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Venetoclax combos prolong progression-free CLL survival
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EHA 2022
FDA panel rejects pimavanserin for Alzheimer’s psychosis
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
In a 9-3 vote, the Psychopharmacologic Drugs Advisory Committee (PDAC) found that the drug’s manufacturer failed to offer convincing evidence of its efficacy in patients with ADP.
The June 17 rejection was the second rejection in as many years for a new indication for pimavanserin, which was approved in 2016 for Parkinson’s disease psychosis (PDP).
In April 2021, the FDA denied Acadia’s supplemental new drug application to expand the drug’s indication to include the treatment of all dementia-related psychosis, regardless of the underlying cause of dementia, citing issues with two studies the company presented as evidence of efficacy.
For the current application, Acadia submitted some new analysis of those studies but limited its application to ADP, which affects up to 30% of patients with Alzheimer’s disease (AD) and currently has no approved treatment.
Committee members who opposed the application were moved by testimony from caregivers and clinicians who treat patients with ADP but ultimately decided the evidence offered by Acadia once again failed to meet the threshold needed to demonstrate efficacy for an expanded indication.
“Sometimes I struggle with a decision on an advisory committee, but not today,” Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., said of his “no” vote.
Lack of efficacy
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
When it rejected Acadia’s original, broader application for pimavanserin for all dementia-related psychosis, the FDA found that the HARMONY phase 3 trial, previously covered by this news organization, was underpowered to assess efficacy in specific dementia patient subgroups and lacked statistical significance of efficacy in patients with AD. In addition, it noted that overall findings appeared to be driven by results in patients with Parkinson’s disease dementia, a condition already covered by the approved indication.
The FDA found that the second study, referred to in the June 17 hearing as Study 019, which was also previously reported by this news organization, was not “an adequate and well-controlled study.”
Specifically, the agency raised concerns about “protocol deviations,” such as the inclusion of patients who lacked clear documentation that psychotic symptoms developed after an AD diagnosis had been established and patients who received exclusionary medications at the time of randomization.
Discussions between Acadia and the FDA continued over the past year, with the company submitting new analyses and responses. An FDA briefing document published in advance of the committee meeting seemed to suggest the agency was satisfied with Acadia’s response.
Lack of diversity
The advisory committee disagreed, pointing to the same concerns raised last year. Members raised concerns about patient diversity in the HARMONY trial, which included an almost entirely White and mostly male study population.
In addition, although the findings at 26 weeks did demonstrate a marked improvement in psychosis symptoms overall, committee members noted that, again, those findings were largely driven by efficacy in patients with Parkinson’s disease dementia, for which the drug is already approved.
When discussing the phase 2 Study 019, the committee noted that while the study met the primary outcome of improvement in psychosis at 6 weeks, those positive responses were not found at any other timepoint in the 12-week study.
“While it might have had a positive numerical effect in the study, the evidence is really not there to support it,” Dr. Follmann said.
Dr. Follmann and other committee members called for additional trials that focus on patients with Alzheimer’s disease, have a longer follow-up, and include more gender and racial diversity in the study population. They also called for more information about any off-label use of pimavanserin for ADP since it was approved for PDP in 2016.
An unmet need
Most individuals who testified during the public comment period pleaded with the committee to vote in favor of the new indication, sharing stories of family members and patients with ADP.
“I have been caring for and studying patients with Alzheimer’s disease and other dementias for more than 30 years, and I can tell you very simply that if left untreated, psychosis has significant and sometimes devastating consequences for our patients,” said Pierre Tariot, MD, director of the Banner Alzheimer’s Institute and a research professor of psychiatry at the University of Arizona College of Medicine, Tucson, and an investigator on the HARMONY trial.
Those on the committee who voted against the application were quick to agree that lack of an approved treatment for ADP presents a hardship.
“I’m a neurologist who has cared for patients for more than 20 years,” said Madhav R. Thambisetty, MD, PhD, senior investigator for the National Institute on Aging and an adjunct professor of neurology at Johns Hopkins University School of Medicine, Baltimore. “I recognize the unmet need in the field, I just think that the unmet need should not be a justification to cut corners.”
The committee did not focus on drug safety or unmet need in its deliberations, although information on both were presented during the meeting.
Commenting on his “no” vote, PDAC member Walter S. Dunn, MD, PhD, assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of Interventional Psychiatry Service at West Los Angeles Veterans Affairs Medical Center, said he hopes that the FDA will consider those issues more broadly as they complete their review.
“The questions before the committee have been narrow and precise, so I trust the agency will take a broader approach in their final decision about approval,” Dr. Dunn said.
Commenting on the decision, Howard Fillit, MD, cofounder and chief science officer, Alzheimer’s Drug Discovery Foundation, called the news disappointing, “but while the unmet need for a treatment for ADP is clear, it is vital that approved treatments meet stringent safety and efficacy criteria so we can offer patients medications with clear benefits.”
The FDA will make its final decision by August 4.
A version of this article first appeared on Medscape.com.
Alcohol, marijuana use declined among youth during pandemic
During the coronavirus pandemic, several substance use behaviors decreased among youths, namely drinking, smoking, vaping, and cannabis use, according to a recent study published in the journal Current Psychiatry Reports.
That likely happened because they had to spend more time at home and less time with their friends, the study authors wrote, adding that youth substance use should be monitored in the post-pandemic years.
“One of the driving factors for youth substance use is access to substances,” Hannah Layman, one of the co-authors and a social and behavioral sciences doctoral student at West Virginia University, said in a statement.
“With stay-at-home orders, virtual schooling, and social distancing, children have been spending more time with family and are more socially isolated from peers than before,” she said. “Although social isolation from peers may have a negative impact on their mental health, it may just be one of the desirable outcomes of the pandemic when considering substance use in children.”
Ms. Layman and colleagues analyzed 49 studies that followed substance use of alcohol, cannabis, tobacco, e-cigarettes/vaping, and other drugs among children, teens, and youths under age 24. The studies spanned across several countries, including 22 in North America and 19 in Europe.
The research team found that most studies across all categories reported reductions in prevalence, except for the category of “other drugs and unspecific drugs,” which included three studies that showed an increase in use and three studies that showed a decrease in use.
Teens and preteens tend to have easier access to alcohol, tobacco, cannabis products, and vaping products and see them as less serious than “hard drugs,” the authors said.
Future research should analyze the long-term effects of the pandemic on youth substance use, the study authors wrote, paying attention to differences by gender and those who face the highest risks for substance use. Previous studies have shown an increase in substance use among youths, particularly among those in low-income neighborhoods or in difficult family circumstances.
“Substance use can affect a young person’s body in many ways, such as the development of mental health issues (depression, anxiety, conduct problems, personality disorders, and suicidal thoughts), injuries due to accidents, decreased bone mineral density, preventing proper brain growth and function, delayed puberty, liver damage, and so much more,” Ms. Layman said.
Increased parent or caregiver supervision can help prevent substance use problems, she noted. Early intervention, open support in conversations, and ongoing education about the dangers of substance use can help as well.
“Our findings also identified the importance of improving youth mental health and the value of telemedicine to address young people’s needs during the pandemic,” she said.
A version of this article first appeared on WebMD.com.
During the coronavirus pandemic, several substance use behaviors decreased among youths, namely drinking, smoking, vaping, and cannabis use, according to a recent study published in the journal Current Psychiatry Reports.
That likely happened because they had to spend more time at home and less time with their friends, the study authors wrote, adding that youth substance use should be monitored in the post-pandemic years.
“One of the driving factors for youth substance use is access to substances,” Hannah Layman, one of the co-authors and a social and behavioral sciences doctoral student at West Virginia University, said in a statement.
“With stay-at-home orders, virtual schooling, and social distancing, children have been spending more time with family and are more socially isolated from peers than before,” she said. “Although social isolation from peers may have a negative impact on their mental health, it may just be one of the desirable outcomes of the pandemic when considering substance use in children.”
Ms. Layman and colleagues analyzed 49 studies that followed substance use of alcohol, cannabis, tobacco, e-cigarettes/vaping, and other drugs among children, teens, and youths under age 24. The studies spanned across several countries, including 22 in North America and 19 in Europe.
The research team found that most studies across all categories reported reductions in prevalence, except for the category of “other drugs and unspecific drugs,” which included three studies that showed an increase in use and three studies that showed a decrease in use.
Teens and preteens tend to have easier access to alcohol, tobacco, cannabis products, and vaping products and see them as less serious than “hard drugs,” the authors said.
Future research should analyze the long-term effects of the pandemic on youth substance use, the study authors wrote, paying attention to differences by gender and those who face the highest risks for substance use. Previous studies have shown an increase in substance use among youths, particularly among those in low-income neighborhoods or in difficult family circumstances.
“Substance use can affect a young person’s body in many ways, such as the development of mental health issues (depression, anxiety, conduct problems, personality disorders, and suicidal thoughts), injuries due to accidents, decreased bone mineral density, preventing proper brain growth and function, delayed puberty, liver damage, and so much more,” Ms. Layman said.
