Richard Mark Kirkner

Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.

And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.

“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.

Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).

Observational registry study shows 43% reduction in primary outcome

The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.

The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.

Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.

Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).

Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.

Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.

“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”

Noncompliance to DOAC therapy a concern

In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”

However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.

“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”

Methods ‘severely flawed’

John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.

“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”

Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.

Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.

Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.

Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.

And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.

“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.

Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).

Observational registry study shows 43% reduction in primary outcome

The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.

The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.

Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.

Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).

Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.

Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.

“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”

Noncompliance to DOAC therapy a concern

In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”

However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.

“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”

Methods ‘severely flawed’

John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.

“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”

Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.

Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.

Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.

Left atrial appendage occlusion (LAAO) for high-risk atrial fibrillation seems to prevent stroke as well as direct oral anticoagulation (DOAC) with a lower risk of major bleeding, according to results of a European study.

And although some experts question the strength of the conclusions, a lead researcher contends the study may provide enough support for interventional cardiologists to consider LAAO in selected patients until randomized clinical trials yield stronger evidence.

“The results suggest LAAO to be superior to DOAC in AF patients who have a predicted high risk of stroke and bleeding and adds to the evidence that LAAO is a promising stroke prevention strategy in selected AF patients,” said lead investigator Jens Erik Nielsen-Kudsk, MD, DMSc, a cardiologist at Aarhus University Hospital in Denmark.

Dr. Nielsen-Kudsk and colleagues wrote in JACC: Cardiovascular Interventions that this is the largest comparative study of LAAO vs. DOAC to date, but they also acknowledged the study limitations: its observational design, unaccounted confounders, potential selection bias, and disparities in the nature of the comparative datasets (a multination cohort vs. a single national registry).

Observational registry study shows 43% reduction in primary outcome

The study compared outcomes of 1,078 patients from the Amulet Observational Study who had LAAO during June 2015–September 2016 with 1,184 patients on DOAC therapy selected by propensity score matching from two Danish national registries. The LAAO population was prospectively enrolled at 61 centers in 17 countries. The study population had a high risk of stroke and bleeding; about one-third had a previous stroke and about three-quarters had a prior bleeding episode. The average age was 75 years.

The LAAO group had almost half the rate of the primary outcome – either stroke, major bleeding, or all-cause death – 256 vs. 461 events in the DOAC group with median follow-up of 2 years. The annualized event rate was significantly lower for the LAAO group: 14.5 vs. 25.7 per 100 patient years in the DOAC group. The researchers calculated the LAAO group had a relative 43% reduction risk.

Of the LAAO group, 155 patients (14.5%) died in the follow-up period, 35% of them from a cardiovascular cause, whereas 308 (26%) of patients in the DOAC group died, with a similar percentage, 36%, from a cardiovascular cause.

Using data from the Danish Cause of Death Registry, the study determined cause of death in the DOAC patients on a more granular level: 9.5% of the deaths were from vascular disease and 4.5% from stroke (the remainder in both groups were from noncardiovascular events).

Stroke incidence was similar between the two groups: 39 in the LAAO group vs. 37 in DOAC patients, conferring an 11% greater risk in the former. The risk of major bleeding and all-cause mortality were significantly lower in LAAO patients, 37% and 47%, respectively. However, 50% of DOAC patients had discontinued therapy after a year of follow-up, and 58% had done so after 2 years.

Dr. Nielsen-Kudsk noted that the findings line up with those from the smaller PRAQUE-17 study comparing LAAO and DOAC. He added that his group is participating in two larger RCTs, CATALYST and CHAMPION-AF, evaluating LAAO and medical therapy in about 6,000 patients combined.

“It will take at least 2 to 5 years before we have data from these randomized LAAO trials,” Dr. Nielsen-Kudsk said. “Meanwhile, based on data from three prior randomized clinical trials, propensity-score matched studies and data from large registries, LAAO should be considered in clinical practice for patients who have a high risk of bleeding or who for any other reason are unsuitable for long-term DOAC treatment.”

Noncompliance to DOAC therapy a concern

In an invited commentary, Mohamad Alkhouli, MD, of the Mayo Medical School, Rochester, Minn., wrote, “These findings provide reassuring evidence supporting the efficacy of LAAO despite the remaining challenges with this therapy.”

However, Dr. Alkhouli pointed out that the high rate of noncompliance among AF patients on DOAC can be a confounding factor for interpreting the efficacy of therapy. “This highlights the challenges of comparing LAAO to DOAC, considering that many patients are actually not on effective anticoagulation, but also suggests a possible real important role for LAAO in addressing the unmet need in stroke prevention in nonvalvular atrial fibrillation,” he said in an interview.

“The study showed a very good safety profile for LAAO,” Dr. Alkhouli added. “However, we should remember that this was an observational study without routine temporal imaging and a relatively short-term follow- up.”

Methods ‘severely flawed’

John Mandrola, MD, an electrophysiologist at Baptist Health in Louisville, Ky., said the study methodology was “severely flawed,” citing its nonrandomized nature and enrollment of only patients with successful implants in the LAAO group. “You have to take all patients who had attempted implants,” he said. Further, the study may be subject to selection bias based on how patients were recruited for the Ampulet Observational Study.

“Comparing LAAO to DOAC is a vital clinical question,” said Dr. Mandrola. “It simply cannot be answered with observational methods like this. It requires a properly powered RCT.”

Dr. Alkhouli said he’s looking forward to results from five large RCTS evaluating LAAO due in 3-5 years. “Until the results of those trials are out, careful patient selection and shared decision-making should continue to govern the rational dissipation of LAAO as a stroke prevention strategy,” he said.

Novo Nordisk Research Foundation supported the study and Abbott provided a grant. Dr. Nielsen-Kudsk disclosed financial relationships with Abbott and Boston Scientific. Coauthors disclosed relationships with Abbott, Boston Scientific, Bayer Vital, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Pfizer, Portolo, and Sanofi.

Dr. Alkhouli disclosed a relationship with Boston Scientific. Dr. Mandrola has no relevant disclosures. He is chief cardiology correspondent for Medscape.com. MDedge is a member of the Medscape Professional Network.

A long-awaited update to asthma management guidelines, developed by an expert panel at the National Heart, Lung, and Blood Institute, has been released.

Courtesy University of Wisconsin Health System

The updated guidelines address six priority topics, including refined recommendations for the use of fractional exhaled nitric oxide (FeNO) testing, intermittent inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and bronchial thermoplasty, but notably exclude any recommendations for the use of fast-emerging biological therapy.

“Biological therapy is the major step forward,” said William W. Busse, MD, professor of allergy and immunology at the University of Wisconsin–Madison, and lead author of the previous guidelines (Bethesda, Md.: NHLBI, 2007). “It wasn’t within the scope of work, so it’s not a criticism, but it is an important shortcoming,” he said. The omission identifies the need for the next update. “This is an area that has to be dealt with,” Dr. Busse stated in an interview.

Including biologic agents would have delayed the release of the recommendations for another year or 2, wrote the expert panel working group of the NHLBI, “and this was felt to be unacceptable.” The working group, overseen by the National Asthma Education and Prevention Program Coordinating Committee, also acknowledged the update is “not a complete revision” of the 2007 guidelines.

The update provides an evidenced-based review of six key topics in asthma care, as Mary Cataletto, MD, FCCP, professor of pediatrics at New York University Long Island, Mineola, pointed out: use of FeNO, indoor allergen mitigation, use of intermittent ICS and LAMA for asthma, role of subcutaneous and sublingual immunotherapy in the treatment of allergic asthma, and the use of bronchial thermoplasty.

“It has been 13 years since the last update and substantial progress has been made since then in understanding how to best treat children and adults with asthma,” said working group member Michael Schatz, MD, MS, FCCP, an allergy specialist at Kaiser Permanente Medical Center in San Diego.

