The real-world Zephyr 2 study, which assessed benralizumab for effectiveness in treating severe eosinophilic asthma, was extended with an analysis of a larger population stratified into three cohorts of participants who were aged 12 years or older. Pre- and posttreatment data showed an improvement in asthma control for each group.

Immunotherapy with monoclonal antibodies designed to block specific inflammatory pathways is a recommended add-on treatment option for adults to manage severe, uncontrolled eosinophilic-dependent (> 150 cells/µl) and corticosteroid-dependent asthma. One such biologic, benralizumab, targets the interleukin-5 receptor alpha chain (IL-5Rα).

For asthma patients who had previously been treated with benralizumab, there were significant reductions in exacerbation rates in the ZEPHYR 1 study. However, information regarding benefit associated with specific profiles was limited, warranting a larger study to address effectiveness when considering various blood eosinophil counts, prior treatments with other biologics, or benralizumab use for up to 24 months, Donna Carstens, MD, of AstraZeneca, Wilmington, Del., and colleagues write.
 

Study details

In the retrospective cohort Zephyr 2 study, which was published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers retrieved deidentified patient information from medical, laboratory, and pharmacy U.S. insurance claims records from the PatientSource and DiagnosticSource databases and compared asthma exacerbation rates before and after treatment with benralizumab.

Age, asthma diagnosis, number of exacerbations, and number of benralizumab treatment records within specified periods were used to identify a total of 1,795 participants for inclusion in the study. The index date for establishing before-treatment and after-treatment index time intervals of 12 months each was defined as the day after the initial benralizumab treatment occurring between November 2017 and June 2019.

The cohort was stratified into three nonmutually exclusive groups consisting of 349 patients who had switched primarily from either omalizumab or mepolizumab biologics to benralizumab; 429 patients subdivided by closest to the index date blood eosinophil counts of less than 150, greater than or equal to 150, 150-299, less than 300, and greater than or equal to 300, and 419 patients with post data collection extended beyond 12 months to 18 or 24 months.

Similarities in baseline patient characteristics that were were observed across the three cohorts included a mean age range of 51-53 years, preponderance of women (67%-69%), obesity diagnosis (31.5%-32.9%), and a mean Charlson Comorbidity Index of 1.47-1.52. Allergic rhinitis was the most frequently reported (60%-67%) comorbidity, followed by hypertension and gastroesophageal reflex.
 

Effectiveness

Benralizumab was found to be a significantly effective treatment for managing severe eosinophilic asthma for all three evaluated cohorts, as evidenced by reductions in asthma exacerbations post-index, compared with pre-index. Specifically, the exacerbation rate for all five subgroups of the blood eosinophil cohort significantly decreased from the pre-index 3.10-3.55 person per year (PPY) rate to a 1.11-1.72 PPY post-index rate, equivalent to a 52%-64% decrease in exacerbations (P < .001 for all pre-index vs. post-index comparisons).

Comparable reductions also occurred with the cohort in which the biologic treatment was changed to benralizumab. A greater effect was observed when the switch was made from omalizumab to benralizumab with a pre-post PPY rate reduction of 3.25-1.25 (62%) than when the switch was made from mepolizumab (pre-post PPY rate reduction was 3.81-1.78 [53%], but both resulted in significant post-treatment improvements (P < .001).

Results from the extended follow-up analysis cohort showed consistency for significant exacerbation rate decline going from a pre-index rate of 3.38 PPY down to 1.34 PPY (60% rate reduction vs. pre-index) in the first 12 post-index months, continuing to decline to 1.18 PPY (65% reduction) over the following six months (both significant at P < .001).

Likewise, the results from the extended follow-up 24-month subgroup presented significant down trending exacerbation rates from pre-index 3.38 PPY to 1.38 (comparative 59% reduction) for the first 12 months continuing down to 1.08 PPY (68% reduction) over the 12-24 month post-index period (both P < .001). In the first and second 12 post-index months for the 24-month subgroup, 39% and 49% of the patients, respectively, experienced no exacerbations.

Following treatment with benralizumab, in addition to the observed decline in asthma exacerbation rates, the need for concomitant asthma medications was also significantly reduced for all three cohorts.

This retrospective ZEPHYR 2 study contributes evidence supporting the significant effectiveness of benralizumab in improving disease management for “specific subsets of severe asthma patients that are frequently seen in real-world practice and may be excluded from clinical trials,” according to the authors. The treatment resulted in reduced rates of asthma exacerbations with defined standards for hospitalizations, visits to emergency department or urgent care, or outpatient visits with separate exacerbations occurring at greater than or equal to 14 days, as reported in database records. Reduction in the rate of asthma exacerbations when benralizumab is switched for another biologic increases the disease management options for achieving optimal patient care, the authors add.

The authors have financial relationships with AstraZeneca, the source of funding for the study.

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

The real-world Zephyr 2 study, which assessed benralizumab for effectiveness in treating severe eosinophilic asthma, was extended with an analysis of a larger population stratified into three cohorts of participants who were aged 12 years or older. Pre- and posttreatment data showed an improvement in asthma control for each group.

Immunotherapy with monoclonal antibodies designed to block specific inflammatory pathways is a recommended add-on treatment option for adults to manage severe, uncontrolled eosinophilic-dependent (> 150 cells/µl) and corticosteroid-dependent asthma. One such biologic, benralizumab, targets the interleukin-5 receptor alpha chain (IL-5Rα).

For asthma patients who had previously been treated with benralizumab, there were significant reductions in exacerbation rates in the ZEPHYR 1 study. However, information regarding benefit associated with specific profiles was limited, warranting a larger study to address effectiveness when considering various blood eosinophil counts, prior treatments with other biologics, or benralizumab use for up to 24 months, Donna Carstens, MD, of AstraZeneca, Wilmington, Del., and colleagues write.
 

Study details

In the retrospective cohort Zephyr 2 study, which was published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers retrieved deidentified patient information from medical, laboratory, and pharmacy U.S. insurance claims records from the PatientSource and DiagnosticSource databases and compared asthma exacerbation rates before and after treatment with benralizumab.

Age, asthma diagnosis, number of exacerbations, and number of benralizumab treatment records within specified periods were used to identify a total of 1,795 participants for inclusion in the study. The index date for establishing before-treatment and after-treatment index time intervals of 12 months each was defined as the day after the initial benralizumab treatment occurring between November 2017 and June 2019.

The cohort was stratified into three nonmutually exclusive groups consisting of 349 patients who had switched primarily from either omalizumab or mepolizumab biologics to benralizumab; 429 patients subdivided by closest to the index date blood eosinophil counts of less than 150, greater than or equal to 150, 150-299, less than 300, and greater than or equal to 300, and 419 patients with post data collection extended beyond 12 months to 18 or 24 months.

Similarities in baseline patient characteristics that were were observed across the three cohorts included a mean age range of 51-53 years, preponderance of women (67%-69%), obesity diagnosis (31.5%-32.9%), and a mean Charlson Comorbidity Index of 1.47-1.52. Allergic rhinitis was the most frequently reported (60%-67%) comorbidity, followed by hypertension and gastroesophageal reflex.
 

Effectiveness

Benralizumab was found to be a significantly effective treatment for managing severe eosinophilic asthma for all three evaluated cohorts, as evidenced by reductions in asthma exacerbations post-index, compared with pre-index. Specifically, the exacerbation rate for all five subgroups of the blood eosinophil cohort significantly decreased from the pre-index 3.10-3.55 person per year (PPY) rate to a 1.11-1.72 PPY post-index rate, equivalent to a 52%-64% decrease in exacerbations (P < .001 for all pre-index vs. post-index comparisons).

Comparable reductions also occurred with the cohort in which the biologic treatment was changed to benralizumab. A greater effect was observed when the switch was made from omalizumab to benralizumab with a pre-post PPY rate reduction of 3.25-1.25 (62%) than when the switch was made from mepolizumab (pre-post PPY rate reduction was 3.81-1.78 [53%], but both resulted in significant post-treatment improvements (P < .001).

Results from the extended follow-up analysis cohort showed consistency for significant exacerbation rate decline going from a pre-index rate of 3.38 PPY down to 1.34 PPY (60% rate reduction vs. pre-index) in the first 12 post-index months, continuing to decline to 1.18 PPY (65% reduction) over the following six months (both significant at P < .001).

Likewise, the results from the extended follow-up 24-month subgroup presented significant down trending exacerbation rates from pre-index 3.38 PPY to 1.38 (comparative 59% reduction) for the first 12 months continuing down to 1.08 PPY (68% reduction) over the 12-24 month post-index period (both P < .001). In the first and second 12 post-index months for the 24-month subgroup, 39% and 49% of the patients, respectively, experienced no exacerbations.

Following treatment with benralizumab, in addition to the observed decline in asthma exacerbation rates, the need for concomitant asthma medications was also significantly reduced for all three cohorts.

This retrospective ZEPHYR 2 study contributes evidence supporting the significant effectiveness of benralizumab in improving disease management for “specific subsets of severe asthma patients that are frequently seen in real-world practice and may be excluded from clinical trials,” according to the authors. The treatment resulted in reduced rates of asthma exacerbations with defined standards for hospitalizations, visits to emergency department or urgent care, or outpatient visits with separate exacerbations occurring at greater than or equal to 14 days, as reported in database records. Reduction in the rate of asthma exacerbations when benralizumab is switched for another biologic increases the disease management options for achieving optimal patient care, the authors add.

The authors have financial relationships with AstraZeneca, the source of funding for the study.

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

The real-world Zephyr 2 study, which assessed benralizumab for effectiveness in treating severe eosinophilic asthma, was extended with an analysis of a larger population stratified into three cohorts of participants who were aged 12 years or older. Pre- and posttreatment data showed an improvement in asthma control for each group.

Immunotherapy with monoclonal antibodies designed to block specific inflammatory pathways is a recommended add-on treatment option for adults to manage severe, uncontrolled eosinophilic-dependent (> 150 cells/µl) and corticosteroid-dependent asthma. One such biologic, benralizumab, targets the interleukin-5 receptor alpha chain (IL-5Rα).

For asthma patients who had previously been treated with benralizumab, there were significant reductions in exacerbation rates in the ZEPHYR 1 study. However, information regarding benefit associated with specific profiles was limited, warranting a larger study to address effectiveness when considering various blood eosinophil counts, prior treatments with other biologics, or benralizumab use for up to 24 months, Donna Carstens, MD, of AstraZeneca, Wilmington, Del., and colleagues write.
 

Study details

In the retrospective cohort Zephyr 2 study, which was published in the Journal of Allergy and Clinical Immunology: In Practice, the researchers retrieved deidentified patient information from medical, laboratory, and pharmacy U.S. insurance claims records from the PatientSource and DiagnosticSource databases and compared asthma exacerbation rates before and after treatment with benralizumab.

Age, asthma diagnosis, number of exacerbations, and number of benralizumab treatment records within specified periods were used to identify a total of 1,795 participants for inclusion in the study. The index date for establishing before-treatment and after-treatment index time intervals of 12 months each was defined as the day after the initial benralizumab treatment occurring between November 2017 and June 2019.

The cohort was stratified into three nonmutually exclusive groups consisting of 349 patients who had switched primarily from either omalizumab or mepolizumab biologics to benralizumab; 429 patients subdivided by closest to the index date blood eosinophil counts of less than 150, greater than or equal to 150, 150-299, less than 300, and greater than or equal to 300, and 419 patients with post data collection extended beyond 12 months to 18 or 24 months.

Similarities in baseline patient characteristics that were were observed across the three cohorts included a mean age range of 51-53 years, preponderance of women (67%-69%), obesity diagnosis (31.5%-32.9%), and a mean Charlson Comorbidity Index of 1.47-1.52. Allergic rhinitis was the most frequently reported (60%-67%) comorbidity, followed by hypertension and gastroesophageal reflex.
 

Effectiveness

Benralizumab was found to be a significantly effective treatment for managing severe eosinophilic asthma for all three evaluated cohorts, as evidenced by reductions in asthma exacerbations post-index, compared with pre-index. Specifically, the exacerbation rate for all five subgroups of the blood eosinophil cohort significantly decreased from the pre-index 3.10-3.55 person per year (PPY) rate to a 1.11-1.72 PPY post-index rate, equivalent to a 52%-64% decrease in exacerbations (P < .001 for all pre-index vs. post-index comparisons).

Comparable reductions also occurred with the cohort in which the biologic treatment was changed to benralizumab. A greater effect was observed when the switch was made from omalizumab to benralizumab with a pre-post PPY rate reduction of 3.25-1.25 (62%) than when the switch was made from mepolizumab (pre-post PPY rate reduction was 3.81-1.78 [53%], but both resulted in significant post-treatment improvements (P < .001).

Results from the extended follow-up analysis cohort showed consistency for significant exacerbation rate decline going from a pre-index rate of 3.38 PPY down to 1.34 PPY (60% rate reduction vs. pre-index) in the first 12 post-index months, continuing to decline to 1.18 PPY (65% reduction) over the following six months (both significant at P < .001).

Likewise, the results from the extended follow-up 24-month subgroup presented significant down trending exacerbation rates from pre-index 3.38 PPY to 1.38 (comparative 59% reduction) for the first 12 months continuing down to 1.08 PPY (68% reduction) over the 12-24 month post-index period (both P < .001). In the first and second 12 post-index months for the 24-month subgroup, 39% and 49% of the patients, respectively, experienced no exacerbations.

Following treatment with benralizumab, in addition to the observed decline in asthma exacerbation rates, the need for concomitant asthma medications was also significantly reduced for all three cohorts.

This retrospective ZEPHYR 2 study contributes evidence supporting the significant effectiveness of benralizumab in improving disease management for “specific subsets of severe asthma patients that are frequently seen in real-world practice and may be excluded from clinical trials,” according to the authors. The treatment resulted in reduced rates of asthma exacerbations with defined standards for hospitalizations, visits to emergency department or urgent care, or outpatient visits with separate exacerbations occurring at greater than or equal to 14 days, as reported in database records. Reduction in the rate of asthma exacerbations when benralizumab is switched for another biologic increases the disease management options for achieving optimal patient care, the authors add.

The authors have financial relationships with AstraZeneca, the source of funding for the study.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer’s disease (AD), new research suggests.

Investigators tested the blood of 1,000 cognitively healthy individuals with and without amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.

“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, said in a release.

At this point, the biomarker is a research tool, but its application in clinical practice “is not very far away,” Dr. Pascoal told this news organization.

The study was published online  in Nature Medicine.  
 

Multicenter study

In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Dr. Pascoal.

This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.

Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.

Post-mortem studies show astrocyte reactivity – changes in glial cells in the brain and spinal cord because of an insult in the brain – is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.

In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Dr. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.

The study included 1,016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants’ mean age was 69.6 years, and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.

Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
 

Early upstream event

The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.

It’s likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Dr. Pascoal.

“Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them,” he said.

Although “we were able to have very good results” in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Dr. Pascoal.

The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Dr. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.

Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.

The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Dr. Pascoal.

This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.

The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. “Our outcome was correlation to tau in the brain, which is something we know will lead to AD.”

Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.

The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer’s Association; Fonds de Recherche du Québec-Santé; Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; and Hjärnfonden.

Dr. Pascoal reports no relevant financial relationships.

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

Sowing the seeds of cancer prevention

Are you looking to add to your quality of life, even though pets are not your speed? Might we suggest something with lower maintenance? Something a little greener?

Indoor plants can purify the air that comes from outside. Researchers at the University of Technology Sydney, in partnership with the plantscaping company Ambius, showed that a “green wall” made up of mixed indoor plants was able to suck up 97% of “the most toxic compounds” from the air in just 8 hours. We’re talking about lung-irritating, headache-inducing, cancer risk–boosting compounds from gasoline fumes, including benzene.

Fraser Torpy/University of Technology Sydney

Public health initiatives often strive to reduce cardiovascular and obesity risks, but breathing seems pretty important too. According to the World Health Organization, household air pollution is responsible for about 2.5 million global premature deaths each year. And since 2020 we’ve become accustomed to spending more time inside and at home.

