Richard Mark Kirkner

Obstructive sleep apnea is becoming more common in children and adolescents as the prevalence of obesity increases, but it may also be a preventable risk factor for cardiovascular disease, according to a new scientific statement from the American Heart Association.

The statement focuses on the links between OSA and CVD risk factors in children and adolescents, and reviews diagnostic strategies and treatments. The writing committee reported that 1%-6% of children and adolescents have OSA, as do up to 60% of adolescents considered obese.

The statement was created by the AHA’s Atherosclerosis, Hypertension, and Obesity in the Young subcommittee of the Council on Cardiovascular Disease in the Young and was published online in the Journal of the American Heart Association.

Carissa M. Baker-Smith, MD, chair of the writing group chair and director of pediatric preventive cardiology at Nemours Cardiac Center, Alfred I. duPont Hospital for Children, Wilmington, Del., explained the rationale for issuing the statement at this time, noting that the relationship between OSA and CVD in adults is well documented.

“There has been less focus on the importance of recognizing and treating sleep apnea in youth,” she said in an interview. “Thus, we felt that it was vitally important to get the word out to parents and to providers that paying attention to the quality and duration of your child’s sleep is vitally important to a child’s long-term heart health. Risk factors for heart disease, when present in childhood, can persist into adulthood.”
 

Clarity on polysomnography

For making the diagnosis of OSA in children, the statement provides clarity on the use of polysomnography and the role of the apnea-hypopnea index, which is lower in children with OSA than in adults. “One controversy, or at least as I saw it, was whether or not polysomnography testing is always required to make the diagnosis of OSA and before proceeding with tonsil and adenoid removal among children for whom enlarged tonsils and adenoids are present,” Dr. Baker-Smith said. “Polysomnography testing is not always needed before an ear, nose, and throat surgeon may recommend surgery.”

The statement also noted that history and physical examination may not yield enough reliable information to distinguish OSA from snoring.

In areas where sleep laboratories that work with children aren’t available, alternative tests such as daytime nap polysomnography, nocturnal oximetry, and nocturnal video recording may be used – with a caveat. “These alternative tests have weaker positive and negative predictive values when compared with polysomnography,” the writing committee noted. Home sleep apnea tests aren’t recommended in children. Questionnaires “are useful as screening, but not as diagnostic tools.”

Pediatric patients being evaluated for OSA should also be screened for hypertension and metabolic syndrome, as well as central nervous system and behavioral disorders. Diagnosing OSA in children and adolescents requires “a high index of suspicion,” the committee wrote.

Pediatricians and pediatric cardiologists should exercise that high index of suspicion when receiving referrals for cardiac evaluations for attention deficit hyperactivity disorder medication, Dr. Baker-Smith said. “Take the time to ask about a child’s sleep – snoring, apnea, etc. – especially if the child has obesity, difficulty focusing during the day, and if there is evidence of systemic hypertension or other signs of metabolic syndrome,” she said.

Risk factors for OSA in children

The statement also reviewed risk factors for OSA, among them obesity, particularly among children younger than 6 years. Other risk factors include upper and lower airway disease, hypotonia, parental history of hyperplasia of the adenoids and tonsils, craniofacial malformations, and neuromuscular disorders. However, the committee cited “limited data” to support that children with congenital heart disease may be at greater risk for OSA and sleep-disordered breathing (SDB).

Black children are at significantly greater risk, and socioeconomic factors “may be potential confounders,” the committee stated. Other risk factors include allergic rhinitis and sickle cell disease.

But the statement underscores that “obesity is the main risk factor” for OSA in children and adolescents, and that the presence of increased inflammation may explain this relationship. Steroids may alleviate these symptoms, even in nonobese children, and removal of the adenoids or tonsils is an option to reduce inflammation in children with OSA.

“Obesity is a significant risk factor for sleep disturbances and obstructive sleep apnea, and the severity of sleep apnea may be improved by weight-loss interventions, which then improves metabolic syndrome factors such as insulin sensitivity,” Dr. Baker-Smith said. “We need to increase awareness about how the rising prevalence of obesity may be impacting sleep quality in kids and recognize sleep-disordered breathing as something that could contribute to risks for hypertension and later cardiovascular disease.”

Children in whom OSA is suspected should also undergo screening for metabolic syndrome, and central nervous system and behavioral disorders.
 

Cardiovascular risks

The statement explores the connection between cardiovascular complications and SDB and OSA in depth.

“Inadequate sleep duration of < 5 hours per night in children and adolescents has been linked to an increased risk of hypertension and is also associated with an increased prevalence of obesity,” the committee wrote.

However, the statement left one question hanging: whether OSA alone or obesity cause higher BP in younger patients with OSA. But the committee concluded that BP levels increase with the severity of OSA, although the effects can vary with age. OSA in children peaks between ages 2 and 8, corresponding to the peak prevalence of hypertrophy of the tonsils and adenoids. Children aged 10-11 with more severe OSA may have BP dysregulation, while older adolescents develop higher sustained BP. Obesity may be a confounder for daytime BP elevations, while nighttime hypertension depends less on obesity and more on OSA severity.

“OSA is associated with abnormal BP in youth and, in particular, higher nighttime blood pressures and loss of the normal decline in BP that should occur during sleep,” Dr. Baker-Smith said. “Children with OSA appear to have higher BP than controls during both sleep and wake times, and BP levels increase with increasing severity of OSA.”

Nonetheless, children with OSA are at greater risk for other cardiovascular problems. Left ventricular hypertrophy may be a secondary outcome. “The presence of obstructive sleep apnea in children is associated with an 11-fold increased risk for LVH in children, a relationship not seen in the presence of primary snoring alone,” Dr. Baker-Smith said.

Dr. Baker-Smith had no relevant disclosures. Coauthor Amal Isaiah, MD, is coinventor of an imaging system for sleep apnea and receives royalties from the University of Maryland. The other coauthors have no relevant financial relationships to disclose.

[email protected]

Obstructive sleep apnea is becoming more common in children and adolescents as the prevalence of obesity increases, but it may also be a preventable risk factor for cardiovascular disease, according to a new scientific statement from the American Heart Association.

The statement focuses on the links between OSA and CVD risk factors in children and adolescents, and reviews diagnostic strategies and treatments. The writing committee reported that 1%-6% of children and adolescents have OSA, as do up to 60% of adolescents considered obese.

The statement was created by the AHA’s Atherosclerosis, Hypertension, and Obesity in the Young subcommittee of the Council on Cardiovascular Disease in the Young and was published online in the Journal of the American Heart Association.

Carissa M. Baker-Smith, MD, chair of the writing group chair and director of pediatric preventive cardiology at Nemours Cardiac Center, Alfred I. duPont Hospital for Children, Wilmington, Del., explained the rationale for issuing the statement at this time, noting that the relationship between OSA and CVD in adults is well documented.

“There has been less focus on the importance of recognizing and treating sleep apnea in youth,” she said in an interview. “Thus, we felt that it was vitally important to get the word out to parents and to providers that paying attention to the quality and duration of your child’s sleep is vitally important to a child’s long-term heart health. Risk factors for heart disease, when present in childhood, can persist into adulthood.”
 

Clarity on polysomnography

For making the diagnosis of OSA in children, the statement provides clarity on the use of polysomnography and the role of the apnea-hypopnea index, which is lower in children with OSA than in adults. “One controversy, or at least as I saw it, was whether or not polysomnography testing is always required to make the diagnosis of OSA and before proceeding with tonsil and adenoid removal among children for whom enlarged tonsils and adenoids are present,” Dr. Baker-Smith said. “Polysomnography testing is not always needed before an ear, nose, and throat surgeon may recommend surgery.”

The statement also noted that history and physical examination may not yield enough reliable information to distinguish OSA from snoring.

In areas where sleep laboratories that work with children aren’t available, alternative tests such as daytime nap polysomnography, nocturnal oximetry, and nocturnal video recording may be used – with a caveat. “These alternative tests have weaker positive and negative predictive values when compared with polysomnography,” the writing committee noted. Home sleep apnea tests aren’t recommended in children. Questionnaires “are useful as screening, but not as diagnostic tools.”

Pediatric patients being evaluated for OSA should also be screened for hypertension and metabolic syndrome, as well as central nervous system and behavioral disorders. Diagnosing OSA in children and adolescents requires “a high index of suspicion,” the committee wrote.

Pediatricians and pediatric cardiologists should exercise that high index of suspicion when receiving referrals for cardiac evaluations for attention deficit hyperactivity disorder medication, Dr. Baker-Smith said. “Take the time to ask about a child’s sleep – snoring, apnea, etc. – especially if the child has obesity, difficulty focusing during the day, and if there is evidence of systemic hypertension or other signs of metabolic syndrome,” she said.

Risk factors for OSA in children

The statement also reviewed risk factors for OSA, among them obesity, particularly among children younger than 6 years. Other risk factors include upper and lower airway disease, hypotonia, parental history of hyperplasia of the adenoids and tonsils, craniofacial malformations, and neuromuscular disorders. However, the committee cited “limited data” to support that children with congenital heart disease may be at greater risk for OSA and sleep-disordered breathing (SDB).

Black children are at significantly greater risk, and socioeconomic factors “may be potential confounders,” the committee stated. Other risk factors include allergic rhinitis and sickle cell disease.

But the statement underscores that “obesity is the main risk factor” for OSA in children and adolescents, and that the presence of increased inflammation may explain this relationship. Steroids may alleviate these symptoms, even in nonobese children, and removal of the adenoids or tonsils is an option to reduce inflammation in children with OSA.

“Obesity is a significant risk factor for sleep disturbances and obstructive sleep apnea, and the severity of sleep apnea may be improved by weight-loss interventions, which then improves metabolic syndrome factors such as insulin sensitivity,” Dr. Baker-Smith said. “We need to increase awareness about how the rising prevalence of obesity may be impacting sleep quality in kids and recognize sleep-disordered breathing as something that could contribute to risks for hypertension and later cardiovascular disease.”

Children in whom OSA is suspected should also undergo screening for metabolic syndrome, and central nervous system and behavioral disorders.
 

Cardiovascular risks

The statement explores the connection between cardiovascular complications and SDB and OSA in depth.

“Inadequate sleep duration of < 5 hours per night in children and adolescents has been linked to an increased risk of hypertension and is also associated with an increased prevalence of obesity,” the committee wrote.

However, the statement left one question hanging: whether OSA alone or obesity cause higher BP in younger patients with OSA. But the committee concluded that BP levels increase with the severity of OSA, although the effects can vary with age. OSA in children peaks between ages 2 and 8, corresponding to the peak prevalence of hypertrophy of the tonsils and adenoids. Children aged 10-11 with more severe OSA may have BP dysregulation, while older adolescents develop higher sustained BP. Obesity may be a confounder for daytime BP elevations, while nighttime hypertension depends less on obesity and more on OSA severity.

“OSA is associated with abnormal BP in youth and, in particular, higher nighttime blood pressures and loss of the normal decline in BP that should occur during sleep,” Dr. Baker-Smith said. “Children with OSA appear to have higher BP than controls during both sleep and wake times, and BP levels increase with increasing severity of OSA.”

Nonetheless, children with OSA are at greater risk for other cardiovascular problems. Left ventricular hypertrophy may be a secondary outcome. “The presence of obstructive sleep apnea in children is associated with an 11-fold increased risk for LVH in children, a relationship not seen in the presence of primary snoring alone,” Dr. Baker-Smith said.

Dr. Baker-Smith had no relevant disclosures. Coauthor Amal Isaiah, MD, is coinventor of an imaging system for sleep apnea and receives royalties from the University of Maryland. The other coauthors have no relevant financial relationships to disclose.

[email protected]

Obstructive sleep apnea is becoming more common in children and adolescents as the prevalence of obesity increases, but it may also be a preventable risk factor for cardiovascular disease, according to a new scientific statement from the American Heart Association.

The statement focuses on the links between OSA and CVD risk factors in children and adolescents, and reviews diagnostic strategies and treatments. The writing committee reported that 1%-6% of children and adolescents have OSA, as do up to 60% of adolescents considered obese.

The statement was created by the AHA’s Atherosclerosis, Hypertension, and Obesity in the Young subcommittee of the Council on Cardiovascular Disease in the Young and was published online in the Journal of the American Heart Association.

Carissa M. Baker-Smith, MD, chair of the writing group chair and director of pediatric preventive cardiology at Nemours Cardiac Center, Alfred I. duPont Hospital for Children, Wilmington, Del., explained the rationale for issuing the statement at this time, noting that the relationship between OSA and CVD in adults is well documented.

“There has been less focus on the importance of recognizing and treating sleep apnea in youth,” she said in an interview. “Thus, we felt that it was vitally important to get the word out to parents and to providers that paying attention to the quality and duration of your child’s sleep is vitally important to a child’s long-term heart health. Risk factors for heart disease, when present in childhood, can persist into adulthood.”
 

Clarity on polysomnography

For making the diagnosis of OSA in children, the statement provides clarity on the use of polysomnography and the role of the apnea-hypopnea index, which is lower in children with OSA than in adults. “One controversy, or at least as I saw it, was whether or not polysomnography testing is always required to make the diagnosis of OSA and before proceeding with tonsil and adenoid removal among children for whom enlarged tonsils and adenoids are present,” Dr. Baker-Smith said. “Polysomnography testing is not always needed before an ear, nose, and throat surgeon may recommend surgery.”

The statement also noted that history and physical examination may not yield enough reliable information to distinguish OSA from snoring.

In areas where sleep laboratories that work with children aren’t available, alternative tests such as daytime nap polysomnography, nocturnal oximetry, and nocturnal video recording may be used – with a caveat. “These alternative tests have weaker positive and negative predictive values when compared with polysomnography,” the writing committee noted. Home sleep apnea tests aren’t recommended in children. Questionnaires “are useful as screening, but not as diagnostic tools.”

Pediatric patients being evaluated for OSA should also be screened for hypertension and metabolic syndrome, as well as central nervous system and behavioral disorders. Diagnosing OSA in children and adolescents requires “a high index of suspicion,” the committee wrote.

