/G5) (32%) or Abbott’s FreeStyle Libre systems (35%).
• Overall, 90% agreed that most sensors were accurate, but just 79% and 78%, respectively, were satisfied with sensor performance on the first and last day of wear.
• Moreover, 42% suspected variations in accuracy from sensor to sensor, and 32% continue to perform finger-stick monitoring more than six times a week.
• Individuals with type 2 diabetes were more likely than those with type 1 diabetes to be concerned about poor sensor performance affecting confidence in making diabetes management decisions (52% vs. 19%).
• Over half reported skin reactions and/or pain with the sensors (53.7% and 55.4%, respectively).
• Concerns about medications affecting sensor accuracy were more common among those with type 2 vs. type 1 diabetes (65% vs. 29%).
• Among overall concerns about substances or situations affecting sensor accuracy, the top choice (47%) was dehydration (despite a lack of supportive published literature), followed by pain medications (43%), cold/flu medications (32%), and coffee (24%).
• Inaccurate/false alarms negatively affected daily life for 36% of participants and diabetes management for 34%.

IN PRACTICE:

“CGM is a game-changing technology and has evolved in the past decade to overcome many technical and usability obstacles. Our survey suggests that there remain areas for further improvement ... Mistrust in CGM performance was more common than expected.”

SOURCE:

The study was done by Elizabeth Holt, of LifeScan, and colleagues. It was published in Clinical Diabetes.

LIMITATIONS:

• The databases used to recruit study participants may not be representative of the entire respective patient populations.
• Exercise wasn’t given as an option for affecting CGM accuracy, which might partly explain the dehydration finding.

DISCLOSURES:

Funding for this study and preparation of the manuscript were provided by LifeScan Inc. Two authors are LifeScan employees, and two others currently work for the T1D Exchange.

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

TOPLINE:

In an online survey of 605 people with diabetes who use insulin and continuous glucose monitors (CGMs), a majority expressed satisfaction with many aspects of the devices’ performance. However, significant proportions also reported concerns about accuracy under certain circumstances and about skin problems.

METHODOLOGY:

Researchers did an online survey of 504 people with type 1 diabetes from the T1D Exchange and 101 with type 2 diabetes from the Dynata database.

TAKEAWAY:

• The Dexcom G6 device was used by 60.7% of all current CGM users, including 69% of those with type 1 diabetes vs. 12% with type 2 diabetes.
• People with type 2 diabetes were more likely to use older Dexcom versions (G4/G5) (32%) or Abbott’s FreeStyle Libre systems (35%).
• Overall, 90% agreed that most sensors were accurate, but just 79% and 78%, respectively, were satisfied with sensor performance on the first and last day of wear.
• Moreover, 42% suspected variations in accuracy from sensor to sensor, and 32% continue to perform finger-stick monitoring more than six times a week.
• Individuals with type 2 diabetes were more likely than those with type 1 diabetes to be concerned about poor sensor performance affecting confidence in making diabetes management decisions (52% vs. 19%).
• Over half reported skin reactions and/or pain with the sensors (53.7% and 55.4%, respectively).
• Concerns about medications affecting sensor accuracy were more common among those with type 2 vs. type 1 diabetes (65% vs. 29%).
• Among overall concerns about substances or situations affecting sensor accuracy, the top choice (47%) was dehydration (despite a lack of supportive published literature), followed by pain medications (43%), cold/flu medications (32%), and coffee (24%).
• Inaccurate/false alarms negatively affected daily life for 36% of participants and diabetes management for 34%.

IN PRACTICE:

“CGM is a game-changing technology and has evolved in the past decade to overcome many technical and usability obstacles. Our survey suggests that there remain areas for further improvement ... Mistrust in CGM performance was more common than expected.”

SOURCE:

The study was done by Elizabeth Holt, of LifeScan, and colleagues. It was published in Clinical Diabetes.

LIMITATIONS:

• The databases used to recruit study participants may not be representative of the entire respective patient populations.
• Exercise wasn’t given as an option for affecting CGM accuracy, which might partly explain the dehydration finding.

DISCLOSURES:

Funding for this study and preparation of the manuscript were provided by LifeScan Inc. Two authors are LifeScan employees, and two others currently work for the T1D Exchange.

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

Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.

The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.

“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.

“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”

Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.

Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.

“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
 

Frailty a clinical syndrome

Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”

Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.

NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.

The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.  

So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.

This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.

Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m² or with valvular AFib were excluded.

Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.

A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.

Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.

After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.

Completely different patients

Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”

Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.

That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.

The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”

The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.

The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.