“This new research proves that plants should not just be seen as ‘nice to have,’ but rather a crucial part of every workplace wellness plan,” Ambius General Manager Johan Hodgson said in statement released by the university.

So don’t spend hundreds of dollars on a fancy air filtration system when a wall of plants can do that for next to nothing. Find what works for you and your space and become a plant parent today! Your lungs will thank you.
 

But officer, I had to swerve to miss the duodenal ampulla

Tiny video capsule endoscopes have been around for many years, but they have one big weakness: The ingestible cameras’ journey through the GI tract is passively driven by gravity and the natural movement of the body, so they often miss potential problem areas.

AnX Robotica

Not anymore. That flaw has been addressed by medical technology company AnX Robotica, which has taken endoscopy to the next level by adding that wondrous directional control device of the modern electronic age, a joystick.

The new system “uses an external magnet and hand-held video game style joysticks to move the capsule in three dimensions,” which allows physicians to “remotely drive a miniature video capsule to all regions of the stomach to visualize and photograph potential problem areas,” according to Andrew C. Meltzer, MD, of George Washington University and associates, who conducted a pilot study funded by AnX Robotica.

The video capsule provided a 95% rate of visualization in the stomachs of 40 patients who were examined at a medical office building by an emergency medicine physician who had no previous specialty training in endoscopy. “Capsules were driven by the ER physician and then the study reports were reviewed by an attending gastroenterologist who was physically off site,” the investigators said in a written statement.

The capsule operator did receive some additional training, and development of artificial intelligence to self-drive the capsule is in the works, but for now, we’re talking about a device controlled by a human using a joystick. And we all know that 50-year-olds are not especially known for their joystick skills. For that we need real experts. Yup, we need to put those joystick-controlled capsule endoscopes in the hands of teenage gamers. Who wants to go first?
 

Maybe AI isn’t ready for the big time after all

“How long before some intrepid stockholder says: ‘Hey, instead of paying doctors, why don’t we just use the free robot instead?’ ” Those words appeared on LOTME but a month ago. After all, the AI is supposed to be smarter and more empathetic than a doctor. And did we mention it’s free? Or at least extremely cheap. Cheaper than, say, a group of recently unionized health care workers.

maewjpho/Thinkstock

In early May, the paid employees manning the National Eating Disorders Association emergency hotline voted to unionize, as they felt overwhelmed and underpaid. Apparently, paying six people an extra few thousand a year was too much for NEDA’s leadership, as they decided a few weeks later to fire those workers, fully closing down the hotline. Instead of talking to a real person, people “calling in” for support would be met with Tessa, a wellness chatbot that would hopefully guide them through their crisis. Key word, hopefully.

In perhaps the least surprising twist of the year, NEDA was forced to walk back its decision about a week after its initial announcement. It all started with a viral Instagram post from a woman who called in and received the following advice from Tessa: Lose 1-2 pounds a week, count calories and work for a 500- to 1,000-calorie deficit, weigh herself weekly, and restrict her diet. Unfortunately, all of these suggestions were things that led to the development of the woman’s eating disorder.

Naturally, NEDA responded in good grace, accusing the woman of lying. A NEDA vice president even left some nasty comments on the post, but hastily deleted them a day later when NEDA announced it was shutting down Tessa “until further notice for a complete investigation.” NEDA’s CEO insisted they hadn’t seen that behavior from Tessa before, calling it a “bug” and insisting the bot would only be down temporarily until the triggers causing the bug were fixed.

In the aftermath, several doctors and psychologists chimed in, terming the rush to automate human roles dangerous and risky. After all, much of what makes these hotlines effective is the volunteers speaking from their own experience. An unsupervised bot doesn’t seem to have what it takes to deal with a mental health crisis, but we’re betting that Tessa will be back. As a wise cephalopod once said: Nobody gives a care about the fate of labor as long as they can get their instant gratification.
 

You can’t spell existential without s-t-e-n-t

This week, we’re including a special “bonus” item that, to be honest, has nothing to do with stents. That’s why our editor is making us call this a “bonus” (and making us use quote marks, too): It doesn’t really have anything to do with stents or health care or those who practice health care. Actually, his exact words were, “You can’t just give the readers someone else’s ****ing list and expect to get paid for it.” Did we mention that he looks like Jack Nicklaus but acts like BoJack Horseman?

Anywaaay, we’re pretty sure that the list in question – “America’s Top 10 Most Googled Existential Questions” – says something about the human condition, just not about stents:

1. Why is the sky blue?

2. What do dreams mean?

3. What is the meaning of life?

4. Why am I so tired?

5. Who am I?

6. What is love?

7. Is a hot dog a sandwich?

8. What came first, the chicken or the egg?

9. What should I do?

10. Do animals have souls?

Sowing the seeds of cancer prevention

Are you looking to add to your quality of life, even though pets are not your speed? Might we suggest something with lower maintenance? Something a little greener?

Indoor plants can purify the air that comes from outside. Researchers at the University of Technology Sydney, in partnership with the plantscaping company Ambius, showed that a “green wall” made up of mixed indoor plants was able to suck up 97% of “the most toxic compounds” from the air in just 8 hours. We’re talking about lung-irritating, headache-inducing, cancer risk–boosting compounds from gasoline fumes, including benzene.

Fraser Torpy/University of Technology Sydney

Public health initiatives often strive to reduce cardiovascular and obesity risks, but breathing seems pretty important too. According to the World Health Organization, household air pollution is responsible for about 2.5 million global premature deaths each year. And since 2020 we’ve become accustomed to spending more time inside and at home.

“This new research proves that plants should not just be seen as ‘nice to have,’ but rather a crucial part of every workplace wellness plan,” Ambius General Manager Johan Hodgson said in statement released by the university.

So don’t spend hundreds of dollars on a fancy air filtration system when a wall of plants can do that for next to nothing. Find what works for you and your space and become a plant parent today! Your lungs will thank you.
 

But officer, I had to swerve to miss the duodenal ampulla

Tiny video capsule endoscopes have been around for many years, but they have one big weakness: The ingestible cameras’ journey through the GI tract is passively driven by gravity and the natural movement of the body, so they often miss potential problem areas.

AnX Robotica

Not anymore. That flaw has been addressed by medical technology company AnX Robotica, which has taken endoscopy to the next level by adding that wondrous directional control device of the modern electronic age, a joystick.

The new system “uses an external magnet and hand-held video game style joysticks to move the capsule in three dimensions,” which allows physicians to “remotely drive a miniature video capsule to all regions of the stomach to visualize and photograph potential problem areas,” according to Andrew C. Meltzer, MD, of George Washington University and associates, who conducted a pilot study funded by AnX Robotica.

The video capsule provided a 95% rate of visualization in the stomachs of 40 patients who were examined at a medical office building by an emergency medicine physician who had no previous specialty training in endoscopy. “Capsules were driven by the ER physician and then the study reports were reviewed by an attending gastroenterologist who was physically off site,” the investigators said in a written statement.

The capsule operator did receive some additional training, and development of artificial intelligence to self-drive the capsule is in the works, but for now, we’re talking about a device controlled by a human using a joystick. And we all know that 50-year-olds are not especially known for their joystick skills. For that we need real experts. Yup, we need to put those joystick-controlled capsule endoscopes in the hands of teenage gamers. Who wants to go first?
 

Maybe AI isn’t ready for the big time after all

“How long before some intrepid stockholder says: ‘Hey, instead of paying doctors, why don’t we just use the free robot instead?’ ” Those words appeared on LOTME but a month ago. After all, the AI is supposed to be smarter and more empathetic than a doctor. And did we mention it’s free? Or at least extremely cheap. Cheaper than, say, a group of recently unionized health care workers.

maewjpho/Thinkstock

In early May, the paid employees manning the National Eating Disorders Association emergency hotline voted to unionize, as they felt overwhelmed and underpaid. Apparently, paying six people an extra few thousand a year was too much for NEDA’s leadership, as they decided a few weeks later to fire those workers, fully closing down the hotline. Instead of talking to a real person, people “calling in” for support would be met with Tessa, a wellness chatbot that would hopefully guide them through their crisis. Key word, hopefully.

In perhaps the least surprising twist of the year, NEDA was forced to walk back its decision about a week after its initial announcement. It all started with a viral Instagram post from a woman who called in and received the following advice from Tessa: Lose 1-2 pounds a week, count calories and work for a 500- to 1,000-calorie deficit, weigh herself weekly, and restrict her diet. Unfortunately, all of these suggestions were things that led to the development of the woman’s eating disorder.

Naturally, NEDA responded in good grace, accusing the woman of lying. A NEDA vice president even left some nasty comments on the post, but hastily deleted them a day later when NEDA announced it was shutting down Tessa “until further notice for a complete investigation.” NEDA’s CEO insisted they hadn’t seen that behavior from Tessa before, calling it a “bug” and insisting the bot would only be down temporarily until the triggers causing the bug were fixed.

In the aftermath, several doctors and psychologists chimed in, terming the rush to automate human roles dangerous and risky. After all, much of what makes these hotlines effective is the volunteers speaking from their own experience. An unsupervised bot doesn’t seem to have what it takes to deal with a mental health crisis, but we’re betting that Tessa will be back. As a wise cephalopod once said: Nobody gives a care about the fate of labor as long as they can get their instant gratification.
 

You can’t spell existential without s-t-e-n-t

This week, we’re including a special “bonus” item that, to be honest, has nothing to do with stents. That’s why our editor is making us call this a “bonus” (and making us use quote marks, too): It doesn’t really have anything to do with stents or health care or those who practice health care. Actually, his exact words were, “You can’t just give the readers someone else’s ****ing list and expect to get paid for it.” Did we mention that he looks like Jack Nicklaus but acts like BoJack Horseman?

Anywaaay, we’re pretty sure that the list in question – “America’s Top 10 Most Googled Existential Questions” – says something about the human condition, just not about stents:

1. Why is the sky blue?

2. What do dreams mean?

3. What is the meaning of life?

4. Why am I so tired?

5. Who am I?

6. What is love?

7. Is a hot dog a sandwich?

8. What came first, the chicken or the egg?

9. What should I do?

10. Do animals have souls?

Sowing the seeds of cancer prevention

Are you looking to add to your quality of life, even though pets are not your speed? Might we suggest something with lower maintenance? Something a little greener?

Indoor plants can purify the air that comes from outside. Researchers at the University of Technology Sydney, in partnership with the plantscaping company Ambius, showed that a “green wall” made up of mixed indoor plants was able to suck up 97% of “the most toxic compounds” from the air in just 8 hours. We’re talking about lung-irritating, headache-inducing, cancer risk–boosting compounds from gasoline fumes, including benzene.

Fraser Torpy/University of Technology Sydney

Public health initiatives often strive to reduce cardiovascular and obesity risks, but breathing seems pretty important too. According to the World Health Organization, household air pollution is responsible for about 2.5 million global premature deaths each year. And since 2020 we’ve become accustomed to spending more time inside and at home.

“This new research proves that plants should not just be seen as ‘nice to have,’ but rather a crucial part of every workplace wellness plan,” Ambius General Manager Johan Hodgson said in statement released by the university.

So don’t spend hundreds of dollars on a fancy air filtration system when a wall of plants can do that for next to nothing. Find what works for you and your space and become a plant parent today! Your lungs will thank you.
 

But officer, I had to swerve to miss the duodenal ampulla

Tiny video capsule endoscopes have been around for many years, but they have one big weakness: The ingestible cameras’ journey through the GI tract is passively driven by gravity and the natural movement of the body, so they often miss potential problem areas.

AnX Robotica

Not anymore. That flaw has been addressed by medical technology company AnX Robotica, which has taken endoscopy to the next level by adding that wondrous directional control device of the modern electronic age, a joystick.

The new system “uses an external magnet and hand-held video game style joysticks to move the capsule in three dimensions,” which allows physicians to “remotely drive a miniature video capsule to all regions of the stomach to visualize and photograph potential problem areas,” according to Andrew C. Meltzer, MD, of George Washington University and associates, who conducted a pilot study funded by AnX Robotica.

The video capsule provided a 95% rate of visualization in the stomachs of 40 patients who were examined at a medical office building by an emergency medicine physician who had no previous specialty training in endoscopy. “Capsules were driven by the ER physician and then the study reports were reviewed by an attending gastroenterologist who was physically off site,” the investigators said in a written statement.

The capsule operator did receive some additional training, and development of artificial intelligence to self-drive the capsule is in the works, but for now, we’re talking about a device controlled by a human using a joystick. And we all know that 50-year-olds are not especially known for their joystick skills. For that we need real experts. Yup, we need to put those joystick-controlled capsule endoscopes in the hands of teenage gamers. Who wants to go first?
 

Maybe AI isn’t ready for the big time after all

“How long before some intrepid stockholder says: ‘Hey, instead of paying doctors, why don’t we just use the free robot instead?’ ” Those words appeared on LOTME but a month ago. After all, the AI is supposed to be smarter and more empathetic than a doctor. And did we mention it’s free? Or at least extremely cheap. Cheaper than, say, a group of recently unionized health care workers.

maewjpho/Thinkstock

In early May, the paid employees manning the National Eating Disorders Association emergency hotline voted to unionize, as they felt overwhelmed and underpaid. Apparently, paying six people an extra few thousand a year was too much for NEDA’s leadership, as they decided a few weeks later to fire those workers, fully closing down the hotline. Instead of talking to a real person, people “calling in” for support would be met with Tessa, a wellness chatbot that would hopefully guide them through their crisis. Key word, hopefully.

In perhaps the least surprising twist of the year, NEDA was forced to walk back its decision about a week after its initial announcement. It all started with a viral Instagram post from a woman who called in and received the following advice from Tessa: Lose 1-2 pounds a week, count calories and work for a 500- to 1,000-calorie deficit, weigh herself weekly, and restrict her diet. Unfortunately, all of these suggestions were things that led to the development of the woman’s eating disorder.

Naturally, NEDA responded in good grace, accusing the woman of lying. A NEDA vice president even left some nasty comments on the post, but hastily deleted them a day later when NEDA announced it was shutting down Tessa “until further notice for a complete investigation.” NEDA’s CEO insisted they hadn’t seen that behavior from Tessa before, calling it a “bug” and insisting the bot would only be down temporarily until the triggers causing the bug were fixed.

In the aftermath, several doctors and psychologists chimed in, terming the rush to automate human roles dangerous and risky. After all, much of what makes these hotlines effective is the volunteers speaking from their own experience. An unsupervised bot doesn’t seem to have what it takes to deal with a mental health crisis, but we’re betting that Tessa will be back. As a wise cephalopod once said: Nobody gives a care about the fate of labor as long as they can get their instant gratification.
 

You can’t spell existential without s-t-e-n-t

This week, we’re including a special “bonus” item that, to be honest, has nothing to do with stents. That’s why our editor is making us call this a “bonus” (and making us use quote marks, too): It doesn’t really have anything to do with stents or health care or those who practice health care. Actually, his exact words were, “You can’t just give the readers someone else’s ****ing list and expect to get paid for it.” Did we mention that he looks like Jack Nicklaus but acts like BoJack Horseman?

Anywaaay, we’re pretty sure that the list in question – “America’s Top 10 Most Googled Existential Questions” – says something about the human condition, just not about stents:

1. Why is the sky blue?

2. What do dreams mean?

3. What is the meaning of life?

4. Why am I so tired?

5. Who am I?

6. What is love?

7. Is a hot dog a sandwich?

8. What came first, the chicken or the egg?

9. What should I do?

10. Do animals have souls?

Immune checkpoint inhibitors are a cornerstone of non–small cell lung cancer (NSCLC) treatment. But there is a question that’s been vexing oncologists for years: When can treatment be stopped?
 