According to Dr. Schatz, the most important updated recommendations are:

• Conditional recommendation for the use of ICS in children aged infant to 4 years with recurrent wheezing with respiratory infections.
• Use of combination ICS-formoterol for maintenance and to relieve flares in patients with moderate to severe asthma.
• Addition of the LAMA inhaled bronchodilator as add-on therapy for severe asthma not controlled by long-acting beta-agonist (LABA)/ICS combination medications.

Another important update, Dr. Cataletto said, is “shared decision-making among members of asthma teams in order to improve asthma care across all age groups.”

In all, the update includes 19 recommendations in the six subject areas. Each recommendation is notated with two values: its strength, either strong or conditional, and the certainty of evidence behind it, either low, moderate, or high. For example, the recommendation for ICS in young children that Dr. Schatz referred to has a conditional strength of recommendation with moderate certainty of evidence.

Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to determine strength of recommendation is a notable innovation of the latest guidelines, Dr. Busse noted.

Recommendations (strength of recommendation/certainty of evidence) include:

• Use of FeNO in children and adults when the asthma diagnosis is uncertain (conditional/moderate) or in those with allergic asthma and an uncertain course of management (conditional/low).
• Avoid standalone FeNO to evaluate asthma control or the likelihood or severity of future exacerbations, or for in infants to 4-year-olds with recurrent wheezing (strong/low for both).
• Avoid allergen mitigation in routine asthma management for patients who don’t have sensitivity to specific indoor allergens (conditional/low).
• Multicomponent allergen-specific mitigation when specific allergen sensitivity has been identified and pest management alone for symptoms related to specific pest exposure (conditional/low for both).
• Impermeable bedding covers should be part of a multicomponent mitigation strategy, not as a standalone tool, for patients with asthma and dust mite sensitivity (conditional/moderate).
• Daily ICS at onset of a respiratory tract infection along with as-needed short-acting beta-agonists in children aged 4 years and younger with recurrent wheezing but no wheezing between infections rather than as-needed standalone SABA (conditional/high).
• For adults and children aged 12 years and older with mild persistent asthma, either daily low-dose ICS with as-needed SABA or as-needed ICS and SABA concomitantly (conditional/moderate).
• Avoid short-course increased ICS dosing for patients aged 4 years and older with good adherence to daily ICS therapy (conditional/low).
• For patients aged 4 years and older with moderate to severe persistent asthma, a preference for combined ICS-formoterol inhaler over higher dose ICS daily and intermittent SABA or daily ICS-LABA with intermittent SABA (strong/high [aged 12 years and older]; moderate [aged 4-11 years]).
• A preference for combined ICS-formoterol for both daily and relief therapy for patients 12 years and older with severe persistent asthma over higher-dose ICS-LABA daily and intermittent SABA (conditional/high).
• A preference for adding LABA rather than LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma (conditional/moderate).
• If LABA isn’t used, add LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma rather than continuing the same dose of ICS alone (conditional/moderate).
• In those same patients already on combined ICS-LABA therapy, add LAMA rather than continuing the same dose of ICS-LABA (conditional/moderate).
• Use subcutaneous immunotherapy as a potential adjunct to standard drug therapy in patients aged 5 years and older with mild to moderate allergic asthma when their asthma is controlled on immunotherapy (conditional/moderate).
• Avoid sublingual immunotherapy in patients with persistent allergic asthma (conditional/moderate).
• Avoid bronchial thermoplasty in those 18 years and older with persistent asthma, but consider it in patients who can accept the short-term worsening symptoms or unknown long-term side effects in exchange for the potential benefits (conditional/moderate).

One of the key elements of the guidelines is the use of the SMART (single maintenance and reliever therapy) approach to evaluate the comparative effectiveness of intermittent ICS with formoterol, Dr. Busse noted. “I think that’s a very significant advance. The literature is replete with evidence to support this. Secondly, it really makes life convenient for patients; you have one inhaler.”

The recommendation on SABA use is also significant, Dr. Busse said. “Data have emerged to suggest that if you’re having a need for one of these rescue medications, it’s due to an increase in inflammation in the lower airway, and you want to give an ICS which will act on the inflammation along with the bronchodilator. That’s a new concept, and it’s a very significant step forward.”

Dr. Schatz disclosed financial relationships with Merck, Teva, and ALK-Abello, but was recused from the writing, discussion, and voting related to the immunotherapy recommendation. Dr. Cataletto and Dr. Busse have no relevant relationships to disclose.

SOURCE: Schatz M et al. J Allergy Clin Immunol. 2020;146:1217-70.

A long-awaited update to asthma management guidelines, developed by an expert panel at the National Heart, Lung, and Blood Institute, has been released.

Courtesy University of Wisconsin Health System

The updated guidelines address six priority topics, including refined recommendations for the use of fractional exhaled nitric oxide (FeNO) testing, intermittent inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and bronchial thermoplasty, but notably exclude any recommendations for the use of fast-emerging biological therapy.

“Biological therapy is the major step forward,” said William W. Busse, MD, professor of allergy and immunology at the University of Wisconsin–Madison, and lead author of the previous guidelines (Bethesda, Md.: NHLBI, 2007). “It wasn’t within the scope of work, so it’s not a criticism, but it is an important shortcoming,” he said. The omission identifies the need for the next update. “This is an area that has to be dealt with,” Dr. Busse stated in an interview.

Including biologic agents would have delayed the release of the recommendations for another year or 2, wrote the expert panel working group of the NHLBI, “and this was felt to be unacceptable.” The working group, overseen by the National Asthma Education and Prevention Program Coordinating Committee, also acknowledged the update is “not a complete revision” of the 2007 guidelines.

The update provides an evidenced-based review of six key topics in asthma care, as Mary Cataletto, MD, FCCP, professor of pediatrics at New York University Long Island, Mineola, pointed out: use of FeNO, indoor allergen mitigation, use of intermittent ICS and LAMA for asthma, role of subcutaneous and sublingual immunotherapy in the treatment of allergic asthma, and the use of bronchial thermoplasty.

“It has been 13 years since the last update and substantial progress has been made since then in understanding how to best treat children and adults with asthma,” said working group member Michael Schatz, MD, MS, FCCP, an allergy specialist at Kaiser Permanente Medical Center in San Diego.

According to Dr. Schatz, the most important updated recommendations are:

• Conditional recommendation for the use of ICS in children aged infant to 4 years with recurrent wheezing with respiratory infections.
• Use of combination ICS-formoterol for maintenance and to relieve flares in patients with moderate to severe asthma.
• Addition of the LAMA inhaled bronchodilator as add-on therapy for severe asthma not controlled by long-acting beta-agonist (LABA)/ICS combination medications.

Another important update, Dr. Cataletto said, is “shared decision-making among members of asthma teams in order to improve asthma care across all age groups.”

In all, the update includes 19 recommendations in the six subject areas. Each recommendation is notated with two values: its strength, either strong or conditional, and the certainty of evidence behind it, either low, moderate, or high. For example, the recommendation for ICS in young children that Dr. Schatz referred to has a conditional strength of recommendation with moderate certainty of evidence.

Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to determine strength of recommendation is a notable innovation of the latest guidelines, Dr. Busse noted.