Pediatricians and pediatric cardiologists should exercise that high index of suspicion when receiving referrals for cardiac evaluations for attention deficit hyperactivity disorder medication, Dr. Baker-Smith said. “Take the time to ask about a child’s sleep – snoring, apnea, etc. – especially if the child has obesity, difficulty focusing during the day, and if there is evidence of systemic hypertension or other signs of metabolic syndrome,” she said.

Risk factors for OSA in children

The statement also reviewed risk factors for OSA, among them obesity, particularly among children younger than 6 years. Other risk factors include upper and lower airway disease, hypotonia, parental history of hyperplasia of the adenoids and tonsils, craniofacial malformations, and neuromuscular disorders. However, the committee cited “limited data” to support that children with congenital heart disease may be at greater risk for OSA and sleep-disordered breathing (SDB).

Black children are at significantly greater risk, and socioeconomic factors “may be potential confounders,” the committee stated. Other risk factors include allergic rhinitis and sickle cell disease.

But the statement underscores that “obesity is the main risk factor” for OSA in children and adolescents, and that the presence of increased inflammation may explain this relationship. Steroids may alleviate these symptoms, even in nonobese children, and removal of the adenoids or tonsils is an option to reduce inflammation in children with OSA.

“Obesity is a significant risk factor for sleep disturbances and obstructive sleep apnea, and the severity of sleep apnea may be improved by weight-loss interventions, which then improves metabolic syndrome factors such as insulin sensitivity,” Dr. Baker-Smith said. “We need to increase awareness about how the rising prevalence of obesity may be impacting sleep quality in kids and recognize sleep-disordered breathing as something that could contribute to risks for hypertension and later cardiovascular disease.”

Children in whom OSA is suspected should also undergo screening for metabolic syndrome, and central nervous system and behavioral disorders.
 

Cardiovascular risks

The statement explores the connection between cardiovascular complications and SDB and OSA in depth.

“Inadequate sleep duration of < 5 hours per night in children and adolescents has been linked to an increased risk of hypertension and is also associated with an increased prevalence of obesity,” the committee wrote.

However, the statement left one question hanging: whether OSA alone or obesity cause higher BP in younger patients with OSA. But the committee concluded that BP levels increase with the severity of OSA, although the effects can vary with age. OSA in children peaks between ages 2 and 8, corresponding to the peak prevalence of hypertrophy of the tonsils and adenoids. Children aged 10-11 with more severe OSA may have BP dysregulation, while older adolescents develop higher sustained BP. Obesity may be a confounder for daytime BP elevations, while nighttime hypertension depends less on obesity and more on OSA severity.

“OSA is associated with abnormal BP in youth and, in particular, higher nighttime blood pressures and loss of the normal decline in BP that should occur during sleep,” Dr. Baker-Smith said. “Children with OSA appear to have higher BP than controls during both sleep and wake times, and BP levels increase with increasing severity of OSA.”

Nonetheless, children with OSA are at greater risk for other cardiovascular problems. Left ventricular hypertrophy may be a secondary outcome. “The presence of obstructive sleep apnea in children is associated with an 11-fold increased risk for LVH in children, a relationship not seen in the presence of primary snoring alone,” Dr. Baker-Smith said.

Dr. Baker-Smith had no relevant disclosures. Coauthor Amal Isaiah, MD, is coinventor of an imaging system for sleep apnea and receives royalties from the University of Maryland. The other coauthors have no relevant financial relationships to disclose.

[email protected]

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at [email protected].

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

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at [email protected].

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

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at [email protected].

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

Therapeutic levels of heparin can have widely varying effects on COVID-19 patients depending on the severity of their disease, according to a multiplatform clinical trial that analyzed patient data from three international trials.

NYU Langone Health

COVID-19 patients in the ICU, or at least receiving ICU-level care, derived no benefit from anticoagulation with heparin, while non–critically ill COVID-19 patients – those who were hospitalized but not receiving ICU-level care – on the same anticoagulation were less likely to progress to need respiratory or cardiovascular organ support despite a slightly heightened risk of bleeding events.

Reporting in two articles published online in the New England Journal of Medicine, authors of three international trials combined their data into one multiplatform trial that makes a strong case for prescribing therapeutic levels of heparin in hospitalized patients not receiving ICU-level care were non–critically ill and critically ill.

“I think this is going to be a game changer,” said Jeffrey S. Berger, MD, ACTIV-4a co–principal investigator and co–first author of the study of non–critically ill patients. “I think that using therapeutic-dose anticoagulation should improve outcomes in the tens of thousands of patients worldwide. I hope our data can have a global impact.”
 

Outcomes based on disease severity

The multiplatform trial analyzed data from the Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC); A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4a); and Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP).

The trial evaluated 2,219 non–critically ill hospitalized patients, 1,181 of whom were randomized to therapeutic-dose anticoagulation; and 1,098 critically ill patients, 534 of whom were prescribed therapeutic levels of heparin.

In the critically ill patients, those on heparin were no more likely to get discharged or spend fewer days on respiratory or CV organ support – oxygen, mechanical ventilation, life support, vasopressors or inotropes – than were those on usual-care thromboprophylaxis. The investigators stopped the trial in both patient populations: in critically ill patients when it became obvious therapeutic-dose anticoagulation was having no impact; and in moderately ill patients when the trial met the prespecified criteria for the superiority of therapeutic-dose anticoagulation.

ICU patients on therapeutic-level heparin spent an average of 1 day free of organ support vs. 4 for patients on usual-care prophylactic antithrombotic drugs. The percentage of patients who survived to hospital discharge was similar in the therapeutic-level and usual-care critically ill patients: 62.7% and 64.5%, respectively. Major bleeding occurred in 3.8% and 2.8%, respectively. Demographic and clinical characteristics were similar between both patient groups.

However, in non–critically ill patients, therapeutic levels of heparin resulted in a marked improvement in outcomes. The researchers estimated that, for every 1,000 hospitalized patients with what they labeled moderate disease, an initial treatment with therapeutic-dose heparin resulted in 40 additional patients surviving compared to usual-care thromboprophylaxis.

The percentages of patients not needing organ support before hospital discharge was 80.2% on therapeutic-dose heparin and 76.4% on usual-care therapy. In terms of adjusted odds ratio, the anticoagulation group had a 27% improved chance of not needing daily organ support.

Those improvements came with an additional seven major bleeding events per 1,000 patients. That broke down to a rate of 1.9% in the therapeutic-dose and 0.9% in the usual-care patients.

As the Delta variant of COVID-19 spreads, Patrick R. Lawler, MD, MPH, principal investigator of the ATTACC trial, said there’s no reason these findings shouldn’t apply for all variants of the disease.

University of Toronto

Dr. Lawler, a physician-scientist at Peter Munk Cardiac Centre at Toronto General Hospital, noted that the multiplatform study did not account for disease variant. “Ongoing clinical trials are tracking the variant patients have or the variants that are most prevalent in an area at that time,” he said. “It may be easier in future trials to look at that question.”
 

Explaining heparin’s varying effects

The study did not specifically sort out why moderately ill patients fared better on heparin than their critically ill counterparts, but Dr. Lawler speculated on possible reasons. “One might be that the extent of illness severity is too extreme in the ICU-level population for heparin to have a beneficial extent,” he said.

He acknowledged that higher rates of macrovascular thrombosis, such as venous thromboembolism, in ICU patients would suggest that heparin would have a greater beneficial effect, but, he added, “it may also suggest how advanced that process is, and perhaps heparin is not adequate to reverse the course at that point given relatively extensive thrombosis and associate organ failure.”

As clinicians have gained experience dealing with COVID-19, they’ve learned that infected patients carry a high burden of macro- and microthrombosis, Dr. Berger said, which may explain why critically ill patients didn’t respond as well to therapeutic levels of heparin. “I think the cat is out of the bag; patients who are severe are too ill to benefit,” he said. “I would think there’s too much microthrombosis that is already in their bodies.”

However, this doesn’t completely rule out therapeutic levels of heparin in critically ill COVID-19 patients. There are some scenarios where it’s needed, said Dr. Berger, associate professor of medicine and surgery and director of the Center for the Prevention of Cardiovascular Disease at New York University Langone Health. “Anyone who has a known clot already, like a known macrothrombosis in their leg or lung, needs to be on full-dose heparin,” he said.

That rationale can help reconcile the different outcomes in the critically and non–critically ill COVID-19 patients, wrote Hugo ten Cate, MD, PhD, of Maastricht University in the Netherlands, wrote in an accompanying editorial. But differences in the study populations may also explain the divergent outcomes, Dr. ten Cate noted.

The studies suggest that critically ill patients may need hon-heparin antithrombotic approaches “or even profibrinolytic strategies,” Dr. Cate wrote, and that the safety and effectiveness of thromboprophylaxis “remains an important question.” Nonetheless, he added, treating physicians must deal with the bleeding risk when using heparin or low-molecular-weight heparin in moderately ill COVID-19 patients.

Deepak L. Bhatt MD, MPH, of Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that reconciling the two studies was “a bit challenging,” because effective therapies tend to have a greater impact in sicker patients.

“Of course, with antithrombotic therapies, bleeding side effects can sometimes overwhelm benefits in patients who are at high risk of both bleeding and ischemic complications, though that does not seem to be the explanation here,” Dr. Bhatt said. “I do think we need more data to clarify exactly which COVID patients benefit from various antithrombotic regimens, and fortunately, there are other ongoing studies, some of which will report relatively soon.”

He concurred with Dr. Berger that patients who need anticoagulation should receive it “apart from their COVID status,” Dr. Bhatt said. “Sick, hospitalized patients with or without COVID should receive appropriate prophylactic doses of anticoagulation.” However, he added, “Whether we should routinely go beyond that in COVID-positive inpatients, I think we need more data.”

The ATTACC platform received grants from the Canadian Institutes of Health Research and several other research foundations. The ACTIV-4a platform received funding from the National Heart, Lung, and Blood Institute. REMAP-CAP received funding from the European Union and several international research foundations, as well as Amgen and Eisai.

Dr. Lawler had no relationships to disclose. Dr. Berger disclosed receiving grants from the NHLBI, and financial relationships with AstraZeneca, Janssen, and Amgen outside the submitted work. Dr. ten Cate reported relationships with Alveron, Coagulation Profile, Portola/Alexion, Bayer, Pfizer, Stago, Leo Pharma, Daiichi, and Gilead/Galapagos. Dr. Bhatt is chair of the data safety and monitoring board of the FREEDOM COVID anticoagulation clinical trial.

Therapeutic levels of heparin can have widely varying effects on COVID-19 patients depending on the severity of their disease, according to a multiplatform clinical trial that analyzed patient data from three international trials.

NYU Langone Health

COVID-19 patients in the ICU, or at least receiving ICU-level care, derived no benefit from anticoagulation with heparin, while non–critically ill COVID-19 patients – those who were hospitalized but not receiving ICU-level care – on the same anticoagulation were less likely to progress to need respiratory or cardiovascular organ support despite a slightly heightened risk of bleeding events.

Reporting in two articles published online in the New England Journal of Medicine, authors of three international trials combined their data into one multiplatform trial that makes a strong case for prescribing therapeutic levels of heparin in hospitalized patients not receiving ICU-level care were non–critically ill and critically ill.

“I think this is going to be a game changer,” said Jeffrey S. Berger, MD, ACTIV-4a co–principal investigator and co–first author of the study of non–critically ill patients. “I think that using therapeutic-dose anticoagulation should improve outcomes in the tens of thousands of patients worldwide. I hope our data can have a global impact.”
 

Outcomes based on disease severity

The multiplatform trial analyzed data from the Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC); A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4a); and Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP).

The trial evaluated 2,219 non–critically ill hospitalized patients, 1,181 of whom were randomized to therapeutic-dose anticoagulation; and 1,098 critically ill patients, 534 of whom were prescribed therapeutic levels of heparin.

In the critically ill patients, those on heparin were no more likely to get discharged or spend fewer days on respiratory or CV organ support – oxygen, mechanical ventilation, life support, vasopressors or inotropes – than were those on usual-care thromboprophylaxis. The investigators stopped the trial in both patient populations: in critically ill patients when it became obvious therapeutic-dose anticoagulation was having no impact; and in moderately ill patients when the trial met the prespecified criteria for the superiority of therapeutic-dose anticoagulation.

ICU patients on therapeutic-level heparin spent an average of 1 day free of organ support vs. 4 for patients on usual-care prophylactic antithrombotic drugs. The percentage of patients who survived to hospital discharge was similar in the therapeutic-level and usual-care critically ill patients: 62.7% and 64.5%, respectively. Major bleeding occurred in 3.8% and 2.8%, respectively. Demographic and clinical characteristics were similar between both patient groups.

However, in non–critically ill patients, therapeutic levels of heparin resulted in a marked improvement in outcomes. The researchers estimated that, for every 1,000 hospitalized patients with what they labeled moderate disease, an initial treatment with therapeutic-dose heparin resulted in 40 additional patients surviving compared to usual-care thromboprophylaxis.

The percentages of patients not needing organ support before hospital discharge was 80.2% on therapeutic-dose heparin and 76.4% on usual-care therapy. In terms of adjusted odds ratio, the anticoagulation group had a 27% improved chance of not needing daily organ support.

Those improvements came with an additional seven major bleeding events per 1,000 patients. That broke down to a rate of 1.9% in the therapeutic-dose and 0.9% in the usual-care patients.

As the Delta variant of COVID-19 spreads, Patrick R. Lawler, MD, MPH, principal investigator of the ATTACC trial, said there’s no reason these findings shouldn’t apply for all variants of the disease.

University of Toronto

Dr. Lawler, a physician-scientist at Peter Munk Cardiac Centre at Toronto General Hospital, noted that the multiplatform study did not account for disease variant. “Ongoing clinical trials are tracking the variant patients have or the variants that are most prevalent in an area at that time,” he said. “It may be easier in future trials to look at that question.”
 

Explaining heparin’s varying effects

The study did not specifically sort out why moderately ill patients fared better on heparin than their critically ill counterparts, but Dr. Lawler speculated on possible reasons. “One might be that the extent of illness severity is too extreme in the ICU-level population for heparin to have a beneficial extent,” he said.