“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”

NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”

The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.

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

Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.

The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.

“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.

“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”

Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.

Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.

“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
 

Frailty a clinical syndrome

Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”

Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.

NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.

The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.  

So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.

This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.

Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m² or with valvular AFib were excluded.

Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.

A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.

Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.

After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.

Completely different patients

Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”

Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.

That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.

The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”

The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.

The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.

“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”

NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”

The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.

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

Switching frail patients with atrial fibrillation (AFib) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.

The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.

“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF[ib], as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.

“The results turned out different than we expected,” Dr. Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of .001.”

Results of FRAIL-AF were presented at the annual congress of the European Society of Cardiology and published online in the journal Circulation.

Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg (Germany), congratulated the researchers on these “astonishing” data.

“The thing I want to emphasize here is that, in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Dr. Schnabel told Dr. Joosten. “We need randomized controlled trials that sometimes give astonishing results.”
 

Frailty a clinical syndrome

Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Dr. Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”

Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF[ib] in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF[ib] patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Dr. Joosten noted, compared with 3.9% per year among nonfrail AFib patients.

NOACs are preferred over VKAs in nonfrail AFib patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable with treatment with warfarin, she noted.

The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AFib patients, but the level of evidence is low.  

So it’s unknown if NOACs are preferred over VKAs in frail AFib patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Dr. Joosten said.

This new trial aimed to answer the question of whether switching frail AFib patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized, controlled superiority trial.

Older AFib patients were deemed frail if they were aged 75 years or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min per 1.73 m² or with valvular AFib were excluded.

Eligible patients were then assigned randomly to switch from their international normalized ratio (INR)–guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome – major bleeding or clinically relevant nonmajor bleeding complication, whichever came first – accounting for death as a competing risk.

A total of 1,330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, 6 patients in the switch-to-NOAC arm, and 1 in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.

Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Nonmajor bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.

After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Dr. Joosten said. The difference appeared to be driven by clinically relevant nonmajor bleeding.

Completely different patients

Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen (the Netherlands). She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF[ib] guidelines, and a note for all the cardiologists – this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”

Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years versus 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.

That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.

The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”

The Netherlands has dedicated thrombosis services that might improve time in therapeutic range for VKA patients, but there is no real difference in TTRs in FRAIL-AF versus the other NOAC trials, Dr. Van Gelder noted.

The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban versus those on 4 or fewer medications.

“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although general practitioners see these patients all the time. “It’s all about frailty.”

NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Dr. Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”

The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi Sankyo. Dr. Joosten reported no relevant financial relationships. Dr. Van Gelder reported no relevant financial relationships.

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

SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.

In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.

HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.

The results were simultaneously published in the Journal of Clinical Oncology.

Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.

And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.

HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.

HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.

After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.

Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”

The current findings focus on the 225 patients in the fixed-dose arm.

About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.

After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.

The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.

Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.

To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.

Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.

The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.

Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.

“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.

Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.

However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”

Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”

The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.

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

SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.

In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.

HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.

The results were simultaneously published in the Journal of Clinical Oncology.

Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.

And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.

HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.

HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.

After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.

Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”

The current findings focus on the 225 patients in the fixed-dose arm.

About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.

After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.

The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.

Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.

To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.

Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.

The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.

Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.

“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.

Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.

However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”

Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”

The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.

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

SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.

In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.

HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.

The results were simultaneously published in the Journal of Clinical Oncology.

Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.

And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.

HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.

HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.

After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.

Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”

The current findings focus on the 225 patients in the fixed-dose arm.

About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.

After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.

The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.

Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.

To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.

Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.

The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.

Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.

“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.

Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.

However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”

Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”

The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.

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

Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.

“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”

Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
 

Aldosterone’s contribution ‘vastly underappreciated’

Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome. 

“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.

Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).

The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.

The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.

Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).

In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.

Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.

Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.

Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.

A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat. 

No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.

The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”

A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
 

‘New dawn’ for therapies targeting aldosterone

The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”

“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.

The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.

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

Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.

“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”

Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
 

Aldosterone’s contribution ‘vastly underappreciated’

Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome. 

“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.

Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).

The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.

The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.

Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).

In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.

Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.

Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.

Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.

A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat. 

No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.

The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”

A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
 

‘New dawn’ for therapies targeting aldosterone

The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”

“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.

The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.

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

Once-daily treatment with the selective aldosterone synthase inhibitor lorundrostat (Mineralys Therapeutics) safely and significantly reduced blood pressure in adults with uncontrolled hypertension in a phase 2, randomized, controlled trial.

