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Hearing loss tied to decline in physical functioning
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
New details of myocarditis linked to COVID vaccines
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
What’s best for diabetes after metformin? GRADE outdated at outset
Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.
. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.
The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.
The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.
For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.
During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
Too soon for take-aways, or are the data already obsolete?
“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.
Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.
“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”
“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.
But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.
“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.
Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.
A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.
Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.
The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”
Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.
“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”
In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.
Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.
They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.
Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
A study with lots of data
The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m2, average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m2. The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.
Patients were then randomized to one of the four agents as add-on treatment.
Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.
The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.
Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin.
A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.
For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.
For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance.
Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.
And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.
Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)
And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
Four drugs performed equally well for some outcomes
Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.
The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.
But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.
GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.
. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.
The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.
The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.
For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.
During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
Too soon for take-aways, or are the data already obsolete?
“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.
Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.
“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”
“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.
But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.
“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.
Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.
A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.
Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.
The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”
Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.
“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”
In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.
Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.
They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.
Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
A study with lots of data
The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m2, average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m2. The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.
Patients were then randomized to one of the four agents as add-on treatment.
Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.
The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.
Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin.
A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.
For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.
For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance.
Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.
And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.
Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)
And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
Four drugs performed equally well for some outcomes
Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.
The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.
But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.
GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.
. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.
The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.
The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.
For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.
During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
Too soon for take-aways, or are the data already obsolete?
“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.
Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.
“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”
“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.
But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.
“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.
Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.
A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.
Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.
The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”
Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.
“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”
In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.
Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.
They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.
Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
A study with lots of data
The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m2, average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m2. The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.
Patients were then randomized to one of the four agents as add-on treatment.
Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.
The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.
Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin.
A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.
For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.
For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance.
Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.
And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.
Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)
And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
Four drugs performed equally well for some outcomes
Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.
The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.
But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.
GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Magnesium is strongly tied to lower risk for intracranial aneurysm
The effects may be partially mediated by magnesium’s influence on systolic blood pressure, new research suggests.
“The modifiable risk factors for intracranial aneurysm are largely unknown. Our findings provided evidence of a causal association between increased serum magnesium levels and reduced risk of intracranial aneurysm,” said Susanna Larsson, PhD, Karolinska Institutet, Stockholm.
These results suggest that raising serum magnesium levels – through a magnesium-rich diet or magnesium supplementation – “may play a role in the primary prevention of intracranial aneurysm and associated hemorrhage,” Dr. Larsson added.
The study was published online June 22 in Neurology.
Lower risk for rupture
The researchers leveraged randomly allocated genetic variants related to serum magnesium concentrations in a two-sample Mendelian randomization (MR) study to assess whether higher genetically predicted serum magnesium correlates with reduced risk for intracranial aneurysm. They also performed a multivariable MR analysis to assess the role blood pressure might play in this association.
Source data came from a genome-wide association study (GWAS) involving 23,829 individuals that previously identified five single-nucleotide polymorphisms associated with serum magnesium. Genetic association estimates for intracranial aneurysm were derived from a GWAS in 79,429 people (7,495 case patients and 71,934 control patients), and genetic association estimates for systolic blood pressure were derived from a GWAS of 757,601 individuals.
The researchers found that higher genetically predicted serum magnesium concentrations were associated with lower risk for intracranial aneurysm.
The odds ratios per 0.1 mmol/L increment in genetically predicted serum magnesium concentrations were 0.66 (95% confidence interval, 0.49-0.91) for intracranial aneurysm (unruptured and ruptured combined), 0.57 (95% CI, 0.30-1.06) for unruptured intracranial aneurysm, and 0.67 (95% CI, 0.48-0.92) for aneurysmal subarachnoid hemorrhage.
Adjustment for genetically predicted systolic blood pressure partially attenuated the associations of genetically predicted serum magnesium with all three outcomes, suggesting that magnesium’s influence was at least partially mediated by systolic blood pressure.
“In addition to a blood pressure lowering effect, increased magnesium concentrations may reduce the risk of intracranial aneurysm rupture by improving endothelial function and reducing oxidative stress,” the investigators noted.
They caution that the data were derived from people of European ancestry, which limits the generalizability to other populations. “Caution should be taken when extrapolating findings from MR to infer the effect of a clinical intervention, and clinical trials are warranted to guide optimal practice,” they added.
Critical role in vascular health
In an accompanying editorial, Joanna Pera, MD, PhD, of Jagiellonian University Medical College, Krakow, Poland, and Christopher Anderson, MD, of Brigham and Women’s Hospital, Boston, noted that the study “adds to our understanding of the importance of magnesium in vascular health particularly related to cerebral aneurysms.”
There is a need for “both mechanistic and potentially therapeutic investigation into the role that magnesium plays in subarachnoid hemorrhage,” they added.
Further, they wrote, the results “raise interesting new questions about the links between circulating magnesium, intracranial aneurysms, and blood pressure. Arterial hypertension is a well-recognized risk factor for intracranial aneurysm development and rupture. Magnesium supplementation may lower blood pressure values.
“Could this mineral prove useful in developing interventions that could prevent intracranial aneurysm development and/or rupture over and above a simple lowering of blood pressure, perhaps through pleiotropic effects on endothelial function or other mechanisms? With these results in hand, work is clearly needed to learn more about the biology of magnesium in the vascular system and in intracranial aneurysm biology in particular,” Dr. Pera and Dr. Anderson concluded.
This study was supported by the Swedish Research Council for Health, Working Life and Welfare, the British Heart Foundation Research Center of Excellence at Imperial College London, and the National Institute for Health Research Clinical Lectureship at St. George’s, University of London. Dr. Larsson has disclosed no relevant financial relationships. Study coauthor Dipender Gill, PhD, is employed part time by Novo Nordisk. Dr. Pera has disclosed no relevant financial relationships. Dr. Anderson has received research support from the Bayer AG and has consulted for ApoPharma and Invitae.
A version of this article first appeared on Medscape.com.
The effects may be partially mediated by magnesium’s influence on systolic blood pressure, new research suggests.
“The modifiable risk factors for intracranial aneurysm are largely unknown. Our findings provided evidence of a causal association between increased serum magnesium levels and reduced risk of intracranial aneurysm,” said Susanna Larsson, PhD, Karolinska Institutet, Stockholm.
These results suggest that raising serum magnesium levels – through a magnesium-rich diet or magnesium supplementation – “may play a role in the primary prevention of intracranial aneurysm and associated hemorrhage,” Dr. Larsson added.
The study was published online June 22 in Neurology.
Lower risk for rupture
The researchers leveraged randomly allocated genetic variants related to serum magnesium concentrations in a two-sample Mendelian randomization (MR) study to assess whether higher genetically predicted serum magnesium correlates with reduced risk for intracranial aneurysm. They also performed a multivariable MR analysis to assess the role blood pressure might play in this association.
Source data came from a genome-wide association study (GWAS) involving 23,829 individuals that previously identified five single-nucleotide polymorphisms associated with serum magnesium. Genetic association estimates for intracranial aneurysm were derived from a GWAS in 79,429 people (7,495 case patients and 71,934 control patients), and genetic association estimates for systolic blood pressure were derived from a GWAS of 757,601 individuals.
The researchers found that higher genetically predicted serum magnesium concentrations were associated with lower risk for intracranial aneurysm.
The odds ratios per 0.1 mmol/L increment in genetically predicted serum magnesium concentrations were 0.66 (95% confidence interval, 0.49-0.91) for intracranial aneurysm (unruptured and ruptured combined), 0.57 (95% CI, 0.30-1.06) for unruptured intracranial aneurysm, and 0.67 (95% CI, 0.48-0.92) for aneurysmal subarachnoid hemorrhage.
Adjustment for genetically predicted systolic blood pressure partially attenuated the associations of genetically predicted serum magnesium with all three outcomes, suggesting that magnesium’s influence was at least partially mediated by systolic blood pressure.
“In addition to a blood pressure lowering effect, increased magnesium concentrations may reduce the risk of intracranial aneurysm rupture by improving endothelial function and reducing oxidative stress,” the investigators noted.
They caution that the data were derived from people of European ancestry, which limits the generalizability to other populations. “Caution should be taken when extrapolating findings from MR to infer the effect of a clinical intervention, and clinical trials are warranted to guide optimal practice,” they added.
Critical role in vascular health
In an accompanying editorial, Joanna Pera, MD, PhD, of Jagiellonian University Medical College, Krakow, Poland, and Christopher Anderson, MD, of Brigham and Women’s Hospital, Boston, noted that the study “adds to our understanding of the importance of magnesium in vascular health particularly related to cerebral aneurysms.”
There is a need for “both mechanistic and potentially therapeutic investigation into the role that magnesium plays in subarachnoid hemorrhage,” they added.
Further, they wrote, the results “raise interesting new questions about the links between circulating magnesium, intracranial aneurysms, and blood pressure. Arterial hypertension is a well-recognized risk factor for intracranial aneurysm development and rupture. Magnesium supplementation may lower blood pressure values.
“Could this mineral prove useful in developing interventions that could prevent intracranial aneurysm development and/or rupture over and above a simple lowering of blood pressure, perhaps through pleiotropic effects on endothelial function or other mechanisms? With these results in hand, work is clearly needed to learn more about the biology of magnesium in the vascular system and in intracranial aneurysm biology in particular,” Dr. Pera and Dr. Anderson concluded.
This study was supported by the Swedish Research Council for Health, Working Life and Welfare, the British Heart Foundation Research Center of Excellence at Imperial College London, and the National Institute for Health Research Clinical Lectureship at St. George’s, University of London. Dr. Larsson has disclosed no relevant financial relationships. Study coauthor Dipender Gill, PhD, is employed part time by Novo Nordisk. Dr. Pera has disclosed no relevant financial relationships. Dr. Anderson has received research support from the Bayer AG and has consulted for ApoPharma and Invitae.