He acknowledged that higher rates of macrovascular thrombosis, such as venous thromboembolism, in ICU patients would suggest that heparin would have a greater beneficial effect, but, he added, “it may also suggest how advanced that process is, and perhaps heparin is not adequate to reverse the course at that point given relatively extensive thrombosis and associate organ failure.”

As clinicians have gained experience dealing with COVID-19, they’ve learned that infected patients carry a high burden of macro- and microthrombosis, Dr. Berger said, which may explain why critically ill patients didn’t respond as well to therapeutic levels of heparin. “I think the cat is out of the bag; patients who are severe are too ill to benefit,” he said. “I would think there’s too much microthrombosis that is already in their bodies.”

However, this doesn’t completely rule out therapeutic levels of heparin in critically ill COVID-19 patients. There are some scenarios where it’s needed, said Dr. Berger, associate professor of medicine and surgery and director of the Center for the Prevention of Cardiovascular Disease at New York University Langone Health. “Anyone who has a known clot already, like a known macrothrombosis in their leg or lung, needs to be on full-dose heparin,” he said.

That rationale can help reconcile the different outcomes in the critically and non–critically ill COVID-19 patients, wrote Hugo ten Cate, MD, PhD, of Maastricht University in the Netherlands, wrote in an accompanying editorial. But differences in the study populations may also explain the divergent outcomes, Dr. ten Cate noted.

The studies suggest that critically ill patients may need hon-heparin antithrombotic approaches “or even profibrinolytic strategies,” Dr. Cate wrote, and that the safety and effectiveness of thromboprophylaxis “remains an important question.” Nonetheless, he added, treating physicians must deal with the bleeding risk when using heparin or low-molecular-weight heparin in moderately ill COVID-19 patients.

Deepak L. Bhatt MD, MPH, of Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that reconciling the two studies was “a bit challenging,” because effective therapies tend to have a greater impact in sicker patients.

“Of course, with antithrombotic therapies, bleeding side effects can sometimes overwhelm benefits in patients who are at high risk of both bleeding and ischemic complications, though that does not seem to be the explanation here,” Dr. Bhatt said. “I do think we need more data to clarify exactly which COVID patients benefit from various antithrombotic regimens, and fortunately, there are other ongoing studies, some of which will report relatively soon.”

He concurred with Dr. Berger that patients who need anticoagulation should receive it “apart from their COVID status,” Dr. Bhatt said. “Sick, hospitalized patients with or without COVID should receive appropriate prophylactic doses of anticoagulation.” However, he added, “Whether we should routinely go beyond that in COVID-positive inpatients, I think we need more data.”

The ATTACC platform received grants from the Canadian Institutes of Health Research and several other research foundations. The ACTIV-4a platform received funding from the National Heart, Lung, and Blood Institute. REMAP-CAP received funding from the European Union and several international research foundations, as well as Amgen and Eisai.

Dr. Lawler had no relationships to disclose. Dr. Berger disclosed receiving grants from the NHLBI, and financial relationships with AstraZeneca, Janssen, and Amgen outside the submitted work. Dr. ten Cate reported relationships with Alveron, Coagulation Profile, Portola/Alexion, Bayer, Pfizer, Stago, Leo Pharma, Daiichi, and Gilead/Galapagos. Dr. Bhatt is chair of the data safety and monitoring board of the FREEDOM COVID anticoagulation clinical trial.

Therapeutic levels of heparin can have widely varying effects on COVID-19 patients depending on the severity of their disease, according to a multiplatform clinical trial that analyzed patient data from three international trials.

NYU Langone Health

COVID-19 patients in the ICU, or at least receiving ICU-level care, derived no benefit from anticoagulation with heparin, while non–critically ill COVID-19 patients – those who were hospitalized but not receiving ICU-level care – on the same anticoagulation were less likely to progress to need respiratory or cardiovascular organ support despite a slightly heightened risk of bleeding events.

Reporting in two articles published online in the New England Journal of Medicine, authors of three international trials combined their data into one multiplatform trial that makes a strong case for prescribing therapeutic levels of heparin in hospitalized patients not receiving ICU-level care were non–critically ill and critically ill.

“I think this is going to be a game changer,” said Jeffrey S. Berger, MD, ACTIV-4a co–principal investigator and co–first author of the study of non–critically ill patients. “I think that using therapeutic-dose anticoagulation should improve outcomes in the tens of thousands of patients worldwide. I hope our data can have a global impact.”
 

Outcomes based on disease severity

The multiplatform trial analyzed data from the Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC); A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4a); and Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP).

The trial evaluated 2,219 non–critically ill hospitalized patients, 1,181 of whom were randomized to therapeutic-dose anticoagulation; and 1,098 critically ill patients, 534 of whom were prescribed therapeutic levels of heparin.

In the critically ill patients, those on heparin were no more likely to get discharged or spend fewer days on respiratory or CV organ support – oxygen, mechanical ventilation, life support, vasopressors or inotropes – than were those on usual-care thromboprophylaxis. The investigators stopped the trial in both patient populations: in critically ill patients when it became obvious therapeutic-dose anticoagulation was having no impact; and in moderately ill patients when the trial met the prespecified criteria for the superiority of therapeutic-dose anticoagulation.

ICU patients on therapeutic-level heparin spent an average of 1 day free of organ support vs. 4 for patients on usual-care prophylactic antithrombotic drugs. The percentage of patients who survived to hospital discharge was similar in the therapeutic-level and usual-care critically ill patients: 62.7% and 64.5%, respectively. Major bleeding occurred in 3.8% and 2.8%, respectively. Demographic and clinical characteristics were similar between both patient groups.

However, in non–critically ill patients, therapeutic levels of heparin resulted in a marked improvement in outcomes. The researchers estimated that, for every 1,000 hospitalized patients with what they labeled moderate disease, an initial treatment with therapeutic-dose heparin resulted in 40 additional patients surviving compared to usual-care thromboprophylaxis.

The percentages of patients not needing organ support before hospital discharge was 80.2% on therapeutic-dose heparin and 76.4% on usual-care therapy. In terms of adjusted odds ratio, the anticoagulation group had a 27% improved chance of not needing daily organ support.

Those improvements came with an additional seven major bleeding events per 1,000 patients. That broke down to a rate of 1.9% in the therapeutic-dose and 0.9% in the usual-care patients.

As the Delta variant of COVID-19 spreads, Patrick R. Lawler, MD, MPH, principal investigator of the ATTACC trial, said there’s no reason these findings shouldn’t apply for all variants of the disease.

University of Toronto

Dr. Lawler, a physician-scientist at Peter Munk Cardiac Centre at Toronto General Hospital, noted that the multiplatform study did not account for disease variant. “Ongoing clinical trials are tracking the variant patients have or the variants that are most prevalent in an area at that time,” he said. “It may be easier in future trials to look at that question.”
 

Explaining heparin’s varying effects

The study did not specifically sort out why moderately ill patients fared better on heparin than their critically ill counterparts, but Dr. Lawler speculated on possible reasons. “One might be that the extent of illness severity is too extreme in the ICU-level population for heparin to have a beneficial extent,” he said.

He acknowledged that higher rates of macrovascular thrombosis, such as venous thromboembolism, in ICU patients would suggest that heparin would have a greater beneficial effect, but, he added, “it may also suggest how advanced that process is, and perhaps heparin is not adequate to reverse the course at that point given relatively extensive thrombosis and associate organ failure.”

As clinicians have gained experience dealing with COVID-19, they’ve learned that infected patients carry a high burden of macro- and microthrombosis, Dr. Berger said, which may explain why critically ill patients didn’t respond as well to therapeutic levels of heparin. “I think the cat is out of the bag; patients who are severe are too ill to benefit,” he said. “I would think there’s too much microthrombosis that is already in their bodies.”

However, this doesn’t completely rule out therapeutic levels of heparin in critically ill COVID-19 patients. There are some scenarios where it’s needed, said Dr. Berger, associate professor of medicine and surgery and director of the Center for the Prevention of Cardiovascular Disease at New York University Langone Health. “Anyone who has a known clot already, like a known macrothrombosis in their leg or lung, needs to be on full-dose heparin,” he said.

That rationale can help reconcile the different outcomes in the critically and non–critically ill COVID-19 patients, wrote Hugo ten Cate, MD, PhD, of Maastricht University in the Netherlands, wrote in an accompanying editorial. But differences in the study populations may also explain the divergent outcomes, Dr. ten Cate noted.

The studies suggest that critically ill patients may need hon-heparin antithrombotic approaches “or even profibrinolytic strategies,” Dr. Cate wrote, and that the safety and effectiveness of thromboprophylaxis “remains an important question.” Nonetheless, he added, treating physicians must deal with the bleeding risk when using heparin or low-molecular-weight heparin in moderately ill COVID-19 patients.

Deepak L. Bhatt MD, MPH, of Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that reconciling the two studies was “a bit challenging,” because effective therapies tend to have a greater impact in sicker patients.

“Of course, with antithrombotic therapies, bleeding side effects can sometimes overwhelm benefits in patients who are at high risk of both bleeding and ischemic complications, though that does not seem to be the explanation here,” Dr. Bhatt said. “I do think we need more data to clarify exactly which COVID patients benefit from various antithrombotic regimens, and fortunately, there are other ongoing studies, some of which will report relatively soon.”

He concurred with Dr. Berger that patients who need anticoagulation should receive it “apart from their COVID status,” Dr. Bhatt said. “Sick, hospitalized patients with or without COVID should receive appropriate prophylactic doses of anticoagulation.” However, he added, “Whether we should routinely go beyond that in COVID-positive inpatients, I think we need more data.”

The ATTACC platform received grants from the Canadian Institutes of Health Research and several other research foundations. The ACTIV-4a platform received funding from the National Heart, Lung, and Blood Institute. REMAP-CAP received funding from the European Union and several international research foundations, as well as Amgen and Eisai.

Dr. Lawler had no relationships to disclose. Dr. Berger disclosed receiving grants from the NHLBI, and financial relationships with AstraZeneca, Janssen, and Amgen outside the submitted work. Dr. ten Cate reported relationships with Alveron, Coagulation Profile, Portola/Alexion, Bayer, Pfizer, Stago, Leo Pharma, Daiichi, and Gilead/Galapagos. Dr. Bhatt is chair of the data safety and monitoring board of the FREEDOM COVID anticoagulation clinical trial.

A blood test that uses a patient’s unique genetic signature has shown some ability to predict nonresponse to tumor necrosis factor inhibitors as treatment for rheumatoid arthritis, an observational clinical study has found, but the test’s predictive accuracy was well below 100%.

The test is the blood-based molecular signature response classifier (MSRC) that uses RNA sequencing data based on 23 different biomarkers: 19 RNA transcripts and 4 clinical features. The clinical features are body mass index, gender, patient global assessment, and anticyclic citrullinated protein (anti-CCP) status.

The NETWORK-004 study, published in Rheumatology and Therapy, was able to stratify patients who were likely to respond inadequately to TNFi therapy and could provide patient-specific information to guide therapy choice in RA patients regardless of whether they’ve already been on TNFi therapy. The study evaluated the MSRC test in 504 patients, 391 of whom were treatment naive.
 

Avoiding ‘fail first’ approach

The idea behind the test is to circumvent the “fail first” approach in finding the right therapy for RA in an individual patient. While the test costs $4,995, Alif Saleh, chief executive officer of Scipher Medicine, which markets the test under the name PrismRA, said in a press release that it has the potential to reduce costs by $19,000 or more per patient per year by avoiding treatments that don’t work. A previous study, which Scipher funded, reported that the test resulted in savings of $7,379 in per-patient costs of ineffective therapy. The same study reported a 25% decrease in costs for ineffective treatments for Medicare-eligible patients.

The price of RA drugs, particularly anti-TNF agents, is hefty and rising. GoodRx has reported that the price of RA drugs increased 92% from 2014 to 2019, and the prices for anti-TNF agents such as etanercept and adalimumab more than doubled in that period. Adalimumab can cost upwards of $84,000 per year while etanercept has a list price of around $72,000 a year. The pharmacy benefit manager WellDyne started covering the test MSRC in February.

Nehad Soloman, MD, a rheumatologist and internist at Midwestern University Arizona College of Osteopathic Medicine in Glendale and a compensated NETWORK-004 investigator, said the MSRC test would be indicated for confirmed RA patients for whom rheumatologists are considering biologic agents, particularly TNFi drugs. “You wouldn’t do it on an RA patient who’s been on several different medications because it doesn’t serve a purpose at that point,” he said.

The potential cost savings may not be the only reason to use the test, Dr. Soloman said. “You don’t want to be dabbling with the wrong drug if there’s another path you can try and save society some money as well as the time and energy it takes to monitor the patients – as well as the patient’s pain,” he said.
 

How the MSRC test works

The MSRC test detects a signal that’s associated with a high or very high likelihood of inadequate response to TNFi therapies and indicates that the patient is unlikely to achieve low disease activity or remission with TNFi therapies. Response is defined as achieving ACR50 – meaning 50% improvement in American College of Rheumatology response criteria – at 6 months.

Test results are reported on a continuous 1-25 scale, explained Slava Akmaev, PhD, chief technology officer and head of therapeutics at Scipher. “The higher the score, the more likely the patient will have an inadequate response to TNFi therapies and be unable to reach low disease activity; the lower the score, the less likely the patient will have an inadequate response to TNFi therapies,” he said. However, Dr. Akmaev noted that a low score does not ensure a positive response to TNFi therapies.

The MSRC test differs from the multibiomarker disease activity blood test (MBDA; marketed as Vectra by Myriad Genetics) in the number of biomarkers it measures: 19 RNA transcripts vs. 12 serum protein biomarkers in MBDA. The MBDA test is also intended to provide a quantitative, objective measurement of RA disease activity rather than to predict nonresponse to TNFi or other biologics. A number of studies have validated the MBDA test for predicting disease control in RA patients, but not necessarily response to TNFi therapy.