A new review of clinical trial data suggests that it is safe to stop immunotherapy after 2 years if the patient is progression free. There was no difference in overall survival between such patients and those who carried on with immunotherapy for another 2 years, so for 4 years in total.

“For patients who are progression free on immunotherapy for NSCLC, it is reasonable to stop therapy at 2 years, rather than continuing indefinitely,”  said the investigators, led by medical oncologist Lova Sun, MD, a lung and head and neck cancer specialist at the University of Pennsylvania, Philadelphia.

“The lack of statistically significant overall survival advantage for” indefinite treatment “on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years,” they added.

The study was published online in JAMA Oncology to coincide with a presentation at the annual meeting of the American Society of Clinical Oncology.

Dr. Sun and colleagues commented that there have been a number of trials that have shown durable benefits persisting long after immunotherapy was stopped at 2 years, but clinicians seem to have been spooked into preferring indefinite treatment by a trial that showed worse survival with nivolumab when it was stopped at 1 year in responders versus ongoing treatment.

In an accompanying editorial, Jack West, MD, a medical oncologist and lung cancer specialist at City of Hope, Duarte, Calif., noted that given the “clear limitations in retrospective clinical data, we may want to wait for prospective randomized clinical trial data, but this will be a difficult study to complete, and results will take many years to become available.

“In the meantime, the perfect should not be the enemy of the good. These data may provide reassurance to us and patients that discontinuing treatment at 2 years can confer the same overall survival as extended treatment with lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” he said.
 

Study details

For their review, Dr. Sun and colleagues included patients with advanced NSCLC called from 280 cancer clinics from across the United States.

The investigators compared overall survival in 113 advanced NSCLC patients treated with up-front immune checkpoint inhibitors (ICIs) for 700-760 days (that is, stopping within 2 years) with survival in 593 patients treated beyond 760 days (the indefinite therapy group).

Patients were diagnosed from 2016 to 2020 at a median age of 69 years and were about evenly split between the sexes. The team noted that although all the patients were progression free at 2 years, only about one in five discontinued ICIs, highlighting “a strong bias toward potential overtreatment [vs.] possible undertreatment,” as Dr. West put it in the editorial.

Approximately half of the patients in both groups were treated initially with immunotherapy alone and the rest in combination with chemotherapy.

The 2-year overall survival from the 760-day mark was 79% in the fixed-duration group versus 81% with indefinite treatment, with no difference on either univariate (hazard ratio, 1.26; P = .36) or multivariable (HR, 1.33; P = .29) analysis adjusting for smoking history, PD-L1 status, histology, and other covariates.

Eleven patients in the fixed-duration cohort (10%) subsequently had progression and were rechallenged with an ICI; all but one with the same ICI used frontline.

Median progression-free survival after rechallenge was 8.1 months, demonstrating that patients can still benefit from ICIs even after discontinuation, the investigators said.

The groups were well balanced except that patients in the fixed-duration group were more likely to be treated at an academic center and have a history of smoking, with a trend toward being more likely to have squamous cell carcinoma. “Even after adjusting for these covariates, there was no overall survival benefit for indefinite-duration therapy,” the team said.

There was no funding for the work. The investigators have numerous pharmaceutical industry ties, including Dr. Sun, who is a consultant for Regeneron, Genmab, Seagen, and Bayer, and disclosed funding from BluePrint Research, Seagen Research, and IO Biotech Research. Dr. West reported receiving personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

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

Immune checkpoint inhibitors are a cornerstone of non–small cell lung cancer (NSCLC) treatment. But there is a question that’s been vexing oncologists for years: When can treatment be stopped?
 

A new review of clinical trial data suggests that it is safe to stop immunotherapy after 2 years if the patient is progression free. There was no difference in overall survival between such patients and those who carried on with immunotherapy for another 2 years, so for 4 years in total.

“For patients who are progression free on immunotherapy for NSCLC, it is reasonable to stop therapy at 2 years, rather than continuing indefinitely,”  said the investigators, led by medical oncologist Lova Sun, MD, a lung and head and neck cancer specialist at the University of Pennsylvania, Philadelphia.

“The lack of statistically significant overall survival advantage for” indefinite treatment “on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years,” they added.

The study was published online in JAMA Oncology to coincide with a presentation at the annual meeting of the American Society of Clinical Oncology.

Dr. Sun and colleagues commented that there have been a number of trials that have shown durable benefits persisting long after immunotherapy was stopped at 2 years, but clinicians seem to have been spooked into preferring indefinite treatment by a trial that showed worse survival with nivolumab when it was stopped at 1 year in responders versus ongoing treatment.

In an accompanying editorial, Jack West, MD, a medical oncologist and lung cancer specialist at City of Hope, Duarte, Calif., noted that given the “clear limitations in retrospective clinical data, we may want to wait for prospective randomized clinical trial data, but this will be a difficult study to complete, and results will take many years to become available.

“In the meantime, the perfect should not be the enemy of the good. These data may provide reassurance to us and patients that discontinuing treatment at 2 years can confer the same overall survival as extended treatment with lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” he said.
 

Study details

For their review, Dr. Sun and colleagues included patients with advanced NSCLC called from 280 cancer clinics from across the United States.

The investigators compared overall survival in 113 advanced NSCLC patients treated with up-front immune checkpoint inhibitors (ICIs) for 700-760 days (that is, stopping within 2 years) with survival in 593 patients treated beyond 760 days (the indefinite therapy group).

Patients were diagnosed from 2016 to 2020 at a median age of 69 years and were about evenly split between the sexes. The team noted that although all the patients were progression free at 2 years, only about one in five discontinued ICIs, highlighting “a strong bias toward potential overtreatment [vs.] possible undertreatment,” as Dr. West put it in the editorial.

Approximately half of the patients in both groups were treated initially with immunotherapy alone and the rest in combination with chemotherapy.

The 2-year overall survival from the 760-day mark was 79% in the fixed-duration group versus 81% with indefinite treatment, with no difference on either univariate (hazard ratio, 1.26; P = .36) or multivariable (HR, 1.33; P = .29) analysis adjusting for smoking history, PD-L1 status, histology, and other covariates.

Eleven patients in the fixed-duration cohort (10%) subsequently had progression and were rechallenged with an ICI; all but one with the same ICI used frontline.

Median progression-free survival after rechallenge was 8.1 months, demonstrating that patients can still benefit from ICIs even after discontinuation, the investigators said.

The groups were well balanced except that patients in the fixed-duration group were more likely to be treated at an academic center and have a history of smoking, with a trend toward being more likely to have squamous cell carcinoma. “Even after adjusting for these covariates, there was no overall survival benefit for indefinite-duration therapy,” the team said.

There was no funding for the work. The investigators have numerous pharmaceutical industry ties, including Dr. Sun, who is a consultant for Regeneron, Genmab, Seagen, and Bayer, and disclosed funding from BluePrint Research, Seagen Research, and IO Biotech Research. Dr. West reported receiving personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

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

Immune checkpoint inhibitors are a cornerstone of non–small cell lung cancer (NSCLC) treatment. But there is a question that’s been vexing oncologists for years: When can treatment be stopped?
 

A new review of clinical trial data suggests that it is safe to stop immunotherapy after 2 years if the patient is progression free. There was no difference in overall survival between such patients and those who carried on with immunotherapy for another 2 years, so for 4 years in total.

“For patients who are progression free on immunotherapy for NSCLC, it is reasonable to stop therapy at 2 years, rather than continuing indefinitely,”  said the investigators, led by medical oncologist Lova Sun, MD, a lung and head and neck cancer specialist at the University of Pennsylvania, Philadelphia.

“The lack of statistically significant overall survival advantage for” indefinite treatment “on adjusted analysis provides reassurance to patients and clinicians who wish to discontinue immunotherapy at 2 years,” they added.

The study was published online in JAMA Oncology to coincide with a presentation at the annual meeting of the American Society of Clinical Oncology.

Dr. Sun and colleagues commented that there have been a number of trials that have shown durable benefits persisting long after immunotherapy was stopped at 2 years, but clinicians seem to have been spooked into preferring indefinite treatment by a trial that showed worse survival with nivolumab when it was stopped at 1 year in responders versus ongoing treatment.

In an accompanying editorial, Jack West, MD, a medical oncologist and lung cancer specialist at City of Hope, Duarte, Calif., noted that given the “clear limitations in retrospective clinical data, we may want to wait for prospective randomized clinical trial data, but this will be a difficult study to complete, and results will take many years to become available.

“In the meantime, the perfect should not be the enemy of the good. These data may provide reassurance to us and patients that discontinuing treatment at 2 years can confer the same overall survival as extended treatment with lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” he said.
 

Study details

For their review, Dr. Sun and colleagues included patients with advanced NSCLC called from 280 cancer clinics from across the United States.

The investigators compared overall survival in 113 advanced NSCLC patients treated with up-front immune checkpoint inhibitors (ICIs) for 700-760 days (that is, stopping within 2 years) with survival in 593 patients treated beyond 760 days (the indefinite therapy group).

Patients were diagnosed from 2016 to 2020 at a median age of 69 years and were about evenly split between the sexes. The team noted that although all the patients were progression free at 2 years, only about one in five discontinued ICIs, highlighting “a strong bias toward potential overtreatment [vs.] possible undertreatment,” as Dr. West put it in the editorial.

Approximately half of the patients in both groups were treated initially with immunotherapy alone and the rest in combination with chemotherapy.

The 2-year overall survival from the 760-day mark was 79% in the fixed-duration group versus 81% with indefinite treatment, with no difference on either univariate (hazard ratio, 1.26; P = .36) or multivariable (HR, 1.33; P = .29) analysis adjusting for smoking history, PD-L1 status, histology, and other covariates.

Eleven patients in the fixed-duration cohort (10%) subsequently had progression and were rechallenged with an ICI; all but one with the same ICI used frontline.

Median progression-free survival after rechallenge was 8.1 months, demonstrating that patients can still benefit from ICIs even after discontinuation, the investigators said.

The groups were well balanced except that patients in the fixed-duration group were more likely to be treated at an academic center and have a history of smoking, with a trend toward being more likely to have squamous cell carcinoma. “Even after adjusting for these covariates, there was no overall survival benefit for indefinite-duration therapy,” the team said.

There was no funding for the work. The investigators have numerous pharmaceutical industry ties, including Dr. Sun, who is a consultant for Regeneron, Genmab, Seagen, and Bayer, and disclosed funding from BluePrint Research, Seagen Research, and IO Biotech Research. Dr. West reported receiving personal fees from AstraZeneca, Genentech/Roche, Merck, and Regeneron.

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

Therapeutic hypothermia (TH) for moderate and severe neonatal encephalopathy has been shown to reduce the risk of newborn death, major neurodevelopmental disability, developmental delay, and cerebral palsy.¹ It is estimated that 8 newborns with moderate or severe neonatal encephalopathy need to be treated with TH to prevent 1 case of cerebral palsy.¹ The key elements of TH include:

• initiate hypothermia within 6 hoursof birth
• cool the newborn to a core temperature of 33.5˚ C to 34.5˚ C (92.3˚ F to 94.1˚ F) for 72 hours
• obtain brain ultrasonography to assess for intracranial hemorrhage
• obtain sequential MRI studies to assess brain structure and function
• initiate EEG monitoring for seizure activity.

During hypothermia the newborn is sedated, and oral feedings are reduced. During TH, important physiological goals are to maintain normal oxygenation, blood pressure, fluid balance, and glucose levels.^1,2

TH: The basics

Most of the major published randomized clinical trials used the following inclusion criteria to initiate TH²:

• gestational age at birth of ≥ 35 weeks
• neonate is within 6 hours of birth
• an Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation at birth or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1
• moderate to severe encephalopathy or the presence of seizures
• absence of recognizable congenital abnormalities at birth.

However, in some institutions, expert neonatologists have developed more liberal criteria for the initiation of TH, to be considered on a case-by-case basis. These more inclusive criteria, which will result in more newborns being treated with TH, include^3:

• gestational age at birth of ≥ 34 weeks
• neonate is within 12 hours of birth
• a sentinel event at birth or Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1 or postnatal cardiopulmonary failure
• moderate to severe encephalopathy or concern for the presence of seizures.

Birth at a gestational age ≤ 34 weeks is a contraindication to TH. Relative contraindications to initiation of TH include: birth weight < 1,750 g, severe congenital anomaly, major genetic disorders, known severe metabolic disorders, major intracranial hemorrhage, severe septicemia, and uncorrectable coagulopathy.³ Adverse outcomes of TH include thrombocytopenia, cardiac arrythmia, and fat necrosis.⁴

Diagnosing neonatal encephalopathy

Neonatal encephalopathy is a clinical diagnosis, defined as abnormal neurologic function in the first few days of life in an infant born at ≥ 35 weeks’ gestation. It is divided into 3 categories: mild (Stage 1), moderate (Stage 2), and severe (Stage 3).^5,6 Institutions vary in the criteria used to differentiate mild from moderate neonatal encephalopathy, the two most frequent forms of encephalopathy. Newborns with mild encephalopathy are not routinely treated with TH because TH has not been shown to be helpful in this setting. Institutions with liberal criteria for diagnosing moderate encephalopathy will initiate TH in more cases. Involvement of a pediatric neurologist in the diagnosis of moderate encephalopathy may help confirm the diagnosis made by the primary neonatologist and provide an independent, second opinion about whether the newborn should be diagnosed with mild or moderate encephalopathy, a clinically important distinction. Physical examination and EEG findings associated with cases of mild, moderate, and severe encephalopathy are presented in TABLE 1.⁷

Continue: Obstetric factors that may be associated with neonatal encephalopathy...

Obstetric factors that may be associated with neonatal encephalopathy

In a retrospective case-control study that included 405 newborns at ≥ 35 weeks’ gestational age with neonatal encephalopathy thought to be due to hypoxia, 8 obstetric factors were identified as being associated with an increased risk of neonatal encephalopathy, including (TABLE 2)⁸:

1. an obstetric sentinel event (uterine rupture, placental abruption, umbilical cord prolapse, maternal collapse, or severe fetal bleeding)

2. shoulder dystocia

3. abnormal cardiotocogram (persistent late or variable decelerations, fetal bradycardia, and/or absent or minimal fetal heart variability)

4. failed vacuum delivery

5. prolonged rupture of the membranes (> 24 hours)

6. tight nuchal cord

7. gestational age at birth > 41 weeks

8. thick meconium. 

Genetic causes of neonatal seizures and neonatal encephalopathy

Many neonatologists practice with the belief that for a newborn with encephalopathy in the setting of a sentinel labor event, a low Apgar score at 5 minutes, an umbilical cord artery pH < 7.00, and/or an elevated lactate level, the diagnosis of hypoxic ischemic encephalopathy is warranted. However, there are many causes of neonatal encephalopathy not related to intrapartum events. For example, neonatal encephalopathy and seizures may be caused by infectious, vascular, metabolic, medications, or congenital problems.¹⁰

There are genetic disorders that can be associated with both neonatal seizures and encephalopathy, suggesting that in some cases the primary cause of the encephalopathy is a genetic problem, not management of labor. Mutations in the potassium channel and sodium channel genes are well recognized causes of neonatal seizures.^11,12 Cerebral palsy, a childhood outcome that may follow neonatal encephalopathy, also has numerous etiologies, including genetic causes. Among 1,345 children with cerebral palsy referred for exome sequencing, investigators reported that a genetic abnormality was identified in 33% of the cases.¹³ Mutations in 86 genes were identified in multiple children. Similar results have been reported in other cohorts.^14-16 Maintaining an open mind about the causes of a case of neonatal encephalopathy and not jumping to a conclusion before completing an evaluation is an optimal approach.

Parent’s evolving emotional and intellectual reaction to the initiation of TH

Initiation of TH for a newborn with encephalopathy catalyzes parents to wonder, “How did my baby develop an encephalopathy?”, “Did my obstetrician’s management of labor and delivery contribute to the outcome?” and “What is the prognosis for my baby?” These are difficult questions with high emotional valence for both patients and clinicians. Obstetricians and neonatologists should collaborate to provide consistent responses to these questions.