Increased parent or caregiver supervision can help prevent substance use problems, she noted. Early intervention, open support in conversations, and ongoing education about the dangers of substance use can help as well.
“Our findings also identified the importance of improving youth mental health and the value of telemedicine to address young people’s needs during the pandemic,” she said.
A version of this article first appeared on WebMD.com.
During the coronavirus pandemic, several substance use behaviors decreased among youths, namely drinking, smoking, vaping, and cannabis use, according to a recent study published in the journal Current Psychiatry Reports.
That likely happened because they had to spend more time at home and less time with their friends, the study authors wrote, adding that youth substance use should be monitored in the post-pandemic years.
“One of the driving factors for youth substance use is access to substances,” Hannah Layman, one of the co-authors and a social and behavioral sciences doctoral student at West Virginia University, said in a statement.
“With stay-at-home orders, virtual schooling, and social distancing, children have been spending more time with family and are more socially isolated from peers than before,” she said. “Although social isolation from peers may have a negative impact on their mental health, it may just be one of the desirable outcomes of the pandemic when considering substance use in children.”
Ms. Layman and colleagues analyzed 49 studies that followed substance use of alcohol, cannabis, tobacco, e-cigarettes/vaping, and other drugs among children, teens, and youths under age 24. The studies spanned across several countries, including 22 in North America and 19 in Europe.
The research team found that most studies across all categories reported reductions in prevalence, except for the category of “other drugs and unspecific drugs,” which included three studies that showed an increase in use and three studies that showed a decrease in use.
Teens and preteens tend to have easier access to alcohol, tobacco, cannabis products, and vaping products and see them as less serious than “hard drugs,” the authors said.
Future research should analyze the long-term effects of the pandemic on youth substance use, the study authors wrote, paying attention to differences by gender and those who face the highest risks for substance use. Previous studies have shown an increase in substance use among youths, particularly among those in low-income neighborhoods or in difficult family circumstances.
“Substance use can affect a young person’s body in many ways, such as the development of mental health issues (depression, anxiety, conduct problems, personality disorders, and suicidal thoughts), injuries due to accidents, decreased bone mineral density, preventing proper brain growth and function, delayed puberty, liver damage, and so much more,” Ms. Layman said.
Increased parent or caregiver supervision can help prevent substance use problems, she noted. Early intervention, open support in conversations, and ongoing education about the dangers of substance use can help as well.
“Our findings also identified the importance of improving youth mental health and the value of telemedicine to address young people’s needs during the pandemic,” she said.
A version of this article first appeared on WebMD.com.
Updates in aspirin use, aducanumab, and CKD diagnostic criteria in geriatric medicine
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).
Aspirin for primary prevention
It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.1
The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.
While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.2
Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia
One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.
Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.4
Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.
Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.5
Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.
In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.6
Overdiagnosis of CKD in older adults
The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m2 for adults aged 65 and older.7
The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.8 In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.
A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.
These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.
2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.
3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.
4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.
5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.
6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.
7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.
8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.
Precision medicine vs. antibiotic resistance
Diversity is an omnipresent element in clinical practice: in the genome, in the environment, in patients’ lifestyles and habits. Precision medicine addresses the variability of the individual to improve diagnosis and treatment. It is increasingly used in specialties such as oncology, neurology, and cardiology. A personalized approach has many objectives, including to optimize treatment, minimize the risk of adverse effects, facilitate early diagnosis, and determine predisposition to disease. Genomic technologies, such as massive sequencing techniques, and tools such as CRISPR-Cas9 are key to the future of personalized medicine.
Jesús Oteo Iglesias, MD, PhD, a specialist in microbiology and director of Spain’s National Center for Microbiology, spoke at the Spanish Association of Infectious Diseases and Clinical Microbiology’s recent conference. He discussed various precision medicine projects aimed at reinforcing the fight against antibiotic resistance.
Infectious diseases are complex because the diversity of the pathogenic microorganism combines with the patient’s own diversity, which influences the interaction between the two, said Dr. Oteo. Thus, the antibiogram and targeted antibiotic treatments (which are chosen according to the species, sensitivity to antimicrobials, type of infection, and patient characteristics) have been established applications of precision medicine for decades. However, multiple tools could further strengthen personalized medicine against multiresistant pathogens.
Therapeutic drug monitoring, in which multiple pharmacokinetic and pharmacodynamic factors are considered, is a strategy with great potential to increase the effectiveness of antibiotics and minimize toxicity. Owing to its costs and the need for trained staff, this tool would be especially indicated in the treatment of patients with more complex conditions, such as those suffering from obesity, complex infections, or infections with multiresistant bacteria, as well as those in critical condition. Multiple computer programs are available to help determine the dosage of antibiotics by estimating drug exposure and to provide recommendations. However, clinical trials are needed to assess the pros and cons of applying therapeutic monitoring for types of antibiotics other than those for which a given type is already used (for example, aminoglycosides and glycopeptides).
One technology that could help in antibiotic use optimization programs is microneedle-based biosensors, which could be implanted in the skin for real-time antibiotic monitoring. This tool “could be the first step in establishing automated antibiotic administration systems, with infusion pumps and feedback systems, like those already used in diabetes for insulin administration,” said Dr. Oteo.
Artificial intelligence could also be a valuable technology for optimization programs. “We should go a step further in the implementation of artificial intelligence through clinical decision support systems,” said Dr. Oteo. This technology would guide the administration of antimicrobials using data extracted from the electronic medical record. However, there are great challenges to overcome in creating these tools, such as the risk of entering erroneous data; the difficulty in entering complex data, such as data relevant to antibiotic resistance; and the variability at the geographic and institutional levels.
Genomics is also a tool with great potential for identifying bacteria’s degree of resistance to antibiotics by studying mutations in chromosomal and acquired genes. A proof-of-concept study evaluated the sensitivity of different Pseudomonas aeruginosa strains to several antibiotics by analyzing genome sequences associated with resistance, said Dr. Otero. The researchers found that this system was effective at predicting the sensitivity of bacteria from genomic data.
In the United States, the PATRIC bioinformatics center, which is financed by the National Institute of Allergy and Infectious Diseases, works with automated learning models to predict the antimicrobial resistance of different species of bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis. These models, which work with genomic data associated with antibiotic resistance phenotypes, are able to identify resistance without prior knowledge of the underlying mechanisms.
Another factor to consider with regard to the use of precision medicine for infectious diseases is the microbiota. Dr. Oteo explained that the pathogenic microorganism interacts not only with the host but also with its microbiota, “which can be diverse, is manifold, and can be very different, depending on the circumstances. These interactions can be translated into ecological and evolutionary pressures that may have clinical significance.” One of the best-known examples is the possibility that a beta-lactamase–producing bacterium benefits other bacteria around it by secreting these enzymes. Furthermore, some known forms of bacterial interaction (such as plasmid transfer) are directly related to antibiotic resistance. Metagenomics, which involves the genetic study of communities of microbes, could provide more information for predicting and avoiding infections by multiresistant pathogens by monitoring the microbiome.
The CRISPR-Cas9 gene editing tool could also be an ally in the fight against antibiotic resistance by eliminating resistance genes and thus making bacteria sensitive to certain antibiotics. Several published preliminary studies indicate that this is possible in vitro. The main challenge for the clinical application of CRISPR is in introducing it into the target microbial population. Use of conjugative plasmids and bacteriophages could perhaps be an option for overcoming this obstacle in the future.
Exploiting the possibilities of precision medicine through use of the most innovative tools in addressing antibiotic resistance is a great challenge, said Dr. Oteo, but the situation demands it, and it is necessary to take small steps to achieve this goal.
A version of this article appeared on Medscape.com. This article was translated from Univadis Spain.
Diversity is an omnipresent element in clinical practice: in the genome, in the environment, in patients’ lifestyles and habits. Precision medicine addresses the variability of the individual to improve diagnosis and treatment. It is increasingly used in specialties such as oncology, neurology, and cardiology. A personalized approach has many objectives, including to optimize treatment, minimize the risk of adverse effects, facilitate early diagnosis, and determine predisposition to disease. Genomic technologies, such as massive sequencing techniques, and tools such as CRISPR-Cas9 are key to the future of personalized medicine.
Jesús Oteo Iglesias, MD, PhD, a specialist in microbiology and director of Spain’s National Center for Microbiology, spoke at the Spanish Association of Infectious Diseases and Clinical Microbiology’s recent conference. He discussed various precision medicine projects aimed at reinforcing the fight against antibiotic resistance.
Infectious diseases are complex because the diversity of the pathogenic microorganism combines with the patient’s own diversity, which influences the interaction between the two, said Dr. Oteo. Thus, the antibiogram and targeted antibiotic treatments (which are chosen according to the species, sensitivity to antimicrobials, type of infection, and patient characteristics) have been established applications of precision medicine for decades. However, multiple tools could further strengthen personalized medicine against multiresistant pathogens.