The “high” category threshold of the MSRC test corresponds to an approximate 90% chance of inadequate response to TNFi therapy, or a 10% chance of responding. The “very high” category threshold corresponds to an approximate 95% chance of inadequate response to TNFi therapy, Dr. Akmaev said.

NETWORK-004 used area under the curve (AUC) to measure the accuracy of the MSRC test. An AUC of 1 represents 100% accuracy. Overall, the MSRC had an AUC of 0.64, or 64% accuracy of predicting patients unlikely to respond to TNFi therapy and to achieve ACR50 at 6 months, with an odds ratio of 4.1 (95% confidence interval, 2.0-8.3; P = .0001).

The predictive accuracy went up to 74% with ORs of 3.4-8.8 for additional endpoints at 3 and 6 months (P < .01). Among patients who had already been on TNFi therapy, the predictive accuracy was 83% and associated with ORs of 3.3-26.6 based on ACR, 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), and Clinical Disease Activity Index (CDAI) metrics.

The investigators also performed an in-cohort cross-validation of the MSRC using baseline blood samples of 245 treatment-naive patients from the CERTAIN study, which yielded a 66% predictive accuracy for the ACR50 outcome at 6 months. Using the 19 RNA transcripts from the test, but not the clinical factors, the predictive accuracy was 62.5%. Using ACR70, CDAI, and DAS28 as measures for 6-month response, the cross-validation analysis of all 23 MSRC features yielded predictive accuracy of 64%-67%.

The study found significant differences in model scores between patients who did and did not have the molecular signal of nonresponse, and the proportion of patients who achieved low disease activity or remission at 6 months based on CDAI and DAS28-CRP measures was greater among those who lacked a molecular signature of nonresponse.

“Those who lack this signature can proceed with TNFi therapy and possibly achieve an increased response rate relative to the unstratified population,” wrote lead study author Stanley B. Cohen, MD, and colleagues.

Daniel E. Furst, MD, emeritus professor at the University of California, Los Angeles, described the design of the NETWORK-004 study as “excellent,” but said that it didn’t overcome potential issues with the MSRC test itself. “The results unfortunately are great for group data but not for individuals, with a predictive area under the curve of 60% to 80%, it really is not that useful,” he said. “Let’s say you’re a patient who’s not doing well, and I do a test and it’s positive; that still means that 20% of the time you will respond.”

He also noted that he coauthored a paper that used decreases in DAS28 to predict nonresponse to certolizumab pegol plus methotrexate with 95% probability in the first 12 weeks of treatment. “That’s closer to what we need,” Dr. Furst said.

However, the MSRC test is a promising sign of where testing for predicting RA therapy is headed, he said. “We are steadily working toward genetic signatures that really are predictive on an individual basis,” Dr. Furst said. “It’s coming; it’s just not here yet.”

Dr. Furst had no relevant financial relationships to disclose. Dr. Soloman is a paid investigator and consultant to Scipher Medicine.
 

A blood test that uses a patient’s unique genetic signature has shown some ability to predict nonresponse to tumor necrosis factor inhibitors as treatment for rheumatoid arthritis, an observational clinical study has found, but the test’s predictive accuracy was well below 100%.

The test is the blood-based molecular signature response classifier (MSRC) that uses RNA sequencing data based on 23 different biomarkers: 19 RNA transcripts and 4 clinical features. The clinical features are body mass index, gender, patient global assessment, and anticyclic citrullinated protein (anti-CCP) status.

The NETWORK-004 study, published in Rheumatology and Therapy, was able to stratify patients who were likely to respond inadequately to TNFi therapy and could provide patient-specific information to guide therapy choice in RA patients regardless of whether they’ve already been on TNFi therapy. The study evaluated the MSRC test in 504 patients, 391 of whom were treatment naive.
 

Avoiding ‘fail first’ approach

The idea behind the test is to circumvent the “fail first” approach in finding the right therapy for RA in an individual patient. While the test costs $4,995, Alif Saleh, chief executive officer of Scipher Medicine, which markets the test under the name PrismRA, said in a press release that it has the potential to reduce costs by $19,000 or more per patient per year by avoiding treatments that don’t work. A previous study, which Scipher funded, reported that the test resulted in savings of $7,379 in per-patient costs of ineffective therapy. The same study reported a 25% decrease in costs for ineffective treatments for Medicare-eligible patients.

The price of RA drugs, particularly anti-TNF agents, is hefty and rising. GoodRx has reported that the price of RA drugs increased 92% from 2014 to 2019, and the prices for anti-TNF agents such as etanercept and adalimumab more than doubled in that period. Adalimumab can cost upwards of $84,000 per year while etanercept has a list price of around $72,000 a year. The pharmacy benefit manager WellDyne started covering the test MSRC in February.

Nehad Soloman, MD, a rheumatologist and internist at Midwestern University Arizona College of Osteopathic Medicine in Glendale and a compensated NETWORK-004 investigator, said the MSRC test would be indicated for confirmed RA patients for whom rheumatologists are considering biologic agents, particularly TNFi drugs. “You wouldn’t do it on an RA patient who’s been on several different medications because it doesn’t serve a purpose at that point,” he said.

The potential cost savings may not be the only reason to use the test, Dr. Soloman said. “You don’t want to be dabbling with the wrong drug if there’s another path you can try and save society some money as well as the time and energy it takes to monitor the patients – as well as the patient’s pain,” he said.
 

How the MSRC test works

The MSRC test detects a signal that’s associated with a high or very high likelihood of inadequate response to TNFi therapies and indicates that the patient is unlikely to achieve low disease activity or remission with TNFi therapies. Response is defined as achieving ACR50 – meaning 50% improvement in American College of Rheumatology response criteria – at 6 months.

Test results are reported on a continuous 1-25 scale, explained Slava Akmaev, PhD, chief technology officer and head of therapeutics at Scipher. “The higher the score, the more likely the patient will have an inadequate response to TNFi therapies and be unable to reach low disease activity; the lower the score, the less likely the patient will have an inadequate response to TNFi therapies,” he said. However, Dr. Akmaev noted that a low score does not ensure a positive response to TNFi therapies.

The MSRC test differs from the multibiomarker disease activity blood test (MBDA; marketed as Vectra by Myriad Genetics) in the number of biomarkers it measures: 19 RNA transcripts vs. 12 serum protein biomarkers in MBDA. The MBDA test is also intended to provide a quantitative, objective measurement of RA disease activity rather than to predict nonresponse to TNFi or other biologics. A number of studies have validated the MBDA test for predicting disease control in RA patients, but not necessarily response to TNFi therapy.

The “high” category threshold of the MSRC test corresponds to an approximate 90% chance of inadequate response to TNFi therapy, or a 10% chance of responding. The “very high” category threshold corresponds to an approximate 95% chance of inadequate response to TNFi therapy, Dr. Akmaev said.

NETWORK-004 used area under the curve (AUC) to measure the accuracy of the MSRC test. An AUC of 1 represents 100% accuracy. Overall, the MSRC had an AUC of 0.64, or 64% accuracy of predicting patients unlikely to respond to TNFi therapy and to achieve ACR50 at 6 months, with an odds ratio of 4.1 (95% confidence interval, 2.0-8.3; P = .0001).

The predictive accuracy went up to 74% with ORs of 3.4-8.8 for additional endpoints at 3 and 6 months (P < .01). Among patients who had already been on TNFi therapy, the predictive accuracy was 83% and associated with ORs of 3.3-26.6 based on ACR, 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), and Clinical Disease Activity Index (CDAI) metrics.

The investigators also performed an in-cohort cross-validation of the MSRC using baseline blood samples of 245 treatment-naive patients from the CERTAIN study, which yielded a 66% predictive accuracy for the ACR50 outcome at 6 months. Using the 19 RNA transcripts from the test, but not the clinical factors, the predictive accuracy was 62.5%. Using ACR70, CDAI, and DAS28 as measures for 6-month response, the cross-validation analysis of all 23 MSRC features yielded predictive accuracy of 64%-67%.

The study found significant differences in model scores between patients who did and did not have the molecular signal of nonresponse, and the proportion of patients who achieved low disease activity or remission at 6 months based on CDAI and DAS28-CRP measures was greater among those who lacked a molecular signature of nonresponse.

“Those who lack this signature can proceed with TNFi therapy and possibly achieve an increased response rate relative to the unstratified population,” wrote lead study author Stanley B. Cohen, MD, and colleagues.

Daniel E. Furst, MD, emeritus professor at the University of California, Los Angeles, described the design of the NETWORK-004 study as “excellent,” but said that it didn’t overcome potential issues with the MSRC test itself. “The results unfortunately are great for group data but not for individuals, with a predictive area under the curve of 60% to 80%, it really is not that useful,” he said. “Let’s say you’re a patient who’s not doing well, and I do a test and it’s positive; that still means that 20% of the time you will respond.”

He also noted that he coauthored a paper that used decreases in DAS28 to predict nonresponse to certolizumab pegol plus methotrexate with 95% probability in the first 12 weeks of treatment. “That’s closer to what we need,” Dr. Furst said.

However, the MSRC test is a promising sign of where testing for predicting RA therapy is headed, he said. “We are steadily working toward genetic signatures that really are predictive on an individual basis,” Dr. Furst said. “It’s coming; it’s just not here yet.”

Dr. Furst had no relevant financial relationships to disclose. Dr. Soloman is a paid investigator and consultant to Scipher Medicine.
 

A blood test that uses a patient’s unique genetic signature has shown some ability to predict nonresponse to tumor necrosis factor inhibitors as treatment for rheumatoid arthritis, an observational clinical study has found, but the test’s predictive accuracy was well below 100%.

The test is the blood-based molecular signature response classifier (MSRC) that uses RNA sequencing data based on 23 different biomarkers: 19 RNA transcripts and 4 clinical features. The clinical features are body mass index, gender, patient global assessment, and anticyclic citrullinated protein (anti-CCP) status.

The NETWORK-004 study, published in Rheumatology and Therapy, was able to stratify patients who were likely to respond inadequately to TNFi therapy and could provide patient-specific information to guide therapy choice in RA patients regardless of whether they’ve already been on TNFi therapy. The study evaluated the MSRC test in 504 patients, 391 of whom were treatment naive.
 

Avoiding ‘fail first’ approach

The idea behind the test is to circumvent the “fail first” approach in finding the right therapy for RA in an individual patient. While the test costs $4,995, Alif Saleh, chief executive officer of Scipher Medicine, which markets the test under the name PrismRA, said in a press release that it has the potential to reduce costs by $19,000 or more per patient per year by avoiding treatments that don’t work. A previous study, which Scipher funded, reported that the test resulted in savings of $7,379 in per-patient costs of ineffective therapy. The same study reported a 25% decrease in costs for ineffective treatments for Medicare-eligible patients.

The price of RA drugs, particularly anti-TNF agents, is hefty and rising. GoodRx has reported that the price of RA drugs increased 92% from 2014 to 2019, and the prices for anti-TNF agents such as etanercept and adalimumab more than doubled in that period. Adalimumab can cost upwards of $84,000 per year while etanercept has a list price of around $72,000 a year. The pharmacy benefit manager WellDyne started covering the test MSRC in February.

Nehad Soloman, MD, a rheumatologist and internist at Midwestern University Arizona College of Osteopathic Medicine in Glendale and a compensated NETWORK-004 investigator, said the MSRC test would be indicated for confirmed RA patients for whom rheumatologists are considering biologic agents, particularly TNFi drugs. “You wouldn’t do it on an RA patient who’s been on several different medications because it doesn’t serve a purpose at that point,” he said.

The potential cost savings may not be the only reason to use the test, Dr. Soloman said. “You don’t want to be dabbling with the wrong drug if there’s another path you can try and save society some money as well as the time and energy it takes to monitor the patients – as well as the patient’s pain,” he said.
 

How the MSRC test works

The MSRC test detects a signal that’s associated with a high or very high likelihood of inadequate response to TNFi therapies and indicates that the patient is unlikely to achieve low disease activity or remission with TNFi therapies. Response is defined as achieving ACR50 – meaning 50% improvement in American College of Rheumatology response criteria – at 6 months.

Test results are reported on a continuous 1-25 scale, explained Slava Akmaev, PhD, chief technology officer and head of therapeutics at Scipher. “The higher the score, the more likely the patient will have an inadequate response to TNFi therapies and be unable to reach low disease activity; the lower the score, the less likely the patient will have an inadequate response to TNFi therapies,” he said. However, Dr. Akmaev noted that a low score does not ensure a positive response to TNFi therapies.

The MSRC test differs from the multibiomarker disease activity blood test (MBDA; marketed as Vectra by Myriad Genetics) in the number of biomarkers it measures: 19 RNA transcripts vs. 12 serum protein biomarkers in MBDA. The MBDA test is also intended to provide a quantitative, objective measurement of RA disease activity rather than to predict nonresponse to TNFi or other biologics. A number of studies have validated the MBDA test for predicting disease control in RA patients, but not necessarily response to TNFi therapy.

The “high” category threshold of the MSRC test corresponds to an approximate 90% chance of inadequate response to TNFi therapy, or a 10% chance of responding. The “very high” category threshold corresponds to an approximate 95% chance of inadequate response to TNFi therapy, Dr. Akmaev said.

NETWORK-004 used area under the curve (AUC) to measure the accuracy of the MSRC test. An AUC of 1 represents 100% accuracy. Overall, the MSRC had an AUC of 0.64, or 64% accuracy of predicting patients unlikely to respond to TNFi therapy and to achieve ACR50 at 6 months, with an odds ratio of 4.1 (95% confidence interval, 2.0-8.3; P = .0001).

The predictive accuracy went up to 74% with ORs of 3.4-8.8 for additional endpoints at 3 and 6 months (P < .01). Among patients who had already been on TNFi therapy, the predictive accuracy was 83% and associated with ORs of 3.3-26.6 based on ACR, 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), and Clinical Disease Activity Index (CDAI) metrics.