The presence of a low umbilical cord artery pH and high lactate in combination with a low Apgar score at 5 minutes may lead the neonatologist to diagnose hypoxic-ischemic encephalopathy in the medical record. The diagnosis of brain hypoxia and ischemia in a newborn may be interpreted by parents as meaning that labor events caused or contributed to the encephalopathy. During the 72 hours of TH, the newborn is sedated and separated from the parents, causing additional emotional stress and uncertainty. When a baby is transferred from a community hospital to a neonatal intensive care unit (NICU) at a tertiary center, the parents may be geographically separated from their baby during a critical period of time, adding to their anxiety. At some point during the care process most newborns treated with TH will have an EEG, brain ultrasound, and brain magnetic resonance imaging (MRI). These data will be discussed with the parent(s) and may cause confusion and additional stress.

The optimal approach to communicating with parents whose newborn is treated with TH continues to evolve. Best practices may include^17-20:

• in-person, regular multidisciplinary family meetings with the parents, including neonatologists, obstetricians, social service specialists and mental health experts when possible
• providing emotional support to parents, recognizing the psychological trauma of the clinical events
• encouraging parents to have physical contact with the newborn during TH
• elevating the role of the parents in the care process by having them participate in care events such as diapering the newborn
• ensuring that clinicians do not blame other clinicians for the clinical outcome
• communicating the results and interpretation of advanced physiological monitoring and imaging studies, with an emphasis on clarity, recognizing the limitations of the studies
• providing educational materials for parents about TH, early intervention programs, and support resources.

Coordinated and consistent communication with the parents is often difficult to facilitate due to many factors, including the unique perspectives and vocabularies of clinicians from different specialties and the difficulty of coordinating communications with all those involved over multiple shifts and sites of care. In terms of vocabulary, neonatologists are comfortable with making a diagnosis of hypoxic-ischemic encephalopathy in a newborn, but obstetricians would prefer that neonatologists use the more generic diagnosis of encephalopathy, holding judgment on the cause until additional data are available. In terms of coordinating communication over multiple shifts and sites of care, interactions between an obstetrician and their patient typically occurs in the postpartum unit, while interactions between neonatologists and parents occur in the NICU.

Parents of a baby with neonatal encephalopathy undergoing TH may have numerous traumatic experiences during the care process. For weeks or months after birth, they may recall or dream about the absence of sounds from their newborn at birth, the resuscitation events including chest compressions and intubation, the shivering of the baby during TH, and the jarring pivot from the expectation of holding and bonding with a healthy newborn to the reality of a sick newborn requiring intensive care. Obstetricians are also traumatized by these events and support from peers and mental health experts may help them recognize, explore, and adapt to the trauma. Neonatologists believe that TH can help improve the childhood outcomes of newborns with encephalopathy, a goal endorsed by all clinicians and family members. ●

Therapeutic hypothermia (TH) for moderate and severe neonatal encephalopathy has been shown to reduce the risk of newborn death, major neurodevelopmental disability, developmental delay, and cerebral palsy.¹ It is estimated that 8 newborns with moderate or severe neonatal encephalopathy need to be treated with TH to prevent 1 case of cerebral palsy.¹ The key elements of TH include:

• initiate hypothermia within 6 hoursof birth
• cool the newborn to a core temperature of 33.5˚ C to 34.5˚ C (92.3˚ F to 94.1˚ F) for 72 hours
• obtain brain ultrasonography to assess for intracranial hemorrhage
• obtain sequential MRI studies to assess brain structure and function
• initiate EEG monitoring for seizure activity.

During hypothermia the newborn is sedated, and oral feedings are reduced. During TH, important physiological goals are to maintain normal oxygenation, blood pressure, fluid balance, and glucose levels.^1,2

TH: The basics

Most of the major published randomized clinical trials used the following inclusion criteria to initiate TH²:

• gestational age at birth of ≥ 35 weeks
• neonate is within 6 hours of birth
• an Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation at birth or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1
• moderate to severe encephalopathy or the presence of seizures
• absence of recognizable congenital abnormalities at birth.

However, in some institutions, expert neonatologists have developed more liberal criteria for the initiation of TH, to be considered on a case-by-case basis. These more inclusive criteria, which will result in more newborns being treated with TH, include^3:

• gestational age at birth of ≥ 34 weeks
• neonate is within 12 hours of birth
• a sentinel event at birth or Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1 or postnatal cardiopulmonary failure
• moderate to severe encephalopathy or concern for the presence of seizures.

Birth at a gestational age ≤ 34 weeks is a contraindication to TH. Relative contraindications to initiation of TH include: birth weight < 1,750 g, severe congenital anomaly, major genetic disorders, known severe metabolic disorders, major intracranial hemorrhage, severe septicemia, and uncorrectable coagulopathy.³ Adverse outcomes of TH include thrombocytopenia, cardiac arrythmia, and fat necrosis.⁴

Diagnosing neonatal encephalopathy

Neonatal encephalopathy is a clinical diagnosis, defined as abnormal neurologic function in the first few days of life in an infant born at ≥ 35 weeks’ gestation. It is divided into 3 categories: mild (Stage 1), moderate (Stage 2), and severe (Stage 3).^5,6 Institutions vary in the criteria used to differentiate mild from moderate neonatal encephalopathy, the two most frequent forms of encephalopathy. Newborns with mild encephalopathy are not routinely treated with TH because TH has not been shown to be helpful in this setting. Institutions with liberal criteria for diagnosing moderate encephalopathy will initiate TH in more cases. Involvement of a pediatric neurologist in the diagnosis of moderate encephalopathy may help confirm the diagnosis made by the primary neonatologist and provide an independent, second opinion about whether the newborn should be diagnosed with mild or moderate encephalopathy, a clinically important distinction. Physical examination and EEG findings associated with cases of mild, moderate, and severe encephalopathy are presented in TABLE 1.⁷

Continue: Obstetric factors that may be associated with neonatal encephalopathy...

Obstetric factors that may be associated with neonatal encephalopathy

In a retrospective case-control study that included 405 newborns at ≥ 35 weeks’ gestational age with neonatal encephalopathy thought to be due to hypoxia, 8 obstetric factors were identified as being associated with an increased risk of neonatal encephalopathy, including (TABLE 2)⁸:

1. an obstetric sentinel event (uterine rupture, placental abruption, umbilical cord prolapse, maternal collapse, or severe fetal bleeding)

2. shoulder dystocia

3. abnormal cardiotocogram (persistent late or variable decelerations, fetal bradycardia, and/or absent or minimal fetal heart variability)

4. failed vacuum delivery

5. prolonged rupture of the membranes (> 24 hours)

6. tight nuchal cord

7. gestational age at birth > 41 weeks

8. thick meconium. 

Genetic causes of neonatal seizures and neonatal encephalopathy

Many neonatologists practice with the belief that for a newborn with encephalopathy in the setting of a sentinel labor event, a low Apgar score at 5 minutes, an umbilical cord artery pH < 7.00, and/or an elevated lactate level, the diagnosis of hypoxic ischemic encephalopathy is warranted. However, there are many causes of neonatal encephalopathy not related to intrapartum events. For example, neonatal encephalopathy and seizures may be caused by infectious, vascular, metabolic, medications, or congenital problems.¹⁰

There are genetic disorders that can be associated with both neonatal seizures and encephalopathy, suggesting that in some cases the primary cause of the encephalopathy is a genetic problem, not management of labor. Mutations in the potassium channel and sodium channel genes are well recognized causes of neonatal seizures.^11,12 Cerebral palsy, a childhood outcome that may follow neonatal encephalopathy, also has numerous etiologies, including genetic causes. Among 1,345 children with cerebral palsy referred for exome sequencing, investigators reported that a genetic abnormality was identified in 33% of the cases.¹³ Mutations in 86 genes were identified in multiple children. Similar results have been reported in other cohorts.^14-16 Maintaining an open mind about the causes of a case of neonatal encephalopathy and not jumping to a conclusion before completing an evaluation is an optimal approach.

Parent’s evolving emotional and intellectual reaction to the initiation of TH

Initiation of TH for a newborn with encephalopathy catalyzes parents to wonder, “How did my baby develop an encephalopathy?”, “Did my obstetrician’s management of labor and delivery contribute to the outcome?” and “What is the prognosis for my baby?” These are difficult questions with high emotional valence for both patients and clinicians. Obstetricians and neonatologists should collaborate to provide consistent responses to these questions.

The presence of a low umbilical cord artery pH and high lactate in combination with a low Apgar score at 5 minutes may lead the neonatologist to diagnose hypoxic-ischemic encephalopathy in the medical record. The diagnosis of brain hypoxia and ischemia in a newborn may be interpreted by parents as meaning that labor events caused or contributed to the encephalopathy. During the 72 hours of TH, the newborn is sedated and separated from the parents, causing additional emotional stress and uncertainty. When a baby is transferred from a community hospital to a neonatal intensive care unit (NICU) at a tertiary center, the parents may be geographically separated from their baby during a critical period of time, adding to their anxiety. At some point during the care process most newborns treated with TH will have an EEG, brain ultrasound, and brain magnetic resonance imaging (MRI). These data will be discussed with the parent(s) and may cause confusion and additional stress.

The optimal approach to communicating with parents whose newborn is treated with TH continues to evolve. Best practices may include^17-20:

• in-person, regular multidisciplinary family meetings with the parents, including neonatologists, obstetricians, social service specialists and mental health experts when possible
• providing emotional support to parents, recognizing the psychological trauma of the clinical events
• encouraging parents to have physical contact with the newborn during TH
• elevating the role of the parents in the care process by having them participate in care events such as diapering the newborn
• ensuring that clinicians do not blame other clinicians for the clinical outcome
• communicating the results and interpretation of advanced physiological monitoring and imaging studies, with an emphasis on clarity, recognizing the limitations of the studies
• providing educational materials for parents about TH, early intervention programs, and support resources.

Coordinated and consistent communication with the parents is often difficult to facilitate due to many factors, including the unique perspectives and vocabularies of clinicians from different specialties and the difficulty of coordinating communications with all those involved over multiple shifts and sites of care. In terms of vocabulary, neonatologists are comfortable with making a diagnosis of hypoxic-ischemic encephalopathy in a newborn, but obstetricians would prefer that neonatologists use the more generic diagnosis of encephalopathy, holding judgment on the cause until additional data are available. In terms of coordinating communication over multiple shifts and sites of care, interactions between an obstetrician and their patient typically occurs in the postpartum unit, while interactions between neonatologists and parents occur in the NICU.

Parents of a baby with neonatal encephalopathy undergoing TH may have numerous traumatic experiences during the care process. For weeks or months after birth, they may recall or dream about the absence of sounds from their newborn at birth, the resuscitation events including chest compressions and intubation, the shivering of the baby during TH, and the jarring pivot from the expectation of holding and bonding with a healthy newborn to the reality of a sick newborn requiring intensive care. Obstetricians are also traumatized by these events and support from peers and mental health experts may help them recognize, explore, and adapt to the trauma. Neonatologists believe that TH can help improve the childhood outcomes of newborns with encephalopathy, a goal endorsed by all clinicians and family members. ●

Therapeutic hypothermia (TH) for moderate and severe neonatal encephalopathy has been shown to reduce the risk of newborn death, major neurodevelopmental disability, developmental delay, and cerebral palsy.¹ It is estimated that 8 newborns with moderate or severe neonatal encephalopathy need to be treated with TH to prevent 1 case of cerebral palsy.¹ The key elements of TH include:

• initiate hypothermia within 6 hoursof birth
• cool the newborn to a core temperature of 33.5˚ C to 34.5˚ C (92.3˚ F to 94.1˚ F) for 72 hours
• obtain brain ultrasonography to assess for intracranial hemorrhage
• obtain sequential MRI studies to assess brain structure and function
• initiate EEG monitoring for seizure activity.

During hypothermia the newborn is sedated, and oral feedings are reduced. During TH, important physiological goals are to maintain normal oxygenation, blood pressure, fluid balance, and glucose levels.^1,2

TH: The basics

Most of the major published randomized clinical trials used the following inclusion criteria to initiate TH²:

• gestational age at birth of ≥ 35 weeks
• neonate is within 6 hours of birth
• an Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation at birth or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1
• moderate to severe encephalopathy or the presence of seizures
• absence of recognizable congenital abnormalities at birth.

However, in some institutions, expert neonatologists have developed more liberal criteria for the initiation of TH, to be considered on a case-by-case basis. These more inclusive criteria, which will result in more newborns being treated with TH, include^3:

• gestational age at birth of ≥ 34 weeks
• neonate is within 12 hours of birth
• a sentinel event at birth or Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1 or postnatal cardiopulmonary failure
• moderate to severe encephalopathy or concern for the presence of seizures.

Birth at a gestational age ≤ 34 weeks is a contraindication to TH. Relative contraindications to initiation of TH include: birth weight < 1,750 g, severe congenital anomaly, major genetic disorders, known severe metabolic disorders, major intracranial hemorrhage, severe septicemia, and uncorrectable coagulopathy.³ Adverse outcomes of TH include thrombocytopenia, cardiac arrythmia, and fat necrosis.⁴

Diagnosing neonatal encephalopathy

Neonatal encephalopathy is a clinical diagnosis, defined as abnormal neurologic function in the first few days of life in an infant born at ≥ 35 weeks’ gestation. It is divided into 3 categories: mild (Stage 1), moderate (Stage 2), and severe (Stage 3).^5,6 Institutions vary in the criteria used to differentiate mild from moderate neonatal encephalopathy, the two most frequent forms of encephalopathy. Newborns with mild encephalopathy are not routinely treated with TH because TH has not been shown to be helpful in this setting. Institutions with liberal criteria for diagnosing moderate encephalopathy will initiate TH in more cases. Involvement of a pediatric neurologist in the diagnosis of moderate encephalopathy may help confirm the diagnosis made by the primary neonatologist and provide an independent, second opinion about whether the newborn should be diagnosed with mild or moderate encephalopathy, a clinically important distinction. Physical examination and EEG findings associated with cases of mild, moderate, and severe encephalopathy are presented in TABLE 1.⁷

Continue: Obstetric factors that may be associated with neonatal encephalopathy...

Obstetric factors that may be associated with neonatal encephalopathy

In a retrospective case-control study that included 405 newborns at ≥ 35 weeks’ gestational age with neonatal encephalopathy thought to be due to hypoxia, 8 obstetric factors were identified as being associated with an increased risk of neonatal encephalopathy, including (TABLE 2)⁸:

1. an obstetric sentinel event (uterine rupture, placental abruption, umbilical cord prolapse, maternal collapse, or severe fetal bleeding)

2. shoulder dystocia

3. abnormal cardiotocogram (persistent late or variable decelerations, fetal bradycardia, and/or absent or minimal fetal heart variability)

4. failed vacuum delivery

5. prolonged rupture of the membranes (> 24 hours)

6. tight nuchal cord

7. gestational age at birth > 41 weeks

8. thick meconium. 

Genetic causes of neonatal seizures and neonatal encephalopathy

Many neonatologists practice with the belief that for a newborn with encephalopathy in the setting of a sentinel labor event, a low Apgar score at 5 minutes, an umbilical cord artery pH < 7.00, and/or an elevated lactate level, the diagnosis of hypoxic ischemic encephalopathy is warranted. However, there are many causes of neonatal encephalopathy not related to intrapartum events. For example, neonatal encephalopathy and seizures may be caused by infectious, vascular, metabolic, medications, or congenital problems.¹⁰

There are genetic disorders that can be associated with both neonatal seizures and encephalopathy, suggesting that in some cases the primary cause of the encephalopathy is a genetic problem, not management of labor. Mutations in the potassium channel and sodium channel genes are well recognized causes of neonatal seizures.^11,12 Cerebral palsy, a childhood outcome that may follow neonatal encephalopathy, also has numerous etiologies, including genetic causes. Among 1,345 children with cerebral palsy referred for exome sequencing, investigators reported that a genetic abnormality was identified in 33% of the cases.¹³ Mutations in 86 genes were identified in multiple children. Similar results have been reported in other cohorts.^14-16 Maintaining an open mind about the causes of a case of neonatal encephalopathy and not jumping to a conclusion before completing an evaluation is an optimal approach.