A version of this article first appeared on Medscape.com.
The effects may be partially mediated by magnesium’s influence on systolic blood pressure, new research suggests.
“The modifiable risk factors for intracranial aneurysm are largely unknown. Our findings provided evidence of a causal association between increased serum magnesium levels and reduced risk of intracranial aneurysm,” said Susanna Larsson, PhD, Karolinska Institutet, Stockholm.
These results suggest that raising serum magnesium levels – through a magnesium-rich diet or magnesium supplementation – “may play a role in the primary prevention of intracranial aneurysm and associated hemorrhage,” Dr. Larsson added.
The study was published online June 22 in Neurology.
Lower risk for rupture
The researchers leveraged randomly allocated genetic variants related to serum magnesium concentrations in a two-sample Mendelian randomization (MR) study to assess whether higher genetically predicted serum magnesium correlates with reduced risk for intracranial aneurysm. They also performed a multivariable MR analysis to assess the role blood pressure might play in this association.
Source data came from a genome-wide association study (GWAS) involving 23,829 individuals that previously identified five single-nucleotide polymorphisms associated with serum magnesium. Genetic association estimates for intracranial aneurysm were derived from a GWAS in 79,429 people (7,495 case patients and 71,934 control patients), and genetic association estimates for systolic blood pressure were derived from a GWAS of 757,601 individuals.
The researchers found that higher genetically predicted serum magnesium concentrations were associated with lower risk for intracranial aneurysm.
The odds ratios per 0.1 mmol/L increment in genetically predicted serum magnesium concentrations were 0.66 (95% confidence interval, 0.49-0.91) for intracranial aneurysm (unruptured and ruptured combined), 0.57 (95% CI, 0.30-1.06) for unruptured intracranial aneurysm, and 0.67 (95% CI, 0.48-0.92) for aneurysmal subarachnoid hemorrhage.
Adjustment for genetically predicted systolic blood pressure partially attenuated the associations of genetically predicted serum magnesium with all three outcomes, suggesting that magnesium’s influence was at least partially mediated by systolic blood pressure.
“In addition to a blood pressure lowering effect, increased magnesium concentrations may reduce the risk of intracranial aneurysm rupture by improving endothelial function and reducing oxidative stress,” the investigators noted.
They caution that the data were derived from people of European ancestry, which limits the generalizability to other populations. “Caution should be taken when extrapolating findings from MR to infer the effect of a clinical intervention, and clinical trials are warranted to guide optimal practice,” they added.
Critical role in vascular health
In an accompanying editorial, Joanna Pera, MD, PhD, of Jagiellonian University Medical College, Krakow, Poland, and Christopher Anderson, MD, of Brigham and Women’s Hospital, Boston, noted that the study “adds to our understanding of the importance of magnesium in vascular health particularly related to cerebral aneurysms.”
There is a need for “both mechanistic and potentially therapeutic investigation into the role that magnesium plays in subarachnoid hemorrhage,” they added.
Further, they wrote, the results “raise interesting new questions about the links between circulating magnesium, intracranial aneurysms, and blood pressure. Arterial hypertension is a well-recognized risk factor for intracranial aneurysm development and rupture. Magnesium supplementation may lower blood pressure values.
“Could this mineral prove useful in developing interventions that could prevent intracranial aneurysm development and/or rupture over and above a simple lowering of blood pressure, perhaps through pleiotropic effects on endothelial function or other mechanisms? With these results in hand, work is clearly needed to learn more about the biology of magnesium in the vascular system and in intracranial aneurysm biology in particular,” Dr. Pera and Dr. Anderson concluded.
This study was supported by the Swedish Research Council for Health, Working Life and Welfare, the British Heart Foundation Research Center of Excellence at Imperial College London, and the National Institute for Health Research Clinical Lectureship at St. George’s, University of London. Dr. Larsson has disclosed no relevant financial relationships. Study coauthor Dipender Gill, PhD, is employed part time by Novo Nordisk. Dr. Pera has disclosed no relevant financial relationships. Dr. Anderson has received research support from the Bayer AG and has consulted for ApoPharma and Invitae.
A version of this article first appeared on Medscape.com.
From Neurology
A pediatrician wonders about the influence of an unhappy teacher
You are seeing a third-grader who has been experiencing some difficulty in school and his parents are wondering if he might have attention-deficit/hyperactivity disorder. In addition to interviewing his parents and doing a complete physical exam, you solicit information from his teacher, whose report confirms his struggles and also raises the possibility of an attention-deficit disorder. While the child has never been a model student, his parents have not voiced concerns at any of his previous health maintenance visits.
The child’s mother mentions that she has heard from another mother whose son and several other boys in the class have been struggling and misbehaving. Math seems to have been a particular problem. You don’t recall seeing any other third-graders whose parents have reported recent-onset school problems. But you practice in a large community with several grade schools spread out over a large county and may not be aware of a cluster.
As you get to know this child and his family better, you decide this doesn’t feel like a textbook case of ADHD, if indeed there is such a thing. You wonder if something is going on at school but you haven’t elicited any history that suggests bullying.
The parents have not expressed any concerns about the teacher, but you are beginning to wonder whether it’s time to consider the teacher’s role in this scenario. You recall reading about an article recently published in the journal Child Development that describes a study of more than 1,500 Head Start students in which the researchers found that teachers’ self-reported depressive symptoms were directly associated with lower math skills acquisition over the academic year.
There has been little published previously on an association between depressive symptoms in a teacher and academic achievement; however, the most quoted article I could find is from 2015 in which researchers studied 523 third-graders and 17 teachers at eight Florida school districts. The investigators found that in classes taught by teachers at increased risk for depression there was a decrease in the “quality of the learning environment” as determined by trained observers who watched classroom videos. It is interesting that a new math curriculum had been introduced during the academic year in which these observations were made.
Teaching can be a tough job and I guess we shouldn’t be surprised that the Rand Corporation has reported that teachers are nearly twice as likely to experience job stress and almost three times as likely to experience depression than is the general adult population.
Even if you have a strong suspicion that a depressed teacher is contributing to your patient’s academic struggles and maybe those of his classmates, what are your options? You don’t have enough information, nor would privacy concerns allow you to speak to the school administration. Your best approach would probably be to share with the child’s parents your concern that “something” in the school environment maybe contributing to the changes they are seeing, being careful to avoid singling out the teacher as the culprit because you really have nothing more than a suspicion. If the situation worsens and more parents share their stories, some of them may be bold enough to speak to the school administration.
I have always thought that here is a role for the principal. He or she may be aware of the teacher’s fragility and may be taking steps to correct the problem – but at a minimum, a visit to the classroom to get a sense for the “quality of the learning environment” would be in order.
Unfortunately, because mental health diagnoses continue to carry a stigma, it is very unlikely that a situation like this will resolve quickly to the benefit of the teacher or your patient and his classmates.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
You are seeing a third-grader who has been experiencing some difficulty in school and his parents are wondering if he might have attention-deficit/hyperactivity disorder. In addition to interviewing his parents and doing a complete physical exam, you solicit information from his teacher, whose report confirms his struggles and also raises the possibility of an attention-deficit disorder. While the child has never been a model student, his parents have not voiced concerns at any of his previous health maintenance visits.
The child’s mother mentions that she has heard from another mother whose son and several other boys in the class have been struggling and misbehaving. Math seems to have been a particular problem. You don’t recall seeing any other third-graders whose parents have reported recent-onset school problems. But you practice in a large community with several grade schools spread out over a large county and may not be aware of a cluster.
As you get to know this child and his family better, you decide this doesn’t feel like a textbook case of ADHD, if indeed there is such a thing. You wonder if something is going on at school but you haven’t elicited any history that suggests bullying.
The parents have not expressed any concerns about the teacher, but you are beginning to wonder whether it’s time to consider the teacher’s role in this scenario. You recall reading about an article recently published in the journal Child Development that describes a study of more than 1,500 Head Start students in which the researchers found that teachers’ self-reported depressive symptoms were directly associated with lower math skills acquisition over the academic year.
There has been little published previously on an association between depressive symptoms in a teacher and academic achievement; however, the most quoted article I could find is from 2015 in which researchers studied 523 third-graders and 17 teachers at eight Florida school districts. The investigators found that in classes taught by teachers at increased risk for depression there was a decrease in the “quality of the learning environment” as determined by trained observers who watched classroom videos. It is interesting that a new math curriculum had been introduced during the academic year in which these observations were made.
Teaching can be a tough job and I guess we shouldn’t be surprised that the Rand Corporation has reported that teachers are nearly twice as likely to experience job stress and almost three times as likely to experience depression than is the general adult population.
Even if you have a strong suspicion that a depressed teacher is contributing to your patient’s academic struggles and maybe those of his classmates, what are your options? You don’t have enough information, nor would privacy concerns allow you to speak to the school administration. Your best approach would probably be to share with the child’s parents your concern that “something” in the school environment maybe contributing to the changes they are seeing, being careful to avoid singling out the teacher as the culprit because you really have nothing more than a suspicion. If the situation worsens and more parents share their stories, some of them may be bold enough to speak to the school administration.
I have always thought that here is a role for the principal. He or she may be aware of the teacher’s fragility and may be taking steps to correct the problem – but at a minimum, a visit to the classroom to get a sense for the “quality of the learning environment” would be in order.