The investigators also performed an in-cohort cross-validation of the MSRC using baseline blood samples of 245 treatment-naive patients from the CERTAIN study, which yielded a 66% predictive accuracy for the ACR50 outcome at 6 months. Using the 19 RNA transcripts from the test, but not the clinical factors, the predictive accuracy was 62.5%. Using ACR70, CDAI, and DAS28 as measures for 6-month response, the cross-validation analysis of all 23 MSRC features yielded predictive accuracy of 64%-67%.

The study found significant differences in model scores between patients who did and did not have the molecular signal of nonresponse, and the proportion of patients who achieved low disease activity or remission at 6 months based on CDAI and DAS28-CRP measures was greater among those who lacked a molecular signature of nonresponse.

“Those who lack this signature can proceed with TNFi therapy and possibly achieve an increased response rate relative to the unstratified population,” wrote lead study author Stanley B. Cohen, MD, and colleagues.

Daniel E. Furst, MD, emeritus professor at the University of California, Los Angeles, described the design of the NETWORK-004 study as “excellent,” but said that it didn’t overcome potential issues with the MSRC test itself. “The results unfortunately are great for group data but not for individuals, with a predictive area under the curve of 60% to 80%, it really is not that useful,” he said. “Let’s say you’re a patient who’s not doing well, and I do a test and it’s positive; that still means that 20% of the time you will respond.”

He also noted that he coauthored a paper that used decreases in DAS28 to predict nonresponse to certolizumab pegol plus methotrexate with 95% probability in the first 12 weeks of treatment. “That’s closer to what we need,” Dr. Furst said.

However, the MSRC test is a promising sign of where testing for predicting RA therapy is headed, he said. “We are steadily working toward genetic signatures that really are predictive on an individual basis,” Dr. Furst said. “It’s coming; it’s just not here yet.”

Dr. Furst had no relevant financial relationships to disclose. Dr. Soloman is a paid investigator and consultant to Scipher Medicine.
 

About one in six patients with heart failure in the United States are skipping doctors’ appointments, not taking their medications as directed, or forgoing some other type of care, and their recalcitrance actually ends up costing the health care system 20%-30% more per patient.

That’s according to a cross-sectional study using data from a large public database reported in JACC: Heart Failure on Aug. 11.

The investigators pooled data on 2,050 patients with HF enrolled in the Medical Expenditure Panel Survey, a public database sponsored by the Agency for Healthcare Research and Quality, from 2004 to 2015. Some 339 of those HF patients were classified in the forgone or delayed (F/D) care group. This is the first study to describe the cost impact of missed care in heart failure, lead author Alexander Thomas, MD, and colleagues wrote.

“I think we make a pretty strong case linking forgone care to higher cost,” Dr. Thomas said in an interview. “Obviously this is a prospective study, so causality is not made based on this study, but there’s a strong association, it appears.” He acknowledged that prospective studies would need to confirm these findings, but added, “I think even this is enough to give us cause to look at the somewhat granular reasons as to why patients are forgoing care.”

Average annual total costs for adults who skipped care were $8,027 higher than for those heart failure patients who kept up with their regimen (P = .02). However, for people 65 and older, the cost differential was even higher: $10,581 (P = .02), which translates into a 50% premium over average costs for compliant elderly patients, noted Dr. Thomas, a cardiovascular medicine fellow at Yale University, New Haven, Conn.

In the nonelderly F/D group, average per-patient costs were $27,000 annually; in the elderly, it was a little over $30,000.

However, nonelderly patients were more likely to forgo care. While 16% of all patients in the study were considered F/D, 27% of nonelderly patients were classified as such vs. 10% of the elderly.
 

Elderly forgoing care drives cost

But, Dr. Thomas said, elderly patients forgoing care drive higher costs because they’re more fragile, have more comorbidities and more advanced heart failure, and tend to decompensate more quickly. “For them, missing one appointment or missing some medications is not nearly as well tolerated as it is in the younger population,” he said. In these elderly patients, inpatient costs accounted for 75% of the increased expense, Dr. Thomas added.

Reasons for forgoing care range from the obvious, such as cost or insurance issues – 191 individuals cited the former, 69 the latter – to more granular reasons, such as transportation issues or lack of time.

The study also found a number of demographic features that were associated with forgone or delayed care: non-Hispanic Black race; lack of insurance; low-income; and worse cardiovascular risk factor profiles.

The study’s call to action is for further research and policy changes aimed at better understanding barriers to care and improving access. “It’s a really great driver for policy interventions to attack this problem and to have the financial backing also to put money and resources into fixing this problem – which is probably not only going to decrease costs and allow more cost-effective care, but lead to better outcomes in this population as well,” Dr. Thomas said.

The sentiment for policy changes was echoed in an accompanying editorial by Khadijah Breathett, MD, MS, a heart failure/transplant cardiologist at the Sarver Heart Center, University of Arizona, Tucson. But she also noted the study exposed insufficiencies with Medicare. In an interview, she expanded on that. 

“Our system is failing this population,” she said of the elderly with heart failure who have forgone care. “I think that’s because of the complexity of our system: One person’s Medicare is different from another’s. There are multiple parts to Medicare that provide different forms of care – hospital care, prescription care, and so forth – and everyone does not necessarily have the same parts.” Also, many Medicare beneficiaries are still working, and “they’re still trying to figure out how to make ends meet,” Dr. Breathett added.

The study also showed that the pre-Medicare population requires the attention of policymakers. “How do we help the younger population so that they don’t develop the comorbidities that worsen their quality of life and contribute to rising hospital costs?” Dr. Breathett said.

Dr. Thomas had no financial relationships to disclose. Dr. Breathett has received grants from the National Heart, Lung, and Blood Institute.

About one in six patients with heart failure in the United States are skipping doctors’ appointments, not taking their medications as directed, or forgoing some other type of care, and their recalcitrance actually ends up costing the health care system 20%-30% more per patient.

That’s according to a cross-sectional study using data from a large public database reported in JACC: Heart Failure on Aug. 11.

The investigators pooled data on 2,050 patients with HF enrolled in the Medical Expenditure Panel Survey, a public database sponsored by the Agency for Healthcare Research and Quality, from 2004 to 2015. Some 339 of those HF patients were classified in the forgone or delayed (F/D) care group. This is the first study to describe the cost impact of missed care in heart failure, lead author Alexander Thomas, MD, and colleagues wrote.

“I think we make a pretty strong case linking forgone care to higher cost,” Dr. Thomas said in an interview. “Obviously this is a prospective study, so causality is not made based on this study, but there’s a strong association, it appears.” He acknowledged that prospective studies would need to confirm these findings, but added, “I think even this is enough to give us cause to look at the somewhat granular reasons as to why patients are forgoing care.”

Average annual total costs for adults who skipped care were $8,027 higher than for those heart failure patients who kept up with their regimen (P = .02). However, for people 65 and older, the cost differential was even higher: $10,581 (P = .02), which translates into a 50% premium over average costs for compliant elderly patients, noted Dr. Thomas, a cardiovascular medicine fellow at Yale University, New Haven, Conn.

In the nonelderly F/D group, average per-patient costs were $27,000 annually; in the elderly, it was a little over $30,000.

However, nonelderly patients were more likely to forgo care. While 16% of all patients in the study were considered F/D, 27% of nonelderly patients were classified as such vs. 10% of the elderly.
 

Elderly forgoing care drives cost

But, Dr. Thomas said, elderly patients forgoing care drive higher costs because they’re more fragile, have more comorbidities and more advanced heart failure, and tend to decompensate more quickly. “For them, missing one appointment or missing some medications is not nearly as well tolerated as it is in the younger population,” he said. In these elderly patients, inpatient costs accounted for 75% of the increased expense, Dr. Thomas added.

Reasons for forgoing care range from the obvious, such as cost or insurance issues – 191 individuals cited the former, 69 the latter – to more granular reasons, such as transportation issues or lack of time.

The study also found a number of demographic features that were associated with forgone or delayed care: non-Hispanic Black race; lack of insurance; low-income; and worse cardiovascular risk factor profiles.

The study’s call to action is for further research and policy changes aimed at better understanding barriers to care and improving access. “It’s a really great driver for policy interventions to attack this problem and to have the financial backing also to put money and resources into fixing this problem – which is probably not only going to decrease costs and allow more cost-effective care, but lead to better outcomes in this population as well,” Dr. Thomas said.

The sentiment for policy changes was echoed in an accompanying editorial by Khadijah Breathett, MD, MS, a heart failure/transplant cardiologist at the Sarver Heart Center, University of Arizona, Tucson. But she also noted the study exposed insufficiencies with Medicare. In an interview, she expanded on that. 

“Our system is failing this population,” she said of the elderly with heart failure who have forgone care. “I think that’s because of the complexity of our system: One person’s Medicare is different from another’s. There are multiple parts to Medicare that provide different forms of care – hospital care, prescription care, and so forth – and everyone does not necessarily have the same parts.” Also, many Medicare beneficiaries are still working, and “they’re still trying to figure out how to make ends meet,” Dr. Breathett added.

The study also showed that the pre-Medicare population requires the attention of policymakers. “How do we help the younger population so that they don’t develop the comorbidities that worsen their quality of life and contribute to rising hospital costs?” Dr. Breathett said.

Dr. Thomas had no financial relationships to disclose. Dr. Breathett has received grants from the National Heart, Lung, and Blood Institute.

About one in six patients with heart failure in the United States are skipping doctors’ appointments, not taking their medications as directed, or forgoing some other type of care, and their recalcitrance actually ends up costing the health care system 20%-30% more per patient.

That’s according to a cross-sectional study using data from a large public database reported in JACC: Heart Failure on Aug. 11.

The investigators pooled data on 2,050 patients with HF enrolled in the Medical Expenditure Panel Survey, a public database sponsored by the Agency for Healthcare Research and Quality, from 2004 to 2015. Some 339 of those HF patients were classified in the forgone or delayed (F/D) care group. This is the first study to describe the cost impact of missed care in heart failure, lead author Alexander Thomas, MD, and colleagues wrote.

“I think we make a pretty strong case linking forgone care to higher cost,” Dr. Thomas said in an interview. “Obviously this is a prospective study, so causality is not made based on this study, but there’s a strong association, it appears.” He acknowledged that prospective studies would need to confirm these findings, but added, “I think even this is enough to give us cause to look at the somewhat granular reasons as to why patients are forgoing care.”

Average annual total costs for adults who skipped care were $8,027 higher than for those heart failure patients who kept up with their regimen (P = .02). However, for people 65 and older, the cost differential was even higher: $10,581 (P = .02), which translates into a 50% premium over average costs for compliant elderly patients, noted Dr. Thomas, a cardiovascular medicine fellow at Yale University, New Haven, Conn.

In the nonelderly F/D group, average per-patient costs were $27,000 annually; in the elderly, it was a little over $30,000.

However, nonelderly patients were more likely to forgo care. While 16% of all patients in the study were considered F/D, 27% of nonelderly patients were classified as such vs. 10% of the elderly.
 

Elderly forgoing care drives cost

But, Dr. Thomas said, elderly patients forgoing care drive higher costs because they’re more fragile, have more comorbidities and more advanced heart failure, and tend to decompensate more quickly. “For them, missing one appointment or missing some medications is not nearly as well tolerated as it is in the younger population,” he said. In these elderly patients, inpatient costs accounted for 75% of the increased expense, Dr. Thomas added.

Reasons for forgoing care range from the obvious, such as cost or insurance issues – 191 individuals cited the former, 69 the latter – to more granular reasons, such as transportation issues or lack of time.

The study also found a number of demographic features that were associated with forgone or delayed care: non-Hispanic Black race; lack of insurance; low-income; and worse cardiovascular risk factor profiles.

The study’s call to action is for further research and policy changes aimed at better understanding barriers to care and improving access. “It’s a really great driver for policy interventions to attack this problem and to have the financial backing also to put money and resources into fixing this problem – which is probably not only going to decrease costs and allow more cost-effective care, but lead to better outcomes in this population as well,” Dr. Thomas said.

The sentiment for policy changes was echoed in an accompanying editorial by Khadijah Breathett, MD, MS, a heart failure/transplant cardiologist at the Sarver Heart Center, University of Arizona, Tucson. But she also noted the study exposed insufficiencies with Medicare. In an interview, she expanded on that. 

“Our system is failing this population,” she said of the elderly with heart failure who have forgone care. “I think that’s because of the complexity of our system: One person’s Medicare is different from another’s. There are multiple parts to Medicare that provide different forms of care – hospital care, prescription care, and so forth – and everyone does not necessarily have the same parts.” Also, many Medicare beneficiaries are still working, and “they’re still trying to figure out how to make ends meet,” Dr. Breathett added.

The study also showed that the pre-Medicare population requires the attention of policymakers. “How do we help the younger population so that they don’t develop the comorbidities that worsen their quality of life and contribute to rising hospital costs?” Dr. Breathett said.

Dr. Thomas had no financial relationships to disclose. Dr. Breathett has received grants from the National Heart, Lung, and Blood Institute.

In patients with intermediate risk of atherosclerotic cardiovascular disease along with risk-enhancing factors, coronary artery calcium scoring may help more precisely calculate their need for statin therapy.

Furthermore, when the need for statin treatment isn’t so clear and patients need additional risk assessment, the scoring can provide further information to personalize clinical decision making, according to a cross-sectional study of 1,688 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) published in JAMA Cardiology.

And regardless of coronary artery calcium (CAC), a low ankle brachial index (ABI) score is a marker for statin therapy, the study found.

The study looked at CAC scoring in the context of ABI and other risk-enhancing factors identified in the 2018 American Heart Association/American College of Cardiology cholesterol management guidelines: a family history of premature atherosclerotic cardiovascular disease (ASCVD), lipid and inflammatory biomarkers, chronic kidney disease, chronic inflammatory conditions, premature menopause or preeclampsia, and South Asian ancestry.

Any number of these factors can indicate the need for statins in people with borderline or intermediate risk. The guidelines also call for selective use of CAC to aid the decision-making process for statin therapy when the risk for developing atherosclerosis isn’t so clear.