Parent’s evolving emotional and intellectual reaction to the initiation of TH

Initiation of TH for a newborn with encephalopathy catalyzes parents to wonder, “How did my baby develop an encephalopathy?”, “Did my obstetrician’s management of labor and delivery contribute to the outcome?” and “What is the prognosis for my baby?” These are difficult questions with high emotional valence for both patients and clinicians. Obstetricians and neonatologists should collaborate to provide consistent responses to these questions.

The presence of a low umbilical cord artery pH and high lactate in combination with a low Apgar score at 5 minutes may lead the neonatologist to diagnose hypoxic-ischemic encephalopathy in the medical record. The diagnosis of brain hypoxia and ischemia in a newborn may be interpreted by parents as meaning that labor events caused or contributed to the encephalopathy. During the 72 hours of TH, the newborn is sedated and separated from the parents, causing additional emotional stress and uncertainty. When a baby is transferred from a community hospital to a neonatal intensive care unit (NICU) at a tertiary center, the parents may be geographically separated from their baby during a critical period of time, adding to their anxiety. At some point during the care process most newborns treated with TH will have an EEG, brain ultrasound, and brain magnetic resonance imaging (MRI). These data will be discussed with the parent(s) and may cause confusion and additional stress.

The optimal approach to communicating with parents whose newborn is treated with TH continues to evolve. Best practices may include^17-20:

• in-person, regular multidisciplinary family meetings with the parents, including neonatologists, obstetricians, social service specialists and mental health experts when possible
• providing emotional support to parents, recognizing the psychological trauma of the clinical events
• encouraging parents to have physical contact with the newborn during TH
• elevating the role of the parents in the care process by having them participate in care events such as diapering the newborn
• ensuring that clinicians do not blame other clinicians for the clinical outcome
• communicating the results and interpretation of advanced physiological monitoring and imaging studies, with an emphasis on clarity, recognizing the limitations of the studies
• providing educational materials for parents about TH, early intervention programs, and support resources.

Coordinated and consistent communication with the parents is often difficult to facilitate due to many factors, including the unique perspectives and vocabularies of clinicians from different specialties and the difficulty of coordinating communications with all those involved over multiple shifts and sites of care. In terms of vocabulary, neonatologists are comfortable with making a diagnosis of hypoxic-ischemic encephalopathy in a newborn, but obstetricians would prefer that neonatologists use the more generic diagnosis of encephalopathy, holding judgment on the cause until additional data are available. In terms of coordinating communication over multiple shifts and sites of care, interactions between an obstetrician and their patient typically occurs in the postpartum unit, while interactions between neonatologists and parents occur in the NICU.

Parents of a baby with neonatal encephalopathy undergoing TH may have numerous traumatic experiences during the care process. For weeks or months after birth, they may recall or dream about the absence of sounds from their newborn at birth, the resuscitation events including chest compressions and intubation, the shivering of the baby during TH, and the jarring pivot from the expectation of holding and bonding with a healthy newborn to the reality of a sick newborn requiring intensive care. Obstetricians are also traumatized by these events and support from peers and mental health experts may help them recognize, explore, and adapt to the trauma. Neonatologists believe that TH can help improve the childhood outcomes of newborns with encephalopathy, a goal endorsed by all clinicians and family members. ●

Hartwig TJ, Ambye L, Gruhn JR, et al. Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study. Lancet. 2023;401:762-771. https://doi.org/10.1016/S0140-6736(22)02610-1.

Expert Commentary

A devastating outcome for women, pregnancy loss is directly proportional to maternal age, estimated to occur in approximately 15% of clinically recognized pregnancies and 30% of preclinical pregnancies.¹ Approximately 80% of pregnancy losses occur in the first trimester.² The frequency of clinically recognized early pregnancy loss for women aged 20–30 years is 9% to 17%, and these rates increase sharply, from 20% at age 35 years to 40% at age 40 years, and 80% at age 45 years. Recurrent pregnancy loss (RPL), defined as the spontaneous loss of 2 or more clinically recognized pregnancies, affects less than 5% of women.³ Genetic testing using chromosomal microarray analysis (CMA) has identified aneuploidy in about 55% of cases of miscarriage.⁴

Following ASRM guidelines for the evaluation of RPL, which consists of analyzing parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances, and autoimmune factors (including antiphospholipid syndrome), no explainable cause is determined in 50% of cases.³ Recently, it has been shown that more than 90% of patients with RPL will have a probable or definitive cause identified when CMA testing on miscarriage tissue with the ASRM evaluation guidelines.⁵

Details of the study

In this prospective cohort study from Denmark, the authors analyzed maternal serum for cell-free fetal DNA (cffDNA) to determine the ploidy status of the pregnancy loss. One thousand women older than age 18 were included (those who demonstrated an ultrasound-confirmed intrauterine pregnancy loss prior to 22 weeks’ gestation). Maternal blood was obtained while pregnancy tissue was in situ or within 24 hours of passage of products of conception (POC), then analyzed by genome-wide sequencing of cffDNA.

For the first 333 recruited women (validation phase), direct sequencing of the POC was performed for sensitivity and specificity. Following the elimination of inconclusive samples, 302 of the 333 cases demonstrated a sensitivity of 85% and specificity of 93%. In the subsequent evaluation of 667 women, researchers analyzed maternal serum from the gestational age of fetuses ranging from 35 days to 149 days.

Results. In total, nearly 90% of cases yielded conclusive results, with 50% euploid, 46% aneuploid, and 4% multiple aneuploidies. Earlier gestational ages (less than 7 weeks) had a no-call rate (ie, inconclusive) of approximately 50% (only based on 16 patients), with results typically obtained in maternal serum following passage of POC; in pregnancies at gestational ages past 7 weeks, the no-call rate was about 10%. In general, the longer the time after the pregnancy tissue passed, the higher likelihood of a no-call result.

Applying the technology of single-nucleotide polymorphism (SNP)-based CMA can improve identification of fetal and/or maternal sources as causes of pregnancy loss with accuracy, but it does require collection of POC. Of note, samples were deficient in this study, the authors cite, in one-third of the cases. Given this limitation of collection, the authors argue for use of the noninvasive method of cffDNA, obtained from maternal serum.

Study strengths and weaknesses

Several weaknesses of this study are highlighted. Of the validation cohort, one-third of pregnancy tissue could not be analyzed due to insufficient collection. Only 73% of cases allowed for DNA isolation from fetal tissue or chorionic villi; in 27% of cases samples were labeled “unknown tissue.” In those cases classified as unknown, 70% were further determined to be maternal. When all female and monosomy cases were excluded in an effort to assuredly reduce the risk of contamination with maternal DNA, sensitivity of the cffDNA testing process declined to 78%. Another limitation was the required short window for maternal blood sampling (within 24 hours) and its impact on the no-call rate.

The authors note an association with later-life morbidity in patients with a history of pregnancy loss and RPL (including cardiovascular disease, type 2 diabetes, and mental health disorders), thereby arguing for cffDNA-based testing versus no causal testing; however, no treatment has been proven to be effective at reducing pregnancy loss. ●

Hartwig TJ, Ambye L, Gruhn JR, et al. Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study. Lancet. 2023;401:762-771. https://doi.org/10.1016/S0140-6736(22)02610-1.

Expert Commentary

A devastating outcome for women, pregnancy loss is directly proportional to maternal age, estimated to occur in approximately 15% of clinically recognized pregnancies and 30% of preclinical pregnancies.¹ Approximately 80% of pregnancy losses occur in the first trimester.² The frequency of clinically recognized early pregnancy loss for women aged 20–30 years is 9% to 17%, and these rates increase sharply, from 20% at age 35 years to 40% at age 40 years, and 80% at age 45 years. Recurrent pregnancy loss (RPL), defined as the spontaneous loss of 2 or more clinically recognized pregnancies, affects less than 5% of women.³ Genetic testing using chromosomal microarray analysis (CMA) has identified aneuploidy in about 55% of cases of miscarriage.⁴

Following ASRM guidelines for the evaluation of RPL, which consists of analyzing parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances, and autoimmune factors (including antiphospholipid syndrome), no explainable cause is determined in 50% of cases.³ Recently, it has been shown that more than 90% of patients with RPL will have a probable or definitive cause identified when CMA testing on miscarriage tissue with the ASRM evaluation guidelines.⁵

Details of the study

In this prospective cohort study from Denmark, the authors analyzed maternal serum for cell-free fetal DNA (cffDNA) to determine the ploidy status of the pregnancy loss. One thousand women older than age 18 were included (those who demonstrated an ultrasound-confirmed intrauterine pregnancy loss prior to 22 weeks’ gestation). Maternal blood was obtained while pregnancy tissue was in situ or within 24 hours of passage of products of conception (POC), then analyzed by genome-wide sequencing of cffDNA.

For the first 333 recruited women (validation phase), direct sequencing of the POC was performed for sensitivity and specificity. Following the elimination of inconclusive samples, 302 of the 333 cases demonstrated a sensitivity of 85% and specificity of 93%. In the subsequent evaluation of 667 women, researchers analyzed maternal serum from the gestational age of fetuses ranging from 35 days to 149 days.

Results. In total, nearly 90% of cases yielded conclusive results, with 50% euploid, 46% aneuploid, and 4% multiple aneuploidies. Earlier gestational ages (less than 7 weeks) had a no-call rate (ie, inconclusive) of approximately 50% (only based on 16 patients), with results typically obtained in maternal serum following passage of POC; in pregnancies at gestational ages past 7 weeks, the no-call rate was about 10%. In general, the longer the time after the pregnancy tissue passed, the higher likelihood of a no-call result.

Applying the technology of single-nucleotide polymorphism (SNP)-based CMA can improve identification of fetal and/or maternal sources as causes of pregnancy loss with accuracy, but it does require collection of POC. Of note, samples were deficient in this study, the authors cite, in one-third of the cases. Given this limitation of collection, the authors argue for use of the noninvasive method of cffDNA, obtained from maternal serum.

Study strengths and weaknesses

Several weaknesses of this study are highlighted. Of the validation cohort, one-third of pregnancy tissue could not be analyzed due to insufficient collection. Only 73% of cases allowed for DNA isolation from fetal tissue or chorionic villi; in 27% of cases samples were labeled “unknown tissue.” In those cases classified as unknown, 70% were further determined to be maternal. When all female and monosomy cases were excluded in an effort to assuredly reduce the risk of contamination with maternal DNA, sensitivity of the cffDNA testing process declined to 78%. Another limitation was the required short window for maternal blood sampling (within 24 hours) and its impact on the no-call rate.

The authors note an association with later-life morbidity in patients with a history of pregnancy loss and RPL (including cardiovascular disease, type 2 diabetes, and mental health disorders), thereby arguing for cffDNA-based testing versus no causal testing; however, no treatment has been proven to be effective at reducing pregnancy loss. ●

Hartwig TJ, Ambye L, Gruhn JR, et al. Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study. Lancet. 2023;401:762-771. https://doi.org/10.1016/S0140-6736(22)02610-1.

Expert Commentary

A devastating outcome for women, pregnancy loss is directly proportional to maternal age, estimated to occur in approximately 15% of clinically recognized pregnancies and 30% of preclinical pregnancies.¹ Approximately 80% of pregnancy losses occur in the first trimester.² The frequency of clinically recognized early pregnancy loss for women aged 20–30 years is 9% to 17%, and these rates increase sharply, from 20% at age 35 years to 40% at age 40 years, and 80% at age 45 years. Recurrent pregnancy loss (RPL), defined as the spontaneous loss of 2 or more clinically recognized pregnancies, affects less than 5% of women.³ Genetic testing using chromosomal microarray analysis (CMA) has identified aneuploidy in about 55% of cases of miscarriage.⁴

Following ASRM guidelines for the evaluation of RPL, which consists of analyzing parental chromosomal abnormalities, congenital and acquired uterine anomalies, endocrine imbalances, and autoimmune factors (including antiphospholipid syndrome), no explainable cause is determined in 50% of cases.³ Recently, it has been shown that more than 90% of patients with RPL will have a probable or definitive cause identified when CMA testing on miscarriage tissue with the ASRM evaluation guidelines.⁵

Details of the study

In this prospective cohort study from Denmark, the authors analyzed maternal serum for cell-free fetal DNA (cffDNA) to determine the ploidy status of the pregnancy loss. One thousand women older than age 18 were included (those who demonstrated an ultrasound-confirmed intrauterine pregnancy loss prior to 22 weeks’ gestation). Maternal blood was obtained while pregnancy tissue was in situ or within 24 hours of passage of products of conception (POC), then analyzed by genome-wide sequencing of cffDNA.

For the first 333 recruited women (validation phase), direct sequencing of the POC was performed for sensitivity and specificity. Following the elimination of inconclusive samples, 302 of the 333 cases demonstrated a sensitivity of 85% and specificity of 93%. In the subsequent evaluation of 667 women, researchers analyzed maternal serum from the gestational age of fetuses ranging from 35 days to 149 days.

Results. In total, nearly 90% of cases yielded conclusive results, with 50% euploid, 46% aneuploid, and 4% multiple aneuploidies. Earlier gestational ages (less than 7 weeks) had a no-call rate (ie, inconclusive) of approximately 50% (only based on 16 patients), with results typically obtained in maternal serum following passage of POC; in pregnancies at gestational ages past 7 weeks, the no-call rate was about 10%. In general, the longer the time after the pregnancy tissue passed, the higher likelihood of a no-call result.

Applying the technology of single-nucleotide polymorphism (SNP)-based CMA can improve identification of fetal and/or maternal sources as causes of pregnancy loss with accuracy, but it does require collection of POC. Of note, samples were deficient in this study, the authors cite, in one-third of the cases. Given this limitation of collection, the authors argue for use of the noninvasive method of cffDNA, obtained from maternal serum.

Study strengths and weaknesses

Several weaknesses of this study are highlighted. Of the validation cohort, one-third of pregnancy tissue could not be analyzed due to insufficient collection. Only 73% of cases allowed for DNA isolation from fetal tissue or chorionic villi; in 27% of cases samples were labeled “unknown tissue.” In those cases classified as unknown, 70% were further determined to be maternal. When all female and monosomy cases were excluded in an effort to assuredly reduce the risk of contamination with maternal DNA, sensitivity of the cffDNA testing process declined to 78%. Another limitation was the required short window for maternal blood sampling (within 24 hours) and its impact on the no-call rate.

The authors note an association with later-life morbidity in patients with a history of pregnancy loss and RPL (including cardiovascular disease, type 2 diabetes, and mental health disorders), thereby arguing for cffDNA-based testing versus no causal testing; however, no treatment has been proven to be effective at reducing pregnancy loss. ●

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Milan – Clinical trial and registry data comparisons between patients with rheumatoid arthritis who take Janus kinase inhibitors (JAKi) such as tofacitinib (Xeljanz) and tumor necrosis factor inhibitors (TNFi) continue to contribute to a better understanding of their efficacy and cardiovascular safety profile, based on presentations given at the annual European Congress of Rheumatology.

Tofacitinib vs. TNFi efficacy with or without history of atherosclerotic CVD

The efficacy of tofacitinib appears to be at least as good as TNFi, regardless of the presence of atherosclerotic cardiovascular disease (ASCVD) and baseline cardiovascular risk, according to a post hoc analysis of the ORAL Surveillance study presented by Maya Buch, MD, PhD, of NIHR Manchester Biomedical Research Centre and University of Manchester, England. ORAL Surveillance was a randomized, open-label, postmarketing safety study sponsored by Pfizer. The study enrolled patients aged 50 or older, with one or more additional CV risk factors, and with active disease despite methotrexate treatment. The cohort included patients treated with the tofacitinib at two different doses (5 mg or 10 mg daily) or TNFi.