Therapeutic drug monitoring, in which multiple pharmacokinetic and pharmacodynamic factors are considered, is a strategy with great potential to increase the effectiveness of antibiotics and minimize toxicity. Owing to its costs and the need for trained staff, this tool would be especially indicated in the treatment of patients with more complex conditions, such as those suffering from obesity, complex infections, or infections with multiresistant bacteria, as well as those in critical condition. Multiple computer programs are available to help determine the dosage of antibiotics by estimating drug exposure and to provide recommendations. However, clinical trials are needed to assess the pros and cons of applying therapeutic monitoring for types of antibiotics other than those for which a given type is already used (for example, aminoglycosides and glycopeptides).
One technology that could help in antibiotic use optimization programs is microneedle-based biosensors, which could be implanted in the skin for real-time antibiotic monitoring. This tool “could be the first step in establishing automated antibiotic administration systems, with infusion pumps and feedback systems, like those already used in diabetes for insulin administration,” said Dr. Oteo.
Artificial intelligence could also be a valuable technology for optimization programs. “We should go a step further in the implementation of artificial intelligence through clinical decision support systems,” said Dr. Oteo. This technology would guide the administration of antimicrobials using data extracted from the electronic medical record. However, there are great challenges to overcome in creating these tools, such as the risk of entering erroneous data; the difficulty in entering complex data, such as data relevant to antibiotic resistance; and the variability at the geographic and institutional levels.
Genomics is also a tool with great potential for identifying bacteria’s degree of resistance to antibiotics by studying mutations in chromosomal and acquired genes. A proof-of-concept study evaluated the sensitivity of different Pseudomonas aeruginosa strains to several antibiotics by analyzing genome sequences associated with resistance, said Dr. Otero. The researchers found that this system was effective at predicting the sensitivity of bacteria from genomic data.
In the United States, the PATRIC bioinformatics center, which is financed by the National Institute of Allergy and Infectious Diseases, works with automated learning models to predict the antimicrobial resistance of different species of bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis. These models, which work with genomic data associated with antibiotic resistance phenotypes, are able to identify resistance without prior knowledge of the underlying mechanisms.
Another factor to consider with regard to the use of precision medicine for infectious diseases is the microbiota. Dr. Oteo explained that the pathogenic microorganism interacts not only with the host but also with its microbiota, “which can be diverse, is manifold, and can be very different, depending on the circumstances. These interactions can be translated into ecological and evolutionary pressures that may have clinical significance.” One of the best-known examples is the possibility that a beta-lactamase–producing bacterium benefits other bacteria around it by secreting these enzymes. Furthermore, some known forms of bacterial interaction (such as plasmid transfer) are directly related to antibiotic resistance. Metagenomics, which involves the genetic study of communities of microbes, could provide more information for predicting and avoiding infections by multiresistant pathogens by monitoring the microbiome.
The CRISPR-Cas9 gene editing tool could also be an ally in the fight against antibiotic resistance by eliminating resistance genes and thus making bacteria sensitive to certain antibiotics. Several published preliminary studies indicate that this is possible in vitro. The main challenge for the clinical application of CRISPR is in introducing it into the target microbial population. Use of conjugative plasmids and bacteriophages could perhaps be an option for overcoming this obstacle in the future.
Exploiting the possibilities of precision medicine through use of the most innovative tools in addressing antibiotic resistance is a great challenge, said Dr. Oteo, but the situation demands it, and it is necessary to take small steps to achieve this goal.
A version of this article appeared on Medscape.com. This article was translated from Univadis Spain.
Diversity is an omnipresent element in clinical practice: in the genome, in the environment, in patients’ lifestyles and habits. Precision medicine addresses the variability of the individual to improve diagnosis and treatment. It is increasingly used in specialties such as oncology, neurology, and cardiology. A personalized approach has many objectives, including to optimize treatment, minimize the risk of adverse effects, facilitate early diagnosis, and determine predisposition to disease. Genomic technologies, such as massive sequencing techniques, and tools such as CRISPR-Cas9 are key to the future of personalized medicine.
Jesús Oteo Iglesias, MD, PhD, a specialist in microbiology and director of Spain’s National Center for Microbiology, spoke at the Spanish Association of Infectious Diseases and Clinical Microbiology’s recent conference. He discussed various precision medicine projects aimed at reinforcing the fight against antibiotic resistance.
Infectious diseases are complex because the diversity of the pathogenic microorganism combines with the patient’s own diversity, which influences the interaction between the two, said Dr. Oteo. Thus, the antibiogram and targeted antibiotic treatments (which are chosen according to the species, sensitivity to antimicrobials, type of infection, and patient characteristics) have been established applications of precision medicine for decades. However, multiple tools could further strengthen personalized medicine against multiresistant pathogens.
Therapeutic drug monitoring, in which multiple pharmacokinetic and pharmacodynamic factors are considered, is a strategy with great potential to increase the effectiveness of antibiotics and minimize toxicity. Owing to its costs and the need for trained staff, this tool would be especially indicated in the treatment of patients with more complex conditions, such as those suffering from obesity, complex infections, or infections with multiresistant bacteria, as well as those in critical condition. Multiple computer programs are available to help determine the dosage of antibiotics by estimating drug exposure and to provide recommendations. However, clinical trials are needed to assess the pros and cons of applying therapeutic monitoring for types of antibiotics other than those for which a given type is already used (for example, aminoglycosides and glycopeptides).
One technology that could help in antibiotic use optimization programs is microneedle-based biosensors, which could be implanted in the skin for real-time antibiotic monitoring. This tool “could be the first step in establishing automated antibiotic administration systems, with infusion pumps and feedback systems, like those already used in diabetes for insulin administration,” said Dr. Oteo.
Artificial intelligence could also be a valuable technology for optimization programs. “We should go a step further in the implementation of artificial intelligence through clinical decision support systems,” said Dr. Oteo. This technology would guide the administration of antimicrobials using data extracted from the electronic medical record. However, there are great challenges to overcome in creating these tools, such as the risk of entering erroneous data; the difficulty in entering complex data, such as data relevant to antibiotic resistance; and the variability at the geographic and institutional levels.
Genomics is also a tool with great potential for identifying bacteria’s degree of resistance to antibiotics by studying mutations in chromosomal and acquired genes. A proof-of-concept study evaluated the sensitivity of different Pseudomonas aeruginosa strains to several antibiotics by analyzing genome sequences associated with resistance, said Dr. Otero. The researchers found that this system was effective at predicting the sensitivity of bacteria from genomic data.
In the United States, the PATRIC bioinformatics center, which is financed by the National Institute of Allergy and Infectious Diseases, works with automated learning models to predict the antimicrobial resistance of different species of bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis. These models, which work with genomic data associated with antibiotic resistance phenotypes, are able to identify resistance without prior knowledge of the underlying mechanisms.
Another factor to consider with regard to the use of precision medicine for infectious diseases is the microbiota. Dr. Oteo explained that the pathogenic microorganism interacts not only with the host but also with its microbiota, “which can be diverse, is manifold, and can be very different, depending on the circumstances. These interactions can be translated into ecological and evolutionary pressures that may have clinical significance.” One of the best-known examples is the possibility that a beta-lactamase–producing bacterium benefits other bacteria around it by secreting these enzymes. Furthermore, some known forms of bacterial interaction (such as plasmid transfer) are directly related to antibiotic resistance. Metagenomics, which involves the genetic study of communities of microbes, could provide more information for predicting and avoiding infections by multiresistant pathogens by monitoring the microbiome.
The CRISPR-Cas9 gene editing tool could also be an ally in the fight against antibiotic resistance by eliminating resistance genes and thus making bacteria sensitive to certain antibiotics. Several published preliminary studies indicate that this is possible in vitro. The main challenge for the clinical application of CRISPR is in introducing it into the target microbial population. Use of conjugative plasmids and bacteriophages could perhaps be an option for overcoming this obstacle in the future.
Exploiting the possibilities of precision medicine through use of the most innovative tools in addressing antibiotic resistance is a great challenge, said Dr. Oteo, but the situation demands it, and it is necessary to take small steps to achieve this goal.
A version of this article appeared on Medscape.com. This article was translated from Univadis Spain.
Children with autism experience more severe sleep apnea
Symptoms of obstructive sleep apnea (OSA) were significantly more common in children with autism spectrum disorder (ASD), compared with controls, based on data from 166 individuals up to age 18 years.
Autism spectrum disorder affects approximately 1 in 54 children in the United States, and recent studies have shown an increased risk of obstructive sleep apnea in this population, compared with the general pediatric population, wrote Pooja Santapuram, MD, of Vanderbilt University, Nashville, Tenn., and colleagues.
In a study published in the International Journal of Pediatric Ototrhinolaryngology , the researchers reviewed data from 166 children and adolescents up to 18 years of age with OSA who underwent adenotonsillectomy at a single center between 2019 and 2021. The primary objective was to assess OSA symptoms in children with and without ASD. The study population included 75 children with ASD and 91 controls. The average age of both the ASD group and control group was approximately 73 months.