“The novel risk-enhancing factors are not perfect,” said lead author Jaideep Patel, MD, director of preventive cardiology at Johns Hopkins Heart Center at Greater Baltimore Medical Center. He noted that the 2018 dyslipidemia guidelines suggested the risk for cardiovascular events rises when new risk-enhancing factors emerge, and that it was difficult to predict the extent to which each enhancer could change the 10-year risk. 
 

Utility of CAC

“In this setting, the most significant finding that supports the utility of CAC scoring is when CAC is absent – a CAC of 0 – even in the setting of any of these enhancers, whether it be single or multiple, the 10-year risk remains extremely low – at the very least below the accepted threshold to initiate statin therapy,” Dr. Patel said.

That threshold is below the 7.5% 10-year ASCVD incidence rate. Over the 12-year mean study follow-up, the ASCVD incidence rate among patients with a CAC score of 0 for all risk-enhancing factors was 7.5 events per 1,000 person years, with one exception: ABI had an incidence rate of 10.4 events per 1,000 person years. “A low ABI score should trigger statin initiation irrespective of CAC score,” Dr. Patel said.

The study found a CAC score of 0 in 45.7% of those with one or two risk-enhancing factors versus 40.3% in those with three or more. “Across all the risk enhancers (except low ABI), the prevalence of CAC of 0 was greater than 50% in women; that is, enhancers overestimate risk,” Dr. Patel said. “The prevalence of CAC of 0 was approximately 40% across all risk enhancers; that is, enhancers overestimate risk.”

Dr. Patel said previous studies have suggested the risk of a major cardiovascular event was almost identical for statin and nonstatin users with a CAC score of 0. “If there is uncertainty about statin use after the physician-patient risk discussion,” he said, “CAC scoring may be helpful to guide the use of statin therapy.”

Senior author Mahmoud Al Rifai, MD, MPH, added: “For example, if CAC was absent, a statin could be deprescribed if there’s disutility on the part of the patient, with ongoing lifestyle and risk factor modification efforts.” Dr. Al Rifai is a cardiology fellow at Baylor College of Medicine, Houston.

Dr. Patel said: “Alternatively, if CAC was present, then it would be prudent to continue statin therapy.”

While South Asian ethnicity is a risk enhancing factor, the investigators acknowledged that MESA didn’t recruit this population group.
 

Study confirms guidelines

The study “supports the contention of the [AHA/ACC] guidelines that, in people who are in this intermediate risk range, there may be factors that either favor statin treatment or suggest that statin treatment could be deferred,” said Neil J. Stone, MD, of Northwestern University, Chicago, and author of the 2013 ASCVD risk calculator. “The guidelines pointed out that risk-enhancing factors may be associated with an increase in lifetime risk, not necessarily short term, and so could inform a more personalized risk discussion.”

The study findings validate the utility of CAC for guiding statin therapy, Dr. Stone said. “For those who have felt that a calcium score is not useful,” he said, “this is additional evidence to show that, in the context of making a decision in those at intermediate risk as proposed by the guidelines, a calcium score is indeed very useful.”

Dr. Stone added: “An important clinical point not mentioned by the authors is that, when the patient has a CAC score of 0 and risk factors, this may be exactly the time to be aggressive with lifestyle to prevent them from developing a positive CAC score and atherosclerosis, because once atherosclerosis is present, treatment may not restore the risk back to the original lower state.”

Dr. Patel, Dr. Al Rifai, and Dr. Stone have no relevant relationships to disclose. A number of study coauthors disclosed multiple financial relationships.

In patients with intermediate risk of atherosclerotic cardiovascular disease along with risk-enhancing factors, coronary artery calcium scoring may help more precisely calculate their need for statin therapy.

Furthermore, when the need for statin treatment isn’t so clear and patients need additional risk assessment, the scoring can provide further information to personalize clinical decision making, according to a cross-sectional study of 1,688 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) published in JAMA Cardiology.

And regardless of coronary artery calcium (CAC), a low ankle brachial index (ABI) score is a marker for statin therapy, the study found.

The study looked at CAC scoring in the context of ABI and other risk-enhancing factors identified in the 2018 American Heart Association/American College of Cardiology cholesterol management guidelines: a family history of premature atherosclerotic cardiovascular disease (ASCVD), lipid and inflammatory biomarkers, chronic kidney disease, chronic inflammatory conditions, premature menopause or preeclampsia, and South Asian ancestry.

Any number of these factors can indicate the need for statins in people with borderline or intermediate risk. The guidelines also call for selective use of CAC to aid the decision-making process for statin therapy when the risk for developing atherosclerosis isn’t so clear.

“The novel risk-enhancing factors are not perfect,” said lead author Jaideep Patel, MD, director of preventive cardiology at Johns Hopkins Heart Center at Greater Baltimore Medical Center. He noted that the 2018 dyslipidemia guidelines suggested the risk for cardiovascular events rises when new risk-enhancing factors emerge, and that it was difficult to predict the extent to which each enhancer could change the 10-year risk. 
 

Utility of CAC

“In this setting, the most significant finding that supports the utility of CAC scoring is when CAC is absent – a CAC of 0 – even in the setting of any of these enhancers, whether it be single or multiple, the 10-year risk remains extremely low – at the very least below the accepted threshold to initiate statin therapy,” Dr. Patel said.

That threshold is below the 7.5% 10-year ASCVD incidence rate. Over the 12-year mean study follow-up, the ASCVD incidence rate among patients with a CAC score of 0 for all risk-enhancing factors was 7.5 events per 1,000 person years, with one exception: ABI had an incidence rate of 10.4 events per 1,000 person years. “A low ABI score should trigger statin initiation irrespective of CAC score,” Dr. Patel said.

The study found a CAC score of 0 in 45.7% of those with one or two risk-enhancing factors versus 40.3% in those with three or more. “Across all the risk enhancers (except low ABI), the prevalence of CAC of 0 was greater than 50% in women; that is, enhancers overestimate risk,” Dr. Patel said. “The prevalence of CAC of 0 was approximately 40% across all risk enhancers; that is, enhancers overestimate risk.”

Dr. Patel said previous studies have suggested the risk of a major cardiovascular event was almost identical for statin and nonstatin users with a CAC score of 0. “If there is uncertainty about statin use after the physician-patient risk discussion,” he said, “CAC scoring may be helpful to guide the use of statin therapy.”

Senior author Mahmoud Al Rifai, MD, MPH, added: “For example, if CAC was absent, a statin could be deprescribed if there’s disutility on the part of the patient, with ongoing lifestyle and risk factor modification efforts.” Dr. Al Rifai is a cardiology fellow at Baylor College of Medicine, Houston.

Dr. Patel said: “Alternatively, if CAC was present, then it would be prudent to continue statin therapy.”

While South Asian ethnicity is a risk enhancing factor, the investigators acknowledged that MESA didn’t recruit this population group.
 

Study confirms guidelines

The study “supports the contention of the [AHA/ACC] guidelines that, in people who are in this intermediate risk range, there may be factors that either favor statin treatment or suggest that statin treatment could be deferred,” said Neil J. Stone, MD, of Northwestern University, Chicago, and author of the 2013 ASCVD risk calculator. “The guidelines pointed out that risk-enhancing factors may be associated with an increase in lifetime risk, not necessarily short term, and so could inform a more personalized risk discussion.”

The study findings validate the utility of CAC for guiding statin therapy, Dr. Stone said. “For those who have felt that a calcium score is not useful,” he said, “this is additional evidence to show that, in the context of making a decision in those at intermediate risk as proposed by the guidelines, a calcium score is indeed very useful.”

Dr. Stone added: “An important clinical point not mentioned by the authors is that, when the patient has a CAC score of 0 and risk factors, this may be exactly the time to be aggressive with lifestyle to prevent them from developing a positive CAC score and atherosclerosis, because once atherosclerosis is present, treatment may not restore the risk back to the original lower state.”

Dr. Patel, Dr. Al Rifai, and Dr. Stone have no relevant relationships to disclose. A number of study coauthors disclosed multiple financial relationships.

In patients with intermediate risk of atherosclerotic cardiovascular disease along with risk-enhancing factors, coronary artery calcium scoring may help more precisely calculate their need for statin therapy.

Furthermore, when the need for statin treatment isn’t so clear and patients need additional risk assessment, the scoring can provide further information to personalize clinical decision making, according to a cross-sectional study of 1,688 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) published in JAMA Cardiology.

And regardless of coronary artery calcium (CAC), a low ankle brachial index (ABI) score is a marker for statin therapy, the study found.

The study looked at CAC scoring in the context of ABI and other risk-enhancing factors identified in the 2018 American Heart Association/American College of Cardiology cholesterol management guidelines: a family history of premature atherosclerotic cardiovascular disease (ASCVD), lipid and inflammatory biomarkers, chronic kidney disease, chronic inflammatory conditions, premature menopause or preeclampsia, and South Asian ancestry.

Any number of these factors can indicate the need for statins in people with borderline or intermediate risk. The guidelines also call for selective use of CAC to aid the decision-making process for statin therapy when the risk for developing atherosclerosis isn’t so clear.

“The novel risk-enhancing factors are not perfect,” said lead author Jaideep Patel, MD, director of preventive cardiology at Johns Hopkins Heart Center at Greater Baltimore Medical Center. He noted that the 2018 dyslipidemia guidelines suggested the risk for cardiovascular events rises when new risk-enhancing factors emerge, and that it was difficult to predict the extent to which each enhancer could change the 10-year risk. 
 

Utility of CAC

“In this setting, the most significant finding that supports the utility of CAC scoring is when CAC is absent – a CAC of 0 – even in the setting of any of these enhancers, whether it be single or multiple, the 10-year risk remains extremely low – at the very least below the accepted threshold to initiate statin therapy,” Dr. Patel said.

That threshold is below the 7.5% 10-year ASCVD incidence rate. Over the 12-year mean study follow-up, the ASCVD incidence rate among patients with a CAC score of 0 for all risk-enhancing factors was 7.5 events per 1,000 person years, with one exception: ABI had an incidence rate of 10.4 events per 1,000 person years. “A low ABI score should trigger statin initiation irrespective of CAC score,” Dr. Patel said.

The study found a CAC score of 0 in 45.7% of those with one or two risk-enhancing factors versus 40.3% in those with three or more. “Across all the risk enhancers (except low ABI), the prevalence of CAC of 0 was greater than 50% in women; that is, enhancers overestimate risk,” Dr. Patel said. “The prevalence of CAC of 0 was approximately 40% across all risk enhancers; that is, enhancers overestimate risk.”

Dr. Patel said previous studies have suggested the risk of a major cardiovascular event was almost identical for statin and nonstatin users with a CAC score of 0. “If there is uncertainty about statin use after the physician-patient risk discussion,” he said, “CAC scoring may be helpful to guide the use of statin therapy.”

Senior author Mahmoud Al Rifai, MD, MPH, added: “For example, if CAC was absent, a statin could be deprescribed if there’s disutility on the part of the patient, with ongoing lifestyle and risk factor modification efforts.” Dr. Al Rifai is a cardiology fellow at Baylor College of Medicine, Houston.

Dr. Patel said: “Alternatively, if CAC was present, then it would be prudent to continue statin therapy.”

While South Asian ethnicity is a risk enhancing factor, the investigators acknowledged that MESA didn’t recruit this population group.
 

Study confirms guidelines

The study “supports the contention of the [AHA/ACC] guidelines that, in people who are in this intermediate risk range, there may be factors that either favor statin treatment or suggest that statin treatment could be deferred,” said Neil J. Stone, MD, of Northwestern University, Chicago, and author of the 2013 ASCVD risk calculator. “The guidelines pointed out that risk-enhancing factors may be associated with an increase in lifetime risk, not necessarily short term, and so could inform a more personalized risk discussion.”

The study findings validate the utility of CAC for guiding statin therapy, Dr. Stone said. “For those who have felt that a calcium score is not useful,” he said, “this is additional evidence to show that, in the context of making a decision in those at intermediate risk as proposed by the guidelines, a calcium score is indeed very useful.”

Dr. Stone added: “An important clinical point not mentioned by the authors is that, when the patient has a CAC score of 0 and risk factors, this may be exactly the time to be aggressive with lifestyle to prevent them from developing a positive CAC score and atherosclerosis, because once atherosclerosis is present, treatment may not restore the risk back to the original lower state.”

Dr. Patel, Dr. Al Rifai, and Dr. Stone have no relevant relationships to disclose. A number of study coauthors disclosed multiple financial relationships.

It follows that, as the prevalence of obesity among people with type 1 diabetes mellitus (T1DM) increases, so would the incidence of nonalcoholic fatty liver (NAFL), as it does in type 2 diabetes.

However, researchers in Finland report that the incidence of NAFL in T1DM is much lower, and that the use of the waist-to-height ratio to calculate midsection girth could be a low-cost alternative to MRI and computed tomography to more precisely diagnose NAFL in T1DM.

In a cross-sectional analysis of 121 adults with T1DM in the Finnish Diabetic Nephropathy study, known as FinnDiane, researchers from the University of Helsinki report in Diabetes Care that a waist-to-height ratio of 0.5 showed a relatively high rate of accuracy for identifying NAFL that was statistically significant (P = .04).

Lead author Erika B. Parente, MD, PhD, a researcher at the Folkhälsän Research Center in Helsinki, noted that the findings do not identify any causality between what the researchers called visceral adiposity and NAFL. “As long as they have accumulation of fat in the center of body and they can develop this low-grade inflammation that also goes to insulin-load sensitivity, people with T1DM can accumulate fat in the liver as do people with T2DM and the general population,” she said in an interview.

These findings build on her group’s previous work published in Scientific Reports showing a strong relationship between waist-to-height ratio and visceral fat percentage in adults with T1DM. The most recent FinnDiane analysis found no similar relationship between NAFL and fat tissue in the hips, arms and legs, and total adipose tissue.
 

Better than BMI as a measure

“We also found that waist-to-height ratio is better than body mass index to identify those individuals at higher risk of having NAFL,” Dr. Parente said. However, it’s not possible to predict which patients referred to imaging evaluation after being screened by waist-to-height ratio of 0.5 will surely have NAFL, she added.

That answer, she said, would require a longitudinal and cost-effectiveness study with larger population.