Given that a prior “post hoc analysis showed differences in the risk of major adverse CV events (MACE) with tofacitinib versus TNFi, depending on the personal history of atherosclerotic cardiovascular disease,” Dr. Buch and coauthors aimed to further characterize the benefit/risk profile of tofacitinib by evaluating its efficacy, compared with TNFi, in patients with a history of ASCVD and baseline CV risk. Out of the 4,362 patients, 640 (14.7%) had a positive history of ASCVD, while 3,722 (85.3%) did not. For the latter group, the 10-year risk of ASCVD was calculated at baseline, which was high (≥ 20%) in 22.5% and intermediate (≥ 7.5% to < 20%) in 39.4%.

The analysis demonstrated that in patients without a history of ASCVD, the odds of achieving either remission (Clinical Disease Activity Index [CDAI] ≤ 2.8) or low disease activity (CDAI ≤ 10) were greater with tofacitinib vs. TNFi. With a history of ASCVD, the likelihood of achieving remission or low disease activity (LDA) was not statistically different between tofacitinib and TNFi. Patients with high or intermediate CV risk scores tended to be more likely to reach remission or LDA with tofacitinib vs. TNFi.

Dr. Buch emphasized that selecting the right therapy for each patient requires careful consideration of potential benefits and risks by the rheumatologist, taking into account individual patient history. “Stratification by baseline risk of CV events may help ensure appropriate and effective use of tofacitinib in patients with RA,” she concluded.

Kim Lauper, MD, of the division of rheumatology at Geneva University Hospitals, who was not involved in the study, commented on the importance of this data: “These findings are important because we currently lack information on how the presence of CV comorbidities can impact the efficacy of RA drugs.”
 

A real-world perspective

MACE occurred at similar rates between JAKi and TNFi, as well as for biologic disease-modifying antirheumatic drugs (bDMARDs) with other modes of action (OMA) vs. TNFi, in the JAK-Pot study, an international collaboration of RA registries, reported Romain Aymon, of Geneva University Hospitals. But a subanalysis of JAK-Pot in patients resembling the population in the ORAL Surveillance trial found that the incidence of MACE was higher in each treatment group, compared with the overall population. However, no significant difference was found between JAKi vs. TNFi and OMA vs. TNFi.

Mr. Aymon said that the analysis is still ongoing, with additional registries being included.

Dr. Lauper, who is the principal investigator of the study presented by Mr. Aymon, noted that “the absence of a difference in MACE risk in the population resembling the ORAL Surveillance study is in contrast with the results from the ORAL Surveillance itself. This may be due to differences in the populations, with the ORAL Surveillance study having a more selected set of patients.”
 

The Dutch perspective

In line with the findings from the JAK-Pot study, a retrospective inception cohort study conducted on a Dutch RA population also revealed no difference in the incidence of cardiovascular events between JAKi starters and bDMARD starters, according to Merel Opdam, MSc, of Sint Maartenskliniek in Ubbergen, the Netherlands, who reported the findings at the meeting. Two subanalyses of the cohort study, funded by Pfizer, also did not show any difference between tofacitinib and baricitinib (Olumiant), compared with DMARDs, or in patients above 65 years of age. The analysis was conducted on 15,191 patients with RA who were initiating treatment with a JAKi or a new bDMARD, selected from IQVIA’s Dutch Real-World Data Longitudinal Prescription database, which covers approximately 63% of outpatient prescriptions in the Netherlands.

“Not all DMARDs have similar effects on cardiovascular outcomes, and observational studies can contribute to understanding the cardiovascular risks associated with JAKi,” Ms. Opdam said.

“Real-world data holds significant importance as it provides insights into a broader spectrum of patients and reflects the actual clinical practice where treatment decisions are tailored to individual patient needs,” commented Anja Strangfeld, MD, PhD, of the German Rheumatism Research Center Berlin, and Charité University Medicine Berlin. She said that registries have a pivotal role in this regard.

Dr. Buch reports serving on a speakers bureau for AbbVie; serving as a consultant to AbbVie, CESAS Medical, Eli Lilly, Galapagos, Gilead, and Pfizer; and receiving grant/research support from Gilead, Pfizer, and UCB. Mr. Aymon and Ms. Opdam report no relevant financial relationships.

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

Expert treatment centers should consider performing certain endoscopic ultrasound (EUS)-guided vascular interventions with current levels of supporting evidence, according to a practice update from the American Gastroenterological Association.

The AGA Institute’s Clinical Practice Update on interventional EUS, published in Clinical Gastroenterology and Hepatology , makes the case for broader adoption of two clinically available interventions – EUS-guided coil injection therapy of gastric varices and EUS-guided portosystemic pressure gradient measurement – while listing key research questions that remain to be answered. The update also describes current evidence for several emerging EUS interventions.

Brigham and Women&#039;s Hospital

The update’s authors, led by Marvin Ryou, MD, of Brigham and Women’s Hospital, Boston, advised, when available, EUS-guided coil injection therapy of gastric varices over conventional direct endoscopic injection with cyanoacrylate glue, noting that EUS guidance “enhances the precision of injection,” expands treatment options to include placement of hemostatic coils, and uses Doppler to provide real-time feedback on hemostasis.

Available evidence suggests that EUS-guided gastric variceal therapy is “safe, with excellent acute hemostasis and low re-bleeding rates, and likely superiority over traditional direct endoscopic glue injection,” Dr. Ryou and colleagues wrote in their update.

Nonetheless, they cautioned, “the development of a consensus technique would be helpful,” better training of technicians is needed, and large, multicenter studies comparing EUS with standard interventional radiology approaches are still needed.

EUS-guided direct measurement of the portosystemic pressure gradient (PPG) may offer improved clinical efficiency over a percutaneous endovascular approach, Dr. Ryou and colleagues determined, notably when there is concern for a pre-sinusoidal cause of portal hypertension. The EUS intervention allows for the “concurrent ability to perform esophagogastroduodenoscopy and EUS as a one-stop shop during which PPG, liver biopsy, and endoscopic features of portal hypertension … can all be evaluated, obtained, and potentially treated during a single procedure.” The authors updated guidance on four emerging interventions for which evidence remains limited: EUS-guided injection therapy of rectal varices, EUS-guided splenic artery embolization, EUS-guided injection therapy in patients with splenic artery pseudoaneurysms, and EUS-guided portal vein sampling.

While the last of these interventions appears safe, the authors cautioned, it should be performed only as part of a research protocol. The authors described an experimental intervention tested in animal models using a EUS-guided intrahepatic portosystemic shunt in which a self-expanding metal stent was deployed via EUS to bridge the hepatic and portal vein and decompress a hypertensive portal system.

The authors cautioned that the guidance was not the product of a formal systematic review, but represented a summary of practical advice gleaned from a literature review to provide practical advice. As a general rule, they said, EUS-guided vascular interventions should be considered when the vascular target occurs in or near the gastrointestinal wall, “which may confer an advantage to an endoscopic rather than percutaneous access,” and when the intervention has “a clinical efficacy and safety profile comparable, if not superior, to current alternatives.” All the interventions described in the clinical practice update satisfy the first condition, but not the second.

Dr. Ryou and two of his three coauthors disclosed financial relationships, including consulting fees and research support, from device manufacturers.

Expert treatment centers should consider performing certain endoscopic ultrasound (EUS)-guided vascular interventions with current levels of supporting evidence, according to a practice update from the American Gastroenterological Association.

The AGA Institute’s Clinical Practice Update on interventional EUS, published in Clinical Gastroenterology and Hepatology , makes the case for broader adoption of two clinically available interventions – EUS-guided coil injection therapy of gastric varices and EUS-guided portosystemic pressure gradient measurement – while listing key research questions that remain to be answered. The update also describes current evidence for several emerging EUS interventions.

Brigham and Women&#039;s Hospital

The update’s authors, led by Marvin Ryou, MD, of Brigham and Women’s Hospital, Boston, advised, when available, EUS-guided coil injection therapy of gastric varices over conventional direct endoscopic injection with cyanoacrylate glue, noting that EUS guidance “enhances the precision of injection,” expands treatment options to include placement of hemostatic coils, and uses Doppler to provide real-time feedback on hemostasis.

Available evidence suggests that EUS-guided gastric variceal therapy is “safe, with excellent acute hemostasis and low re-bleeding rates, and likely superiority over traditional direct endoscopic glue injection,” Dr. Ryou and colleagues wrote in their update.

Nonetheless, they cautioned, “the development of a consensus technique would be helpful,” better training of technicians is needed, and large, multicenter studies comparing EUS with standard interventional radiology approaches are still needed.

EUS-guided direct measurement of the portosystemic pressure gradient (PPG) may offer improved clinical efficiency over a percutaneous endovascular approach, Dr. Ryou and colleagues determined, notably when there is concern for a pre-sinusoidal cause of portal hypertension. The EUS intervention allows for the “concurrent ability to perform esophagogastroduodenoscopy and EUS as a one-stop shop during which PPG, liver biopsy, and endoscopic features of portal hypertension … can all be evaluated, obtained, and potentially treated during a single procedure.” The authors updated guidance on four emerging interventions for which evidence remains limited: EUS-guided injection therapy of rectal varices, EUS-guided splenic artery embolization, EUS-guided injection therapy in patients with splenic artery pseudoaneurysms, and EUS-guided portal vein sampling.

While the last of these interventions appears safe, the authors cautioned, it should be performed only as part of a research protocol. The authors described an experimental intervention tested in animal models using a EUS-guided intrahepatic portosystemic shunt in which a self-expanding metal stent was deployed via EUS to bridge the hepatic and portal vein and decompress a hypertensive portal system.

The authors cautioned that the guidance was not the product of a formal systematic review, but represented a summary of practical advice gleaned from a literature review to provide practical advice. As a general rule, they said, EUS-guided vascular interventions should be considered when the vascular target occurs in or near the gastrointestinal wall, “which may confer an advantage to an endoscopic rather than percutaneous access,” and when the intervention has “a clinical efficacy and safety profile comparable, if not superior, to current alternatives.” All the interventions described in the clinical practice update satisfy the first condition, but not the second.

Dr. Ryou and two of his three coauthors disclosed financial relationships, including consulting fees and research support, from device manufacturers.

Expert treatment centers should consider performing certain endoscopic ultrasound (EUS)-guided vascular interventions with current levels of supporting evidence, according to a practice update from the American Gastroenterological Association.

The AGA Institute’s Clinical Practice Update on interventional EUS, published in Clinical Gastroenterology and Hepatology , makes the case for broader adoption of two clinically available interventions – EUS-guided coil injection therapy of gastric varices and EUS-guided portosystemic pressure gradient measurement – while listing key research questions that remain to be answered. The update also describes current evidence for several emerging EUS interventions.

Brigham and Women&#039;s Hospital

The update’s authors, led by Marvin Ryou, MD, of Brigham and Women’s Hospital, Boston, advised, when available, EUS-guided coil injection therapy of gastric varices over conventional direct endoscopic injection with cyanoacrylate glue, noting that EUS guidance “enhances the precision of injection,” expands treatment options to include placement of hemostatic coils, and uses Doppler to provide real-time feedback on hemostasis.

Available evidence suggests that EUS-guided gastric variceal therapy is “safe, with excellent acute hemostasis and low re-bleeding rates, and likely superiority over traditional direct endoscopic glue injection,” Dr. Ryou and colleagues wrote in their update.

Nonetheless, they cautioned, “the development of a consensus technique would be helpful,” better training of technicians is needed, and large, multicenter studies comparing EUS with standard interventional radiology approaches are still needed.

EUS-guided direct measurement of the portosystemic pressure gradient (PPG) may offer improved clinical efficiency over a percutaneous endovascular approach, Dr. Ryou and colleagues determined, notably when there is concern for a pre-sinusoidal cause of portal hypertension. The EUS intervention allows for the “concurrent ability to perform esophagogastroduodenoscopy and EUS as a one-stop shop during which PPG, liver biopsy, and endoscopic features of portal hypertension … can all be evaluated, obtained, and potentially treated during a single procedure.” The authors updated guidance on four emerging interventions for which evidence remains limited: EUS-guided injection therapy of rectal varices, EUS-guided splenic artery embolization, EUS-guided injection therapy in patients with splenic artery pseudoaneurysms, and EUS-guided portal vein sampling.

While the last of these interventions appears safe, the authors cautioned, it should be performed only as part of a research protocol. The authors described an experimental intervention tested in animal models using a EUS-guided intrahepatic portosystemic shunt in which a self-expanding metal stent was deployed via EUS to bridge the hepatic and portal vein and decompress a hypertensive portal system.

The authors cautioned that the guidance was not the product of a formal systematic review, but represented a summary of practical advice gleaned from a literature review to provide practical advice. As a general rule, they said, EUS-guided vascular interventions should be considered when the vascular target occurs in or near the gastrointestinal wall, “which may confer an advantage to an endoscopic rather than percutaneous access,” and when the intervention has “a clinical efficacy and safety profile comparable, if not superior, to current alternatives.” All the interventions described in the clinical practice update satisfy the first condition, but not the second.

Dr. Ryou and two of his three coauthors disclosed financial relationships, including consulting fees and research support, from device manufacturers.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Pacing as a device therapy for heart failure (HF) is headed for what is probably its next big advance.
 

After decades of biventricular (BiV) pacemaker success in resynchronizing the ventricles and improving clinical outcomes, relatively new conduction-system pacing (CSP) techniques that avoid the pitfalls of right-ventricular (RV) pacing using BiV lead systems have been supplanting traditional cardiac resynchronization therapy (CRT) in selected patients at some major centers. In fact, they are solidly ensconced in a new guideline document addressing indications for CSP and BiV pacing in HF.

But in the new guideline, CSP, using an endocardial lead to the His bundle or left-bundle branch (LBB) area, is nearly always a second-tier option, an alternative when BiV pacing isn’t appropriate or can’t be engaged.

That’s mainly because the limited, mostly observational evidence supporting CSP in the document can’t measure up to the clinical experience and plethora of large, randomized trials behind BiV-CRT.

But that shortfall is headed for change. Several new comparative studies, including a small, randomized trial, have added significantly to evidence suggesting that CSP is at least as effective as traditional CRT for procedural, functional safety, and clinical outcomes.

The new studies “are inherently prone to bias, but their results are really good,” observed Juan C. Diaz, MD. They show improvements in left ventricular ejection fraction (LVEF) and symptoms with CSP that are “outstanding compared to what we have been doing for the last 20 years,” he said in an interview.

Dr. Diaz, Clínica Las Vegas, Medellin, Colombia, is an investigator with the observational SYNCHRONY, which is among the new CSP studies formally presented at the annual scientific sessions of the Heart Rhythm Society. He is also lead author on its same-day publication in JACC: Clinical Electrophysiology.

Dr. Diaz said that CSP, which sustains pacing via the native conduction system, makes more “physiologic sense” than BiV pacing and represents “a step forward” for HF device therapy.

SYNCHRONY compared LBB-area with BiV pacing as the initial strategy for achieving cardiac resynchronization in patients with ischemic or nonischemic cardiomyopathy.

CSP is “a long way” from replacing conventional CRT, he said. But the new studies at the HRS sessions should help extend His-bundle and LBB-area pacing to more patients, he added, given the significant long-term “drawbacks” of BiV pacing. These include inevitable RV pacing, multiple leads, and the risks associated with chronic transvenous leads.

Zachary Goldberger, MD, University of Wisconsin–Madison, went a bit further in support of CSP as invited discussant for the SYNCHRONY presentation.

Given that it improved LVEF, heart failure class, HF hospitalizations (HFH), and mortality in that study and others, Dr. Goldberger said, CSP could potentially “become the dominant mode of resynchronization going forward.”

Other experts at the meeting saw CSP’s potential more as one of several pacing techniques that could be brought to bear for patients with CRT indications.