Eight weeks after adding lorundrostat (50 mg or 100 mg once daily) or placebo to background therapy, the medication lowered seated automated office systolic BP significantly more than placebo (−9.6 mm Hg with 50 mg; −7.8 mm Hg with 100 mg), with the greatest effects seen in adults with obesity.

“We need new drugs for treatment-resistant hypertension,” study investigator Steven Nissen, MD, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, said in an interview. Lorundrostat represents a “new class” of antihypertensive that “looks to be safe and we’re seeing very large reductions in blood pressure.”

Results of the Target-HTN trial were published online in JAMA to coincide with presentation at the Hypertension Scientific Sessions, sponsored by the American Heart Association.
 

Aldosterone’s contribution ‘vastly underappreciated’

Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome. 

“Aldosterone’s contribution to uncontrolled hypertension is vastly underappreciated,” first author and study presenter Luke Laffin, MD, also with the Cleveland Clinic, said in an interview.

Aldosterone synthase inhibitors are a novel class of BP-lowering medications that decrease aldosterone production. Lorundrostat is one of two such agents in advanced clinical development. The other is baxdrostat (CinCor Pharma/AstraZeneca).

The Target-HTN randomized, placebo-controlled, dose-ranging trial enrolled 200 adults (mean age, 66 years; 60% women) with uncontrolled hypertension while taking two or more antihypertensive medications; 42% of participants were taking three or more antihypertensive medications, 48% were obese and 40% had diabetes.

The study population was divided into two cohorts: an initial cohort of 163 adults with suppressed plasma renin activity at baseline (PRA ≤ 1.0 ng/mL per hour) and elevated plasma aldosterone (≥ 1.0 ng/dL) and a second cohort of 37 adults with PRA greater than 1.0 ng/mL per hour.

Participants were randomly assigned to placebo or one of five doses of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily).

In the second cohort, participants were randomly assigned (1:6) to placebo or lorundrostat 100 mg once daily. The primary endpoint was change in automated office systolic BP from baseline to week 8.

Among participants with suppressed PRA, following 8 weeks of treatment, changes in office systolic BP of −14.1, −13.2, and −6.9 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once-daily lorundrostat, respectively, compared with a change of −4.1 mm Hg with placebo.

Reductions in systolic BP in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively.

Among participants without suppressed PRA, lorundrostat 100 mg once daily decreased systolic BP by 11.4 mm Hg, similar to BP reduction in those with suppressed PRA receiving the same dose.

A prespecified subgroup analysis showed that participants with obesity demonstrated greater BP lowering in response to lorundrostat. 

No instances of cortisol insufficiency occurred. Six participants had increases in serum potassium above 6.0 mEq/L (6.0 mmol/L) that corrected with dose reduction or drug discontinuation.

The increase in serum potassium is “expected and manageable,” Dr. Laffin said in an interview. “Anytime you disrupt aldosterone production, you’re going to have to have an increase in serum potassium, but it’s very manageable and not something that is worrisome.”

A phase 2 trial in 300 adults with uncontrolled hypertension is currently underway. The trial will evaluate the BP-lowering effects of lorundrostat, administered on a background of a standardized antihypertensive medication regimen. A larger phase 3 study will start before the end of the year.
 

‘New dawn’ for therapies targeting aldosterone

The author of an editorial in JAMA noted that more 70 years after the first isolation of aldosterone, then called electrocortin, “there is a new dawn for therapies targeting aldosterone.”

“There is now real potential to provide better-targeted treatment for patients in whom aldosterone excess is known to contribute to their clinical condition and influence their clinical outcome, notably those with difficult-to-control hypertension, obesity, heart failure, chronic kidney disease, and the many with yet-to-be-diagnosed primary aldosteronism,” said Bryan Williams, MD, University College London.

The trial was funded by Mineralys Therapeutics, which is developing lorundrostat. Dr. Laffin reported that the Cleveland Clinic, his employer, was a study site for the Target-HTN trial and that C5Research, the academic research organization of the Cleveland Clinic, receives payment for services related to other Mineralys clinical trials. Dr. Laffin also reported receipt of personal fees from Medtronic, Lilly, and Crispr Therapeutics, grants from AstraZeneca, and stock options for LucidAct Health and Gordy Health. Dr. Nissen reported receipt of grants from Mineralys during the conduct of the study and grants from AbbVie, AstraZeneca, Amgen, Bristol-Myers Squibb, Lilly, Esperion Therapeutics, Medtronic, grants from MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. Dr. Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.

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

COVID vaccines will have a new formulation in 2023, according to a decision announced by the U.S. Food and Drug Administration, that will focus efforts on circulating variants. The move pushes last year’s bivalent vaccines out of circulation because they will no longer be authorized for use in the United States.