OSA meets ASD
Obstructive sleep apnea is common in autism spectrum disorder. Children with OSA can present with a range of symptoms, including loud snoring, excessive daytime sleepiness, and changes in cognitive function. Some of these symptoms can overlap with and exacerbate symptoms of ASD, potentially delaying OSA diagnosis in children with both conditions. The primary objective of this study was to assess between-group difference in OSA symptomatology and age at OSA diagnosis in children with and without ASD. To do so, a retrospective chart review was conducted on the 166 pediatric patients.
Overall, significantly more OSA symptoms were reported in children with ASD, compared with controls (P < .001).
Lower autism severity was associated with an increased number of reported OSA symptoms (P = .006). There was not a significant between-group difference in age at OSA diagnosis (P = .999); however, lower autism severity was also associated with an increased age at diagnosis (P = .002). These findings suggest that OSA may present with a higher symptom burden in children with ASD, and children with lower ASD severity often experience delays in OSA diagnosis.
Interestingly, despite the known associations between obesity and OSA, children with an increased body mass index were not diagnosed with OSA at an earlier age in this sample population, the researchers indicated.
Because the current study revealed that children with less severe ASD are more likely to report an increased number of OSA symptoms and be diagnosed at a later age than children without ASD, clinicians should have a heightened sense for OSA evaluation in children with ASD, particularly in children with a lower severity of ASD and an increased BMI, the researchers concluded.
The research study was not externally funded, and the researchers reported that they had no conflicts of interest.
Symptoms of obstructive sleep apnea (OSA) were significantly more common in children with autism spectrum disorder (ASD), compared with controls, based on data from 166 individuals up to age 18 years.
Autism spectrum disorder affects approximately 1 in 54 children in the United States, and recent studies have shown an increased risk of obstructive sleep apnea in this population, compared with the general pediatric population, wrote Pooja Santapuram, MD, of Vanderbilt University, Nashville, Tenn., and colleagues.
In a study published in the International Journal of Pediatric Ototrhinolaryngology , the researchers reviewed data from 166 children and adolescents up to 18 years of age with OSA who underwent adenotonsillectomy at a single center between 2019 and 2021. The primary objective was to assess OSA symptoms in children with and without ASD. The study population included 75 children with ASD and 91 controls. The average age of both the ASD group and control group was approximately 73 months.
OSA meets ASD
Obstructive sleep apnea is common in autism spectrum disorder. Children with OSA can present with a range of symptoms, including loud snoring, excessive daytime sleepiness, and changes in cognitive function. Some of these symptoms can overlap with and exacerbate symptoms of ASD, potentially delaying OSA diagnosis in children with both conditions. The primary objective of this study was to assess between-group difference in OSA symptomatology and age at OSA diagnosis in children with and without ASD. To do so, a retrospective chart review was conducted on the 166 pediatric patients.
Overall, significantly more OSA symptoms were reported in children with ASD, compared with controls (P < .001).
Lower autism severity was associated with an increased number of reported OSA symptoms (P = .006). There was not a significant between-group difference in age at OSA diagnosis (P = .999); however, lower autism severity was also associated with an increased age at diagnosis (P = .002). These findings suggest that OSA may present with a higher symptom burden in children with ASD, and children with lower ASD severity often experience delays in OSA diagnosis.
Interestingly, despite the known associations between obesity and OSA, children with an increased body mass index were not diagnosed with OSA at an earlier age in this sample population, the researchers indicated.
Because the current study revealed that children with less severe ASD are more likely to report an increased number of OSA symptoms and be diagnosed at a later age than children without ASD, clinicians should have a heightened sense for OSA evaluation in children with ASD, particularly in children with a lower severity of ASD and an increased BMI, the researchers concluded.
The research study was not externally funded, and the researchers reported that they had no conflicts of interest.
Symptoms of obstructive sleep apnea (OSA) were significantly more common in children with autism spectrum disorder (ASD), compared with controls, based on data from 166 individuals up to age 18 years.
Autism spectrum disorder affects approximately 1 in 54 children in the United States, and recent studies have shown an increased risk of obstructive sleep apnea in this population, compared with the general pediatric population, wrote Pooja Santapuram, MD, of Vanderbilt University, Nashville, Tenn., and colleagues.
In a study published in the International Journal of Pediatric Ototrhinolaryngology , the researchers reviewed data from 166 children and adolescents up to 18 years of age with OSA who underwent adenotonsillectomy at a single center between 2019 and 2021. The primary objective was to assess OSA symptoms in children with and without ASD. The study population included 75 children with ASD and 91 controls. The average age of both the ASD group and control group was approximately 73 months.
OSA meets ASD
Obstructive sleep apnea is common in autism spectrum disorder. Children with OSA can present with a range of symptoms, including loud snoring, excessive daytime sleepiness, and changes in cognitive function. Some of these symptoms can overlap with and exacerbate symptoms of ASD, potentially delaying OSA diagnosis in children with both conditions. The primary objective of this study was to assess between-group difference in OSA symptomatology and age at OSA diagnosis in children with and without ASD. To do so, a retrospective chart review was conducted on the 166 pediatric patients.
Overall, significantly more OSA symptoms were reported in children with ASD, compared with controls (P < .001).
Lower autism severity was associated with an increased number of reported OSA symptoms (P = .006). There was not a significant between-group difference in age at OSA diagnosis (P = .999); however, lower autism severity was also associated with an increased age at diagnosis (P = .002). These findings suggest that OSA may present with a higher symptom burden in children with ASD, and children with lower ASD severity often experience delays in OSA diagnosis.
Interestingly, despite the known associations between obesity and OSA, children with an increased body mass index were not diagnosed with OSA at an earlier age in this sample population, the researchers indicated.
Because the current study revealed that children with less severe ASD are more likely to report an increased number of OSA symptoms and be diagnosed at a later age than children without ASD, clinicians should have a heightened sense for OSA evaluation in children with ASD, particularly in children with a lower severity of ASD and an increased BMI, the researchers concluded.
The research study was not externally funded, and the researchers reported that they had no conflicts of interest.
FROM THE INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY
Understanding filler reversal with hyaluronidase
Hyaluronic acid is the most common filler used in the United States for cosmetic procedures. . However, there has been little research and there are no formal clinical guidelines on its use. Hyaluronidase is approved by the Food and Drug Administration for several indications, but its use in cosmetic procedures is off-label.
Hyaluronic acid filler complications can be local and transient or delayed and/or dangerous. Local reactions generally improve over time or respond to symptomatic care. But granulomatous reactions, misplaced injection, adverse aesthetic outcomes, and vascular occlusion are some of the detrimental outcomes that require immediate treatment, often using hyaluronidase, a naturally occurring enzyme that degrades hyaluronic acid.
Hyaluronic acid products vary in concentration, cross-linking, type of cross-linker used, and particle size, and therefore display different degradation patterns with hyaluronidase. The three hyaluronidase products available also vary in concentration, source, and enzyme activity. Hyaluronidase has a half-life of 2 minutes but has a duration of action of 24-48 hours depending on the product used.
In an interesting study by Casabona G et al., the dose and activity of five hyaluronidase products available worldwide were used to degrade five different fillers (Juvederm Volbella, Voluma, and Ultraplus; Belotero, and Belotero Balance) with various concentrations and cross-linking in human skin. The results showed that the Vycross products (Juvederm Voluma) are the least sensitive to hyaluronidase and require the greatest concentration of hyaluronidase and a longer time for dissolution requiring up to three times more hyaluronidase to degrade the same volume of other hyaluronic acid products.
In addition, the ovine hyaluronidase product marketed in the United States as Vitrase had the greatest activity against the range of hyaluronic acids used in the trial. Higher concentrations of hyaluronidase also could produce type-I hypersensitivity reactions and angioedema in susceptible patients as evidenced by eosinophilic tissue reactions at concentrations greater than 300 IU.
Hyaluronidase is stored at cool temperatures (35-46° F). It can be reconstituted with saline, water, or bacteriostatic saline for reducing injection site pain; however, it should not be mixed with local anesthetic. The volume of diluent used depends on the surface area treated and ranges from 1 mL to 10 mL. Smaller volumes are used for more concentrated local injection and larger volumes for more precise dosing.
For impending necrosis, hyaluronidase should be used within minutes to hours of blanching of the skin and the area should be flooded every 30 minutes until the tissue has reperfused. Depending on the type of filler used, the volume of injection varies and the area should continually be injected and tissue response observed. A high-dosed large-volume protocol allows the tissue perfusion to gradually infiltrate the vessel walls. Recommendations are 2 mL of bacteriostatic saline diluted with a vial of hyaluronidase. Retrobulbar injection of hyaluronidase within minutes of retinal artery occlusion in doses of 150-200 units in 2-4 mL of diluent into the inferolateral orbit by an experienced ophthalmologist or oculoplastic surgeon is recommended.
Although there is no consensus, there are various clinical studies using hyaluronidase dilutions varying between 5 and 30 units to break down 0.1mg/mL of hyaluronic acid for the reversal of facial hyaluronic acid fillers. In my clinical experience, the recommendation is that, apart from necrosis, the concentration used is titrated to clinical efficacy, which can also be done over multiple appointments every 48 hours until the desired outcome is achieved.