Unfortunately, because mental health diagnoses continue to carry a stigma, it is very unlikely that a situation like this will resolve quickly to the benefit of the teacher or your patient and his classmates.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
You are seeing a third-grader who has been experiencing some difficulty in school and his parents are wondering if he might have attention-deficit/hyperactivity disorder. In addition to interviewing his parents and doing a complete physical exam, you solicit information from his teacher, whose report confirms his struggles and also raises the possibility of an attention-deficit disorder. While the child has never been a model student, his parents have not voiced concerns at any of his previous health maintenance visits.
The child’s mother mentions that she has heard from another mother whose son and several other boys in the class have been struggling and misbehaving. Math seems to have been a particular problem. You don’t recall seeing any other third-graders whose parents have reported recent-onset school problems. But you practice in a large community with several grade schools spread out over a large county and may not be aware of a cluster.
As you get to know this child and his family better, you decide this doesn’t feel like a textbook case of ADHD, if indeed there is such a thing. You wonder if something is going on at school but you haven’t elicited any history that suggests bullying.
The parents have not expressed any concerns about the teacher, but you are beginning to wonder whether it’s time to consider the teacher’s role in this scenario. You recall reading about an article recently published in the journal Child Development that describes a study of more than 1,500 Head Start students in which the researchers found that teachers’ self-reported depressive symptoms were directly associated with lower math skills acquisition over the academic year.
There has been little published previously on an association between depressive symptoms in a teacher and academic achievement; however, the most quoted article I could find is from 2015 in which researchers studied 523 third-graders and 17 teachers at eight Florida school districts. The investigators found that in classes taught by teachers at increased risk for depression there was a decrease in the “quality of the learning environment” as determined by trained observers who watched classroom videos. It is interesting that a new math curriculum had been introduced during the academic year in which these observations were made.
Teaching can be a tough job and I guess we shouldn’t be surprised that the Rand Corporation has reported that teachers are nearly twice as likely to experience job stress and almost three times as likely to experience depression than is the general adult population.
Even if you have a strong suspicion that a depressed teacher is contributing to your patient’s academic struggles and maybe those of his classmates, what are your options? You don’t have enough information, nor would privacy concerns allow you to speak to the school administration. Your best approach would probably be to share with the child’s parents your concern that “something” in the school environment maybe contributing to the changes they are seeing, being careful to avoid singling out the teacher as the culprit because you really have nothing more than a suspicion. If the situation worsens and more parents share their stories, some of them may be bold enough to speak to the school administration.
I have always thought that here is a role for the principal. He or she may be aware of the teacher’s fragility and may be taking steps to correct the problem – but at a minimum, a visit to the classroom to get a sense for the “quality of the learning environment” would be in order.
Unfortunately, because mental health diagnoses continue to carry a stigma, it is very unlikely that a situation like this will resolve quickly to the benefit of the teacher or your patient and his classmates.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Screen pregnant women for OSA, given known risks
Pregnant women who have even mild sleep apnea should be treated for their sleep-disordered breathing given what is known about associated risks for hypertensive disorders of pregnancy and gestational diabetes, Carolyn M. D’Ambrosio, MS, MD, FCCP, said at the virtual annual meeting of the Associated Professional Sleep Societies.
“This is the current standard of care,” Dr. D’Ambrosio said. “Although guidelines on this issue are not hard and fast, I’d say that knowing what we know about the risk of adverse [maternal] outcomes, we should all try to treat these problems as soon as they’re identified” and then repeat polysomnography or home sleep testing 3-6 months post partum to “be sure the sleep-disordered breathing has resolved.”
Estimates of obstructive sleep apnea (OSA) prevalence range from approximately 9% in the first trimester to 20% in the third trimester. Yet recognizing the significance of OSA in pregnant women and identifying women for testing remains a major challenge. “Most women won’t [report sleep problems] because it’s pretty much common folklore that you don’t sleep well when you’re pregnant,” said Dr. D’Ambrosio, associate professor of medicine at Harvard Medical School, Boston, and current past-chair of the Women’s Lung Health Network for CHEST.
Many obstetricians and obstetrics providers, meanwhile, do not adequately screen. Typical screening tools like the Epworth Sleepiness Scale have low sensitivity and specificity during pregnancy, which means that inquiries about sleepiness, snoring, and disruptions in sleep are important, as is attention to potential risks for OSA posed by obesity, chronic hypertension, and neck circumference.
Only about a quarter of women in the United States snore during pregnancy, she noted. Snoring prevalence does increase as pregnancy progresses, reaching up to almost 50% in during the third trimester in some studies.
A four-variable screening tool reported almost 10 years ago for pregnant women is reliable for gauging risk, Dr. D’Ambrosio said. The model considers self-reported frequent snoring (more than three times/week), chronic hypertension, advanced maternal age, and a pregestational body mass index of at least 30 kg/m2. “If these [factors] are present, the patient is at significant risk for OSA and should be strongly considered for testing,” she said.
Home sleep apnea testing (HSAT) is validated for pregnant women but “it can underestimate,” she said. “If you get a negative result and [have clinical suspicion], then don’t stop there.”
And considering that the prevalence of OSA – at all levels of severity – increases as pregnancy progresses, it’s important to continue talking about sleep with patients who have frequent snoring, for instance, but negative sleep test results early in pregnancy. “They could develop [OSA] as time goes on,” she said.
Associated risk factors
Independent associations between sleep-disordered breathing and adverse maternal outcomes were demonstrated in a prospective cohort study published several years ago of 3,705 women who underwent HSAT in early and mid-pregnancy. The adjusted odds ratios for preeclampsia when sleep-disordered breathing (an apnea-hypopnea index of ≥5) was present early in pregnancy and in mid-pregnancy were 1.94 and 1.95, respectively.
For hypertensive disorders of pregnancy more broadly, the ORs were 1.46 and 1.73, and for gestational diabetes, the ORs were 3.47 and 2.79.
“Faced with the question about why it’s important to diagnosis and treat OSA [during pregnancy] since the pregnancy will be over in a few months, I go to this study,” Dr. D’Ambrosio said. “Waiting until the end of pregnancy is not safe. There are increased risks of very serious conditions if sleep apnea is there and it’s not treated.”
Another study demonstrating a link between OSA and maternal outcomes looked over 1.5 million deliveries in the United States and found a significantly higher prevalence of gestational diabetes (OR, 2.08), gestational hypertension (OR, 1.77), preeclampsia (OR, 2.07), and eclampsia (OR, 2.70) in pregnant women with OSA than without, after adjusting for maternal obesity. Associations remained significant after adjusting for a more comprehensive list of covariates.
Multiple potential casual pathways are at play, Dr. D’Ambrosio said. Short sleep duration decreases leptin and increases ghrelin levels, for instance, and sleep fragmentation activates the HPA axis and increases cortisol. Intermittent hypoxemia affects sympathetic activity, and intrathoracic pressure swings cause increased oxidative stress and systemic inflammation.
The resulting endothelial dysfunction, glucose dysfunction, and dyslipidemia can drive the adverse maternal outcomes documented in these studies, she said, noting that the adverse outcomes can have long-term cardiovascular consequences.
Continuous positive airway pressure therapy is well tolerated in pregnancy, and given pregnancy’s continual weight change, auto-titrating CPAP may be the best option, she said.
There is “some limited data that treatment improves maternal outcomes, and we’re still working on trying to get better data and more solid recommendations,” Dr. D’Ambrosio said. There currently are no guidelines covering the diagnosis and management of OSA during pregnancy.
“We’ve come a long way ... but we still have more to do,” she said. “We have a long way to go to getting [OSA in pregnant women] well recognized, with screening techniques and diagnosis.”
Asked after the meeting about Dr. D’Ambrosio’s messages, Anita Rajagopal, MD, said that OSA screening during pregnancy needs to be improved through more collaboration “with our ob.gyn. and primary care colleagues.”
Too often, she said, “the signs and symptoms of OSA in pregnancy are written off as ‘just harmless snoring’ while in fact the patient has treatable sleep disordered breathing with potential adverse effects.” Dr. Rajagopal is department medical director for sleep medicine at Community Physician Network and medical director of the Community Health Network Sleep-Wake Disorders Center, both in Indianapolis.
Dr. D’Ambrosio reported that she has no potential conflicts of interest related to the material she presented, and Dr. Rajagopal stated she has no potential conflicts of interest.
Pregnant women who have even mild sleep apnea should be treated for their sleep-disordered breathing given what is known about associated risks for hypertensive disorders of pregnancy and gestational diabetes, Carolyn M. D’Ambrosio, MS, MD, FCCP, said at the virtual annual meeting of the Associated Professional Sleep Societies.
“This is the current standard of care,” Dr. D’Ambrosio said. “Although guidelines on this issue are not hard and fast, I’d say that knowing what we know about the risk of adverse [maternal] outcomes, we should all try to treat these problems as soon as they’re identified” and then repeat polysomnography or home sleep testing 3-6 months post partum to “be sure the sleep-disordered breathing has resolved.”
Estimates of obstructive sleep apnea (OSA) prevalence range from approximately 9% in the first trimester to 20% in the third trimester. Yet recognizing the significance of OSA in pregnant women and identifying women for testing remains a major challenge. “Most women won’t [report sleep problems] because it’s pretty much common folklore that you don’t sleep well when you’re pregnant,” said Dr. D’Ambrosio, associate professor of medicine at Harvard Medical School, Boston, and current past-chair of the Women’s Lung Health Network for CHEST.
Many obstetricians and obstetrics providers, meanwhile, do not adequately screen. Typical screening tools like the Epworth Sleepiness Scale have low sensitivity and specificity during pregnancy, which means that inquiries about sleepiness, snoring, and disruptions in sleep are important, as is attention to potential risks for OSA posed by obesity, chronic hypertension, and neck circumference.