Recommendations (strength of recommendation/certainty of evidence) include:

• Use of FeNO in children and adults when the asthma diagnosis is uncertain (conditional/moderate) or in those with allergic asthma and an uncertain course of management (conditional/low).
• Avoid standalone FeNO to evaluate asthma control or the likelihood or severity of future exacerbations, or for in infants to 4-year-olds with recurrent wheezing (strong/low for both).
• Avoid allergen mitigation in routine asthma management for patients who don’t have sensitivity to specific indoor allergens (conditional/low).
• Multicomponent allergen-specific mitigation when specific allergen sensitivity has been identified and pest management alone for symptoms related to specific pest exposure (conditional/low for both).
• Impermeable bedding covers should be part of a multicomponent mitigation strategy, not as a standalone tool, for patients with asthma and dust mite sensitivity (conditional/moderate).
• Daily ICS at onset of a respiratory tract infection along with as-needed short-acting beta-agonists in children aged 4 years and younger with recurrent wheezing but no wheezing between infections rather than as-needed standalone SABA (conditional/high).
• For adults and children aged 12 years and older with mild persistent asthma, either daily low-dose ICS with as-needed SABA or as-needed ICS and SABA concomitantly (conditional/moderate).
• Avoid short-course increased ICS dosing for patients aged 4 years and older with good adherence to daily ICS therapy (conditional/low).
• For patients aged 4 years and older with moderate to severe persistent asthma, a preference for combined ICS-formoterol inhaler over higher dose ICS daily and intermittent SABA or daily ICS-LABA with intermittent SABA (strong/high [aged 12 years and older]; moderate [aged 4-11 years]).
• A preference for combined ICS-formoterol for both daily and relief therapy for patients 12 years and older with severe persistent asthma over higher-dose ICS-LABA daily and intermittent SABA (conditional/high).
• A preference for adding LABA rather than LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma (conditional/moderate).
• If LABA isn’t used, add LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma rather than continuing the same dose of ICS alone (conditional/moderate).
• In those same patients already on combined ICS-LABA therapy, add LAMA rather than continuing the same dose of ICS-LABA (conditional/moderate).
• Use subcutaneous immunotherapy as a potential adjunct to standard drug therapy in patients aged 5 years and older with mild to moderate allergic asthma when their asthma is controlled on immunotherapy (conditional/moderate).
• Avoid sublingual immunotherapy in patients with persistent allergic asthma (conditional/moderate).
• Avoid bronchial thermoplasty in those 18 years and older with persistent asthma, but consider it in patients who can accept the short-term worsening symptoms or unknown long-term side effects in exchange for the potential benefits (conditional/moderate).

One of the key elements of the guidelines is the use of the SMART (single maintenance and reliever therapy) approach to evaluate the comparative effectiveness of intermittent ICS with formoterol, Dr. Busse noted. “I think that’s a very significant advance. The literature is replete with evidence to support this. Secondly, it really makes life convenient for patients; you have one inhaler.”

The recommendation on SABA use is also significant, Dr. Busse said. “Data have emerged to suggest that if you’re having a need for one of these rescue medications, it’s due to an increase in inflammation in the lower airway, and you want to give an ICS which will act on the inflammation along with the bronchodilator. That’s a new concept, and it’s a very significant step forward.”

Dr. Schatz disclosed financial relationships with Merck, Teva, and ALK-Abello, but was recused from the writing, discussion, and voting related to the immunotherapy recommendation. Dr. Cataletto and Dr. Busse have no relevant relationships to disclose.

SOURCE: Schatz M et al. J Allergy Clin Immunol. 2020;146:1217-70.

A long-awaited update to asthma management guidelines, developed by an expert panel at the National Heart, Lung, and Blood Institute, has been released.

Courtesy University of Wisconsin Health System

The updated guidelines address six priority topics, including refined recommendations for the use of fractional exhaled nitric oxide (FeNO) testing, intermittent inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and bronchial thermoplasty, but notably exclude any recommendations for the use of fast-emerging biological therapy.

“Biological therapy is the major step forward,” said William W. Busse, MD, professor of allergy and immunology at the University of Wisconsin–Madison, and lead author of the previous guidelines (Bethesda, Md.: NHLBI, 2007). “It wasn’t within the scope of work, so it’s not a criticism, but it is an important shortcoming,” he said. The omission identifies the need for the next update. “This is an area that has to be dealt with,” Dr. Busse stated in an interview.

Including biologic agents would have delayed the release of the recommendations for another year or 2, wrote the expert panel working group of the NHLBI, “and this was felt to be unacceptable.” The working group, overseen by the National Asthma Education and Prevention Program Coordinating Committee, also acknowledged the update is “not a complete revision” of the 2007 guidelines.

The update provides an evidenced-based review of six key topics in asthma care, as Mary Cataletto, MD, FCCP, professor of pediatrics at New York University Long Island, Mineola, pointed out: use of FeNO, indoor allergen mitigation, use of intermittent ICS and LAMA for asthma, role of subcutaneous and sublingual immunotherapy in the treatment of allergic asthma, and the use of bronchial thermoplasty.

“It has been 13 years since the last update and substantial progress has been made since then in understanding how to best treat children and adults with asthma,” said working group member Michael Schatz, MD, MS, FCCP, an allergy specialist at Kaiser Permanente Medical Center in San Diego.

According to Dr. Schatz, the most important updated recommendations are:

• Conditional recommendation for the use of ICS in children aged infant to 4 years with recurrent wheezing with respiratory infections.
• Use of combination ICS-formoterol for maintenance and to relieve flares in patients with moderate to severe asthma.
• Addition of the LAMA inhaled bronchodilator as add-on therapy for severe asthma not controlled by long-acting beta-agonist (LABA)/ICS combination medications.

Another important update, Dr. Cataletto said, is “shared decision-making among members of asthma teams in order to improve asthma care across all age groups.”

In all, the update includes 19 recommendations in the six subject areas. Each recommendation is notated with two values: its strength, either strong or conditional, and the certainty of evidence behind it, either low, moderate, or high. For example, the recommendation for ICS in young children that Dr. Schatz referred to has a conditional strength of recommendation with moderate certainty of evidence.

Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to determine strength of recommendation is a notable innovation of the latest guidelines, Dr. Busse noted.

Recommendations (strength of recommendation/certainty of evidence) include:

• Use of FeNO in children and adults when the asthma diagnosis is uncertain (conditional/moderate) or in those with allergic asthma and an uncertain course of management (conditional/low).
• Avoid standalone FeNO to evaluate asthma control or the likelihood or severity of future exacerbations, or for in infants to 4-year-olds with recurrent wheezing (strong/low for both).
• Avoid allergen mitigation in routine asthma management for patients who don’t have sensitivity to specific indoor allergens (conditional/low).
• Multicomponent allergen-specific mitigation when specific allergen sensitivity has been identified and pest management alone for symptoms related to specific pest exposure (conditional/low for both).
• Impermeable bedding covers should be part of a multicomponent mitigation strategy, not as a standalone tool, for patients with asthma and dust mite sensitivity (conditional/moderate).
• Daily ICS at onset of a respiratory tract infection along with as-needed short-acting beta-agonists in children aged 4 years and younger with recurrent wheezing but no wheezing between infections rather than as-needed standalone SABA (conditional/high).
• For adults and children aged 12 years and older with mild persistent asthma, either daily low-dose ICS with as-needed SABA or as-needed ICS and SABA concomitantly (conditional/moderate).
• Avoid short-course increased ICS dosing for patients aged 4 years and older with good adherence to daily ICS therapy (conditional/low).
• For patients aged 4 years and older with moderate to severe persistent asthma, a preference for combined ICS-formoterol inhaler over higher dose ICS daily and intermittent SABA or daily ICS-LABA with intermittent SABA (strong/high [aged 12 years and older]; moderate [aged 4-11 years]).
• A preference for combined ICS-formoterol for both daily and relief therapy for patients 12 years and older with severe persistent asthma over higher-dose ICS-LABA daily and intermittent SABA (conditional/high).
• A preference for adding LABA rather than LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma (conditional/moderate).
• If LABA isn’t used, add LAMA to ICS in patients aged 12 years and older with uncontrolled persistent asthma rather than continuing the same dose of ICS alone (conditional/moderate).
• In those same patients already on combined ICS-LABA therapy, add LAMA rather than continuing the same dose of ICS-LABA (conditional/moderate).
• Use subcutaneous immunotherapy as a potential adjunct to standard drug therapy in patients aged 5 years and older with mild to moderate allergic asthma when their asthma is controlled on immunotherapy (conditional/moderate).
• Avoid sublingual immunotherapy in patients with persistent allergic asthma (conditional/moderate).
• Avoid bronchial thermoplasty in those 18 years and older with persistent asthma, but consider it in patients who can accept the short-term worsening symptoms or unknown long-term side effects in exchange for the potential benefits (conditional/moderate).