Complications from hyaluronidase injection include local tissue erythema, edema, pain, allergic reactions, and anaphylaxis. An intradermal patch test of 10-20 units of hyaluronidase in the forearm can be done in patients with a history of allergy to hyaluronidase, which, in people with sensitivity, results in a wheal within 30 minutes of injection. If a patient has a positive patch test, hyaluronidase cannot be used. In addition, a history of allergic reactions to bees may pose a heightened reaction to hyaluronidase and is a contraindication to use.
It is recommended that any practitioner using hyaluronic acid fillers keep 2-3 vials of hyaluronidase available at all times in the event of a vascular emergency. Stability, storage, and expiration dates should also be monitored closely.
Dr. Talakoub and Naissan O. Wesley, MD, are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. Write to them at [email protected]. Dr. Talakoub has no relevant disclosures.
References
Casabona G et al. Dermatol Surg. 2018 Nov;44 Suppl 1:S42-S50.
DeLorenzi C. Aesthet Surg J. 2017 Jul 1;37(7):814-25.
Juhász MLW et al. Dermatol Surg. 2017 Jun;43(6):841-7.
King M. J Clin Aesthet Dermatol. 2016 Nov; 9(11):E6–8.
Kim M et al. J Clin Aesthet Dermatol. 2018 Jun;11(6):E61-8.
Hyaluronic acid is the most common filler used in the United States for cosmetic procedures. . However, there has been little research and there are no formal clinical guidelines on its use. Hyaluronidase is approved by the Food and Drug Administration for several indications, but its use in cosmetic procedures is off-label.
Hyaluronic acid filler complications can be local and transient or delayed and/or dangerous. Local reactions generally improve over time or respond to symptomatic care. But granulomatous reactions, misplaced injection, adverse aesthetic outcomes, and vascular occlusion are some of the detrimental outcomes that require immediate treatment, often using hyaluronidase, a naturally occurring enzyme that degrades hyaluronic acid.
Hyaluronic acid products vary in concentration, cross-linking, type of cross-linker used, and particle size, and therefore display different degradation patterns with hyaluronidase. The three hyaluronidase products available also vary in concentration, source, and enzyme activity. Hyaluronidase has a half-life of 2 minutes but has a duration of action of 24-48 hours depending on the product used.
In an interesting study by Casabona G et al., the dose and activity of five hyaluronidase products available worldwide were used to degrade five different fillers (Juvederm Volbella, Voluma, and Ultraplus; Belotero, and Belotero Balance) with various concentrations and cross-linking in human skin. The results showed that the Vycross products (Juvederm Voluma) are the least sensitive to hyaluronidase and require the greatest concentration of hyaluronidase and a longer time for dissolution requiring up to three times more hyaluronidase to degrade the same volume of other hyaluronic acid products.
In addition, the ovine hyaluronidase product marketed in the United States as Vitrase had the greatest activity against the range of hyaluronic acids used in the trial. Higher concentrations of hyaluronidase also could produce type-I hypersensitivity reactions and angioedema in susceptible patients as evidenced by eosinophilic tissue reactions at concentrations greater than 300 IU.
Hyaluronidase is stored at cool temperatures (35-46° F). It can be reconstituted with saline, water, or bacteriostatic saline for reducing injection site pain; however, it should not be mixed with local anesthetic. The volume of diluent used depends on the surface area treated and ranges from 1 mL to 10 mL. Smaller volumes are used for more concentrated local injection and larger volumes for more precise dosing.
For impending necrosis, hyaluronidase should be used within minutes to hours of blanching of the skin and the area should be flooded every 30 minutes until the tissue has reperfused. Depending on the type of filler used, the volume of injection varies and the area should continually be injected and tissue response observed. A high-dosed large-volume protocol allows the tissue perfusion to gradually infiltrate the vessel walls. Recommendations are 2 mL of bacteriostatic saline diluted with a vial of hyaluronidase. Retrobulbar injection of hyaluronidase within minutes of retinal artery occlusion in doses of 150-200 units in 2-4 mL of diluent into the inferolateral orbit by an experienced ophthalmologist or oculoplastic surgeon is recommended.
Although there is no consensus, there are various clinical studies using hyaluronidase dilutions varying between 5 and 30 units to break down 0.1mg/mL of hyaluronic acid for the reversal of facial hyaluronic acid fillers. In my clinical experience, the recommendation is that, apart from necrosis, the concentration used is titrated to clinical efficacy, which can also be done over multiple appointments every 48 hours until the desired outcome is achieved.
Complications from hyaluronidase injection include local tissue erythema, edema, pain, allergic reactions, and anaphylaxis. An intradermal patch test of 10-20 units of hyaluronidase in the forearm can be done in patients with a history of allergy to hyaluronidase, which, in people with sensitivity, results in a wheal within 30 minutes of injection. If a patient has a positive patch test, hyaluronidase cannot be used. In addition, a history of allergic reactions to bees may pose a heightened reaction to hyaluronidase and is a contraindication to use.
It is recommended that any practitioner using hyaluronic acid fillers keep 2-3 vials of hyaluronidase available at all times in the event of a vascular emergency. Stability, storage, and expiration dates should also be monitored closely.
Dr. Talakoub and Naissan O. Wesley, MD, are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. Write to them at [email protected]. Dr. Talakoub has no relevant disclosures.
References
Casabona G et al. Dermatol Surg. 2018 Nov;44 Suppl 1:S42-S50.
DeLorenzi C. Aesthet Surg J. 2017 Jul 1;37(7):814-25.
Juhász MLW et al. Dermatol Surg. 2017 Jun;43(6):841-7.
King M. J Clin Aesthet Dermatol. 2016 Nov; 9(11):E6–8.
Kim M et al. J Clin Aesthet Dermatol. 2018 Jun;11(6):E61-8.
Hyaluronic acid is the most common filler used in the United States for cosmetic procedures. . However, there has been little research and there are no formal clinical guidelines on its use. Hyaluronidase is approved by the Food and Drug Administration for several indications, but its use in cosmetic procedures is off-label.
Hyaluronic acid filler complications can be local and transient or delayed and/or dangerous. Local reactions generally improve over time or respond to symptomatic care. But granulomatous reactions, misplaced injection, adverse aesthetic outcomes, and vascular occlusion are some of the detrimental outcomes that require immediate treatment, often using hyaluronidase, a naturally occurring enzyme that degrades hyaluronic acid.
Hyaluronic acid products vary in concentration, cross-linking, type of cross-linker used, and particle size, and therefore display different degradation patterns with hyaluronidase. The three hyaluronidase products available also vary in concentration, source, and enzyme activity. Hyaluronidase has a half-life of 2 minutes but has a duration of action of 24-48 hours depending on the product used.
In an interesting study by Casabona G et al., the dose and activity of five hyaluronidase products available worldwide were used to degrade five different fillers (Juvederm Volbella, Voluma, and Ultraplus; Belotero, and Belotero Balance) with various concentrations and cross-linking in human skin. The results showed that the Vycross products (Juvederm Voluma) are the least sensitive to hyaluronidase and require the greatest concentration of hyaluronidase and a longer time for dissolution requiring up to three times more hyaluronidase to degrade the same volume of other hyaluronic acid products.
In addition, the ovine hyaluronidase product marketed in the United States as Vitrase had the greatest activity against the range of hyaluronic acids used in the trial. Higher concentrations of hyaluronidase also could produce type-I hypersensitivity reactions and angioedema in susceptible patients as evidenced by eosinophilic tissue reactions at concentrations greater than 300 IU.
Hyaluronidase is stored at cool temperatures (35-46° F). It can be reconstituted with saline, water, or bacteriostatic saline for reducing injection site pain; however, it should not be mixed with local anesthetic. The volume of diluent used depends on the surface area treated and ranges from 1 mL to 10 mL. Smaller volumes are used for more concentrated local injection and larger volumes for more precise dosing.
For impending necrosis, hyaluronidase should be used within minutes to hours of blanching of the skin and the area should be flooded every 30 minutes until the tissue has reperfused. Depending on the type of filler used, the volume of injection varies and the area should continually be injected and tissue response observed. A high-dosed large-volume protocol allows the tissue perfusion to gradually infiltrate the vessel walls. Recommendations are 2 mL of bacteriostatic saline diluted with a vial of hyaluronidase. Retrobulbar injection of hyaluronidase within minutes of retinal artery occlusion in doses of 150-200 units in 2-4 mL of diluent into the inferolateral orbit by an experienced ophthalmologist or oculoplastic surgeon is recommended.
Although there is no consensus, there are various clinical studies using hyaluronidase dilutions varying between 5 and 30 units to break down 0.1mg/mL of hyaluronic acid for the reversal of facial hyaluronic acid fillers. In my clinical experience, the recommendation is that, apart from necrosis, the concentration used is titrated to clinical efficacy, which can also be done over multiple appointments every 48 hours until the desired outcome is achieved.