Only about a quarter of women in the United States snore during pregnancy, she noted. Snoring prevalence does increase as pregnancy progresses, reaching up to almost 50% in during the third trimester in some studies.
A four-variable screening tool reported almost 10 years ago for pregnant women is reliable for gauging risk, Dr. D’Ambrosio said. The model considers self-reported frequent snoring (more than three times/week), chronic hypertension, advanced maternal age, and a pregestational body mass index of at least 30 kg/m2. “If these [factors] are present, the patient is at significant risk for OSA and should be strongly considered for testing,” she said.
Home sleep apnea testing (HSAT) is validated for pregnant women but “it can underestimate,” she said. “If you get a negative result and [have clinical suspicion], then don’t stop there.”
And considering that the prevalence of OSA – at all levels of severity – increases as pregnancy progresses, it’s important to continue talking about sleep with patients who have frequent snoring, for instance, but negative sleep test results early in pregnancy. “They could develop [OSA] as time goes on,” she said.
Associated risk factors
Independent associations between sleep-disordered breathing and adverse maternal outcomes were demonstrated in a prospective cohort study published several years ago of 3,705 women who underwent HSAT in early and mid-pregnancy. The adjusted odds ratios for preeclampsia when sleep-disordered breathing (an apnea-hypopnea index of ≥5) was present early in pregnancy and in mid-pregnancy were 1.94 and 1.95, respectively.
For hypertensive disorders of pregnancy more broadly, the ORs were 1.46 and 1.73, and for gestational diabetes, the ORs were 3.47 and 2.79.
“Faced with the question about why it’s important to diagnosis and treat OSA [during pregnancy] since the pregnancy will be over in a few months, I go to this study,” Dr. D’Ambrosio said. “Waiting until the end of pregnancy is not safe. There are increased risks of very serious conditions if sleep apnea is there and it’s not treated.”
Another study demonstrating a link between OSA and maternal outcomes looked over 1.5 million deliveries in the United States and found a significantly higher prevalence of gestational diabetes (OR, 2.08), gestational hypertension (OR, 1.77), preeclampsia (OR, 2.07), and eclampsia (OR, 2.70) in pregnant women with OSA than without, after adjusting for maternal obesity. Associations remained significant after adjusting for a more comprehensive list of covariates.
Multiple potential casual pathways are at play, Dr. D’Ambrosio said. Short sleep duration decreases leptin and increases ghrelin levels, for instance, and sleep fragmentation activates the HPA axis and increases cortisol. Intermittent hypoxemia affects sympathetic activity, and intrathoracic pressure swings cause increased oxidative stress and systemic inflammation.
The resulting endothelial dysfunction, glucose dysfunction, and dyslipidemia can drive the adverse maternal outcomes documented in these studies, she said, noting that the adverse outcomes can have long-term cardiovascular consequences.
Continuous positive airway pressure therapy is well tolerated in pregnancy, and given pregnancy’s continual weight change, auto-titrating CPAP may be the best option, she said.
There is “some limited data that treatment improves maternal outcomes, and we’re still working on trying to get better data and more solid recommendations,” Dr. D’Ambrosio said. There currently are no guidelines covering the diagnosis and management of OSA during pregnancy.
“We’ve come a long way ... but we still have more to do,” she said. “We have a long way to go to getting [OSA in pregnant women] well recognized, with screening techniques and diagnosis.”
Asked after the meeting about Dr. D’Ambrosio’s messages, Anita Rajagopal, MD, said that OSA screening during pregnancy needs to be improved through more collaboration “with our ob.gyn. and primary care colleagues.”
Too often, she said, “the signs and symptoms of OSA in pregnancy are written off as ‘just harmless snoring’ while in fact the patient has treatable sleep disordered breathing with potential adverse effects.” Dr. Rajagopal is department medical director for sleep medicine at Community Physician Network and medical director of the Community Health Network Sleep-Wake Disorders Center, both in Indianapolis.
Dr. D’Ambrosio reported that she has no potential conflicts of interest related to the material she presented, and Dr. Rajagopal stated she has no potential conflicts of interest.
Pregnant women who have even mild sleep apnea should be treated for their sleep-disordered breathing given what is known about associated risks for hypertensive disorders of pregnancy and gestational diabetes, Carolyn M. D’Ambrosio, MS, MD, FCCP, said at the virtual annual meeting of the Associated Professional Sleep Societies.
“This is the current standard of care,” Dr. D’Ambrosio said. “Although guidelines on this issue are not hard and fast, I’d say that knowing what we know about the risk of adverse [maternal] outcomes, we should all try to treat these problems as soon as they’re identified” and then repeat polysomnography or home sleep testing 3-6 months post partum to “be sure the sleep-disordered breathing has resolved.”
Estimates of obstructive sleep apnea (OSA) prevalence range from approximately 9% in the first trimester to 20% in the third trimester. Yet recognizing the significance of OSA in pregnant women and identifying women for testing remains a major challenge. “Most women won’t [report sleep problems] because it’s pretty much common folklore that you don’t sleep well when you’re pregnant,” said Dr. D’Ambrosio, associate professor of medicine at Harvard Medical School, Boston, and current past-chair of the Women’s Lung Health Network for CHEST.
Many obstetricians and obstetrics providers, meanwhile, do not adequately screen. Typical screening tools like the Epworth Sleepiness Scale have low sensitivity and specificity during pregnancy, which means that inquiries about sleepiness, snoring, and disruptions in sleep are important, as is attention to potential risks for OSA posed by obesity, chronic hypertension, and neck circumference.
Only about a quarter of women in the United States snore during pregnancy, she noted. Snoring prevalence does increase as pregnancy progresses, reaching up to almost 50% in during the third trimester in some studies.
A four-variable screening tool reported almost 10 years ago for pregnant women is reliable for gauging risk, Dr. D’Ambrosio said. The model considers self-reported frequent snoring (more than three times/week), chronic hypertension, advanced maternal age, and a pregestational body mass index of at least 30 kg/m2. “If these [factors] are present, the patient is at significant risk for OSA and should be strongly considered for testing,” she said.
Home sleep apnea testing (HSAT) is validated for pregnant women but “it can underestimate,” she said. “If you get a negative result and [have clinical suspicion], then don’t stop there.”
And considering that the prevalence of OSA – at all levels of severity – increases as pregnancy progresses, it’s important to continue talking about sleep with patients who have frequent snoring, for instance, but negative sleep test results early in pregnancy. “They could develop [OSA] as time goes on,” she said.
Associated risk factors
Independent associations between sleep-disordered breathing and adverse maternal outcomes were demonstrated in a prospective cohort study published several years ago of 3,705 women who underwent HSAT in early and mid-pregnancy. The adjusted odds ratios for preeclampsia when sleep-disordered breathing (an apnea-hypopnea index of ≥5) was present early in pregnancy and in mid-pregnancy were 1.94 and 1.95, respectively.
For hypertensive disorders of pregnancy more broadly, the ORs were 1.46 and 1.73, and for gestational diabetes, the ORs were 3.47 and 2.79.
“Faced with the question about why it’s important to diagnosis and treat OSA [during pregnancy] since the pregnancy will be over in a few months, I go to this study,” Dr. D’Ambrosio said. “Waiting until the end of pregnancy is not safe. There are increased risks of very serious conditions if sleep apnea is there and it’s not treated.”
Another study demonstrating a link between OSA and maternal outcomes looked over 1.5 million deliveries in the United States and found a significantly higher prevalence of gestational diabetes (OR, 2.08), gestational hypertension (OR, 1.77), preeclampsia (OR, 2.07), and eclampsia (OR, 2.70) in pregnant women with OSA than without, after adjusting for maternal obesity. Associations remained significant after adjusting for a more comprehensive list of covariates.
Multiple potential casual pathways are at play, Dr. D’Ambrosio said. Short sleep duration decreases leptin and increases ghrelin levels, for instance, and sleep fragmentation activates the HPA axis and increases cortisol. Intermittent hypoxemia affects sympathetic activity, and intrathoracic pressure swings cause increased oxidative stress and systemic inflammation.
The resulting endothelial dysfunction, glucose dysfunction, and dyslipidemia can drive the adverse maternal outcomes documented in these studies, she said, noting that the adverse outcomes can have long-term cardiovascular consequences.
Continuous positive airway pressure therapy is well tolerated in pregnancy, and given pregnancy’s continual weight change, auto-titrating CPAP may be the best option, she said.
There is “some limited data that treatment improves maternal outcomes, and we’re still working on trying to get better data and more solid recommendations,” Dr. D’Ambrosio said. There currently are no guidelines covering the diagnosis and management of OSA during pregnancy.
“We’ve come a long way ... but we still have more to do,” she said. “We have a long way to go to getting [OSA in pregnant women] well recognized, with screening techniques and diagnosis.”
Asked after the meeting about Dr. D’Ambrosio’s messages, Anita Rajagopal, MD, said that OSA screening during pregnancy needs to be improved through more collaboration “with our ob.gyn. and primary care colleagues.”
Too often, she said, “the signs and symptoms of OSA in pregnancy are written off as ‘just harmless snoring’ while in fact the patient has treatable sleep disordered breathing with potential adverse effects.” Dr. Rajagopal is department medical director for sleep medicine at Community Physician Network and medical director of the Community Health Network Sleep-Wake Disorders Center, both in Indianapolis.
Dr. D’Ambrosio reported that she has no potential conflicts of interest related to the material she presented, and Dr. Rajagopal stated she has no potential conflicts of interest.
FROM SLEEP 2021
A less expensive, more convenient treatment option for MS?
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) may soon have another less expensive, more convenient treatment option compared with other agents in the same drug class, new research suggests.