One of the key elements of the guidelines is the use of the SMART (single maintenance and reliever therapy) approach to evaluate the comparative effectiveness of intermittent ICS with formoterol, Dr. Busse noted. “I think that’s a very significant advance. The literature is replete with evidence to support this. Secondly, it really makes life convenient for patients; you have one inhaler.”

The recommendation on SABA use is also significant, Dr. Busse said. “Data have emerged to suggest that if you’re having a need for one of these rescue medications, it’s due to an increase in inflammation in the lower airway, and you want to give an ICS which will act on the inflammation along with the bronchodilator. That’s a new concept, and it’s a very significant step forward.”

Dr. Schatz disclosed financial relationships with Merck, Teva, and ALK-Abello, but was recused from the writing, discussion, and voting related to the immunotherapy recommendation. Dr. Cataletto and Dr. Busse have no relevant relationships to disclose.

SOURCE: Schatz M et al. J Allergy Clin Immunol. 2020;146:1217-70.

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

Reports of signs of heart failure in adults with COVID-19 have been rare – just four such cases have been published since the outbreak started in China – and now a team of pediatric cardiologists in New York have reported a case of acute but reversible myocardial injury in an infant with COVID-19.

Madhu S. et al. J Am Coll Cardiol Case Rep. 2020 doi: 10.1016/j.jaccas.2020.09.031

SOURCE: Sharma M et al. JACC Case Rep. 2020. doi: 10.1016/j.jaccas.2020.09.031.

Reports of signs of heart failure in adults with COVID-19 have been rare – just four such cases have been published since the outbreak started in China – and now a team of pediatric cardiologists in New York have reported a case of acute but reversible myocardial injury in an infant with COVID-19.

Madhu S. et al. J Am Coll Cardiol Case Rep. 2020 doi: 10.1016/j.jaccas.2020.09.031

SOURCE: Sharma M et al. JACC Case Rep. 2020. doi: 10.1016/j.jaccas.2020.09.031.

Reports of signs of heart failure in adults with COVID-19 have been rare – just four such cases have been published since the outbreak started in China – and now a team of pediatric cardiologists in New York have reported a case of acute but reversible myocardial injury in an infant with COVID-19.

Madhu S. et al. J Am Coll Cardiol Case Rep. 2020 doi: 10.1016/j.jaccas.2020.09.031

SOURCE: Sharma M et al. JACC Case Rep. 2020. doi: 10.1016/j.jaccas.2020.09.031.

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

Safety measures for lab monitoring of mineralocorticoid receptor agonist therapy, performance measures for sacubitril/valsartan, cardiac resynchronization therapy and titration of medications, and quality measures based on patient-reported outcomes are among the updates the joint task force of the American College of Cardiology and the American Heart Association have made to performance and quality measures for managing adults with heart failure.

The revisions, published online Nov. 2 in the Journal of the American College of Cardiology, update the 2011 ACC/AHA heart failure measure set, writing committee vice chair Gregg C. Fonarow, MD, said in an interview. The 2011 measure set predates the 2015 approval of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan for heart failure in adults.
 

Measures stress dosages, strength of evidence

“For the first time the heart failure performance measure sets also focus on not just the use of guideline-recommended medication at any dose, but on utilizing the doses that are evidence-based and guideline recommended so long as they are well tolerated,” said Dr. Fonarow, interim chief of cardiology at the University of California, Los Angeles. “The measure set now includes assessment of patients being treated with doses of medications at 50% or greater of target dose in the absence of contraindications or documented intolerance.”

The update includes seven new performance measures, two quality measures, and one structural measure. The performance measures come from the strongest recommendations – that is, a class of recommendation of 1 (strong) or 3 (no benefit or harmful, process to be avoided) – in the 2017 ACC/AHA/Heart Failure Society of American heart failure guideline update published in Circulation.

In addition to the 2017 update, the writing committee also reviewed existing performance measures. “Those management strategies, diagnostic testing, medications, and devices with the strongest evidence and highest level of guideline recommendations were further considered for inclusion in the performance measure set,” Dr. Fonarow said. “The measures went through extensive review by peer reviewers and approval from the organizations represented.”

Specifically, the update includes measures for monitoring serum potassium after starting mineralocorticoid receptor antagonists therapy, and cardiac resynchronization therapy for patients with heart failure with reduced ejection fraction already on guideline-directed therapy. “This therapy can significantly improve functional capacity and outcomes in appropriately selected patients,” Dr. Fonarow said.
 

New and retired measures

The update adds two performance measures for titration of medications based on dose, either reaching 50% of the recommended dose for a variety of medications, including ARNI, or documenting that the dose wasn’t tolerated for other reason for not using the dose.

The new structural measure calls for facility participation in a heart failure registry. The revised measure set now consists of 18 measures in all.

The update retired one measure from the 2011 set: left ventricular ejection fraction assessment for inpatients. The committee cited its use above 97% as the reason, but LVEF in outpatients remains a measure.

The following tree measures have been revised:

• Patient self-care education has moved from performance measure to quality measure because of concerns about the accuracy of self-care education documentation and limited evidence of improved outcomes with better documentation.
• ACE inhibitor or angiotensin receptor blocker therapy for left ventricular systolic dysfunction adds ARNI therapy to align with the 2017 ACC/AHA/HFSA update.
• Postdischarge appointments shifts from performance to quality measure and include a 7-day limit.

Measures future research should focus on, noted Dr. Fonarow, include the use of sodium glucose cotransporter 2 (SGLT2) inhibitors for heart failure, including in patients without diabetes. “Since the ACC/AHA heart failure guidelines had not yet been updated to recommend these therapies they could not be included in this performance measure set,” he said.

He also said “an urgent need” exists for further research into treatments for heart failure with preserved ejection fraction along with optimal implementation strategies.  

“If these ACC/AHA heart failure performance measures were applied in all settings in which patients with heart failure in the United States are being cared for, and optimal and equitable conformity with each of these measures were achieved, over 100,000 lives a year of patients with heart failure could be saved,” he said. “There’s in an urgent need to measure and improve heart failure care quality.”

Dr. Fonarow reported financial relationships with Abbott, Amgen, AstraZeneca, CHF Solutions, Janssen, Medtronic, Merck, and Novartis.

SOURCE: American College of Cardiology/American Heart Association Task Force on Performance Measures. J Am Coll Cardiol. 2020 Nov 2;76:2527-64.

Safety measures for lab monitoring of mineralocorticoid receptor agonist therapy, performance measures for sacubitril/valsartan, cardiac resynchronization therapy and titration of medications, and quality measures based on patient-reported outcomes are among the updates the joint task force of the American College of Cardiology and the American Heart Association have made to performance and quality measures for managing adults with heart failure.

The revisions, published online Nov. 2 in the Journal of the American College of Cardiology, update the 2011 ACC/AHA heart failure measure set, writing committee vice chair Gregg C. Fonarow, MD, said in an interview. The 2011 measure set predates the 2015 approval of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan for heart failure in adults.
 

Measures stress dosages, strength of evidence

“For the first time the heart failure performance measure sets also focus on not just the use of guideline-recommended medication at any dose, but on utilizing the doses that are evidence-based and guideline recommended so long as they are well tolerated,” said Dr. Fonarow, interim chief of cardiology at the University of California, Los Angeles. “The measure set now includes assessment of patients being treated with doses of medications at 50% or greater of target dose in the absence of contraindications or documented intolerance.”