Complications from hyaluronidase injection include local tissue erythema, edema, pain, allergic reactions, and anaphylaxis. An intradermal patch test of 10-20 units of hyaluronidase in the forearm can be done in patients with a history of allergy to hyaluronidase, which, in people with sensitivity, results in a wheal within 30 minutes of injection. If a patient has a positive patch test, hyaluronidase cannot be used. In addition, a history of allergic reactions to bees may pose a heightened reaction to hyaluronidase and is a contraindication to use.
It is recommended that any practitioner using hyaluronic acid fillers keep 2-3 vials of hyaluronidase available at all times in the event of a vascular emergency. Stability, storage, and expiration dates should also be monitored closely.
Dr. Talakoub and Naissan O. Wesley, MD, are cocontributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. Write to them at [email protected]. Dr. Talakoub has no relevant disclosures.
References
Casabona G et al. Dermatol Surg. 2018 Nov;44 Suppl 1:S42-S50.
DeLorenzi C. Aesthet Surg J. 2017 Jul 1;37(7):814-25.
Juhász MLW et al. Dermatol Surg. 2017 Jun;43(6):841-7.
King M. J Clin Aesthet Dermatol. 2016 Nov; 9(11):E6–8.
Kim M et al. J Clin Aesthet Dermatol. 2018 Jun;11(6):E61-8.
Hidradenitis Suppurativa: The Basics
Remnant cholesterol improves CV risk prediction
, a new study suggests.
The study, which followed almost 42,000 Danish individuals without a history of ischemic cardiovascular disease, diabetes, or statin use for more than 10 years, found that elevated remnant cholesterol appropriately reclassified up to 40% of those who later experienced myocardial infarction and ischemic heart disease.
“The clinical implications of our study include that doctors and patients should be aware of remnant cholesterol levels to prevent future risk of MI and ischemic heart disease,” the authors conclude.
They suggest that the development of a cardiovascular risk algorithm, including remnant cholesterol together with LDL cholesterol, would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting.
They note that physicians are encouraged to evaluate non-HDL cholesterol and/or apolipoprotein B rather than LDL cholesterol and certainly not yet remnant cholesterol, possibly because of the limited availability of remnant cholesterol values in some parts of the world.
However, they point out that remnant cholesterol can be calculated with a standard lipid profile without additional cost, which is currently already the standard procedure in the greater Copenhagen area.
“This means that the use of remnant cholesterol is easy to introduce into daily clinical practice,” they say.
The study was published online in the Journal of the American College of Cardiology.
The authors, Takahito Doi, MD, Anne Langsted, MD, and Børge Nordestgaard, from Copenhagen University Hospital, Denmark, explain that remnant cholesterol is total cholesterol minus LDL-cholesterol minus HDL-cholesterol and includes the cholesterol content of the triglyceride-rich very-low-density lipoproteins, intermediate-density lipoproteins, and chylomicron remnants in the nonfasting state.
“When these particles enter the arterial wall, they are taken up by macrophages to produce foam cells, and therefore elevated remnant cholesterol likely enhance accumulation of cholesterol in the arterial wall, leading to progression of atherosclerosis and in consequence ischemic heart disease,” they note.
They point out that most guidelines for assessment of the 10-year risk of ischemic heart and atherosclerotic cardiovascular disease include levels of total and HDL cholesterol, but remnant cholesterol levels are not included.
They conducted the current study to investigate whether elevated remnant cholesterol would lead to appropriate reclassification of individuals who later experienced MI or ischemic heart disease.
The researchers analyzed data from the Copenhagen General Population Study, which recruited individuals from the White Danish general population from 2003-2015 and followed them until 2018. Information on lifestyle, health, and medication, including statin therapy, was obtained through a questionnaire, and participants underwent physical examinations and had nonfasting blood samples drawn for biochemical measurements.
For the current study, they included 41,928 individuals aged 40-100 years enrolled before 2009 without a history of ischemic cardiovascular disease, diabetes, and statin use at baseline. The median follow-up time was 12 years. Information on diagnoses of MI and ischemic heart disease was collected from the national Danish Causes of Death Registry and all hospital admissions and diagnoses entered in the national Danish Patient Registry.
During the first 10 years of follow-up there were 1,063 MIs and 1,460 ischemic heart disease events (death of ischemic heart disease, nonfatal MI, and coronary revascularization).
Results showed that in models based on conventional risk factors estimating risk of heart disease of above or below 5% in 10 years, adding remnant cholesterol at levels above the 95th percentile, appropriately reclassified 23% of individuals who had an MI and 21% of individuals who had an ischemic heart disease event.
Using remnant cholesterol levels above the 75th percentile appropriately reclassified 10% of those who had an MI and 8% of those who had an ischemic heart disease event. No events were reclassified incorrectly.
Using measurements of remnant cholesterol also improved reclassification of individuals with heart disease risk above or below 7.5% or 10% in 10 years.
When reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% of individuals with MI and 41% with ischemic heart disease events were reclassified appropriately.
In an editorial accompanying publication of the study in JACC, Peter Wilson, MD, Emory University School of Medicine, Atlanta, and Alan Remaley, MD, National Heart, Lung, and Blood Institute, say these findings rekindle interest in atherogenic nonfasting lipid measurements and emphasize an important role for elevated nonfasting remnant cholesterol as a value-added predictor of ischemic events.
The editorialists note that both fasting and nonfasting lipid values provide useful information for atherosclerotic cardiovascular disease (ASCVD) risk estimation, and elevated nonfasting remnant cholesterol appears to help identify persons at greater risk for an initial cardiovascular ischemic event.
They add that very elevated levels (above the 75th percentile) of nonfasting remnant cholesterol deserve further evaluation as a potentially valuable “modifier of ASCVD risk,” and replication of the results could move these findings forward to potentially improve prognostication and care for patients at risk for ischemic heart disease events.
An indirect measure of triglycerides
Dr. Wilson explained that remnant cholesterol is an indirect measure of triglycerides beyond LDL levels, and it is thus including a new lipid measurement in risk prediction.
“We are completely focused on LDL cholesterol,” he said. “This opens it up a bit by adding in another measure that takes into account triglycerides as well as LDL.”
He also pointed out that use of a nonfasting sample is another advantage of measuring remnant cholesterol.
“An accurate measure of LDL needs a fasting sample, which is a nuisance, whereas remnant cholesterol can be measured in a nonfasting blood sample, so it is more convenient,” Dr. Wilson said.
While this study shows this measure is helpful for risk prediction in the primary prevention population, Dr. Wilson believes remnant cholesterol could be most useful in helping to guide further medication choice in patients who are already taking statins.
“Statins mainly target LDL, but if we can also measure nonfasting triglycerides this will be helpful. It may help us select some patients who may need a different type of drug to use in addition to statins that lowers triglycerides,” he said.
This work was supported by the Global Excellence Programme, the Research Fund for the Capital Region of Denmark, the Japanese College of Cardiology Overseas Research Fellowship, and the Scandinavia Japan Sasakawa Foundation. Mr. Nordestgaard has reported consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. Dr. Doi has reported talks sponsored by MSD.
A version of this article first appeared on Medscape.com.
, a new study suggests.
The study, which followed almost 42,000 Danish individuals without a history of ischemic cardiovascular disease, diabetes, or statin use for more than 10 years, found that elevated remnant cholesterol appropriately reclassified up to 40% of those who later experienced myocardial infarction and ischemic heart disease.
“The clinical implications of our study include that doctors and patients should be aware of remnant cholesterol levels to prevent future risk of MI and ischemic heart disease,” the authors conclude.
They suggest that the development of a cardiovascular risk algorithm, including remnant cholesterol together with LDL cholesterol, would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting.
They note that physicians are encouraged to evaluate non-HDL cholesterol and/or apolipoprotein B rather than LDL cholesterol and certainly not yet remnant cholesterol, possibly because of the limited availability of remnant cholesterol values in some parts of the world.
However, they point out that remnant cholesterol can be calculated with a standard lipid profile without additional cost, which is currently already the standard procedure in the greater Copenhagen area.
“This means that the use of remnant cholesterol is easy to introduce into daily clinical practice,” they say.
The study was published online in the Journal of the American College of Cardiology.
The authors, Takahito Doi, MD, Anne Langsted, MD, and Børge Nordestgaard, from Copenhagen University Hospital, Denmark, explain that remnant cholesterol is total cholesterol minus LDL-cholesterol minus HDL-cholesterol and includes the cholesterol content of the triglyceride-rich very-low-density lipoproteins, intermediate-density lipoproteins, and chylomicron remnants in the nonfasting state.
“When these particles enter the arterial wall, they are taken up by macrophages to produce foam cells, and therefore elevated remnant cholesterol likely enhance accumulation of cholesterol in the arterial wall, leading to progression of atherosclerosis and in consequence ischemic heart disease,” they note.
They point out that most guidelines for assessment of the 10-year risk of ischemic heart and atherosclerotic cardiovascular disease include levels of total and HDL cholesterol, but remnant cholesterol levels are not included.
They conducted the current study to investigate whether elevated remnant cholesterol would lead to appropriate reclassification of individuals who later experienced MI or ischemic heart disease.