“Conduction system pacing is going to be a huge complement to biventricular pacing,” to which about 30% of patients have a “less than optimal response,” said Pugazhendhi Vijayaraman, MD, chief of clinical electrophysiology, Geisinger Heart Institute, Danville, Pa.

“I don’t think it needs to replace biventricular pacing, because biventricular pacing is a well-established, incredibly powerful therapy,” he told this news organization. But CSP is likely to provide “a good alternative option” in patients with poor responses to BiV-CRT.

It may, however, render some current BiV-pacing alternatives “obsolete,” Dr. Vijayaraman observed. “At our center, at least for the last 5 years, no patient has needed epicardial surgical left ventricular lead placement” because CSP was a better backup option.

Dr. Vijayaraman presented two of the meeting’s CSP vs. BiV pacing comparisons. In one, the 100-patient randomized HOT-CRT trial, contractile function improved significantly on CSP, which could be either His-bundle or LBB-area pacing.

He also presented an observational study of LBB-area pacing at 15 centers in Asia, Europe, and North America and led the authors of its simultaneous publication in the Journal of the American College of Cardiology.

“I think left-bundle conduction system pacing is the future, for sure,” Jagmeet P. Singh, MD, DPhil, told this news organization. Still, it doesn’t always work and when it does, it “doesn’t work equally in all patients,” he said.

“Conduction system pacing certainly makes a lot of sense,” especially in patients with left-bundle-branch block (LBBB), and “maybe not as a primary approach but certainly as a secondary approach,” said Dr. Singh, Massachusetts General Hospital, Boston, who is not a coauthor on any of the three studies.

He acknowledged that CSP may work well as a first-line option in patients with LBBB at some experienced centers. For those without LBBB or who have an intraventricular conduction delay, who represent 45%-50% of current CRT cases, Dr. Singh observed, “there’s still more evidence” that BiV-CRT is a more appropriate initial approach.

Standard CRT may fail, however, even in some patients who otherwise meet guideline-based indications. “We don’t really understand all the mechanisms for nonresponse in conventional biventricular pacing,” observed Niraj Varma, MD, PhD, Cleveland Clinic, also not involved with any of the three studies.

In some groups, including “patients with larger ventricles,” for example, BiV-CRT doesn’t always narrow the electrocardiographic QRS complex or preexcite delayed left ventricular (LV) activation, hallmarks of successful CRT, he said in an interview.

“I think we need to understand why this occurs in both situations,” but in such cases, CSP alone or as an adjunct to direct LV pacing may be successful. “Sometimes we need both an LV lead and the conduction-system pacing lead.”

Narrower, more efficient use of CSP as a BiV-CRT alternative may also boost its chances for success, Dr. Varma added. “I think we need to refine patient selection.”
 

HOT-CRT: Randomized CSP vs. BiV pacing trial

Conducted at three centers in a single health system, the His-optimized cardiac resynchronization therapy study (HOT-CRT) randomly assigned 100 patients with primary or secondary CRT indications to either to CSP – by either His-bundle or LBB-area pacing – or to standard BiV-CRT as the first-line resynchronization method.

Treatment crossovers, allowed for either pacing modality in the event of implantation failure, occurred in two patients and nine patients initially assigned to CSP and BiV pacing, respectively (4% vs. 18%), Dr. Vijayaraman reported.

International comparison of CSP and BiV pacing

In Dr. Vijayaraman’s other study, the observational comparison of LBB-area pacing and BiV-CRT, the CSP technique emerged as a “reasonable alternative to biventricular pacing, not only for improvement in LV function but also to reduce adverse clinical outcomes.”

Indeed, in the international study of 1,778 mostly male patients with primary or secondary CRT indications who received LBB-area or BiV pacing (797 and 981 patients, respectively), those on CSP saw a significant drop in risk for the primary endpoint, death or HFH.

Mean LVEF improved from 27% to 41% in the LBB-area pacing group and 27% to 37% with BiV pacing (P < .001 for both changes) over a follow-up averaging 33 months. The difference in improvement between CSP and BiV pacing was significant at P < .001.

In adjusted analysis, the risk for death or HFH was greater for BiV-pacing patients, a difference driven by HFH events.

• Death or HF: hazard ratio, 1.49 (95% confidence interval, 1.21-1.84; P < .001).
• Death: HR, 1.14 (95% CI, 0.88-1.48; P = .313).
• HFH: HR, 1.49 (95% CI, 1.16-1.92; P = .002)

The analysis has all the “inherent biases” of an observational study. The risk for patient-selection bias, however, was somewhat mitigated by consistent practice patterns at participating centers, Dr. Vijayaraman told this news organization.

For example, he said, operators at six of the institutions were most likely to use CSP as the first-line approach, and the same number of centers usually went with BiV pacing.
 

SYNCHRONY: First-line LBB-area pacing vs. BiV-CRT

Outcomes using the two approaches were similar in the prospective, international, observational study of 371 patients with ischemic or nonischemic cardiomyopathy and standard CRT indications. Allocation of 128 patients to LBB-area pacing and 243 to BiV-CRT was based on patient and operator preferences, reported Jorge Romero Jr, MD, Brigham and Women’s Hospital, Boston, at the HRS sessions.

Risk for the death-HFH primary endpoint dropped 38% for those initially treated with LBB-area pacing, compared with BiV pacing, primarily because of a lower HFH risk:

• Death or HFH: HR, 0.62 (95% CI, 0.41-0.93; P = .02).
• Death: HR, 0.57 (95% CI, 0.25-1.32; P = .19).
• HFH: HR, 0.61 (95% CI, 0.34-0.93; P = .02)

Patients in the CSP group were also more likely to improve by at least one NYHA (New York Heart Association) class (80.4% vs. 67.9%; P < .001), consistent with their greater absolute change in LVEF (8.0 vs. 3.9 points; P < .01).

The findings “suggest that LBBAP [left-bundle branch area pacing] is an excellent alternative to BiV pacing,” with a comparable safety profile, write Jayanthi N. Koneru, MBBS, and Kenneth A. Ellenbogen, MD, in an editorial accompanying the published SYNCHRONY report.

“The differences in improvement of LVEF are encouraging for both groups,” but were superior for LBB-area pacing, continue Dr. Koneru and Dr. Ellenbogen, both with Virginia Commonwealth University Medical Center, Richmond. “Whether these results would have regressed to the mean over a longer period of follow-up or diverge further with LBB-area pacing continuing to be superior is unknown.”
 

Years for an answer?

A large randomized comparison of CSP and BiV-CRT, called Left vs. Left, is currently in early stages, Sana M. Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said in a media presentation on two of the presented studies. It has a planned enrollment of more than 2,100 patients on optimal meds with an LVEF of 50% or lower and either a QRS duration of at least 130 ms or an anticipated burden of RV pacing exceeding 40%.

The trial, she said, “will take years to give an answer, but it is actually designed to address the question of whether a composite endpoint of time to death or heart failure hospitalization can be improved with conduction system pacing vs. biventricular pacing.”

Dr. Al-Khatib is a coauthor on the new guideline covering both CSP and BiV-CRT in HF, as are Dr. Cha, Dr. Varma, Dr. Singh, Dr. Vijayaraman, and Dr. Goldberger; Dr. Ellenbogen is one of the reviewers.

Dr. Diaz discloses receiving honoraria or fees for speaking or teaching from Bayer Healthcare, Pfizer, AstraZeneca, Boston Scientific, and Medtronic. Dr. Vijayaraman discloses receiving honoraria or fees for speaking, teaching, or consulting for Abbott, Medtronic, Biotronik, and Boston Scientific; and receiving research grants from Medtronic. Dr. Varma discloses receiving honoraria or fees for speaking or consulting as an independent contractor for Medtronic, Boston Scientific, Biotronik, Impulse Dynamics USA, Cardiologs, Abbott, Pacemate, Implicity, and EP Solutions. Dr. Singh discloses receiving fees for consulting from EBR Systems, Merit Medical Systems, New Century Health, Biotronik, Abbott, Medtronic, MicroPort Scientific, Cardiologs, Sanofi, CVRx, Impulse Dynamics USA, Octagos, Implicity, Orchestra Biomed, Rhythm Management Group, and Biosense Webster; and receiving honoraria or fees for speaking and teaching from Medscape. Dr. Cha had no relevant financial relationships. Dr. Romero discloses receiving research grants from Biosense Webster; and speaking or receiving honoraria or fees for consulting, speaking, or teaching, or serving on a board for Sanofi, Boston Scientific, and AtriCure. Dr. Koneru discloses consulting for Medtronic and receiving honoraria from Abbott. Dr. Ellenbogen discloses consulting or lecturing for or receiving honoraria from Medtronic, Boston Scientific, and Abbott. Dr. Goldberger discloses receiving royalty income from and serving as an independent contractor for Elsevier. Dr. Al-Khatib discloses receiving research grants from Medtronic and Boston Scientific.

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

Pacing as a device therapy for heart failure (HF) is headed for what is probably its next big advance.
 

After decades of biventricular (BiV) pacemaker success in resynchronizing the ventricles and improving clinical outcomes, relatively new conduction-system pacing (CSP) techniques that avoid the pitfalls of right-ventricular (RV) pacing using BiV lead systems have been supplanting traditional cardiac resynchronization therapy (CRT) in selected patients at some major centers. In fact, they are solidly ensconced in a new guideline document addressing indications for CSP and BiV pacing in HF.

But in the new guideline, CSP, using an endocardial lead to the His bundle or left-bundle branch (LBB) area, is nearly always a second-tier option, an alternative when BiV pacing isn’t appropriate or can’t be engaged.

That’s mainly because the limited, mostly observational evidence supporting CSP in the document can’t measure up to the clinical experience and plethora of large, randomized trials behind BiV-CRT.

But that shortfall is headed for change. Several new comparative studies, including a small, randomized trial, have added significantly to evidence suggesting that CSP is at least as effective as traditional CRT for procedural, functional safety, and clinical outcomes.

The new studies “are inherently prone to bias, but their results are really good,” observed Juan C. Diaz, MD. They show improvements in left ventricular ejection fraction (LVEF) and symptoms with CSP that are “outstanding compared to what we have been doing for the last 20 years,” he said in an interview.

Dr. Diaz, Clínica Las Vegas, Medellin, Colombia, is an investigator with the observational SYNCHRONY, which is among the new CSP studies formally presented at the annual scientific sessions of the Heart Rhythm Society. He is also lead author on its same-day publication in JACC: Clinical Electrophysiology.

Dr. Diaz said that CSP, which sustains pacing via the native conduction system, makes more “physiologic sense” than BiV pacing and represents “a step forward” for HF device therapy.

SYNCHRONY compared LBB-area with BiV pacing as the initial strategy for achieving cardiac resynchronization in patients with ischemic or nonischemic cardiomyopathy.

CSP is “a long way” from replacing conventional CRT, he said. But the new studies at the HRS sessions should help extend His-bundle and LBB-area pacing to more patients, he added, given the significant long-term “drawbacks” of BiV pacing. These include inevitable RV pacing, multiple leads, and the risks associated with chronic transvenous leads.

Zachary Goldberger, MD, University of Wisconsin–Madison, went a bit further in support of CSP as invited discussant for the SYNCHRONY presentation.

Given that it improved LVEF, heart failure class, HF hospitalizations (HFH), and mortality in that study and others, Dr. Goldberger said, CSP could potentially “become the dominant mode of resynchronization going forward.”

Other experts at the meeting saw CSP’s potential more as one of several pacing techniques that could be brought to bear for patients with CRT indications.

“Conduction system pacing is going to be a huge complement to biventricular pacing,” to which about 30% of patients have a “less than optimal response,” said Pugazhendhi Vijayaraman, MD, chief of clinical electrophysiology, Geisinger Heart Institute, Danville, Pa.

“I don’t think it needs to replace biventricular pacing, because biventricular pacing is a well-established, incredibly powerful therapy,” he told this news organization. But CSP is likely to provide “a good alternative option” in patients with poor responses to BiV-CRT.

It may, however, render some current BiV-pacing alternatives “obsolete,” Dr. Vijayaraman observed. “At our center, at least for the last 5 years, no patient has needed epicardial surgical left ventricular lead placement” because CSP was a better backup option.

Dr. Vijayaraman presented two of the meeting’s CSP vs. BiV pacing comparisons. In one, the 100-patient randomized HOT-CRT trial, contractile function improved significantly on CSP, which could be either His-bundle or LBB-area pacing.

He also presented an observational study of LBB-area pacing at 15 centers in Asia, Europe, and North America and led the authors of its simultaneous publication in the Journal of the American College of Cardiology.

“I think left-bundle conduction system pacing is the future, for sure,” Jagmeet P. Singh, MD, DPhil, told this news organization. Still, it doesn’t always work and when it does, it “doesn’t work equally in all patients,” he said.

“Conduction system pacing certainly makes a lot of sense,” especially in patients with left-bundle-branch block (LBBB), and “maybe not as a primary approach but certainly as a secondary approach,” said Dr. Singh, Massachusetts General Hospital, Boston, who is not a coauthor on any of the three studies.

He acknowledged that CSP may work well as a first-line option in patients with LBBB at some experienced centers. For those without LBBB or who have an intraventricular conduction delay, who represent 45%-50% of current CRT cases, Dr. Singh observed, “there’s still more evidence” that BiV-CRT is a more appropriate initial approach.

Standard CRT may fail, however, even in some patients who otherwise meet guideline-based indications. “We don’t really understand all the mechanisms for nonresponse in conventional biventricular pacing,” observed Niraj Varma, MD, PhD, Cleveland Clinic, also not involved with any of the three studies.

In some groups, including “patients with larger ventricles,” for example, BiV-CRT doesn’t always narrow the electrocardiographic QRS complex or preexcite delayed left ventricular (LV) activation, hallmarks of successful CRT, he said in an interview.

“I think we need to understand why this occurs in both situations,” but in such cases, CSP alone or as an adjunct to direct LV pacing may be successful. “Sometimes we need both an LV lead and the conduction-system pacing lead.”

Narrower, more efficient use of CSP as a BiV-CRT alternative may also boost its chances for success, Dr. Varma added. “I think we need to refine patient selection.”
 

HOT-CRT: Randomized CSP vs. BiV pacing trial

Conducted at three centers in a single health system, the His-optimized cardiac resynchronization therapy study (HOT-CRT) randomly assigned 100 patients with primary or secondary CRT indications to either to CSP – by either His-bundle or LBB-area pacing – or to standard BiV-CRT as the first-line resynchronization method.

Treatment crossovers, allowed for either pacing modality in the event of implantation failure, occurred in two patients and nine patients initially assigned to CSP and BiV pacing, respectively (4% vs. 18%), Dr. Vijayaraman reported.

International comparison of CSP and BiV pacing

In Dr. Vijayaraman’s other study, the observational comparison of LBB-area pacing and BiV-CRT, the CSP technique emerged as a “reasonable alternative to biventricular pacing, not only for improvement in LV function but also to reduce adverse clinical outcomes.”

Indeed, in the international study of 1,778 mostly male patients with primary or secondary CRT indications who received LBB-area or BiV pacing (797 and 981 patients, respectively), those on CSP saw a significant drop in risk for the primary endpoint, death or HFH.

Mean LVEF improved from 27% to 41% in the LBB-area pacing group and 27% to 37% with BiV pacing (P < .001 for both changes) over a follow-up averaging 33 months. The difference in improvement between CSP and BiV pacing was significant at P < .001.

In adjusted analysis, the risk for death or HFH was greater for BiV-pacing patients, a difference driven by HFH events.

• Death or HF: hazard ratio, 1.49 (95% confidence interval, 1.21-1.84; P < .001).
• Death: HR, 1.14 (95% CI, 0.88-1.48; P = .313).
• HFH: HR, 1.49 (95% CI, 1.16-1.92; P = .002)

The analysis has all the “inherent biases” of an observational study. The risk for patient-selection bias, however, was somewhat mitigated by consistent practice patterns at participating centers, Dr. Vijayaraman told this news organization.