The waist-to-height ratio cutoff of 0.5 showed an 86% sensitivity and 55% specificity for NAFL, whereas BMI of 26.6 kg/m² showed an 79% sensitivity and 57% specificity.

“The most important message from our research is that health care professionals should be aware that individuals with T1DM can have NAFL, and waist-to-height ratio may help to identify those at higher risk,” she said.

The prevalence of NAFL among the adults with T1DM in the study was 11.6%, which is lower than the prevalence other studies reported in T2DM – 76% in a U.S. study – and in the general population – ranging from 19% to 46%. This underscores, Dr. Parente noted, the importance of using waist-to-height ratio in T1DM patients to determine the status of NAFL.

She said that few studies have investigated the consequences of NAFL in T1DM, pointing to two that linked NAFL with chronic kidney disease and cardiovascular disease in T1DM (Diabetes Care. 2014;37:1729-36; J Hepatol. 2010;53:713-8). “Most of the studies about the consequences of NAFL included people with T2DM,” she said. “From our research, we cannot conclude about the impact of NAFL in cardiovascular or kidney complications in our population because this is a cross-sectional study.”

That question may be answered by a future follow-up study of the ongoing FinnDiane study, she said.

The study is a “good reminder” that people with central adiposity and metabolic syndrome can develop NAFL disease, said Jeanne Marie Clark, MD, MPH, of Johns Hopkins University, Baltimore. “Even patients we may not think of having insulin resistance, such as those with T1DM.”

However, Dr. Clark added, “I do not think we can really determine which measure of central adiposity is best.” She noted that the study was “pretty small” with only 14 patients who had NAFL disease. “Waist-to-height ratio is certainly a reasonable option,” she added. “Waist circumference alone is known to be a strong predictor. I would say some measure is better than none, and it should be more routine in clinical practice.”

Dr. Parente disclosed financial relationships with Eli Lilly, Abbott, AstraZeneca, Sanofi, and Boehringer Ingelheim. Two of eight coauthors disclosed financial relationships with AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Fresenius, GE Healthcare, Medscape, Merck Sharpe and Dohme, Mundipharma, Novo Nordisk, Peer-Voice, Sanofi, and Sciarc. The remaining coauthors had no disclosures.

Dr. Clark had no disclosures.

It follows that, as the prevalence of obesity among people with type 1 diabetes mellitus (T1DM) increases, so would the incidence of nonalcoholic fatty liver (NAFL), as it does in type 2 diabetes.

However, researchers in Finland report that the incidence of NAFL in T1DM is much lower, and that the use of the waist-to-height ratio to calculate midsection girth could be a low-cost alternative to MRI and computed tomography to more precisely diagnose NAFL in T1DM.

In a cross-sectional analysis of 121 adults with T1DM in the Finnish Diabetic Nephropathy study, known as FinnDiane, researchers from the University of Helsinki report in Diabetes Care that a waist-to-height ratio of 0.5 showed a relatively high rate of accuracy for identifying NAFL that was statistically significant (P = .04).

Lead author Erika B. Parente, MD, PhD, a researcher at the Folkhälsän Research Center in Helsinki, noted that the findings do not identify any causality between what the researchers called visceral adiposity and NAFL. “As long as they have accumulation of fat in the center of body and they can develop this low-grade inflammation that also goes to insulin-load sensitivity, people with T1DM can accumulate fat in the liver as do people with T2DM and the general population,” she said in an interview.

These findings build on her group’s previous work published in Scientific Reports showing a strong relationship between waist-to-height ratio and visceral fat percentage in adults with T1DM. The most recent FinnDiane analysis found no similar relationship between NAFL and fat tissue in the hips, arms and legs, and total adipose tissue.
 

Better than BMI as a measure

“We also found that waist-to-height ratio is better than body mass index to identify those individuals at higher risk of having NAFL,” Dr. Parente said. However, it’s not possible to predict which patients referred to imaging evaluation after being screened by waist-to-height ratio of 0.5 will surely have NAFL, she added.

That answer, she said, would require a longitudinal and cost-effectiveness study with larger population.

The waist-to-height ratio cutoff of 0.5 showed an 86% sensitivity and 55% specificity for NAFL, whereas BMI of 26.6 kg/m² showed an 79% sensitivity and 57% specificity.

“The most important message from our research is that health care professionals should be aware that individuals with T1DM can have NAFL, and waist-to-height ratio may help to identify those at higher risk,” she said.

The prevalence of NAFL among the adults with T1DM in the study was 11.6%, which is lower than the prevalence other studies reported in T2DM – 76% in a U.S. study – and in the general population – ranging from 19% to 46%. This underscores, Dr. Parente noted, the importance of using waist-to-height ratio in T1DM patients to determine the status of NAFL.

She said that few studies have investigated the consequences of NAFL in T1DM, pointing to two that linked NAFL with chronic kidney disease and cardiovascular disease in T1DM (Diabetes Care. 2014;37:1729-36; J Hepatol. 2010;53:713-8). “Most of the studies about the consequences of NAFL included people with T2DM,” she said. “From our research, we cannot conclude about the impact of NAFL in cardiovascular or kidney complications in our population because this is a cross-sectional study.”

That question may be answered by a future follow-up study of the ongoing FinnDiane study, she said.

The study is a “good reminder” that people with central adiposity and metabolic syndrome can develop NAFL disease, said Jeanne Marie Clark, MD, MPH, of Johns Hopkins University, Baltimore. “Even patients we may not think of having insulin resistance, such as those with T1DM.”

However, Dr. Clark added, “I do not think we can really determine which measure of central adiposity is best.” She noted that the study was “pretty small” with only 14 patients who had NAFL disease. “Waist-to-height ratio is certainly a reasonable option,” she added. “Waist circumference alone is known to be a strong predictor. I would say some measure is better than none, and it should be more routine in clinical practice.”

Dr. Parente disclosed financial relationships with Eli Lilly, Abbott, AstraZeneca, Sanofi, and Boehringer Ingelheim. Two of eight coauthors disclosed financial relationships with AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Fresenius, GE Healthcare, Medscape, Merck Sharpe and Dohme, Mundipharma, Novo Nordisk, Peer-Voice, Sanofi, and Sciarc. The remaining coauthors had no disclosures.

Dr. Clark had no disclosures.

It follows that, as the prevalence of obesity among people with type 1 diabetes mellitus (T1DM) increases, so would the incidence of nonalcoholic fatty liver (NAFL), as it does in type 2 diabetes.

However, researchers in Finland report that the incidence of NAFL in T1DM is much lower, and that the use of the waist-to-height ratio to calculate midsection girth could be a low-cost alternative to MRI and computed tomography to more precisely diagnose NAFL in T1DM.

In a cross-sectional analysis of 121 adults with T1DM in the Finnish Diabetic Nephropathy study, known as FinnDiane, researchers from the University of Helsinki report in Diabetes Care that a waist-to-height ratio of 0.5 showed a relatively high rate of accuracy for identifying NAFL that was statistically significant (P = .04).

Lead author Erika B. Parente, MD, PhD, a researcher at the Folkhälsän Research Center in Helsinki, noted that the findings do not identify any causality between what the researchers called visceral adiposity and NAFL. “As long as they have accumulation of fat in the center of body and they can develop this low-grade inflammation that also goes to insulin-load sensitivity, people with T1DM can accumulate fat in the liver as do people with T2DM and the general population,” she said in an interview.

These findings build on her group’s previous work published in Scientific Reports showing a strong relationship between waist-to-height ratio and visceral fat percentage in adults with T1DM. The most recent FinnDiane analysis found no similar relationship between NAFL and fat tissue in the hips, arms and legs, and total adipose tissue.
 

Better than BMI as a measure

“We also found that waist-to-height ratio is better than body mass index to identify those individuals at higher risk of having NAFL,” Dr. Parente said. However, it’s not possible to predict which patients referred to imaging evaluation after being screened by waist-to-height ratio of 0.5 will surely have NAFL, she added.

That answer, she said, would require a longitudinal and cost-effectiveness study with larger population.

The waist-to-height ratio cutoff of 0.5 showed an 86% sensitivity and 55% specificity for NAFL, whereas BMI of 26.6 kg/m² showed an 79% sensitivity and 57% specificity.

“The most important message from our research is that health care professionals should be aware that individuals with T1DM can have NAFL, and waist-to-height ratio may help to identify those at higher risk,” she said.

The prevalence of NAFL among the adults with T1DM in the study was 11.6%, which is lower than the prevalence other studies reported in T2DM – 76% in a U.S. study – and in the general population – ranging from 19% to 46%. This underscores, Dr. Parente noted, the importance of using waist-to-height ratio in T1DM patients to determine the status of NAFL.

She said that few studies have investigated the consequences of NAFL in T1DM, pointing to two that linked NAFL with chronic kidney disease and cardiovascular disease in T1DM (Diabetes Care. 2014;37:1729-36; J Hepatol. 2010;53:713-8). “Most of the studies about the consequences of NAFL included people with T2DM,” she said. “From our research, we cannot conclude about the impact of NAFL in cardiovascular or kidney complications in our population because this is a cross-sectional study.”

That question may be answered by a future follow-up study of the ongoing FinnDiane study, she said.

The study is a “good reminder” that people with central adiposity and metabolic syndrome can develop NAFL disease, said Jeanne Marie Clark, MD, MPH, of Johns Hopkins University, Baltimore. “Even patients we may not think of having insulin resistance, such as those with T1DM.”

However, Dr. Clark added, “I do not think we can really determine which measure of central adiposity is best.” She noted that the study was “pretty small” with only 14 patients who had NAFL disease. “Waist-to-height ratio is certainly a reasonable option,” she added. “Waist circumference alone is known to be a strong predictor. I would say some measure is better than none, and it should be more routine in clinical practice.”

Dr. Parente disclosed financial relationships with Eli Lilly, Abbott, AstraZeneca, Sanofi, and Boehringer Ingelheim. Two of eight coauthors disclosed financial relationships with AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Fresenius, GE Healthcare, Medscape, Merck Sharpe and Dohme, Mundipharma, Novo Nordisk, Peer-Voice, Sanofi, and Sciarc. The remaining coauthors had no disclosures.

Dr. Clark had no disclosures.

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

With the COVID-19 pandemic, already high rates of suicide, depression, and burnout among physicians became even more acute. Yet, 3 years after the Federation of State Medical Boards issued recommendations on what questions about mental health status license applications should – or mostly should not – include, only North Carolina fully complies with all four recommendations, and most states comply with two or fewer, a study of state medical board applications has found (JAMA. 2021 May 18;325[19];2017-8).

Questions about mental health history or “its hypothetical effect on competency,” violate the Americans with Disabilities Act, the study authors stated. In a research letter to JAMA, the authors also reported that five state boards do not comply with any of the FSMB recommendations. Twenty-four states comply with three of the four recommendations.

Overall, the mean consistency score was 2.1, which means state medical licensing applications typically run afoul of the Americans With Disabilities Act when it comes to mental health history of applicants.

“No one should ever wonder, ‘Will I lose my job, or should I get help?’ ” said co–senior author Jessica A. Gold, MD, MS, a psychiatrist at Washington University in St. Louis. “This should absolutely never be a question on someone’s mind. And the fact that it is, in medicine, is a problem that needs to be solved. I hope that people are beginning to see that, and we can make a change to get people the help they need before it is too late.”
 

High rates of depression, suicide

She noted that before COVID-19, physicians already had higher rates of depression, burnout, and suicide than the general population. “Over COVID-19, it has become clear that the mental health of physicians has become additionally compounded,” Dr. Gold said.

One study found that physicians had a 44% higher rate of suicide (PLoS One. 2019 Dec;14[12]:e0226361), but they’re notoriously reluctant to seek out mental health care. A 2017 study reported that 40% of physicians would be reluctant to seek mental health care because of concerns about their licensure (Mayo Clin Proc. 2017;92[10]:1486-93).

As the pandemic went on, Dr. Gold and her colleagues decided to study whether state boards had improved their compliance with the FSMB recommendations issued in 2018. Those recommendations include these four limitations regarding questions about mental health conditions on license applications:

• Include only when they result in impairment.
• Include only when the mental health conditions are current – that is, when they’ve occurred within the past 2 years.
• Provide safe haven nonreporting – that is, allow physicians to not report previously diagnosed and treated mental health conditions if they’re being monitored and are in good standing with a physician health program.
• Include supportive or nonjudgmental language about seeking mental health care.

The study considered board applications that had questions about mental health status as consistent with the first three recommendations. Seventeen states complied.

Thirty-nine state boards complied with the first recommendation regarding impairment; 41 with the second recommendation about near-term history; 25 with safe-haven nonreporting. Only eight states were consistent with the recommendation on supportive language.

The ADA limits inquiries about an applicant’s impairment to only current conditions. In a 2017 study, only 21 state boards had limited questions to current impairment. “This is a significant improvement, but this still means the rest of the states are violating an actual law,” Dr. Gold said. “Another plus is that 17 states asked no questions at all that could require mental health disclosure. This, too is significant because it highlights change in thinking.”

But still, the fact that five states didn’t comply with any recommendation and only one followed all of them is “utterly unacceptable,” Dr. Gold said. “Instead, we should have universal adoption of FSMB recommendations.”
 

Time to remove stigma

Michael F. Myers, MD, a clinical psychiatrist at the State University of New York, Brooklyn, said removing the stigma of seeking help for mental health conditions is especially important for physicians. He’s written several books about physician mental health, including his latest, “Becoming a Doctor’s Doctor: A Memoir.”

“I would say at least 15% of the families that I interviewed who lost a physician loved one to suicide have said the doctor was petrified of going for professional help because of fears of what this could do to their medical license,” he said. “It is extremely important that those licensing questions will be either brought up to speed, or ­– the ones that are clearly violating the ADA – that they be removed.”

Applications for hospital privileges can also run afoul of the same ADA standard, Dr. Myers added. “Physicians have told me that when they go to get medical privileges at a medical center, they get asked all kinds of questions that are outdated, that are intrusive, that violate the ADA,” he said.