The researchers analyzed data from the Copenhagen General Population Study, which recruited individuals from the White Danish general population from 2003-2015 and followed them until 2018. Information on lifestyle, health, and medication, including statin therapy, was obtained through a questionnaire, and participants underwent physical examinations and had nonfasting blood samples drawn for biochemical measurements.
For the current study, they included 41,928 individuals aged 40-100 years enrolled before 2009 without a history of ischemic cardiovascular disease, diabetes, and statin use at baseline. The median follow-up time was 12 years. Information on diagnoses of MI and ischemic heart disease was collected from the national Danish Causes of Death Registry and all hospital admissions and diagnoses entered in the national Danish Patient Registry.
During the first 10 years of follow-up there were 1,063 MIs and 1,460 ischemic heart disease events (death of ischemic heart disease, nonfatal MI, and coronary revascularization).
Results showed that in models based on conventional risk factors estimating risk of heart disease of above or below 5% in 10 years, adding remnant cholesterol at levels above the 95th percentile, appropriately reclassified 23% of individuals who had an MI and 21% of individuals who had an ischemic heart disease event.
Using remnant cholesterol levels above the 75th percentile appropriately reclassified 10% of those who had an MI and 8% of those who had an ischemic heart disease event. No events were reclassified incorrectly.
Using measurements of remnant cholesterol also improved reclassification of individuals with heart disease risk above or below 7.5% or 10% in 10 years.
When reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% of individuals with MI and 41% with ischemic heart disease events were reclassified appropriately.
In an editorial accompanying publication of the study in JACC, Peter Wilson, MD, Emory University School of Medicine, Atlanta, and Alan Remaley, MD, National Heart, Lung, and Blood Institute, say these findings rekindle interest in atherogenic nonfasting lipid measurements and emphasize an important role for elevated nonfasting remnant cholesterol as a value-added predictor of ischemic events.
The editorialists note that both fasting and nonfasting lipid values provide useful information for atherosclerotic cardiovascular disease (ASCVD) risk estimation, and elevated nonfasting remnant cholesterol appears to help identify persons at greater risk for an initial cardiovascular ischemic event.
They add that very elevated levels (above the 75th percentile) of nonfasting remnant cholesterol deserve further evaluation as a potentially valuable “modifier of ASCVD risk,” and replication of the results could move these findings forward to potentially improve prognostication and care for patients at risk for ischemic heart disease events.
An indirect measure of triglycerides
Dr. Wilson explained that remnant cholesterol is an indirect measure of triglycerides beyond LDL levels, and it is thus including a new lipid measurement in risk prediction.
“We are completely focused on LDL cholesterol,” he said. “This opens it up a bit by adding in another measure that takes into account triglycerides as well as LDL.”
He also pointed out that use of a nonfasting sample is another advantage of measuring remnant cholesterol.
“An accurate measure of LDL needs a fasting sample, which is a nuisance, whereas remnant cholesterol can be measured in a nonfasting blood sample, so it is more convenient,” Dr. Wilson said.
While this study shows this measure is helpful for risk prediction in the primary prevention population, Dr. Wilson believes remnant cholesterol could be most useful in helping to guide further medication choice in patients who are already taking statins.
“Statins mainly target LDL, but if we can also measure nonfasting triglycerides this will be helpful. It may help us select some patients who may need a different type of drug to use in addition to statins that lowers triglycerides,” he said.
This work was supported by the Global Excellence Programme, the Research Fund for the Capital Region of Denmark, the Japanese College of Cardiology Overseas Research Fellowship, and the Scandinavia Japan Sasakawa Foundation. Mr. Nordestgaard has reported consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. Dr. Doi has reported talks sponsored by MSD.
A version of this article first appeared on Medscape.com.
, a new study suggests.
The study, which followed almost 42,000 Danish individuals without a history of ischemic cardiovascular disease, diabetes, or statin use for more than 10 years, found that elevated remnant cholesterol appropriately reclassified up to 40% of those who later experienced myocardial infarction and ischemic heart disease.
“The clinical implications of our study include that doctors and patients should be aware of remnant cholesterol levels to prevent future risk of MI and ischemic heart disease,” the authors conclude.
They suggest that the development of a cardiovascular risk algorithm, including remnant cholesterol together with LDL cholesterol, would help to better identify high-risk individuals who could be candidates for statins in a primary prevention setting.
They note that physicians are encouraged to evaluate non-HDL cholesterol and/or apolipoprotein B rather than LDL cholesterol and certainly not yet remnant cholesterol, possibly because of the limited availability of remnant cholesterol values in some parts of the world.
However, they point out that remnant cholesterol can be calculated with a standard lipid profile without additional cost, which is currently already the standard procedure in the greater Copenhagen area.
“This means that the use of remnant cholesterol is easy to introduce into daily clinical practice,” they say.
The study was published online in the Journal of the American College of Cardiology.
The authors, Takahito Doi, MD, Anne Langsted, MD, and Børge Nordestgaard, from Copenhagen University Hospital, Denmark, explain that remnant cholesterol is total cholesterol minus LDL-cholesterol minus HDL-cholesterol and includes the cholesterol content of the triglyceride-rich very-low-density lipoproteins, intermediate-density lipoproteins, and chylomicron remnants in the nonfasting state.
“When these particles enter the arterial wall, they are taken up by macrophages to produce foam cells, and therefore elevated remnant cholesterol likely enhance accumulation of cholesterol in the arterial wall, leading to progression of atherosclerosis and in consequence ischemic heart disease,” they note.
They point out that most guidelines for assessment of the 10-year risk of ischemic heart and atherosclerotic cardiovascular disease include levels of total and HDL cholesterol, but remnant cholesterol levels are not included.
They conducted the current study to investigate whether elevated remnant cholesterol would lead to appropriate reclassification of individuals who later experienced MI or ischemic heart disease.
The researchers analyzed data from the Copenhagen General Population Study, which recruited individuals from the White Danish general population from 2003-2015 and followed them until 2018. Information on lifestyle, health, and medication, including statin therapy, was obtained through a questionnaire, and participants underwent physical examinations and had nonfasting blood samples drawn for biochemical measurements.
For the current study, they included 41,928 individuals aged 40-100 years enrolled before 2009 without a history of ischemic cardiovascular disease, diabetes, and statin use at baseline. The median follow-up time was 12 years. Information on diagnoses of MI and ischemic heart disease was collected from the national Danish Causes of Death Registry and all hospital admissions and diagnoses entered in the national Danish Patient Registry.
During the first 10 years of follow-up there were 1,063 MIs and 1,460 ischemic heart disease events (death of ischemic heart disease, nonfatal MI, and coronary revascularization).
Results showed that in models based on conventional risk factors estimating risk of heart disease of above or below 5% in 10 years, adding remnant cholesterol at levels above the 95th percentile, appropriately reclassified 23% of individuals who had an MI and 21% of individuals who had an ischemic heart disease event.
Using remnant cholesterol levels above the 75th percentile appropriately reclassified 10% of those who had an MI and 8% of those who had an ischemic heart disease event. No events were reclassified incorrectly.
Using measurements of remnant cholesterol also improved reclassification of individuals with heart disease risk above or below 7.5% or 10% in 10 years.
When reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% of individuals with MI and 41% with ischemic heart disease events were reclassified appropriately.
In an editorial accompanying publication of the study in JACC, Peter Wilson, MD, Emory University School of Medicine, Atlanta, and Alan Remaley, MD, National Heart, Lung, and Blood Institute, say these findings rekindle interest in atherogenic nonfasting lipid measurements and emphasize an important role for elevated nonfasting remnant cholesterol as a value-added predictor of ischemic events.
The editorialists note that both fasting and nonfasting lipid values provide useful information for atherosclerotic cardiovascular disease (ASCVD) risk estimation, and elevated nonfasting remnant cholesterol appears to help identify persons at greater risk for an initial cardiovascular ischemic event.
They add that very elevated levels (above the 75th percentile) of nonfasting remnant cholesterol deserve further evaluation as a potentially valuable “modifier of ASCVD risk,” and replication of the results could move these findings forward to potentially improve prognostication and care for patients at risk for ischemic heart disease events.
An indirect measure of triglycerides
Dr. Wilson explained that remnant cholesterol is an indirect measure of triglycerides beyond LDL levels, and it is thus including a new lipid measurement in risk prediction.
“We are completely focused on LDL cholesterol,” he said. “This opens it up a bit by adding in another measure that takes into account triglycerides as well as LDL.”
He also pointed out that use of a nonfasting sample is another advantage of measuring remnant cholesterol.
“An accurate measure of LDL needs a fasting sample, which is a nuisance, whereas remnant cholesterol can be measured in a nonfasting blood sample, so it is more convenient,” Dr. Wilson said.
While this study shows this measure is helpful for risk prediction in the primary prevention population, Dr. Wilson believes remnant cholesterol could be most useful in helping to guide further medication choice in patients who are already taking statins.
“Statins mainly target LDL, but if we can also measure nonfasting triglycerides this will be helpful. It may help us select some patients who may need a different type of drug to use in addition to statins that lowers triglycerides,” he said.