The updated mRNA vaccines for 2023-2024 are being revised to include a single component that corresponds to the Omicron variant XBB.1.5. Like the bivalents offered before, the new monovalents are being manufactured by Moderna and Pfizer.

The new vaccines are authorized for use in individuals age 6 months and older.  And the new options are being developed using a similar process as previous formulations, according to the FDA.
 

Targeting circulating variants

In recent studies, regulators point out the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5, BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with previous versions of the vaccines against corresponding prior variants.

“This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants,” according to the report.

Hundreds of millions of people in the United States have already received previously approved mRNA COVID vaccines, according to regulators who say the benefit-to-risk profile is well understood as they move forward with new formulations.

“Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “The public can be assured that these updated vaccines have met the agency’s rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated.”
 

Timing the effort

On Sept. 12 the U.S. Centers for Disease Control and Prevention recommended that everyone 6 months and older get an updated COVID-19 vaccine. Updated vaccines from Pfizer-BioNTech and Moderna will be available later this week, according to the agency.

This article was updated 9/14/23.

A version of this article appeared on Medscape.com.

COVID vaccines will have a new formulation in 2023, according to a decision announced by the U.S. Food and Drug Administration, that will focus efforts on circulating variants. The move pushes last year’s bivalent vaccines out of circulation because they will no longer be authorized for use in the United States.

The updated mRNA vaccines for 2023-2024 are being revised to include a single component that corresponds to the Omicron variant XBB.1.5. Like the bivalents offered before, the new monovalents are being manufactured by Moderna and Pfizer.

The new vaccines are authorized for use in individuals age 6 months and older.  And the new options are being developed using a similar process as previous formulations, according to the FDA.
 

Targeting circulating variants

In recent studies, regulators point out the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5, BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with previous versions of the vaccines against corresponding prior variants.

“This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants,” according to the report.

Hundreds of millions of people in the United States have already received previously approved mRNA COVID vaccines, according to regulators who say the benefit-to-risk profile is well understood as they move forward with new formulations.

“Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “The public can be assured that these updated vaccines have met the agency’s rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated.”
 

Timing the effort

On Sept. 12 the U.S. Centers for Disease Control and Prevention recommended that everyone 6 months and older get an updated COVID-19 vaccine. Updated vaccines from Pfizer-BioNTech and Moderna will be available later this week, according to the agency.

This article was updated 9/14/23.

A version of this article appeared on Medscape.com.

COVID vaccines will have a new formulation in 2023, according to a decision announced by the U.S. Food and Drug Administration, that will focus efforts on circulating variants. The move pushes last year’s bivalent vaccines out of circulation because they will no longer be authorized for use in the United States.

The updated mRNA vaccines for 2023-2024 are being revised to include a single component that corresponds to the Omicron variant XBB.1.5. Like the bivalents offered before, the new monovalents are being manufactured by Moderna and Pfizer.

The new vaccines are authorized for use in individuals age 6 months and older.  And the new options are being developed using a similar process as previous formulations, according to the FDA.
 

Targeting circulating variants

In recent studies, regulators point out the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5, BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with previous versions of the vaccines against corresponding prior variants.

“This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants,” according to the report.

Hundreds of millions of people in the United States have already received previously approved mRNA COVID vaccines, according to regulators who say the benefit-to-risk profile is well understood as they move forward with new formulations.

“Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a statement. “The public can be assured that these updated vaccines have met the agency’s rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated.”
 

Timing the effort

On Sept. 12 the U.S. Centers for Disease Control and Prevention recommended that everyone 6 months and older get an updated COVID-19 vaccine. Updated vaccines from Pfizer-BioNTech and Moderna will be available later this week, according to the agency.

This article was updated 9/14/23.

A version of this article appeared on Medscape.com.

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

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

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

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

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

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

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

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

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

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

CASTLE-HTx key findings

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

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

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

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

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

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

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

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

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

How can AFib ablation have such big, early effects?

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

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

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

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

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

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

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

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

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

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

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

Rhythm control

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

CASTLE-HTx key findings

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

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

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

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

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

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

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

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

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

How can AFib ablation have such big, early effects?

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

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

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

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

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

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

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

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

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

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

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

Rhythm control

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

CASTLE-HTx key findings

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

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

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

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

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

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

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

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

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

How can AFib ablation have such big, early effects?

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

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

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

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

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

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

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

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

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

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

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

Rhythm control

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

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

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

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

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

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

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

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

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

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

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

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

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


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