The positive results suggest “another strong and reasonably safe medication might be available to increase the repertoire of effective medicines that we can offer MS patients,” said Lawrence Steinman, MD, professor of neurology, Stanford (Calif.) University. “These are delightful data in my opinion,” he added.
The findings were presented at the 2021 Congress of the European Academy of Neurology.
‘Glycoengineered’ antibody
If approved by the U.S. Food and Drug Administration, ublituximab would become the only glycoengineered anti-CD20 monoclonal antibody for MS. Glycoengineering involves changing protein-associated carbohydrates to alter pharmacokinetic properties.
There are currently two approved anti-CD20 agents for MS, but both require 4-hour infusions. For many patients, this means “at least half their day is shot,” Dr. Steinman said. “A lot of people don’t want to or can’t miss a half day of work.” Ublituximab can be infused more rapidly, he noted.
For the study, the investigators analyzed data from the ULTIMATE I and ULTIMATE II studies, which included 1,089 mostly White patients with MS. Almost all participants had the relapsing-remitting form of the disease and were between 18 and 55 years of age (average age, 36 years). Their scores on the Expanded Disability Status Scale (EDSS) were from 0 to 5.5, and they had been neurologically stable for at least 30 days prior to screening.
Participants were required to have experienced two or more relapses within the previous 2 years or one or more relapses in the year prior and/or had one gadolinium-enhancing lesion in the year prior to screening.
The study population was mostly from the Ukraine and Russia. It is more difficult to recruit patients into MS drug studies in the United States and Western Europe because many patients in these countries are already receiving approved drugs, which deters enrollment, explained Dr. Steinman.
Investigators randomly assigned the participants to receive the investigational drug or 14 mg of oral teriflunomide, a drug that blocks the proliferation of immune cells, once daily. The ublituximab group received an initial infusion of 150 mg over 4 hours and then a 1-hour infusion of 450 mg every 6 months over the course of the 96-week study.
Primary outcomes met
For ULTIMATE I, the primary outcome was ARR. Results showed that this rate was 0.076 for the ublituximab group and 0.188 for the teriflunomide group, resulting in a 60% relative reduction (adjusted ARR ratio, 0.406; 95% confidence interval, 0.268-0.615; P < .0001).
In ULTIMATE II, the ARR was 0.091 for ublituximab and 0.178 for teriflunomide, for a relative reduction of 49% (ARR ratio, 0.509; 95% CI, 0.330-0.784; P = .0022).
One way of interpreting these data is that patients are likely to have only one relapse in 10 years, said Dr. Steinman. “So that was very good news.”
It is not clear why relative reductions for ARR differed between the two studies; “probably the real number is somewhere between 60% and 49%,” Dr. Steinman said.
From MRI scans, the total number of relevant lesions was reduced by 97% with ublituximab compared with teriflunomide in ULTIMATE I and by 96% in trial II.
Another “piece of really good news” from the studies is that the drug led to a significant improvement in disability, rather than “just slowing it down,” Dr. Steinman noted.
There was a 116% increased chance of confirmed disability improvement (CDI) with ublituximab versus teriflunomide in the first trial (P = .003) and a 103% increased chance of CDI in the second trial (P = .0026).
The percentage of patients who had no evidence of disease activity was 198% for the patients who received the trial drug in comparison with the control group in trial I and 277% in trial II (P < .0001 for both trials).
A life changer?
Dr. Steinman said the “robust” findings suggest that patients with MS “won’t have a relapse and will improve. Those are two pretty good messages for somebody with this wretched disease.”
The investigational drug was generally well tolerated. The percentage of adverse events (AEs) with the study drug was about the same as with the comparator. About 9.5% of the ublituximab group had a serious AE, compared with 6.2% of the teriflunomide group.
The ublituximab group had more infections (4.0% vs. 2.6%), which Dr. Steinman said is not surprising because the drug is a potent immune suppressant. “It’s an unfortunate consequence of this kind of strong biologic that knocks down a whole arm of the immune system. The wonder to me is that these are still rather infrequent,” he said.
If approved, “it will be interesting to see how regulatory agencies handle this in terms of risk mitigation,” said Dr. Steinman. He added that a warning label might be a consideration.
However, the safety of this drug “is certainly acceptable,” said Dr. Steinman. “In general, this drug is not that different from the other drugs in the class of anti-CD20s.”
Dr. Steinman noted that he understands why some patients prefer an oral drug and may have an “aversion to getting stuck with a needle,” but he pointed out that teriflunomide has some drawbacks. For example, it tends to thin hair.
“For people who have had relapses, people who are unable to do what they want to in life – attend school, hold down jobs, exercise – this new drug could really be life changing,” he said.
He added that he would “strongly urge” his own family and relatives, if they had MS, to take one of the anti-CD20 drugs.
Ublituximab also has a number of advantages over the other agents in the same class. Not only does it work well, have an acceptable safety profile, and require a shorter infusion time, but it could also be less costly, Dr. Steinman noted. “The company has said it intends to come in at a lower price point,” he said.
The company is now planning to prepare a biological license application for use in MS. Interestingly, the drug, in combination with umbralisib (Ukoniq), is already under review by the FDA for use in chronic lymphoctytic leukemia and small lymphocytic lymphoma.
Striking improvement
When session chair Marcello Moccio, MD, Multiple Sclerosis Clinical Care and Research Center, Federico II University, Naples, Italy, asked Dr. Steinman to elaborate on the “very strong effect” of the drug with regard to improving disability, Dr. Steinman said the improvement was “striking.”
Being able to talk to patients about possible improvement rather than about delaying disability “is really gratifying” and provides a “much more constructive and optimistic outlook,” he said.
He noted that as physicians improve their management of patients with MS “and are paying attention to things that we haven’t over the years, like vitamin D and even mental health,” disability progression management “is getting better.”
Dr. Steinman is a consultant for TG Therapeutics.
A version of this article first appeared on Medscape.com.
From EAN 2021
Expert shares practical considerations when prescribing dupilumab
.
This scenario was illustrated in a 2020 retrospective study of 179 adults with AD who were cared for at the University of Pittsburgh Medical Center, which found that 37% did not start dupilumab, mainly due to insurance denial (19%) and high copay (11%).
“We’ve all seen this in our practice,” Amy S. Paller, MD, said during the Revolutionizing Atopic Dermatitis symposium. “We’ve also seen the denials until we get step therapy in there, so if I have a child whom I want to treat with dupilumab for safety reasons, I don’t like being told that I’m going to have to use cyclosporine or methotrexate or a medication that I think may have higher risks and certainly [would] require blood monitoring–yet that’s the state for some patients.”
Dupilumab, an interleukin-4 receptor alpha antagonist, is approved for treatment of moderate to severe AD in patients ages 6 and older.
When working to obtain insurance approval of dupilumab, Dr. Paller reminded dermatologists to document that the patient has moderate to severe AD “and document the negative effect on quality of life in order to try to help make it easier to get these medications for our patients.”
Starting patients on dupilumab
Dr. Paller, the Walter J. Hamlin Chair and Professor of Dermatology at Northwestern University, Chicago, said that if patients are on another systemic medication prior to starting dupilumab, she allows a transition period of 1-2 months. “Don’t just stop that drug because it’s ‘not working,’ ” she said. “I usually do a full dose for the first month, and a half dose for the next month before starting dupilumab. Also, don’t stop the use of topical corticosteroids. They can increase treatment response by 10%-20%, even when patients are on dupilumab.”
She recommends a 3- to 4-month trial of dupilumab while monitoring changes in disease severity, itch, and quality of life. “Usually there’s evidence of early improvement by 2 months in those who are going to do well enough to stay on the drug by about 4 months out,” she said. “In my experience, most pediatric patients do very well. In those with an inadequate response, about 50% will do better if you can increase the dose or frequency. Flares can still occur in those who do well. I usually push topicals when that happens.”
If patients respond well after starting dupilumab, Dr. Paller recommends that they continue on the drug for at least a year before considering a taper with the hope of “resetting” the immune system and having sustained improvement off drug. “Some parents and patients don’t want to stop the drug,” but for those who do, she tells them that she does not want to abruptly stop treatment, but to “space out the dosing” instead. “If someone is pretty much clear with the medication and is able to continue with topicals as you dial down, that’s great. But don’t even think about taking them off if somebody’s not clear or virtually clear, particularly if they start to flare with lower frequency.”
Data on effectiveness
Real-world data suggest that the effectiveness of dupilumab is similar to the efficacy seen in clinical trials. For example, a recently published systematic review and meta-analysis of 3,303 AD patients on dupilumab found that after 16 weeks of therapy, 60% achieved a 75% improvement in the Eczema Area and Severity (EASI75) score, and 27% achieved an EASI90. In a Dutch study of 210 adults treated with dupilumab for 52 weeks, enrolled in a Dutch registry, the mean percent reduction in EASI score was 70% at 16 weeks and 76.6% by 52 weeks.
In addition, there was at least a 4-point improvement in the Patient-Oriented Eczema Measure (POEM) score and at least a 4-point improvement in the Itch Numeric Rating Scale (NRS), said Dr. Paller, who was not involved in the study. “These patient-reported improvements were seen very early on,” she noted.
What about drug survival at 1 year? In a retrospective cohort study that drew from insurance databases, 1,963 adults given dupilumab were studied for a mean of 315 days. The rate of persistence was 92% at 6 months and 77% at 12 months. “That means that it’s still effective,” Dr. Paller said.
While that is a short period of time, she compared these results with long-term survival of nonsteroid systemic immunosuppressants such as cyclosporine, referring to a study of adults with AD treated with systemic immunosuppressants, which found “a 32% persistence rate at 12 months in drugs that require more monitoring, so more burden.”
