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Migraine-related stigma is common and underappreciated
, new research shows. Results from the OVERCOME population-based survey study, which included more than 59,000 respondents, showed about 32% reported experiencing migraine-related stigma “often” or “very often.”
Even those experiencing only a few headaches per month said they experienced negative attitudes from others about migraine.
“We have been utterly blind to the burden people with migraine experience in terms of how their disease is appreciated by others. It’s time to get busy and address this very stubborn social phenomenon,” said the study’s coinvestigator, Robert E. Shapiro, MD, PhD, professor emeritus, department of neurological sciences, Larner College of Medicine, University of Vermont, Burlington.
The findings were presented at the annual meeting of the American Headache Society.
Population-based research
Stigma is defined as the discounting or discrediting of an individual with a trait that deviates from social norms. To date, there have been no significant population-based studies of how these attitudes affect individuals with migraine.
OVERCOME is a cross-sectional, longitudinal, prospective, web-based survey conducted in a representative sample of the United States population. For this new analysis, researchers pooled data from surveys conducted in 2018, 2019, and 2020.
The analysis included 59,004 respondents (mean age, 41.3 years; 75% women; 70% White) who reported one or more headache or migraine attacks during the previous 12 months and who met criteria for migraine from the International Classification of Headache Disorders. Among the patients, 35% had a college degree, and 89% suffered episodic-type headaches.
Researchers used the following four patient-reported outcome measures:
- Migraine Disability Assessment, which quantifies number of days missed at work, home, or social events over the previous 3 months
- Migraine Interictal Burden Scale–4, which measures burden of migraine between attacks over the previous 4 weeks
- Migraine-Specific Quality of Life Role-Function Restrictive, which assesses the functional effect of migraine on social and work-related activities over the previous 4 weeks
- Migraine-Related Stigma
For the latter, the investigators used two measures – the degree to which others think migraine is used to acquire secondary gain, such as avoiding commitments, and the degree to which others minimize the burden of migraine.
One of the most stigmatizing disorders
Results showed that 31.7% of participants reported experiencing stigmatization from one or both migraine-related stigma categories often or very often – a result Dr. Shapiro characterized as “pretty shocking.”
Participants with chronic headaches, defined as having 15 or more headache days per month, made up 11% of the sample. About 47% of these respondents felt stigma often or very often.
However, even 25% of participants with three or fewer headache days per month reported stigma.
“This is a fundamental tip that we are not really understanding the concerns that drive burden for people living with this disabling disease,” Dr. Shapiro said.
Some previous studies that compared levels of stigmatizing attitudes regarding various diseases showed that migraine is more stigmatized than even epilepsy, a condition “equated with demonic possession in biblical times,” he noted.
One study used machine learning to measure the number of pejorative or negative terms associated with various diseases. “Shockingly, migraine was one of the most stigmatized diseases,” said Dr. Shapiro. “It was as stigmatized as gonorrhea by certain measures.”
Results from the new study showed that, irrespective of the number of headache days experienced per month, there was a threefold increase in interictal burden among those reporting stigma often or very often, compared with those who didn’t report stigma.
Large impact on QoL
“Stigma is a social concept, so maybe it’s not surprising that it would be present whether or not someone is experiencing other symptoms of migraine,” said Dr. Shapiro.
Across all monthly headache days, experiencing more migraine-related stigma was associated with increased disability and decreased quality of life.
Dr. Shapiro noted that when it comes to migraine-specific quality of life, stigma appears to have more of an effect than number of headache days. “That means there are big gaps in our appreciation for what drives the burdens in the patient experience of living with this disabling disease,” he said.
He added that headache’s place within the migraine sphere needs to be reconsidered. “Its singular emphasis has limited our full appreciation of this disease and how we should be paying attention to the things that are important to patients,” he said.
Dr. Shapiro predicts that future clinical trials will include migraine-related stigma as a measure to guide trial enrollment.
In addition, researchers are now digging deeper to try to understand what factors are most likely to drive stigma. “We need to understand why those attitudes are held and who is more likely to hold those attitudes, and that may allow us to develop mitigating strategies to reduce those attitudes,” said Dr. Shapiro.
‘Worrisome’ findings
Commenting on the findings, Deborah Friedman, MD, professor, departments of neurology and of ophthalmology, UT Southwestern Medical Center, Dallas, said the data on stigma were “worrisome.”
Missing social occasions and lost productivity may make migraine more visible to others so perhaps may “provoke stigma or stigmatizing comments or stigmatizing attitudes,” said Dr. Friedman, who was not involved with the research.
She noted that patients with migraine might also have trouble functioning in the workplace. “They may not be able to tolerate the computer screen or smells of perfume at the office and not get accommodation for that,” she said.
In addition to external stigma, which was investigated in the study, individuals with migraine may also experience internal stigma – blaming themselves for their disease, which may make it less likely they will seek care, said Dr. Friedman.
“That’s a huge problem,” she added.