For example, he said, operators at six of the institutions were most likely to use CSP as the first-line approach, and the same number of centers usually went with BiV pacing.
 

SYNCHRONY: First-line LBB-area pacing vs. BiV-CRT

Outcomes using the two approaches were similar in the prospective, international, observational study of 371 patients with ischemic or nonischemic cardiomyopathy and standard CRT indications. Allocation of 128 patients to LBB-area pacing and 243 to BiV-CRT was based on patient and operator preferences, reported Jorge Romero Jr, MD, Brigham and Women’s Hospital, Boston, at the HRS sessions.

Risk for the death-HFH primary endpoint dropped 38% for those initially treated with LBB-area pacing, compared with BiV pacing, primarily because of a lower HFH risk:

• Death or HFH: HR, 0.62 (95% CI, 0.41-0.93; P = .02).
• Death: HR, 0.57 (95% CI, 0.25-1.32; P = .19).
• HFH: HR, 0.61 (95% CI, 0.34-0.93; P = .02)

Patients in the CSP group were also more likely to improve by at least one NYHA (New York Heart Association) class (80.4% vs. 67.9%; P < .001), consistent with their greater absolute change in LVEF (8.0 vs. 3.9 points; P < .01).

The findings “suggest that LBBAP [left-bundle branch area pacing] is an excellent alternative to BiV pacing,” with a comparable safety profile, write Jayanthi N. Koneru, MBBS, and Kenneth A. Ellenbogen, MD, in an editorial accompanying the published SYNCHRONY report.

“The differences in improvement of LVEF are encouraging for both groups,” but were superior for LBB-area pacing, continue Dr. Koneru and Dr. Ellenbogen, both with Virginia Commonwealth University Medical Center, Richmond. “Whether these results would have regressed to the mean over a longer period of follow-up or diverge further with LBB-area pacing continuing to be superior is unknown.”
 

Years for an answer?

A large randomized comparison of CSP and BiV-CRT, called Left vs. Left, is currently in early stages, Sana M. Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said in a media presentation on two of the presented studies. It has a planned enrollment of more than 2,100 patients on optimal meds with an LVEF of 50% or lower and either a QRS duration of at least 130 ms or an anticipated burden of RV pacing exceeding 40%.

The trial, she said, “will take years to give an answer, but it is actually designed to address the question of whether a composite endpoint of time to death or heart failure hospitalization can be improved with conduction system pacing vs. biventricular pacing.”

Dr. Al-Khatib is a coauthor on the new guideline covering both CSP and BiV-CRT in HF, as are Dr. Cha, Dr. Varma, Dr. Singh, Dr. Vijayaraman, and Dr. Goldberger; Dr. Ellenbogen is one of the reviewers.

Dr. Diaz discloses receiving honoraria or fees for speaking or teaching from Bayer Healthcare, Pfizer, AstraZeneca, Boston Scientific, and Medtronic. Dr. Vijayaraman discloses receiving honoraria or fees for speaking, teaching, or consulting for Abbott, Medtronic, Biotronik, and Boston Scientific; and receiving research grants from Medtronic. Dr. Varma discloses receiving honoraria or fees for speaking or consulting as an independent contractor for Medtronic, Boston Scientific, Biotronik, Impulse Dynamics USA, Cardiologs, Abbott, Pacemate, Implicity, and EP Solutions. Dr. Singh discloses receiving fees for consulting from EBR Systems, Merit Medical Systems, New Century Health, Biotronik, Abbott, Medtronic, MicroPort Scientific, Cardiologs, Sanofi, CVRx, Impulse Dynamics USA, Octagos, Implicity, Orchestra Biomed, Rhythm Management Group, and Biosense Webster; and receiving honoraria or fees for speaking and teaching from Medscape. Dr. Cha had no relevant financial relationships. Dr. Romero discloses receiving research grants from Biosense Webster; and speaking or receiving honoraria or fees for consulting, speaking, or teaching, or serving on a board for Sanofi, Boston Scientific, and AtriCure. Dr. Koneru discloses consulting for Medtronic and receiving honoraria from Abbott. Dr. Ellenbogen discloses consulting or lecturing for or receiving honoraria from Medtronic, Boston Scientific, and Abbott. Dr. Goldberger discloses receiving royalty income from and serving as an independent contractor for Elsevier. Dr. Al-Khatib discloses receiving research grants from Medtronic and Boston Scientific.

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

Pacing as a device therapy for heart failure (HF) is headed for what is probably its next big advance.
 

After decades of biventricular (BiV) pacemaker success in resynchronizing the ventricles and improving clinical outcomes, relatively new conduction-system pacing (CSP) techniques that avoid the pitfalls of right-ventricular (RV) pacing using BiV lead systems have been supplanting traditional cardiac resynchronization therapy (CRT) in selected patients at some major centers. In fact, they are solidly ensconced in a new guideline document addressing indications for CSP and BiV pacing in HF.

But in the new guideline, CSP, using an endocardial lead to the His bundle or left-bundle branch (LBB) area, is nearly always a second-tier option, an alternative when BiV pacing isn’t appropriate or can’t be engaged.

That’s mainly because the limited, mostly observational evidence supporting CSP in the document can’t measure up to the clinical experience and plethora of large, randomized trials behind BiV-CRT.

But that shortfall is headed for change. Several new comparative studies, including a small, randomized trial, have added significantly to evidence suggesting that CSP is at least as effective as traditional CRT for procedural, functional safety, and clinical outcomes.

The new studies “are inherently prone to bias, but their results are really good,” observed Juan C. Diaz, MD. They show improvements in left ventricular ejection fraction (LVEF) and symptoms with CSP that are “outstanding compared to what we have been doing for the last 20 years,” he said in an interview.

Dr. Diaz, Clínica Las Vegas, Medellin, Colombia, is an investigator with the observational SYNCHRONY, which is among the new CSP studies formally presented at the annual scientific sessions of the Heart Rhythm Society. He is also lead author on its same-day publication in JACC: Clinical Electrophysiology.

Dr. Diaz said that CSP, which sustains pacing via the native conduction system, makes more “physiologic sense” than BiV pacing and represents “a step forward” for HF device therapy.

SYNCHRONY compared LBB-area with BiV pacing as the initial strategy for achieving cardiac resynchronization in patients with ischemic or nonischemic cardiomyopathy.

CSP is “a long way” from replacing conventional CRT, he said. But the new studies at the HRS sessions should help extend His-bundle and LBB-area pacing to more patients, he added, given the significant long-term “drawbacks” of BiV pacing. These include inevitable RV pacing, multiple leads, and the risks associated with chronic transvenous leads.

Zachary Goldberger, MD, University of Wisconsin–Madison, went a bit further in support of CSP as invited discussant for the SYNCHRONY presentation.

Given that it improved LVEF, heart failure class, HF hospitalizations (HFH), and mortality in that study and others, Dr. Goldberger said, CSP could potentially “become the dominant mode of resynchronization going forward.”

Other experts at the meeting saw CSP’s potential more as one of several pacing techniques that could be brought to bear for patients with CRT indications.

“Conduction system pacing is going to be a huge complement to biventricular pacing,” to which about 30% of patients have a “less than optimal response,” said Pugazhendhi Vijayaraman, MD, chief of clinical electrophysiology, Geisinger Heart Institute, Danville, Pa.

“I don’t think it needs to replace biventricular pacing, because biventricular pacing is a well-established, incredibly powerful therapy,” he told this news organization. But CSP is likely to provide “a good alternative option” in patients with poor responses to BiV-CRT.

It may, however, render some current BiV-pacing alternatives “obsolete,” Dr. Vijayaraman observed. “At our center, at least for the last 5 years, no patient has needed epicardial surgical left ventricular lead placement” because CSP was a better backup option.

Dr. Vijayaraman presented two of the meeting’s CSP vs. BiV pacing comparisons. In one, the 100-patient randomized HOT-CRT trial, contractile function improved significantly on CSP, which could be either His-bundle or LBB-area pacing.

He also presented an observational study of LBB-area pacing at 15 centers in Asia, Europe, and North America and led the authors of its simultaneous publication in the Journal of the American College of Cardiology.

“I think left-bundle conduction system pacing is the future, for sure,” Jagmeet P. Singh, MD, DPhil, told this news organization. Still, it doesn’t always work and when it does, it “doesn’t work equally in all patients,” he said.

“Conduction system pacing certainly makes a lot of sense,” especially in patients with left-bundle-branch block (LBBB), and “maybe not as a primary approach but certainly as a secondary approach,” said Dr. Singh, Massachusetts General Hospital, Boston, who is not a coauthor on any of the three studies.

He acknowledged that CSP may work well as a first-line option in patients with LBBB at some experienced centers. For those without LBBB or who have an intraventricular conduction delay, who represent 45%-50% of current CRT cases, Dr. Singh observed, “there’s still more evidence” that BiV-CRT is a more appropriate initial approach.

Standard CRT may fail, however, even in some patients who otherwise meet guideline-based indications. “We don’t really understand all the mechanisms for nonresponse in conventional biventricular pacing,” observed Niraj Varma, MD, PhD, Cleveland Clinic, also not involved with any of the three studies.

In some groups, including “patients with larger ventricles,” for example, BiV-CRT doesn’t always narrow the electrocardiographic QRS complex or preexcite delayed left ventricular (LV) activation, hallmarks of successful CRT, he said in an interview.

“I think we need to understand why this occurs in both situations,” but in such cases, CSP alone or as an adjunct to direct LV pacing may be successful. “Sometimes we need both an LV lead and the conduction-system pacing lead.”

Narrower, more efficient use of CSP as a BiV-CRT alternative may also boost its chances for success, Dr. Varma added. “I think we need to refine patient selection.”
 

HOT-CRT: Randomized CSP vs. BiV pacing trial

Conducted at three centers in a single health system, the His-optimized cardiac resynchronization therapy study (HOT-CRT) randomly assigned 100 patients with primary or secondary CRT indications to either to CSP – by either His-bundle or LBB-area pacing – or to standard BiV-CRT as the first-line resynchronization method.

Treatment crossovers, allowed for either pacing modality in the event of implantation failure, occurred in two patients and nine patients initially assigned to CSP and BiV pacing, respectively (4% vs. 18%), Dr. Vijayaraman reported.

International comparison of CSP and BiV pacing

In Dr. Vijayaraman’s other study, the observational comparison of LBB-area pacing and BiV-CRT, the CSP technique emerged as a “reasonable alternative to biventricular pacing, not only for improvement in LV function but also to reduce adverse clinical outcomes.”

Indeed, in the international study of 1,778 mostly male patients with primary or secondary CRT indications who received LBB-area or BiV pacing (797 and 981 patients, respectively), those on CSP saw a significant drop in risk for the primary endpoint, death or HFH.

Mean LVEF improved from 27% to 41% in the LBB-area pacing group and 27% to 37% with BiV pacing (P < .001 for both changes) over a follow-up averaging 33 months. The difference in improvement between CSP and BiV pacing was significant at P < .001.

In adjusted analysis, the risk for death or HFH was greater for BiV-pacing patients, a difference driven by HFH events.

• Death or HF: hazard ratio, 1.49 (95% confidence interval, 1.21-1.84; P < .001).
• Death: HR, 1.14 (95% CI, 0.88-1.48; P = .313).
• HFH: HR, 1.49 (95% CI, 1.16-1.92; P = .002)

The analysis has all the “inherent biases” of an observational study. The risk for patient-selection bias, however, was somewhat mitigated by consistent practice patterns at participating centers, Dr. Vijayaraman told this news organization.

For example, he said, operators at six of the institutions were most likely to use CSP as the first-line approach, and the same number of centers usually went with BiV pacing.
 

SYNCHRONY: First-line LBB-area pacing vs. BiV-CRT

Outcomes using the two approaches were similar in the prospective, international, observational study of 371 patients with ischemic or nonischemic cardiomyopathy and standard CRT indications. Allocation of 128 patients to LBB-area pacing and 243 to BiV-CRT was based on patient and operator preferences, reported Jorge Romero Jr, MD, Brigham and Women’s Hospital, Boston, at the HRS sessions.

Risk for the death-HFH primary endpoint dropped 38% for those initially treated with LBB-area pacing, compared with BiV pacing, primarily because of a lower HFH risk:

• Death or HFH: HR, 0.62 (95% CI, 0.41-0.93; P = .02).
• Death: HR, 0.57 (95% CI, 0.25-1.32; P = .19).
• HFH: HR, 0.61 (95% CI, 0.34-0.93; P = .02)

Patients in the CSP group were also more likely to improve by at least one NYHA (New York Heart Association) class (80.4% vs. 67.9%; P < .001), consistent with their greater absolute change in LVEF (8.0 vs. 3.9 points; P < .01).

The findings “suggest that LBBAP [left-bundle branch area pacing] is an excellent alternative to BiV pacing,” with a comparable safety profile, write Jayanthi N. Koneru, MBBS, and Kenneth A. Ellenbogen, MD, in an editorial accompanying the published SYNCHRONY report.

“The differences in improvement of LVEF are encouraging for both groups,” but were superior for LBB-area pacing, continue Dr. Koneru and Dr. Ellenbogen, both with Virginia Commonwealth University Medical Center, Richmond. “Whether these results would have regressed to the mean over a longer period of follow-up or diverge further with LBB-area pacing continuing to be superior is unknown.”
 

Years for an answer?

A large randomized comparison of CSP and BiV-CRT, called Left vs. Left, is currently in early stages, Sana M. Al-Khatib, MD, MHS, Duke University Medical Center, Durham, N.C., said in a media presentation on two of the presented studies. It has a planned enrollment of more than 2,100 patients on optimal meds with an LVEF of 50% or lower and either a QRS duration of at least 130 ms or an anticipated burden of RV pacing exceeding 40%.

The trial, she said, “will take years to give an answer, but it is actually designed to address the question of whether a composite endpoint of time to death or heart failure hospitalization can be improved with conduction system pacing vs. biventricular pacing.”

Dr. Al-Khatib is a coauthor on the new guideline covering both CSP and BiV-CRT in HF, as are Dr. Cha, Dr. Varma, Dr. Singh, Dr. Vijayaraman, and Dr. Goldberger; Dr. Ellenbogen is one of the reviewers.

Dr. Diaz discloses receiving honoraria or fees for speaking or teaching from Bayer Healthcare, Pfizer, AstraZeneca, Boston Scientific, and Medtronic. Dr. Vijayaraman discloses receiving honoraria or fees for speaking, teaching, or consulting for Abbott, Medtronic, Biotronik, and Boston Scientific; and receiving research grants from Medtronic. Dr. Varma discloses receiving honoraria or fees for speaking or consulting as an independent contractor for Medtronic, Boston Scientific, Biotronik, Impulse Dynamics USA, Cardiologs, Abbott, Pacemate, Implicity, and EP Solutions. Dr. Singh discloses receiving fees for consulting from EBR Systems, Merit Medical Systems, New Century Health, Biotronik, Abbott, Medtronic, MicroPort Scientific, Cardiologs, Sanofi, CVRx, Impulse Dynamics USA, Octagos, Implicity, Orchestra Biomed, Rhythm Management Group, and Biosense Webster; and receiving honoraria or fees for speaking and teaching from Medscape. Dr. Cha had no relevant financial relationships. Dr. Romero discloses receiving research grants from Biosense Webster; and speaking or receiving honoraria or fees for consulting, speaking, or teaching, or serving on a board for Sanofi, Boston Scientific, and AtriCure. Dr. Koneru discloses consulting for Medtronic and receiving honoraria from Abbott. Dr. Ellenbogen discloses consulting or lecturing for or receiving honoraria from Medtronic, Boston Scientific, and Abbott. Dr. Goldberger discloses receiving royalty income from and serving as an independent contractor for Elsevier. Dr. Al-Khatib discloses receiving research grants from Medtronic and Boston Scientific.

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