The update includes seven new performance measures, two quality measures, and one structural measure. The performance measures come from the strongest recommendations – that is, a class of recommendation of 1 (strong) or 3 (no benefit or harmful, process to be avoided) – in the 2017 ACC/AHA/Heart Failure Society of American heart failure guideline update published in Circulation.

In addition to the 2017 update, the writing committee also reviewed existing performance measures. “Those management strategies, diagnostic testing, medications, and devices with the strongest evidence and highest level of guideline recommendations were further considered for inclusion in the performance measure set,” Dr. Fonarow said. “The measures went through extensive review by peer reviewers and approval from the organizations represented.”

Specifically, the update includes measures for monitoring serum potassium after starting mineralocorticoid receptor antagonists therapy, and cardiac resynchronization therapy for patients with heart failure with reduced ejection fraction already on guideline-directed therapy. “This therapy can significantly improve functional capacity and outcomes in appropriately selected patients,” Dr. Fonarow said.
 

New and retired measures

The update adds two performance measures for titration of medications based on dose, either reaching 50% of the recommended dose for a variety of medications, including ARNI, or documenting that the dose wasn’t tolerated for other reason for not using the dose.

The new structural measure calls for facility participation in a heart failure registry. The revised measure set now consists of 18 measures in all.

The update retired one measure from the 2011 set: left ventricular ejection fraction assessment for inpatients. The committee cited its use above 97% as the reason, but LVEF in outpatients remains a measure.

The following tree measures have been revised:

• Patient self-care education has moved from performance measure to quality measure because of concerns about the accuracy of self-care education documentation and limited evidence of improved outcomes with better documentation.
• ACE inhibitor or angiotensin receptor blocker therapy for left ventricular systolic dysfunction adds ARNI therapy to align with the 2017 ACC/AHA/HFSA update.
• Postdischarge appointments shifts from performance to quality measure and include a 7-day limit.

Measures future research should focus on, noted Dr. Fonarow, include the use of sodium glucose cotransporter 2 (SGLT2) inhibitors for heart failure, including in patients without diabetes. “Since the ACC/AHA heart failure guidelines had not yet been updated to recommend these therapies they could not be included in this performance measure set,” he said.

He also said “an urgent need” exists for further research into treatments for heart failure with preserved ejection fraction along with optimal implementation strategies.  

“If these ACC/AHA heart failure performance measures were applied in all settings in which patients with heart failure in the United States are being cared for, and optimal and equitable conformity with each of these measures were achieved, over 100,000 lives a year of patients with heart failure could be saved,” he said. “There’s in an urgent need to measure and improve heart failure care quality.”

Dr. Fonarow reported financial relationships with Abbott, Amgen, AstraZeneca, CHF Solutions, Janssen, Medtronic, Merck, and Novartis.

SOURCE: American College of Cardiology/American Heart Association Task Force on Performance Measures. J Am Coll Cardiol. 2020 Nov 2;76:2527-64.

Safety measures for lab monitoring of mineralocorticoid receptor agonist therapy, performance measures for sacubitril/valsartan, cardiac resynchronization therapy and titration of medications, and quality measures based on patient-reported outcomes are among the updates the joint task force of the American College of Cardiology and the American Heart Association have made to performance and quality measures for managing adults with heart failure.

The revisions, published online Nov. 2 in the Journal of the American College of Cardiology, update the 2011 ACC/AHA heart failure measure set, writing committee vice chair Gregg C. Fonarow, MD, said in an interview. The 2011 measure set predates the 2015 approval of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan for heart failure in adults.
 

Measures stress dosages, strength of evidence

“For the first time the heart failure performance measure sets also focus on not just the use of guideline-recommended medication at any dose, but on utilizing the doses that are evidence-based and guideline recommended so long as they are well tolerated,” said Dr. Fonarow, interim chief of cardiology at the University of California, Los Angeles. “The measure set now includes assessment of patients being treated with doses of medications at 50% or greater of target dose in the absence of contraindications or documented intolerance.”

The update includes seven new performance measures, two quality measures, and one structural measure. The performance measures come from the strongest recommendations – that is, a class of recommendation of 1 (strong) or 3 (no benefit or harmful, process to be avoided) – in the 2017 ACC/AHA/Heart Failure Society of American heart failure guideline update published in Circulation.

In addition to the 2017 update, the writing committee also reviewed existing performance measures. “Those management strategies, diagnostic testing, medications, and devices with the strongest evidence and highest level of guideline recommendations were further considered for inclusion in the performance measure set,” Dr. Fonarow said. “The measures went through extensive review by peer reviewers and approval from the organizations represented.”

Specifically, the update includes measures for monitoring serum potassium after starting mineralocorticoid receptor antagonists therapy, and cardiac resynchronization therapy for patients with heart failure with reduced ejection fraction already on guideline-directed therapy. “This therapy can significantly improve functional capacity and outcomes in appropriately selected patients,” Dr. Fonarow said.
 

New and retired measures

The update adds two performance measures for titration of medications based on dose, either reaching 50% of the recommended dose for a variety of medications, including ARNI, or documenting that the dose wasn’t tolerated for other reason for not using the dose.

The new structural measure calls for facility participation in a heart failure registry. The revised measure set now consists of 18 measures in all.

The update retired one measure from the 2011 set: left ventricular ejection fraction assessment for inpatients. The committee cited its use above 97% as the reason, but LVEF in outpatients remains a measure.

The following tree measures have been revised:

• Patient self-care education has moved from performance measure to quality measure because of concerns about the accuracy of self-care education documentation and limited evidence of improved outcomes with better documentation.
• ACE inhibitor or angiotensin receptor blocker therapy for left ventricular systolic dysfunction adds ARNI therapy to align with the 2017 ACC/AHA/HFSA update.
• Postdischarge appointments shifts from performance to quality measure and include a 7-day limit.

Measures future research should focus on, noted Dr. Fonarow, include the use of sodium glucose cotransporter 2 (SGLT2) inhibitors for heart failure, including in patients without diabetes. “Since the ACC/AHA heart failure guidelines had not yet been updated to recommend these therapies they could not be included in this performance measure set,” he said.

He also said “an urgent need” exists for further research into treatments for heart failure with preserved ejection fraction along with optimal implementation strategies.  

“If these ACC/AHA heart failure performance measures were applied in all settings in which patients with heart failure in the United States are being cared for, and optimal and equitable conformity with each of these measures were achieved, over 100,000 lives a year of patients with heart failure could be saved,” he said. “There’s in an urgent need to measure and improve heart failure care quality.”

Dr. Fonarow reported financial relationships with Abbott, Amgen, AstraZeneca, CHF Solutions, Janssen, Medtronic, Merck, and Novartis.

SOURCE: American College of Cardiology/American Heart Association Task Force on Performance Measures. J Am Coll Cardiol. 2020 Nov 2;76:2527-64.

A mutation of the ODC1 gene, which plays a key role in polyamine metabolism, has been implicated in a syndromic neurodevelopmental disorder first described in 2018 and linked to a number of dysmorphic features and brain abnormalities, but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.

Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.

Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
 

Pathophysiology and phenotypes

In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.” 

In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.

“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”

One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”

These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.

They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.

MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.

Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.

Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.

With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.

Another hypothesis purports that potential of elevated levels of toxic aldehydes/H₂O₂ similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
 

Treatment

Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.

One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.

Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.

Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.

Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”

Dr. Rodan has no relevant financial relationships to disclose.

A mutation of the ODC1 gene, which plays a key role in polyamine metabolism, has been implicated in a syndromic neurodevelopmental disorder first described in 2018 and linked to a number of dysmorphic features and brain abnormalities, but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.

Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.

Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
 

Pathophysiology and phenotypes

In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.” 

In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.

“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”

One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”

These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.

They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.

MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.

Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.

Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.