Dr. Paller disclosed that she is a consultant to and/or an investigator for dupilumab (Dupixent) manufacturers Regeneron and Sanofi, AbbVie, Arena, Bausch, Bristol Myers Squibb, Dermavant, Eli Lilly, Incyte, Forte, LEO Pharma, LifeMax, Pfizer, and RAPT Therapeutics.
.
This scenario was illustrated in a 2020 retrospective study of 179 adults with AD who were cared for at the University of Pittsburgh Medical Center, which found that 37% did not start dupilumab, mainly due to insurance denial (19%) and high copay (11%).
“We’ve all seen this in our practice,” Amy S. Paller, MD, said during the Revolutionizing Atopic Dermatitis symposium. “We’ve also seen the denials until we get step therapy in there, so if I have a child whom I want to treat with dupilumab for safety reasons, I don’t like being told that I’m going to have to use cyclosporine or methotrexate or a medication that I think may have higher risks and certainly [would] require blood monitoring–yet that’s the state for some patients.”
Dupilumab, an interleukin-4 receptor alpha antagonist, is approved for treatment of moderate to severe AD in patients ages 6 and older.
When working to obtain insurance approval of dupilumab, Dr. Paller reminded dermatologists to document that the patient has moderate to severe AD “and document the negative effect on quality of life in order to try to help make it easier to get these medications for our patients.”
Starting patients on dupilumab
Dr. Paller, the Walter J. Hamlin Chair and Professor of Dermatology at Northwestern University, Chicago, said that if patients are on another systemic medication prior to starting dupilumab, she allows a transition period of 1-2 months. “Don’t just stop that drug because it’s ‘not working,’ ” she said. “I usually do a full dose for the first month, and a half dose for the next month before starting dupilumab. Also, don’t stop the use of topical corticosteroids. They can increase treatment response by 10%-20%, even when patients are on dupilumab.”
She recommends a 3- to 4-month trial of dupilumab while monitoring changes in disease severity, itch, and quality of life. “Usually there’s evidence of early improvement by 2 months in those who are going to do well enough to stay on the drug by about 4 months out,” she said. “In my experience, most pediatric patients do very well. In those with an inadequate response, about 50% will do better if you can increase the dose or frequency. Flares can still occur in those who do well. I usually push topicals when that happens.”
If patients respond well after starting dupilumab, Dr. Paller recommends that they continue on the drug for at least a year before considering a taper with the hope of “resetting” the immune system and having sustained improvement off drug. “Some parents and patients don’t want to stop the drug,” but for those who do, she tells them that she does not want to abruptly stop treatment, but to “space out the dosing” instead. “If someone is pretty much clear with the medication and is able to continue with topicals as you dial down, that’s great. But don’t even think about taking them off if somebody’s not clear or virtually clear, particularly if they start to flare with lower frequency.”
Data on effectiveness
Real-world data suggest that the effectiveness of dupilumab is similar to the efficacy seen in clinical trials. For example, a recently published systematic review and meta-analysis of 3,303 AD patients on dupilumab found that after 16 weeks of therapy, 60% achieved a 75% improvement in the Eczema Area and Severity (EASI75) score, and 27% achieved an EASI90. In a Dutch study of 210 adults treated with dupilumab for 52 weeks, enrolled in a Dutch registry, the mean percent reduction in EASI score was 70% at 16 weeks and 76.6% by 52 weeks.
In addition, there was at least a 4-point improvement in the Patient-Oriented Eczema Measure (POEM) score and at least a 4-point improvement in the Itch Numeric Rating Scale (NRS), said Dr. Paller, who was not involved in the study. “These patient-reported improvements were seen very early on,” she noted.
What about drug survival at 1 year? In a retrospective cohort study that drew from insurance databases, 1,963 adults given dupilumab were studied for a mean of 315 days. The rate of persistence was 92% at 6 months and 77% at 12 months. “That means that it’s still effective,” Dr. Paller said.
While that is a short period of time, she compared these results with long-term survival of nonsteroid systemic immunosuppressants such as cyclosporine, referring to a study of adults with AD treated with systemic immunosuppressants, which found “a 32% persistence rate at 12 months in drugs that require more monitoring, so more burden.”
Dr. Paller disclosed that she is a consultant to and/or an investigator for dupilumab (Dupixent) manufacturers Regeneron and Sanofi, AbbVie, Arena, Bausch, Bristol Myers Squibb, Dermavant, Eli Lilly, Incyte, Forte, LEO Pharma, LifeMax, Pfizer, and RAPT Therapeutics.
.
This scenario was illustrated in a 2020 retrospective study of 179 adults with AD who were cared for at the University of Pittsburgh Medical Center, which found that 37% did not start dupilumab, mainly due to insurance denial (19%) and high copay (11%).
“We’ve all seen this in our practice,” Amy S. Paller, MD, said during the Revolutionizing Atopic Dermatitis symposium. “We’ve also seen the denials until we get step therapy in there, so if I have a child whom I want to treat with dupilumab for safety reasons, I don’t like being told that I’m going to have to use cyclosporine or methotrexate or a medication that I think may have higher risks and certainly [would] require blood monitoring–yet that’s the state for some patients.”
Dupilumab, an interleukin-4 receptor alpha antagonist, is approved for treatment of moderate to severe AD in patients ages 6 and older.
When working to obtain insurance approval of dupilumab, Dr. Paller reminded dermatologists to document that the patient has moderate to severe AD “and document the negative effect on quality of life in order to try to help make it easier to get these medications for our patients.”
Starting patients on dupilumab
Dr. Paller, the Walter J. Hamlin Chair and Professor of Dermatology at Northwestern University, Chicago, said that if patients are on another systemic medication prior to starting dupilumab, she allows a transition period of 1-2 months. “Don’t just stop that drug because it’s ‘not working,’ ” she said. “I usually do a full dose for the first month, and a half dose for the next month before starting dupilumab. Also, don’t stop the use of topical corticosteroids. They can increase treatment response by 10%-20%, even when patients are on dupilumab.”
She recommends a 3- to 4-month trial of dupilumab while monitoring changes in disease severity, itch, and quality of life. “Usually there’s evidence of early improvement by 2 months in those who are going to do well enough to stay on the drug by about 4 months out,” she said. “In my experience, most pediatric patients do very well. In those with an inadequate response, about 50% will do better if you can increase the dose or frequency. Flares can still occur in those who do well. I usually push topicals when that happens.”
If patients respond well after starting dupilumab, Dr. Paller recommends that they continue on the drug for at least a year before considering a taper with the hope of “resetting” the immune system and having sustained improvement off drug. “Some parents and patients don’t want to stop the drug,” but for those who do, she tells them that she does not want to abruptly stop treatment, but to “space out the dosing” instead. “If someone is pretty much clear with the medication and is able to continue with topicals as you dial down, that’s great. But don’t even think about taking them off if somebody’s not clear or virtually clear, particularly if they start to flare with lower frequency.”
Data on effectiveness
Real-world data suggest that the effectiveness of dupilumab is similar to the efficacy seen in clinical trials. For example, a recently published systematic review and meta-analysis of 3,303 AD patients on dupilumab found that after 16 weeks of therapy, 60% achieved a 75% improvement in the Eczema Area and Severity (EASI75) score, and 27% achieved an EASI90. In a Dutch study of 210 adults treated with dupilumab for 52 weeks, enrolled in a Dutch registry, the mean percent reduction in EASI score was 70% at 16 weeks and 76.6% by 52 weeks.
In addition, there was at least a 4-point improvement in the Patient-Oriented Eczema Measure (POEM) score and at least a 4-point improvement in the Itch Numeric Rating Scale (NRS), said Dr. Paller, who was not involved in the study. “These patient-reported improvements were seen very early on,” she noted.
What about drug survival at 1 year? In a retrospective cohort study that drew from insurance databases, 1,963 adults given dupilumab were studied for a mean of 315 days. The rate of persistence was 92% at 6 months and 77% at 12 months. “That means that it’s still effective,” Dr. Paller said.
While that is a short period of time, she compared these results with long-term survival of nonsteroid systemic immunosuppressants such as cyclosporine, referring to a study of adults with AD treated with systemic immunosuppressants, which found “a 32% persistence rate at 12 months in drugs that require more monitoring, so more burden.”
Dr. Paller disclosed that she is a consultant to and/or an investigator for dupilumab (Dupixent) manufacturers Regeneron and Sanofi, AbbVie, Arena, Bausch, Bristol Myers Squibb, Dermavant, Eli Lilly, Incyte, Forte, LEO Pharma, LifeMax, Pfizer, and RAPT Therapeutics.
FROM REVOLUTIONIZING AD 2021
Obesity hypoventilation: Moving the needle on underrecognition
Obesity hypoventilation syndrome (OHS) is bound to be increasing because of the rising obesity epidemic but is underrecognized and “frequently underdiagnosed,” Saiprakash B. Venkateshiah, MD, said at the virtual annual meeting of the Associated Professional Sleep Societies.
The condition, which can cause significant morbidity and mortality, is defined by the combination of obesity and awake alveolar hypoventilation (PaCO2 ≥45 mm Hg), with the exclusion of alternate causes of hypoventilation. Sleep-disordered breathing (SDB) is almost universally present, with approximately 90% of individuals with OHS also having obstructive sleep apnea (OSA), most often severe, and approximately 10% having sleep-related hypoventilation, or a “pure hypoventilation subtype, if you will,” said Dr. Venkateshiah, assistant professor of medicine at Emory University, Atlanta.
The prevalence of OHS in the general population is unknown, but its prevalence in patients who present for the evaluation of SDB has ranged from 8%-20% across multiple studies, he said. Up to 40% of patients with OHS present for the first time with acute hypercapnic respiratory failure, which has an in-hospital mortality of 18%.