The OVERCOME study is funded by Lilly. Dr. Shapiro has been compensated by Lilly as a research consultant and as a member of the data monitoring committee for clinical trials for galcanezumab, a Lilly pharmaceutical. Dr. Friedman has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Results from the OVERCOME population-based survey study, which included more than 59,000 respondents, showed about 32% reported experiencing migraine-related stigma “often” or “very often.”
Even those experiencing only a few headaches per month said they experienced negative attitudes from others about migraine.
“We have been utterly blind to the burden people with migraine experience in terms of how their disease is appreciated by others. It’s time to get busy and address this very stubborn social phenomenon,” said the study’s coinvestigator, Robert E. Shapiro, MD, PhD, professor emeritus, department of neurological sciences, Larner College of Medicine, University of Vermont, Burlington.
The findings were presented at the annual meeting of the American Headache Society.
Population-based research
Stigma is defined as the discounting or discrediting of an individual with a trait that deviates from social norms. To date, there have been no significant population-based studies of how these attitudes affect individuals with migraine.
OVERCOME is a cross-sectional, longitudinal, prospective, web-based survey conducted in a representative sample of the United States population. For this new analysis, researchers pooled data from surveys conducted in 2018, 2019, and 2020.
The analysis included 59,004 respondents (mean age, 41.3 years; 75% women; 70% White) who reported one or more headache or migraine attacks during the previous 12 months and who met criteria for migraine from the International Classification of Headache Disorders. Among the patients, 35% had a college degree, and 89% suffered episodic-type headaches.
Researchers used the following four patient-reported outcome measures:
- Migraine Disability Assessment, which quantifies number of days missed at work, home, or social events over the previous 3 months
- Migraine Interictal Burden Scale–4, which measures burden of migraine between attacks over the previous 4 weeks
- Migraine-Specific Quality of Life Role-Function Restrictive, which assesses the functional effect of migraine on social and work-related activities over the previous 4 weeks
- Migraine-Related Stigma
For the latter, the investigators used two measures – the degree to which others think migraine is used to acquire secondary gain, such as avoiding commitments, and the degree to which others minimize the burden of migraine.
One of the most stigmatizing disorders
Results showed that 31.7% of participants reported experiencing stigmatization from one or both migraine-related stigma categories often or very often – a result Dr. Shapiro characterized as “pretty shocking.”
Participants with chronic headaches, defined as having 15 or more headache days per month, made up 11% of the sample. About 47% of these respondents felt stigma often or very often.
However, even 25% of participants with three or fewer headache days per month reported stigma.
“This is a fundamental tip that we are not really understanding the concerns that drive burden for people living with this disabling disease,” Dr. Shapiro said.
Some previous studies that compared levels of stigmatizing attitudes regarding various diseases showed that migraine is more stigmatized than even epilepsy, a condition “equated with demonic possession in biblical times,” he noted.
One study used machine learning to measure the number of pejorative or negative terms associated with various diseases. “Shockingly, migraine was one of the most stigmatized diseases,” said Dr. Shapiro. “It was as stigmatized as gonorrhea by certain measures.”
Results from the new study showed that, irrespective of the number of headache days experienced per month, there was a threefold increase in interictal burden among those reporting stigma often or very often, compared with those who didn’t report stigma.
Large impact on QoL
“Stigma is a social concept, so maybe it’s not surprising that it would be present whether or not someone is experiencing other symptoms of migraine,” said Dr. Shapiro.
Across all monthly headache days, experiencing more migraine-related stigma was associated with increased disability and decreased quality of life.
Dr. Shapiro noted that when it comes to migraine-specific quality of life, stigma appears to have more of an effect than number of headache days. “That means there are big gaps in our appreciation for what drives the burdens in the patient experience of living with this disabling disease,” he said.
He added that headache’s place within the migraine sphere needs to be reconsidered. “Its singular emphasis has limited our full appreciation of this disease and how we should be paying attention to the things that are important to patients,” he said.
Dr. Shapiro predicts that future clinical trials will include migraine-related stigma as a measure to guide trial enrollment.
In addition, researchers are now digging deeper to try to understand what factors are most likely to drive stigma. “We need to understand why those attitudes are held and who is more likely to hold those attitudes, and that may allow us to develop mitigating strategies to reduce those attitudes,” said Dr. Shapiro.
‘Worrisome’ findings
Commenting on the findings, Deborah Friedman, MD, professor, departments of neurology and of ophthalmology, UT Southwestern Medical Center, Dallas, said the data on stigma were “worrisome.”
Missing social occasions and lost productivity may make migraine more visible to others so perhaps may “provoke stigma or stigmatizing comments or stigmatizing attitudes,” said Dr. Friedman, who was not involved with the research.
She noted that patients with migraine might also have trouble functioning in the workplace. “They may not be able to tolerate the computer screen or smells of perfume at the office and not get accommodation for that,” she said.
In addition to external stigma, which was investigated in the study, individuals with migraine may also experience internal stigma – blaming themselves for their disease, which may make it less likely they will seek care, said Dr. Friedman.
“That’s a huge problem,” she added.