Credentialing is another area that Dr. Gold and her colleagues are interested in studying, she said. “Sometimes the licensing applications can be fine, but then the hospital someone is applying to work at can ask the same illegal questions anyway,” she said. “So it doesn’t matter that the state fixed the problem because the hospital asked them anyway. You feel your job is at risk in the same way, so you still don’t get help.”

Dr. Gold and Dr. Myers have no relevant financial relationships to disclose.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

Hemoglobin A1c above 5% but below the prediabetes cutoff of 5.5% is an additional potential biomarker of subclinical atherosclerosis in people with low cardiovascular disease risk, according to an analysis of data on almost 4,000 middle-aged individuals.

Mount Sinai Heart/CCA 3.0

“If one looks at the incidence of generalized subclinical atherosclerosis, we are not talking small numbers,” senior study author Valentin Fuster, MD, PhD, said in an interview. “We are talking about between 45% and 82% of this middle-age population that already has atherosclerotic disease subclinically.

“Actually,” he added, “the disease was extensive in 5%-30% of these individuals of middle age.”

The study included 3,973 participants from the Progression of Early Subclinical Atherosclerosis study who did not have diabetes. A1c showed an association with the prevalence and multiterritorial extent of subclinical atherosclerosis as measured by two-dimensional ultrasound and coronary artery calcium score (CACS; P < .001). For example, those with A1c above 6.1% (133 participants) had a 33.1% rate of generalized subclinical atherosclerosis, compared with 4.9% for those with A1c below 4.8% (243), the lowest-score group in the study.

Patients in the subprediabetes band, between 5.0% and 5.5%, had significantly higher rates of generalized subclinical atherosclerosis than did the lowest-score group: 8% in the 4.9%-5.0% group (375 participants); 9.9% in the 5.1%-5.2% range (687); 10.3% in the 5.3%-5.4% group (928); and 11.5% in the 5.5%-5.6% group (842).

Those in the 5.1%-5.2% and 5/3%-5.4% A1c groups had a 27% greater chance of having subclinical atherosclerosis, while those in the 5.5%-5.6% group had a 36% greater risk, according to an odds ratio analysis adjusted for established cardiovascular risk factors. The risks were even higher for patients with prediabetes, the researchers reported in the Journal of the American College of Cardiology.
 

A call for earlier intervention

Notably, the study found that fasting plasma glucose testing did not yield a similar association between A1c and atherosclerosis.

“The message is that we all talk about people when they are close to the development of cardiovascular events, and here we are talking about people who we should pay attention to much earlier,” said Dr. Fuster, physician-in-chief at Icahn School of Medicine at Mount Sinai in New York and director of the National Center for Cardiovascular Investigation in Madrid, where the observational study originated said. “People should be sensitized to HbA1c much more than they would’ve been in the past, and I think this study actually validates that.”

Christie Ballantyne, MD, noted in an interview that these findings support the utility of A1c for predicting CVD risk.

“I think more and more we should be ordering a HbA1c” during routine physical exams, Dr. Ballantyne said. “You don’t have to be obese to get it; there are lots of people, maybe they’re slightly overweight. It’s a reasonable test to be getting when you get to middle age and older to get an idea for assessing for both developing diabetes and also the presence of atherosclerosis and the risk for having cardiovascular events.”

Dr. Ballantyne, chief of cardiology at Baylor College of Medicine and director of cardiovascular disease prevention at Methodist DeBakey Heart Center in Houston, coauthored an editorial comment on the study.

Clinicians typically start to manage CVD and diabetes risk “late in the process,” Dr. Ballantyne said. This study suggested that earlier use of antidiabetes therapies, namely peptide-1 agonists and semisynthetic glucagon-like peptide-2 inhibitors, may be warranted in patients with intermediate risk of CVD.

“It’s just more data for the rationale that, perhaps we could end up doing trials to show we can take high-risk people and prevent them from getting both heart disease and diabetes,” Dr. Ballantyne added. “Could we start a little earlier with better precision?”

These finding don’t yet call for a change in how cardiologists and endocrinologists manage patients on the cusp of prediabetes, said Paul S. Jellinger, MD, of Hollywood, Fla., and a professor at the University of Miami. “The endpoint of subclinical atherosclerosis does not necessarily translate into the harder endpoint of CVD events, although there is certainly reason to believe it does,” he said in an interview, noting that he’s often used CACS to stratify atherosclerotic CVD risk in patients.

The first clinical trial of fecal microbiota transplantation in patients with psoriatic arthritis has found the procedure to be as safe as a sham procedure, but it didn’t show any effectiveness in decreasing PsA symptoms over 6 months, a team of researchers in Denmark reported in Annals of the Rheumatic Diseases (2021 Apr 29. 10.1136/annrheumdis-2020-219511).

ChrisChrisW/Getty Images

Nonetheless, the investigators said the trial indicates fecal microbiota transplantation (FMT) is worthy of further study.

“Overall, we think that the results are very interesting and that the feasibility and safety aspects as well as the clinical results of the trial may encourage more research into the potential of FMT in the treatment of inflammatory arthritis and may help guide the direction of future trials within the field,” lead author Maja S. Kragsnaes, MD, PhD, and principal investigator Torkell Ellingsen, MD, PhD, of Odense (Denmark) University Hospital said together in an interview.

“The most important findings from this trial is that FMT appears to be safe in patients with PsA and that the patients find the treatment acceptable, and it supports future research into the therapeutic potential of FMT in PsA,” they said.

The study evaluated 6-month outcomes of 31 patients randomized to the FMT and sham groups. FMT patients were three times more likely to experience treatment failure – defined by the need for treatment intensification – with failure rates of 60% versus 20% in the sham group.

As a secondary endpoint, the study used 6-month change in the Health Assessment Questionnaire Disability Index (HAQ-DI) and 20% improvement in American College of Rheumatology criteria (ACR20). The sham group demonstrated a greater decrease in HAQ-DI, indicating better physical function (–0.30 vs. –0.07; P = .031). The proportion of ACR20 responders was similar between both groups: 47% for the FMT patients (7 of 15) and 53% for sham (8 of 15).

The study included adults aged 18-75 years with active peripheral disease, defined as three or more swollen joints, who’d been taking at least15 mg methotrexate a week for at least 3 months before enrolling in the study, with a washout period of 12 weeks (26 weeks for those on biologic agents). Four healthy donors provided the stool transplants.

In the study, Dr. Kragsnaes and Dr. Ellingsen acknowledged that FMT has been shown to be safe for Clostridioides difficile infection or inflammatory bowel disease when “thoroughly screened stool” is used. “Hence,” they wrote, “our findings add to the growing body of evidence suggesting a gut-joint axis in the pathogenesis of PsA.”

Factors that may influence the effectiveness of FMT in PsA merit further investigation, Dr. Kragsnaes and Dr. Ellingsen said. “From FMT trials in patients with active ulcerative colitis, higher dose and repeated administration appear to be effective and safe in inducing remission,” they said in their joint statement, pointing to research from China.

“Moreover,” they added, “successes of FMT in inflammatory bowel disease appear to have been driven by ‘superdonors’ characterized by the presence or absence of specific bacteria species.”

They said will continue to investigate the effectiveness of FMT in immune-mediated diseases, including how to characterize superdonors.

“We will conduct new randomized trials using different FMT strategies – by changing the type of administration form, dose, and treatment frequency – to explore whether microbial dysbiosis or specific bacteria are common or decisive mediators of disease activity in inflammatory diseases and whether this proposed relation can be modified without exacerbating the disease,” Dr. Kragsnaes and Dr. Ellingsen said.

Dr. Kragsnaes and Dr. Ellingsen had no relevant financial relationships to disclose.

The first clinical trial of fecal microbiota transplantation in patients with psoriatic arthritis has found the procedure to be as safe as a sham procedure, but it didn’t show any effectiveness in decreasing PsA symptoms over 6 months, a team of researchers in Denmark reported in Annals of the Rheumatic Diseases (2021 Apr 29. 10.1136/annrheumdis-2020-219511).

ChrisChrisW/Getty Images

Nonetheless, the investigators said the trial indicates fecal microbiota transplantation (FMT) is worthy of further study.

“Overall, we think that the results are very interesting and that the feasibility and safety aspects as well as the clinical results of the trial may encourage more research into the potential of FMT in the treatment of inflammatory arthritis and may help guide the direction of future trials within the field,” lead author Maja S. Kragsnaes, MD, PhD, and principal investigator Torkell Ellingsen, MD, PhD, of Odense (Denmark) University Hospital said together in an interview.

“The most important findings from this trial is that FMT appears to be safe in patients with PsA and that the patients find the treatment acceptable, and it supports future research into the therapeutic potential of FMT in PsA,” they said.

The study evaluated 6-month outcomes of 31 patients randomized to the FMT and sham groups. FMT patients were three times more likely to experience treatment failure – defined by the need for treatment intensification – with failure rates of 60% versus 20% in the sham group.

As a secondary endpoint, the study used 6-month change in the Health Assessment Questionnaire Disability Index (HAQ-DI) and 20% improvement in American College of Rheumatology criteria (ACR20). The sham group demonstrated a greater decrease in HAQ-DI, indicating better physical function (–0.30 vs. –0.07; P = .031). The proportion of ACR20 responders was similar between both groups: 47% for the FMT patients (7 of 15) and 53% for sham (8 of 15).

The study included adults aged 18-75 years with active peripheral disease, defined as three or more swollen joints, who’d been taking at least15 mg methotrexate a week for at least 3 months before enrolling in the study, with a washout period of 12 weeks (26 weeks for those on biologic agents). Four healthy donors provided the stool transplants.

In the study, Dr. Kragsnaes and Dr. Ellingsen acknowledged that FMT has been shown to be safe for Clostridioides difficile infection or inflammatory bowel disease when “thoroughly screened stool” is used. “Hence,” they wrote, “our findings add to the growing body of evidence suggesting a gut-joint axis in the pathogenesis of PsA.”

Factors that may influence the effectiveness of FMT in PsA merit further investigation, Dr. Kragsnaes and Dr. Ellingsen said. “From FMT trials in patients with active ulcerative colitis, higher dose and repeated administration appear to be effective and safe in inducing remission,” they said in their joint statement, pointing to research from China.

“Moreover,” they added, “successes of FMT in inflammatory bowel disease appear to have been driven by ‘superdonors’ characterized by the presence or absence of specific bacteria species.”

They said will continue to investigate the effectiveness of FMT in immune-mediated diseases, including how to characterize superdonors.

“We will conduct new randomized trials using different FMT strategies – by changing the type of administration form, dose, and treatment frequency – to explore whether microbial dysbiosis or specific bacteria are common or decisive mediators of disease activity in inflammatory diseases and whether this proposed relation can be modified without exacerbating the disease,” Dr. Kragsnaes and Dr. Ellingsen said.

Dr. Kragsnaes and Dr. Ellingsen had no relevant financial relationships to disclose.

The first clinical trial of fecal microbiota transplantation in patients with psoriatic arthritis has found the procedure to be as safe as a sham procedure, but it didn’t show any effectiveness in decreasing PsA symptoms over 6 months, a team of researchers in Denmark reported in Annals of the Rheumatic Diseases (2021 Apr 29. 10.1136/annrheumdis-2020-219511).

ChrisChrisW/Getty Images

Nonetheless, the investigators said the trial indicates fecal microbiota transplantation (FMT) is worthy of further study.

“Overall, we think that the results are very interesting and that the feasibility and safety aspects as well as the clinical results of the trial may encourage more research into the potential of FMT in the treatment of inflammatory arthritis and may help guide the direction of future trials within the field,” lead author Maja S. Kragsnaes, MD, PhD, and principal investigator Torkell Ellingsen, MD, PhD, of Odense (Denmark) University Hospital said together in an interview.

“The most important findings from this trial is that FMT appears to be safe in patients with PsA and that the patients find the treatment acceptable, and it supports future research into the therapeutic potential of FMT in PsA,” they said.

The study evaluated 6-month outcomes of 31 patients randomized to the FMT and sham groups. FMT patients were three times more likely to experience treatment failure – defined by the need for treatment intensification – with failure rates of 60% versus 20% in the sham group.

As a secondary endpoint, the study used 6-month change in the Health Assessment Questionnaire Disability Index (HAQ-DI) and 20% improvement in American College of Rheumatology criteria (ACR20). The sham group demonstrated a greater decrease in HAQ-DI, indicating better physical function (–0.30 vs. –0.07; P = .031). The proportion of ACR20 responders was similar between both groups: 47% for the FMT patients (7 of 15) and 53% for sham (8 of 15).

The study included adults aged 18-75 years with active peripheral disease, defined as three or more swollen joints, who’d been taking at least15 mg methotrexate a week for at least 3 months before enrolling in the study, with a washout period of 12 weeks (26 weeks for those on biologic agents). Four healthy donors provided the stool transplants.

In the study, Dr. Kragsnaes and Dr. Ellingsen acknowledged that FMT has been shown to be safe for Clostridioides difficile infection or inflammatory bowel disease when “thoroughly screened stool” is used. “Hence,” they wrote, “our findings add to the growing body of evidence suggesting a gut-joint axis in the pathogenesis of PsA.”

Factors that may influence the effectiveness of FMT in PsA merit further investigation, Dr. Kragsnaes and Dr. Ellingsen said. “From FMT trials in patients with active ulcerative colitis, higher dose and repeated administration appear to be effective and safe in inducing remission,” they said in their joint statement, pointing to research from China.

“Moreover,” they added, “successes of FMT in inflammatory bowel disease appear to have been driven by ‘superdonors’ characterized by the presence or absence of specific bacteria species.”

They said will continue to investigate the effectiveness of FMT in immune-mediated diseases, including how to characterize superdonors.

“We will conduct new randomized trials using different FMT strategies – by changing the type of administration form, dose, and treatment frequency – to explore whether microbial dysbiosis or specific bacteria are common or decisive mediators of disease activity in inflammatory diseases and whether this proposed relation can be modified without exacerbating the disease,” Dr. Kragsnaes and Dr. Ellingsen said.

Dr. Kragsnaes and Dr. Ellingsen had no relevant financial relationships to disclose.