Postmenopausal women appear to have a higher prevalence, compared with premenopausal women and men, he noted, and women appear to be more likely than men to present with the clinical phenotype of OHS without associated OSA.
The arterial blood gas measurement needed to document alveolar hypoventilation and definitively diagnosis OHA is a “simple and economical test,” he said, “but it is logistically very difficult to obtain [these measurements] routinely in all patients in the clinic ... and is one of the reasons why OSH is underdiagnosed.”
Guideline advice
A practice guideline published in 2019 by the American Thoracic Society suggests that, for obese patients with SDB and a low to moderate probability of having OSH, a serum bicarbonate level be measured first. “In patients with serum bicarbonate less than 27 mmol/L, clinicians might forgo measuring PaCO2, as the diagnosis in them is very unlikely,” Dr. Venkateshiah said, referring to the guideline. “In patients with a serum bicarbonate greater than 27, you might need to measure PaCO2 to confirm or rule out the diagnosis of OHS.”
(Patients strongly suspected of having OHS, with more than a low to moderate probability – those in whom arterial blood gases should be measured – are “usually severely obese with typical signs and symptoms such as dyspnea, nocturia, lower-extremity edema, excessive daytime sleepiness, fatigue, loud disruptive snoring, witnessed apneas, as well as mild hypoxemia during wake and/or significant hypoxemia during sleep,” the ATS guideline says.)
The guideline panel considered the use of oxygen saturation measured with pulse oximetry during wakefulness to screen for OHS and decided to advise against it because of the paucity of evidence-based literature, Dr. Venkateshiah noted. (In making its five conditional recommendations, the guideline panel cited an overall very low quality of evidence.)
Symptoms of OHS overlap with those of OSA (for example, daytime hypersomnolence, witnessed apneas, loud snoring, and morning headaches), so “symptoms alone cannot be used to discriminate between the two disorders,” he advised. Signs of OHS commonly seen in clinical exams, however, are low resting daytime oxygen saturations and lower-extremity edema. A sleep study, he added, is needed to document and characterize SDB in patients with OHS.
Positive airway pressure therapy is the first-line treatment for OHS, and long-term outcomes of patients with OHS on PAP treatment are significantly better, compared with untreated individuals. There is no strong evidence to recommend one form of PAP therapy over another for patients with OHS and concomitant severe OSA, he said, but “the bottom line” from both short- and long-term randomized clinical trials comparing CPAP with noninvasive ventilation “is that CPAP is equivalent to noninvasive ventilation as far as outcomes are concerned.”
The ATS guideline panel recommends continuous positive airway pressure therapy for patients with OHS and severe OSA. And for OHS with nonsevere OSA, bilevel PAP is traditionally used – including pure hypoventilators, Dr. Venkateshiah said.
Weight-loss interventions are paramount, since “the primary driver of OHS is obesity,” he said at the meeting. There are only a few studies that have looked at bariatric surgery in patients with OHS, he said, “but they did note significant improvements in gas exchange, sleep apnea, lung volumes and pulmonary hypertension.”
The ATS guideline suggests weight-loss interventions that produce sustained weight loss of 25%-30% of the actual body weight. Such interventions are “most likely required to achieve resolution of hypoventilation,” Dr. Venkateshiah said.
OHS vs. COPD
In a separate presentation on OHS, Michelle Cao, DO, clinical associate professor at Stanford (Calif.) University, emphasized the importance of distinguishing the patient with OHS from the patient with hypercapnic chronic obstructive pulmonary disease (COPD). Spirometry and the flow volume curve can help rule out hypercapnic COPD and other conditions that cause daytime hypoventilation.
A study published in 2016 of 600 hospitalized patients determined to have unequivocal OHS found that 43% had been misdiagnosed as having COPD and none had been previously diagnosed with OHS, Dr. Cao noted. Patients in the study had a mean age of 58 and a mean body mass index of 48.2 kg/m2; 64% were women.
Dr. Venkateshiah and Dr. Cao had no relevant disclosures.
Obesity hypoventilation syndrome (OHS) is bound to be increasing because of the rising obesity epidemic but is underrecognized and “frequently underdiagnosed,” Saiprakash B. Venkateshiah, MD, said at the virtual annual meeting of the Associated Professional Sleep Societies.
The condition, which can cause significant morbidity and mortality, is defined by the combination of obesity and awake alveolar hypoventilation (PaCO2 ≥45 mm Hg), with the exclusion of alternate causes of hypoventilation. Sleep-disordered breathing (SDB) is almost universally present, with approximately 90% of individuals with OHS also having obstructive sleep apnea (OSA), most often severe, and approximately 10% having sleep-related hypoventilation, or a “pure hypoventilation subtype, if you will,” said Dr. Venkateshiah, assistant professor of medicine at Emory University, Atlanta.
The prevalence of OHS in the general population is unknown, but its prevalence in patients who present for the evaluation of SDB has ranged from 8%-20% across multiple studies, he said. Up to 40% of patients with OHS present for the first time with acute hypercapnic respiratory failure, which has an in-hospital mortality of 18%.
Postmenopausal women appear to have a higher prevalence, compared with premenopausal women and men, he noted, and women appear to be more likely than men to present with the clinical phenotype of OHS without associated OSA.
The arterial blood gas measurement needed to document alveolar hypoventilation and definitively diagnosis OHA is a “simple and economical test,” he said, “but it is logistically very difficult to obtain [these measurements] routinely in all patients in the clinic ... and is one of the reasons why OSH is underdiagnosed.”
Guideline advice
A practice guideline published in 2019 by the American Thoracic Society suggests that, for obese patients with SDB and a low to moderate probability of having OSH, a serum bicarbonate level be measured first. “In patients with serum bicarbonate less than 27 mmol/L, clinicians might forgo measuring PaCO2, as the diagnosis in them is very unlikely,” Dr. Venkateshiah said, referring to the guideline. “In patients with a serum bicarbonate greater than 27, you might need to measure PaCO2 to confirm or rule out the diagnosis of OHS.”
(Patients strongly suspected of having OHS, with more than a low to moderate probability – those in whom arterial blood gases should be measured – are “usually severely obese with typical signs and symptoms such as dyspnea, nocturia, lower-extremity edema, excessive daytime sleepiness, fatigue, loud disruptive snoring, witnessed apneas, as well as mild hypoxemia during wake and/or significant hypoxemia during sleep,” the ATS guideline says.)
The guideline panel considered the use of oxygen saturation measured with pulse oximetry during wakefulness to screen for OHS and decided to advise against it because of the paucity of evidence-based literature, Dr. Venkateshiah noted. (In making its five conditional recommendations, the guideline panel cited an overall very low quality of evidence.)
Symptoms of OHS overlap with those of OSA (for example, daytime hypersomnolence, witnessed apneas, loud snoring, and morning headaches), so “symptoms alone cannot be used to discriminate between the two disorders,” he advised. Signs of OHS commonly seen in clinical exams, however, are low resting daytime oxygen saturations and lower-extremity edema. A sleep study, he added, is needed to document and characterize SDB in patients with OHS.
Positive airway pressure therapy is the first-line treatment for OHS, and long-term outcomes of patients with OHS on PAP treatment are significantly better, compared with untreated individuals. There is no strong evidence to recommend one form of PAP therapy over another for patients with OHS and concomitant severe OSA, he said, but “the bottom line” from both short- and long-term randomized clinical trials comparing CPAP with noninvasive ventilation “is that CPAP is equivalent to noninvasive ventilation as far as outcomes are concerned.”
The ATS guideline panel recommends continuous positive airway pressure therapy for patients with OHS and severe OSA. And for OHS with nonsevere OSA, bilevel PAP is traditionally used – including pure hypoventilators, Dr. Venkateshiah said.
Weight-loss interventions are paramount, since “the primary driver of OHS is obesity,” he said at the meeting. There are only a few studies that have looked at bariatric surgery in patients with OHS, he said, “but they did note significant improvements in gas exchange, sleep apnea, lung volumes and pulmonary hypertension.”
The ATS guideline suggests weight-loss interventions that produce sustained weight loss of 25%-30% of the actual body weight. Such interventions are “most likely required to achieve resolution of hypoventilation,” Dr. Venkateshiah said.
OHS vs. COPD
In a separate presentation on OHS, Michelle Cao, DO, clinical associate professor at Stanford (Calif.) University, emphasized the importance of distinguishing the patient with OHS from the patient with hypercapnic chronic obstructive pulmonary disease (COPD). Spirometry and the flow volume curve can help rule out hypercapnic COPD and other conditions that cause daytime hypoventilation.
A study published in 2016 of 600 hospitalized patients determined to have unequivocal OHS found that 43% had been misdiagnosed as having COPD and none had been previously diagnosed with OHS, Dr. Cao noted. Patients in the study had a mean age of 58 and a mean body mass index of 48.2 kg/m2; 64% were women.
Dr. Venkateshiah and Dr. Cao had no relevant disclosures.
Obesity hypoventilation syndrome (OHS) is bound to be increasing because of the rising obesity epidemic but is underrecognized and “frequently underdiagnosed,” Saiprakash B. Venkateshiah, MD, said at the virtual annual meeting of the Associated Professional Sleep Societies.
The condition, which can cause significant morbidity and mortality, is defined by the combination of obesity and awake alveolar hypoventilation (PaCO2 ≥45 mm Hg), with the exclusion of alternate causes of hypoventilation. Sleep-disordered breathing (SDB) is almost universally present, with approximately 90% of individuals with OHS also having obstructive sleep apnea (OSA), most often severe, and approximately 10% having sleep-related hypoventilation, or a “pure hypoventilation subtype, if you will,” said Dr. Venkateshiah, assistant professor of medicine at Emory University, Atlanta.