This work was supported by the Global Excellence Programme, the Research Fund for the Capital Region of Denmark, the Japanese College of Cardiology Overseas Research Fellowship, and the Scandinavia Japan Sasakawa Foundation. Mr. Nordestgaard has reported consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. Dr. Doi has reported talks sponsored by MSD.
A version of this article first appeared on Medscape.com.
Metastatic lobular, ductal cancers respond similarly
CHICAGO – Metastatic invasive lobular breast cancers (ILC) that are hormone receptor (HR)-positive and HER2-negative have therapeutic outcomes similar to those of invasive ductal cancer (IDC) following treatment with endocrine therapy combined with a CDK4/6 inhibitor, mTOR inhibitor, or PI3K inhibitor, according to a new retrospective analysis of patients treated at MD Anderson Cancer Center.
between the two subtypes, according to Jason A. Mouabbi, MD, who presented the results at the annual meeting of the American Society of Clinical Oncology.
“All the studies that were done were driven by ductal patients, so you can never take conclusions for the lobular patients. We have a big database at MD Anderson, so we can really study a large number of patients and get some signals whether or not patients would benefit from that therapy or not,” said Dr. Mouabbi, a lobular breast cancer specialist at MD Anderson Cancer Center.
The results of the study are important since patients often come to physicians with sophisticated understanding of their disease, he said. Patients with lobular cancer naturally wonder if a therapeutic regimen tested primarily in IDC will benefit them. “For the longest time, we said, ‘we have no data,’ ” said Dr. Mouabbi.
The new study should offer patients and physicians some reassurance. “We found that all of them benefit from it and most importantly, they all benefit from it (with) the same magnitude,” Dr. Mouabbi said.
The researchers analyzed data from 2,971 patients (82% IDC, 14% ILC, 4% mixed) treated between 2010 and 2021. The median age was 50 in all groups. Eighty percent were White, 10% were Hispanic, and 5% were Black. Ninety-nine percent had estrogen receptor (ER) + tumors, and 88% had progesterone positive (PR) + tumors.
A total of 1,895 patients received CDK4/6 inhibitors, 1,027 received everolimus, and 49 received alpelisib. There was no statistically significant difference in overall survival or progression-free survival between the two cancer types in any of the treatment groups.
Despite the similar outcomes, the two conditions remain unique. IDC is a disease of cells from the ducts that deliver milk, while ILC arises in cells that produce milk. Nearly 95% of ILC cases are hormone-positive, compared to 50%-55% of IDC.
So, while existing treatments seem to benefit both groups, there are nonetheless plans to develop therapeutic strategies tailored to lobular cancer.
Dr. Mouabbi’s group has compared molecular profiles of ILC and IDC tumors to better understand how to target them individually. Almost all ILC cancers have a mutation in a gene called CDH1, which leads to loss of an anchoring protein. They believe this causes a unique growth pattern of thin tendrils, rather than the onion-like growths of IDC. A therapy targeting this mutation could provide a specific benefit for lobular breast cancer.
There are other differences: PI3 kinases are mutated in about 60% of ILC tumors, versus about 30% of IDC tumors, and other genes mutated at lower frequencies are also different between the two subtypes. “So there are a lot of (approaches) we are trying to initiate in lobular cancer because we have awareness now that they are different,” Dr. Mouabbi said.
The study received no external funding.
CHICAGO – Metastatic invasive lobular breast cancers (ILC) that are hormone receptor (HR)-positive and HER2-negative have therapeutic outcomes similar to those of invasive ductal cancer (IDC) following treatment with endocrine therapy combined with a CDK4/6 inhibitor, mTOR inhibitor, or PI3K inhibitor, according to a new retrospective analysis of patients treated at MD Anderson Cancer Center.
between the two subtypes, according to Jason A. Mouabbi, MD, who presented the results at the annual meeting of the American Society of Clinical Oncology.
“All the studies that were done were driven by ductal patients, so you can never take conclusions for the lobular patients. We have a big database at MD Anderson, so we can really study a large number of patients and get some signals whether or not patients would benefit from that therapy or not,” said Dr. Mouabbi, a lobular breast cancer specialist at MD Anderson Cancer Center.
The results of the study are important since patients often come to physicians with sophisticated understanding of their disease, he said. Patients with lobular cancer naturally wonder if a therapeutic regimen tested primarily in IDC will benefit them. “For the longest time, we said, ‘we have no data,’ ” said Dr. Mouabbi.
The new study should offer patients and physicians some reassurance. “We found that all of them benefit from it and most importantly, they all benefit from it (with) the same magnitude,” Dr. Mouabbi said.
The researchers analyzed data from 2,971 patients (82% IDC, 14% ILC, 4% mixed) treated between 2010 and 2021. The median age was 50 in all groups. Eighty percent were White, 10% were Hispanic, and 5% were Black. Ninety-nine percent had estrogen receptor (ER) + tumors, and 88% had progesterone positive (PR) + tumors.
A total of 1,895 patients received CDK4/6 inhibitors, 1,027 received everolimus, and 49 received alpelisib. There was no statistically significant difference in overall survival or progression-free survival between the two cancer types in any of the treatment groups.
Despite the similar outcomes, the two conditions remain unique. IDC is a disease of cells from the ducts that deliver milk, while ILC arises in cells that produce milk. Nearly 95% of ILC cases are hormone-positive, compared to 50%-55% of IDC.
So, while existing treatments seem to benefit both groups, there are nonetheless plans to develop therapeutic strategies tailored to lobular cancer.
Dr. Mouabbi’s group has compared molecular profiles of ILC and IDC tumors to better understand how to target them individually. Almost all ILC cancers have a mutation in a gene called CDH1, which leads to loss of an anchoring protein. They believe this causes a unique growth pattern of thin tendrils, rather than the onion-like growths of IDC. A therapy targeting this mutation could provide a specific benefit for lobular breast cancer.
There are other differences: PI3 kinases are mutated in about 60% of ILC tumors, versus about 30% of IDC tumors, and other genes mutated at lower frequencies are also different between the two subtypes. “So there are a lot of (approaches) we are trying to initiate in lobular cancer because we have awareness now that they are different,” Dr. Mouabbi said.
The study received no external funding.
CHICAGO – Metastatic invasive lobular breast cancers (ILC) that are hormone receptor (HR)-positive and HER2-negative have therapeutic outcomes similar to those of invasive ductal cancer (IDC) following treatment with endocrine therapy combined with a CDK4/6 inhibitor, mTOR inhibitor, or PI3K inhibitor, according to a new retrospective analysis of patients treated at MD Anderson Cancer Center.
between the two subtypes, according to Jason A. Mouabbi, MD, who presented the results at the annual meeting of the American Society of Clinical Oncology.
“All the studies that were done were driven by ductal patients, so you can never take conclusions for the lobular patients. We have a big database at MD Anderson, so we can really study a large number of patients and get some signals whether or not patients would benefit from that therapy or not,” said Dr. Mouabbi, a lobular breast cancer specialist at MD Anderson Cancer Center.
The results of the study are important since patients often come to physicians with sophisticated understanding of their disease, he said. Patients with lobular cancer naturally wonder if a therapeutic regimen tested primarily in IDC will benefit them. “For the longest time, we said, ‘we have no data,’ ” said Dr. Mouabbi.
The new study should offer patients and physicians some reassurance. “We found that all of them benefit from it and most importantly, they all benefit from it (with) the same magnitude,” Dr. Mouabbi said.
The researchers analyzed data from 2,971 patients (82% IDC, 14% ILC, 4% mixed) treated between 2010 and 2021. The median age was 50 in all groups. Eighty percent were White, 10% were Hispanic, and 5% were Black. Ninety-nine percent had estrogen receptor (ER) + tumors, and 88% had progesterone positive (PR) + tumors.
A total of 1,895 patients received CDK4/6 inhibitors, 1,027 received everolimus, and 49 received alpelisib. There was no statistically significant difference in overall survival or progression-free survival between the two cancer types in any of the treatment groups.
Despite the similar outcomes, the two conditions remain unique. IDC is a disease of cells from the ducts that deliver milk, while ILC arises in cells that produce milk. Nearly 95% of ILC cases are hormone-positive, compared to 50%-55% of IDC.
So, while existing treatments seem to benefit both groups, there are nonetheless plans to develop therapeutic strategies tailored to lobular cancer.
Dr. Mouabbi’s group has compared molecular profiles of ILC and IDC tumors to better understand how to target them individually. Almost all ILC cancers have a mutation in a gene called CDH1, which leads to loss of an anchoring protein. They believe this causes a unique growth pattern of thin tendrils, rather than the onion-like growths of IDC. A therapy targeting this mutation could provide a specific benefit for lobular breast cancer.
There are other differences: PI3 kinases are mutated in about 60% of ILC tumors, versus about 30% of IDC tumors, and other genes mutated at lower frequencies are also different between the two subtypes. “So there are a lot of (approaches) we are trying to initiate in lobular cancer because we have awareness now that they are different,” Dr. Mouabbi said.
The study received no external funding.
AT ASCO 2022