With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.

Another hypothesis purports that potential of elevated levels of toxic aldehydes/H₂O₂ similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
 

Treatment

Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.

One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.

Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.

Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.

Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”

Dr. Rodan has no relevant financial relationships to disclose.

A mutation of the ODC1 gene, which plays a key role in polyamine metabolism, has been implicated in a syndromic neurodevelopmental disorder first described in 2018 and linked to a number of dysmorphic features and brain abnormalities, but it may be treated with diet modifications and available therapies, according to the researcher whose group first identified the disorder.

Lance Rodan, MD, of Boston Children’s Hospital and Harvard Medical School, reported on research into ODC1 gain-of-function disorder –named for ornithine decarboxylase 1, the rate-limiting enzyme involved in polyamine synthesis – in the Linda De Meirleir Neurometabolic award lecture at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Dr. Rodan and colleagues first described ODC1 disorder in a multicenter case series.

Dr. Rodan noted that dysregulated polyamine levels are associated with cancer, and that ODC1 is expressed “ubiquitously” throughout the body.
 

Pathophysiology and phenotypes

In an interview, he described the metabolic process more fully. “GI flora can produce putrescine, which is the polyamine that accumulates in excess in the ODC1 gain-of-function disorder. It is yet to be elucidated if decreasing putrescine production by GI flora and/or reducing dietary sources of putrescine may play a role in the management of this disorder.” 

In the De Meirleir lecture, Dr. Rodan described four patients from his group’s published case series, all found to have heterozygous de novo variants in the ODC1 gene, along with a fifth patient reported by Caleb Bupp, MD, and colleagues at Michigan State University, East Lansing.

“There’s a recognizable phenotype to this disorder,” Dr. Rodan said. “These individuals have neurodevelopment abnormalities. They may have behavioral concerns. They have low-tone central hypertonia and macrocephaly.”

One of the most distinctive characteristics of ODC1 disorder is alopecia, he said, “which in almost everybody with this condition involves the eyebrows and eyelashes and in some individuals also involves the scalp hair.”

These patients also have what Dr. Rodan called “a common yet subtle facial gestalt.” That can include hypertelorism, spareness of the eyebrows and eyelashes, and a tubular- shaped nose with a short columella and a short philtrum.

They may also have abnormalities of the nails and cryptorchidism, and typically a prenatal history of polyhydramnios, he said.

MRI findings include prominent perivascular spaces, periventricular cysts, abnormal white matter and corpus callosum abnormalities, he said, adding that the fetal case MRI demonstrated subepidermal cysts, white matter cysts in the temporal pole, deficiency of the falx cerebri and abnormal white-matter signals.

Biochemical features of ODC1 disorder include increased N-acetylputrescine levels with normal spermine and spermidine levels, Dr. Rodan said. He also noted that Dr. Bupp’s group reported increased putrescine in fibroblasts and increased ODC1 protein levels in red blood cells.

Dr. Rodan also described possible molecular mechanisms in ODC1 disorder. One was the location of the ODC1 variants: all were reported closely located to truncating variants in the final exon of the ODC1 gene. This allows truncating proteins to survive, adding to the degradation that results in a net gain-of-function of ODC1 enzyme activity.

With regard to pathophysiology of ODC1 disorder, Dr. Rodan noted that research has implicated chronically elevated putrescine levels in the alopecia, a finding animal models support. “Since putrescine is a precursor for gamma-aminobutyric acid, it’s possible perturbed GABA levels may also be involved,” he said. Abnormal modulation N-methyl-D-aspirate receptors may also be involved, he said.

Another hypothesis purports that potential of elevated levels of toxic aldehydes/H₂O₂ similar to Snyder-Robinson syndrome, the better known polyamine-related neurometabolic disorder. “Along those lines, maybe there’s also a secondary mitochondrial or lysosomal dysfunction, but this is something that’s still being actively studied,” Dr. Rodan said.
 

Treatment

Because ODC1 disorder was only first described 2 years ago, research into treatment is nascent. “In terms of management, I think one of the more fundamental questions is whether this is more of a static developmental disorder or whether this actually represents a progressive degenerative disorder,” Dr. Rodan said.

One potential treatment that has been explored, he said, is difluoromethylornithine, a synthetic ODC1 inhibitor already Food and Drug Administration approved for African sleeping sickness and as a topical treatment for hirsutism. It is also the subject of ongoing clinical trials in colon cancer and neuroblastoma. Potential side effects include myelosuppression, seizures and hearing loss.

Dr. Rodan noted that a single-center study reported that difluoromethylornithine in a 3-year-old patient with ODC1 disorder reduced ODC protein activity and putrescine to control levels.

Other potential treatments include the natural ODC1 inhibitors agmatine and turmeric/curcumin, flagyl/rifaximin to decrease putrescine production in the gut, a low-dairy diet to lower putrescine levels, and antioxidants. “There could be a role for antioxidant stress similar to what is seen in Snyder-Robinson syndrome,” Dr. Rodan said.

Based on mouse studies, patients with ODC1 may be at risk of skin cancer, so regular skin checks along with sun protection should be part of management, he said. “This also raises the question of whether there should be surveillance for other types of cancer given the role of polyamine in various types of tumors.”

Dr. Rodan has no relevant financial relationships to disclose.

Maintaining antiseizure medication in infants who have had acute symptomatic neonatal seizures has been standard practice, but a prospective, observational, comparative effectiveness study calls that practice into question, providing evidence that discontinuing therapy at discharge poses no harm to children and has no effect on the development of epilepsies.

“The balance of evidence supports discontinuing antiseizure medication after resolution of acute symptomatic neonatal seizures and before discharge home from the neonatal seizure admission,” said Hannah C. Glass, MDCM, MAS, of the University of California, San Francisco, Benioff Children’s Hospital, co-principal investigator, who presented results of the study at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Renee Shellhaas, MD, MS, clinical associate professor of pediatrics at C.S. Mott Children’s Hospital, University of Michigan, was the other co-principal investigator.

“Although other, smaller studies have suggested it is safe to discontinue antiseizure medication after resolution of acute symptomatic seizures, the practice of early discontinuation has been very variable and depends largely on individual provider preference,” Dr. Glass said in an interview. “In our study, two-thirds of newborns with acute symptomatic seizures were maintained on antiseizure medication at the time of hospital discharge. Thus, a change to early medication discontinuation represents a major shift.” 

The study evaluated 270 infants at nine centers enrolled in the Neonatal Seizure Registry and born from July 2015 through March 2018. Inclusion criteria were acute symptomatic seizures that occurred at up to 44 weeks postmenstrual age. In this cohort, 36% of patients had antiseizure medication discontinued after a median of 6 days; the remainder stayed on antiseizure medication after discharge at a median of 4 months.

The patients were followed for 2 years. The primary outcome was functional development measured by the Warner Initial Development Evaluation of Adaptive and Functional Skills (WIDEA-FS) assessment. The secondary outcome was epilepsy defined by International League Against Epilepsy (ILAE) criteria. Follow-up consisted of phone calls and chart reviews at 12, 18, and 24 months.

“The primary outcome, functional development, was not significantly different between those children who were maintained on antiseizure medication as compared with those who were discontinued,” Dr. Glass said.

After propensity adjustment, the discontinued ASM group had an estimated WIDEA-FS score 4 points higher on average, she said. “The confidence intervals met our a priori noninferiority limit, indicating no harm to neurodevelopment for discontinuing antiseizure medication before discharge home from the neonatal seizure admission,” Dr. Glass noted.

The study also found that 13% of all participants developed epilepsy at a median of 8 months. “There was no significant difference in the frequency or timing of epilepsy between the two groups,” she said.

“We conclude there is no clear rationale for antiseizure medication maintenance,” Dr. Glass said. “There is no benefit to neurodevelopment, it prolongs the exposure to potentially harmful antiseizure medications, it does not significantly delay the onset of epilepsy, and the earliest-onset epilepsies occur in spite of antiseizure medication.”