The prevalence of OHS in the general population is unknown, but its prevalence in patients who present for the evaluation of SDB has ranged from 8%-20% across multiple studies, he said. Up to 40% of patients with OHS present for the first time with acute hypercapnic respiratory failure, which has an in-hospital mortality of 18%.
Postmenopausal women appear to have a higher prevalence, compared with premenopausal women and men, he noted, and women appear to be more likely than men to present with the clinical phenotype of OHS without associated OSA.
The arterial blood gas measurement needed to document alveolar hypoventilation and definitively diagnosis OHA is a “simple and economical test,” he said, “but it is logistically very difficult to obtain [these measurements] routinely in all patients in the clinic ... and is one of the reasons why OSH is underdiagnosed.”
Guideline advice
A practice guideline published in 2019 by the American Thoracic Society suggests that, for obese patients with SDB and a low to moderate probability of having OSH, a serum bicarbonate level be measured first. “In patients with serum bicarbonate less than 27 mmol/L, clinicians might forgo measuring PaCO2, as the diagnosis in them is very unlikely,” Dr. Venkateshiah said, referring to the guideline. “In patients with a serum bicarbonate greater than 27, you might need to measure PaCO2 to confirm or rule out the diagnosis of OHS.”
(Patients strongly suspected of having OHS, with more than a low to moderate probability – those in whom arterial blood gases should be measured – are “usually severely obese with typical signs and symptoms such as dyspnea, nocturia, lower-extremity edema, excessive daytime sleepiness, fatigue, loud disruptive snoring, witnessed apneas, as well as mild hypoxemia during wake and/or significant hypoxemia during sleep,” the ATS guideline says.)
The guideline panel considered the use of oxygen saturation measured with pulse oximetry during wakefulness to screen for OHS and decided to advise against it because of the paucity of evidence-based literature, Dr. Venkateshiah noted. (In making its five conditional recommendations, the guideline panel cited an overall very low quality of evidence.)
Symptoms of OHS overlap with those of OSA (for example, daytime hypersomnolence, witnessed apneas, loud snoring, and morning headaches), so “symptoms alone cannot be used to discriminate between the two disorders,” he advised. Signs of OHS commonly seen in clinical exams, however, are low resting daytime oxygen saturations and lower-extremity edema. A sleep study, he added, is needed to document and characterize SDB in patients with OHS.
Positive airway pressure therapy is the first-line treatment for OHS, and long-term outcomes of patients with OHS on PAP treatment are significantly better, compared with untreated individuals. There is no strong evidence to recommend one form of PAP therapy over another for patients with OHS and concomitant severe OSA, he said, but “the bottom line” from both short- and long-term randomized clinical trials comparing CPAP with noninvasive ventilation “is that CPAP is equivalent to noninvasive ventilation as far as outcomes are concerned.”
The ATS guideline panel recommends continuous positive airway pressure therapy for patients with OHS and severe OSA. And for OHS with nonsevere OSA, bilevel PAP is traditionally used – including pure hypoventilators, Dr. Venkateshiah said.
Weight-loss interventions are paramount, since “the primary driver of OHS is obesity,” he said at the meeting. There are only a few studies that have looked at bariatric surgery in patients with OHS, he said, “but they did note significant improvements in gas exchange, sleep apnea, lung volumes and pulmonary hypertension.”
The ATS guideline suggests weight-loss interventions that produce sustained weight loss of 25%-30% of the actual body weight. Such interventions are “most likely required to achieve resolution of hypoventilation,” Dr. Venkateshiah said.
OHS vs. COPD
In a separate presentation on OHS, Michelle Cao, DO, clinical associate professor at Stanford (Calif.) University, emphasized the importance of distinguishing the patient with OHS from the patient with hypercapnic chronic obstructive pulmonary disease (COPD). Spirometry and the flow volume curve can help rule out hypercapnic COPD and other conditions that cause daytime hypoventilation.
A study published in 2016 of 600 hospitalized patients determined to have unequivocal OHS found that 43% had been misdiagnosed as having COPD and none had been previously diagnosed with OHS, Dr. Cao noted. Patients in the study had a mean age of 58 and a mean body mass index of 48.2 kg/m2; 64% were women.
Dr. Venkateshiah and Dr. Cao had no relevant disclosures.
FROM SLEEP 2021
Hotspotting does not reduce readmissions
Background: In the United States, 5% of the population use half of the annual spending for health care services and 1% account for approximately a quarter of annual spending, considered “superutilizers” of U.S. health care services. The Camden Coalition of Healthcare Providers (the Coalition) developed a model using hospital admission data to identify superutilizers, termed “hotspotting,” which has gained national recognition. Unlike other similar programs, this model targets a more diverse population with higher utilization than other programs that have been studied.
Study design: Randomized, controlled trial.
Setting: Two hospitals in Camden, N.J., from June 2, 2014, to March 31, 2018.
Synopsis: Eight-hundred superutilizers (at least one hospital admission at any of the four Camden-area hospital systems in the past 6 months, greater than one chronic medical condition, more than one high-risk traits/conditions) were randomly assigned to the intervention group or usual care. Once enrolled in the hospital, a multidisciplinary team began working with the patient in the intervention group on discharge. Team members conducted home visits, scheduled/took patients to appointments, managed medications, monitored and coached patients in disease-specific self-care, and assisted with applying for social and other assistive programs.
The readmission rate within 180 days after hospital discharge (primary outcome) between groups was not significant, with 62.3% readmitted in the intervention group and 61.7% in the control group. There was also no effect on the defined secondary outcomes (number of readmissions, proportion of patients with more than two readmissions, hospital days, charges, payments received, mortality).
The trial was not powered to detect smaller reductions in readmissions or to analyze effects within specific subgroups.
Bottom line: The addition of the Coalition’s program to patients with very high use of health care services did not decrease hospital readmission rate when compared to usual care.
Citation: Finkelstein A et al. Health care hotspotting – a randomized, controlled trial. N Engl J Med. 2020;382:152-62.
Dr. Trammell-Velasquez is a hospitalist and associate professor of medicine at University of Texas Health, San Antonio.
Background: In the United States, 5% of the population use half of the annual spending for health care services and 1% account for approximately a quarter of annual spending, considered “superutilizers” of U.S. health care services. The Camden Coalition of Healthcare Providers (the Coalition) developed a model using hospital admission data to identify superutilizers, termed “hotspotting,” which has gained national recognition. Unlike other similar programs, this model targets a more diverse population with higher utilization than other programs that have been studied.
Study design: Randomized, controlled trial.
Setting: Two hospitals in Camden, N.J., from June 2, 2014, to March 31, 2018.
Synopsis: Eight-hundred superutilizers (at least one hospital admission at any of the four Camden-area hospital systems in the past 6 months, greater than one chronic medical condition, more than one high-risk traits/conditions) were randomly assigned to the intervention group or usual care. Once enrolled in the hospital, a multidisciplinary team began working with the patient in the intervention group on discharge. Team members conducted home visits, scheduled/took patients to appointments, managed medications, monitored and coached patients in disease-specific self-care, and assisted with applying for social and other assistive programs.
The readmission rate within 180 days after hospital discharge (primary outcome) between groups was not significant, with 62.3% readmitted in the intervention group and 61.7% in the control group. There was also no effect on the defined secondary outcomes (number of readmissions, proportion of patients with more than two readmissions, hospital days, charges, payments received, mortality).
The trial was not powered to detect smaller reductions in readmissions or to analyze effects within specific subgroups.
Bottom line: The addition of the Coalition’s program to patients with very high use of health care services did not decrease hospital readmission rate when compared to usual care.
Citation: Finkelstein A et al. Health care hotspotting – a randomized, controlled trial. N Engl J Med. 2020;382:152-62.
Dr. Trammell-Velasquez is a hospitalist and associate professor of medicine at University of Texas Health, San Antonio.
Background: In the United States, 5% of the population use half of the annual spending for health care services and 1% account for approximately a quarter of annual spending, considered “superutilizers” of U.S. health care services. The Camden Coalition of Healthcare Providers (the Coalition) developed a model using hospital admission data to identify superutilizers, termed “hotspotting,” which has gained national recognition. Unlike other similar programs, this model targets a more diverse population with higher utilization than other programs that have been studied.
Study design: Randomized, controlled trial.
Setting: Two hospitals in Camden, N.J., from June 2, 2014, to March 31, 2018.
Synopsis: Eight-hundred superutilizers (at least one hospital admission at any of the four Camden-area hospital systems in the past 6 months, greater than one chronic medical condition, more than one high-risk traits/conditions) were randomly assigned to the intervention group or usual care. Once enrolled in the hospital, a multidisciplinary team began working with the patient in the intervention group on discharge. Team members conducted home visits, scheduled/took patients to appointments, managed medications, monitored and coached patients in disease-specific self-care, and assisted with applying for social and other assistive programs.
The readmission rate within 180 days after hospital discharge (primary outcome) between groups was not significant, with 62.3% readmitted in the intervention group and 61.7% in the control group. There was also no effect on the defined secondary outcomes (number of readmissions, proportion of patients with more than two readmissions, hospital days, charges, payments received, mortality).
The trial was not powered to detect smaller reductions in readmissions or to analyze effects within specific subgroups.
Bottom line: The addition of the Coalition’s program to patients with very high use of health care services did not decrease hospital readmission rate when compared to usual care.
Citation: Finkelstein A et al. Health care hotspotting – a randomized, controlled trial. N Engl J Med. 2020;382:152-62.
Dr. Trammell-Velasquez is a hospitalist and associate professor of medicine at University of Texas Health, San Antonio.