The Patient-Centered Outcomes Research Institute (PCORI) and Pediatric Epilepsy Research Foundation funded the study. Dr. Glass has no other financial relationships to disclose.

SOURCE: Glass HC et al. CNS-ICNA 2020. Presentation PL58.

Maintaining antiseizure medication in infants who have had acute symptomatic neonatal seizures has been standard practice, but a prospective, observational, comparative effectiveness study calls that practice into question, providing evidence that discontinuing therapy at discharge poses no harm to children and has no effect on the development of epilepsies.

“The balance of evidence supports discontinuing antiseizure medication after resolution of acute symptomatic neonatal seizures and before discharge home from the neonatal seizure admission,” said Hannah C. Glass, MDCM, MAS, of the University of California, San Francisco, Benioff Children’s Hospital, co-principal investigator, who presented results of the study at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Renee Shellhaas, MD, MS, clinical associate professor of pediatrics at C.S. Mott Children’s Hospital, University of Michigan, was the other co-principal investigator.

“Although other, smaller studies have suggested it is safe to discontinue antiseizure medication after resolution of acute symptomatic seizures, the practice of early discontinuation has been very variable and depends largely on individual provider preference,” Dr. Glass said in an interview. “In our study, two-thirds of newborns with acute symptomatic seizures were maintained on antiseizure medication at the time of hospital discharge. Thus, a change to early medication discontinuation represents a major shift.” 

The study evaluated 270 infants at nine centers enrolled in the Neonatal Seizure Registry and born from July 2015 through March 2018. Inclusion criteria were acute symptomatic seizures that occurred at up to 44 weeks postmenstrual age. In this cohort, 36% of patients had antiseizure medication discontinued after a median of 6 days; the remainder stayed on antiseizure medication after discharge at a median of 4 months.

The patients were followed for 2 years. The primary outcome was functional development measured by the Warner Initial Development Evaluation of Adaptive and Functional Skills (WIDEA-FS) assessment. The secondary outcome was epilepsy defined by International League Against Epilepsy (ILAE) criteria. Follow-up consisted of phone calls and chart reviews at 12, 18, and 24 months.

“The primary outcome, functional development, was not significantly different between those children who were maintained on antiseizure medication as compared with those who were discontinued,” Dr. Glass said.

After propensity adjustment, the discontinued ASM group had an estimated WIDEA-FS score 4 points higher on average, she said. “The confidence intervals met our a priori noninferiority limit, indicating no harm to neurodevelopment for discontinuing antiseizure medication before discharge home from the neonatal seizure admission,” Dr. Glass noted.

The study also found that 13% of all participants developed epilepsy at a median of 8 months. “There was no significant difference in the frequency or timing of epilepsy between the two groups,” she said.

“We conclude there is no clear rationale for antiseizure medication maintenance,” Dr. Glass said. “There is no benefit to neurodevelopment, it prolongs the exposure to potentially harmful antiseizure medications, it does not significantly delay the onset of epilepsy, and the earliest-onset epilepsies occur in spite of antiseizure medication.”

The Patient-Centered Outcomes Research Institute (PCORI) and Pediatric Epilepsy Research Foundation funded the study. Dr. Glass has no other financial relationships to disclose.

SOURCE: Glass HC et al. CNS-ICNA 2020. Presentation PL58.

Maintaining antiseizure medication in infants who have had acute symptomatic neonatal seizures has been standard practice, but a prospective, observational, comparative effectiveness study calls that practice into question, providing evidence that discontinuing therapy at discharge poses no harm to children and has no effect on the development of epilepsies.

“The balance of evidence supports discontinuing antiseizure medication after resolution of acute symptomatic neonatal seizures and before discharge home from the neonatal seizure admission,” said Hannah C. Glass, MDCM, MAS, of the University of California, San Francisco, Benioff Children’s Hospital, co-principal investigator, who presented results of the study at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Renee Shellhaas, MD, MS, clinical associate professor of pediatrics at C.S. Mott Children’s Hospital, University of Michigan, was the other co-principal investigator.

“Although other, smaller studies have suggested it is safe to discontinue antiseizure medication after resolution of acute symptomatic seizures, the practice of early discontinuation has been very variable and depends largely on individual provider preference,” Dr. Glass said in an interview. “In our study, two-thirds of newborns with acute symptomatic seizures were maintained on antiseizure medication at the time of hospital discharge. Thus, a change to early medication discontinuation represents a major shift.” 

The study evaluated 270 infants at nine centers enrolled in the Neonatal Seizure Registry and born from July 2015 through March 2018. Inclusion criteria were acute symptomatic seizures that occurred at up to 44 weeks postmenstrual age. In this cohort, 36% of patients had antiseizure medication discontinued after a median of 6 days; the remainder stayed on antiseizure medication after discharge at a median of 4 months.

The patients were followed for 2 years. The primary outcome was functional development measured by the Warner Initial Development Evaluation of Adaptive and Functional Skills (WIDEA-FS) assessment. The secondary outcome was epilepsy defined by International League Against Epilepsy (ILAE) criteria. Follow-up consisted of phone calls and chart reviews at 12, 18, and 24 months.

“The primary outcome, functional development, was not significantly different between those children who were maintained on antiseizure medication as compared with those who were discontinued,” Dr. Glass said.

After propensity adjustment, the discontinued ASM group had an estimated WIDEA-FS score 4 points higher on average, she said. “The confidence intervals met our a priori noninferiority limit, indicating no harm to neurodevelopment for discontinuing antiseizure medication before discharge home from the neonatal seizure admission,” Dr. Glass noted.

The study also found that 13% of all participants developed epilepsy at a median of 8 months. “There was no significant difference in the frequency or timing of epilepsy between the two groups,” she said.

“We conclude there is no clear rationale for antiseizure medication maintenance,” Dr. Glass said. “There is no benefit to neurodevelopment, it prolongs the exposure to potentially harmful antiseizure medications, it does not significantly delay the onset of epilepsy, and the earliest-onset epilepsies occur in spite of antiseizure medication.”

The Patient-Centered Outcomes Research Institute (PCORI) and Pediatric Epilepsy Research Foundation funded the study. Dr. Glass has no other financial relationships to disclose.

SOURCE: Glass HC et al. CNS-ICNA 2020. Presentation PL58.

Improved molecular characterization of mixed glioneuronal and neuronal tumors is driving the World Health Organization to update its classification system for pediatric brain tumors, and that will have far-reaching implications for how clinicians diagnose and manage these rare and often debilitating malignancies, a leading European researcher reported at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“These pediatric neuronal/glioneuronal tumors are quite heterogeneous in terms of the number of different tumors and subclasses of tumors going into these groups, but they have some molecular features in common,” said David T.W. Jones, PhD, of Hopp Children’s Cancer Center in Heidelberg, Germany. “Together they represent quite a sizable portion of all childhood brain tumors, so it’s important to recognize and understand them.”

Dr. Jones noted that updated WHO classifications would add six new descriptions to the category of mixed glioneuronal tumors and one to the list of neuronal tumors. A working group of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, known as cIMPACT-NOW, has recommended the expanded classifications for central nervous system tumors.

“The molecular understandings of pediatric neuro-glial tumors are critical in their management,” Roger Packer, MD, senior vice president of the Center for Neuroscience and Behavioral Health at Children’s National in Washington, said in an interview, especially as treatments targeting specific molecular structures emerge. “For those with tumors not amenable to safe, total resections, there’s little evidence that radiation or chemotherapy are effective, and molecular-targeted therapy, guided by the molecular genetic composition, increases the safe use of these new agents.”

Dr. Jones noted that “as a minimum” molecular diagnostics of pediatric low-grade glioneuronal and neuronal tumors should include a BRAF gene mutation and fusion status, as well as FGFR1 mutation plus fusion or rearrangement status.

“Ideally,” he added, “it should also have a broader copy number profile, whether that’s based on sequencing or SNP arrays or DNA methylation rate, a global DNA methylation profile to get those global molecular patterns, and also wider gene and RNA sequence to pick up some of those rarer alterations that may not be covered by targeted BRAF and FGFR1 mutations.”

The updated tumor classification will evolve to include novel tumor classes, as well as links or overlaps between the tumor classes and their characteristic underlying kinetic alterations, he noted. “Some of these profiling measures will actually be required to generate a fully WHO-compatible pathological diagnosis,” Dr. Jones said.

“This group of tumors are now just better molecularly characterized than it was 5 years ago, so in the last few years we’ve really made tremendous progress in understanding what alterations are driving some of these tumors,” he said. “That knowledge is now providing a basis for improved diagnosis and also for starting to plan more targeted treatment strategies.”

But, he added, there’s still a lot to learn about how these oncogenic mechanisms drive tumor pathogenesis. “What is the clinical costs when we really start getting down into defining these distinct molecular groups?” he said. “What are their different responses to treatment depending on different levels, where the MEKi [mitogen-activated protein kinase inhibitor] pathway might be activated and, for example, response to treatment of different subclasses of one tumor?”

Large, collaborative clinical studies will be needed to get those answers, he said.

“There are certainly some therapeutic opportunities arising in this group of tumors now, but in order to really translate those into a clinical benefit, we’re really going to need some careful planning of international studies because of the relative rarity of some of these groups,” he said.

Dr. Jones has no relevant financial relationships to disclose.

Improved molecular characterization of mixed glioneuronal and neuronal tumors is driving the World Health Organization to update its classification system for pediatric brain tumors, and that will have far-reaching implications for how clinicians diagnose and manage these rare and often debilitating malignancies, a leading European researcher reported at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“These pediatric neuronal/glioneuronal tumors are quite heterogeneous in terms of the number of different tumors and subclasses of tumors going into these groups, but they have some molecular features in common,” said David T.W. Jones, PhD, of Hopp Children’s Cancer Center in Heidelberg, Germany. “Together they represent quite a sizable portion of all childhood brain tumors, so it’s important to recognize and understand them.”

Dr. Jones noted that updated WHO classifications would add six new descriptions to the category of mixed glioneuronal tumors and one to the list of neuronal tumors. A working group of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, known as cIMPACT-NOW, has recommended the expanded classifications for central nervous system tumors.

“The molecular understandings of pediatric neuro-glial tumors are critical in their management,” Roger Packer, MD, senior vice president of the Center for Neuroscience and Behavioral Health at Children’s National in Washington, said in an interview, especially as treatments targeting specific molecular structures emerge. “For those with tumors not amenable to safe, total resections, there’s little evidence that radiation or chemotherapy are effective, and molecular-targeted therapy, guided by the molecular genetic composition, increases the safe use of these new agents.”

Dr. Jones noted that “as a minimum” molecular diagnostics of pediatric low-grade glioneuronal and neuronal tumors should include a BRAF gene mutation and fusion status, as well as FGFR1 mutation plus fusion or rearrangement status.

“Ideally,” he added, “it should also have a broader copy number profile, whether that’s based on sequencing or SNP arrays or DNA methylation rate, a global DNA methylation profile to get those global molecular patterns, and also wider gene and RNA sequence to pick up some of those rarer alterations that may not be covered by targeted BRAF and FGFR1 mutations.”

The updated tumor classification will evolve to include novel tumor classes, as well as links or overlaps between the tumor classes and their characteristic underlying kinetic alterations, he noted. “Some of these profiling measures will actually be required to generate a fully WHO-compatible pathological diagnosis,” Dr. Jones said.

“This group of tumors are now just better molecularly characterized than it was 5 years ago, so in the last few years we’ve really made tremendous progress in understanding what alterations are driving some of these tumors,” he said. “That knowledge is now providing a basis for improved diagnosis and also for starting to plan more targeted treatment strategies.”

But, he added, there’s still a lot to learn about how these oncogenic mechanisms drive tumor pathogenesis. “What is the clinical costs when we really start getting down into defining these distinct molecular groups?” he said. “What are their different responses to treatment depending on different levels, where the MEKi [mitogen-activated protein kinase inhibitor] pathway might be activated and, for example, response to treatment of different subclasses of one tumor?”

Large, collaborative clinical studies will be needed to get those answers, he said.

“There are certainly some therapeutic opportunities arising in this group of tumors now, but in order to really translate those into a clinical benefit, we’re really going to need some careful planning of international studies because of the relative rarity of some of these groups,” he said.

Dr. Jones has no relevant financial relationships to disclose.

Improved molecular characterization of mixed glioneuronal and neuronal tumors is driving the World Health Organization to update its classification system for pediatric brain tumors, and that will have far-reaching implications for how clinicians diagnose and manage these rare and often debilitating malignancies, a leading European researcher reported at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“These pediatric neuronal/glioneuronal tumors are quite heterogeneous in terms of the number of different tumors and subclasses of tumors going into these groups, but they have some molecular features in common,” said David T.W. Jones, PhD, of Hopp Children’s Cancer Center in Heidelberg, Germany. “Together they represent quite a sizable portion of all childhood brain tumors, so it’s important to recognize and understand them.”

Dr. Jones noted that updated WHO classifications would add six new descriptions to the category of mixed glioneuronal tumors and one to the list of neuronal tumors. A working group of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, known as cIMPACT-NOW, has recommended the expanded classifications for central nervous system tumors.

“The molecular understandings of pediatric neuro-glial tumors are critical in their management,” Roger Packer, MD, senior vice president of the Center for Neuroscience and Behavioral Health at Children’s National in Washington, said in an interview, especially as treatments targeting specific molecular structures emerge. “For those with tumors not amenable to safe, total resections, there’s little evidence that radiation or chemotherapy are effective, and molecular-targeted therapy, guided by the molecular genetic composition, increases the safe use of these new agents.”

Dr. Jones noted that “as a minimum” molecular diagnostics of pediatric low-grade glioneuronal and neuronal tumors should include a BRAF gene mutation and fusion status, as well as FGFR1 mutation plus fusion or rearrangement status.

“Ideally,” he added, “it should also have a broader copy number profile, whether that’s based on sequencing or SNP arrays or DNA methylation rate, a global DNA methylation profile to get those global molecular patterns, and also wider gene and RNA sequence to pick up some of those rarer alterations that may not be covered by targeted BRAF and FGFR1 mutations.”

The updated tumor classification will evolve to include novel tumor classes, as well as links or overlaps between the tumor classes and their characteristic underlying kinetic alterations, he noted. “Some of these profiling measures will actually be required to generate a fully WHO-compatible pathological diagnosis,” Dr. Jones said.

“This group of tumors are now just better molecularly characterized than it was 5 years ago, so in the last few years we’ve really made tremendous progress in understanding what alterations are driving some of these tumors,” he said. “That knowledge is now providing a basis for improved diagnosis and also for starting to plan more targeted treatment strategies.”

But, he added, there’s still a lot to learn about how these oncogenic mechanisms drive tumor pathogenesis. “What is the clinical costs when we really start getting down into defining these distinct molecular groups?” he said. “What are their different responses to treatment depending on different levels, where the MEKi [mitogen-activated protein kinase inhibitor] pathway might be activated and, for example, response to treatment of different subclasses of one tumor?”

Large, collaborative clinical studies will be needed to get those answers, he said.

“There are certainly some therapeutic opportunities arising in this group of tumors now, but in order to really translate those into a clinical benefit, we’re really going to need some careful planning of international studies because of the relative rarity of some of these groups,” he said.

Dr. Jones has no relevant financial relationships to disclose.