The OVERCOME study is funded by Lilly. Dr. Shapiro has been compensated by Lilly as a research consultant and as a member of the data monitoring committee for clinical trials for galcanezumab, a Lilly pharmaceutical. Dr. Friedman has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. Results from the OVERCOME population-based survey study, which included more than 59,000 respondents, showed about 32% reported experiencing migraine-related stigma “often” or “very often.”
Even those experiencing only a few headaches per month said they experienced negative attitudes from others about migraine.
“We have been utterly blind to the burden people with migraine experience in terms of how their disease is appreciated by others. It’s time to get busy and address this very stubborn social phenomenon,” said the study’s coinvestigator, Robert E. Shapiro, MD, PhD, professor emeritus, department of neurological sciences, Larner College of Medicine, University of Vermont, Burlington.
The findings were presented at the annual meeting of the American Headache Society.
Population-based research
Stigma is defined as the discounting or discrediting of an individual with a trait that deviates from social norms. To date, there have been no significant population-based studies of how these attitudes affect individuals with migraine.
OVERCOME is a cross-sectional, longitudinal, prospective, web-based survey conducted in a representative sample of the United States population. For this new analysis, researchers pooled data from surveys conducted in 2018, 2019, and 2020.
The analysis included 59,004 respondents (mean age, 41.3 years; 75% women; 70% White) who reported one or more headache or migraine attacks during the previous 12 months and who met criteria for migraine from the International Classification of Headache Disorders. Among the patients, 35% had a college degree, and 89% suffered episodic-type headaches.
Researchers used the following four patient-reported outcome measures:
- Migraine Disability Assessment, which quantifies number of days missed at work, home, or social events over the previous 3 months
- Migraine Interictal Burden Scale–4, which measures burden of migraine between attacks over the previous 4 weeks
- Migraine-Specific Quality of Life Role-Function Restrictive, which assesses the functional effect of migraine on social and work-related activities over the previous 4 weeks
- Migraine-Related Stigma
For the latter, the investigators used two measures – the degree to which others think migraine is used to acquire secondary gain, such as avoiding commitments, and the degree to which others minimize the burden of migraine.
One of the most stigmatizing disorders
Results showed that 31.7% of participants reported experiencing stigmatization from one or both migraine-related stigma categories often or very often – a result Dr. Shapiro characterized as “pretty shocking.”
Participants with chronic headaches, defined as having 15 or more headache days per month, made up 11% of the sample. About 47% of these respondents felt stigma often or very often.
However, even 25% of participants with three or fewer headache days per month reported stigma.
“This is a fundamental tip that we are not really understanding the concerns that drive burden for people living with this disabling disease,” Dr. Shapiro said.
Some previous studies that compared levels of stigmatizing attitudes regarding various diseases showed that migraine is more stigmatized than even epilepsy, a condition “equated with demonic possession in biblical times,” he noted.
One study used machine learning to measure the number of pejorative or negative terms associated with various diseases. “Shockingly, migraine was one of the most stigmatized diseases,” said Dr. Shapiro. “It was as stigmatized as gonorrhea by certain measures.”
Results from the new study showed that, irrespective of the number of headache days experienced per month, there was a threefold increase in interictal burden among those reporting stigma often or very often, compared with those who didn’t report stigma.
Large impact on QoL
“Stigma is a social concept, so maybe it’s not surprising that it would be present whether or not someone is experiencing other symptoms of migraine,” said Dr. Shapiro.
Across all monthly headache days, experiencing more migraine-related stigma was associated with increased disability and decreased quality of life.
Dr. Shapiro noted that when it comes to migraine-specific quality of life, stigma appears to have more of an effect than number of headache days. “That means there are big gaps in our appreciation for what drives the burdens in the patient experience of living with this disabling disease,” he said.
He added that headache’s place within the migraine sphere needs to be reconsidered. “Its singular emphasis has limited our full appreciation of this disease and how we should be paying attention to the things that are important to patients,” he said.
Dr. Shapiro predicts that future clinical trials will include migraine-related stigma as a measure to guide trial enrollment.
In addition, researchers are now digging deeper to try to understand what factors are most likely to drive stigma. “We need to understand why those attitudes are held and who is more likely to hold those attitudes, and that may allow us to develop mitigating strategies to reduce those attitudes,” said Dr. Shapiro.
‘Worrisome’ findings
Commenting on the findings, Deborah Friedman, MD, professor, departments of neurology and of ophthalmology, UT Southwestern Medical Center, Dallas, said the data on stigma were “worrisome.”
Missing social occasions and lost productivity may make migraine more visible to others so perhaps may “provoke stigma or stigmatizing comments or stigmatizing attitudes,” said Dr. Friedman, who was not involved with the research.
She noted that patients with migraine might also have trouble functioning in the workplace. “They may not be able to tolerate the computer screen or smells of perfume at the office and not get accommodation for that,” she said.
In addition to external stigma, which was investigated in the study, individuals with migraine may also experience internal stigma – blaming themselves for their disease, which may make it less likely they will seek care, said Dr. Friedman.
“That’s a huge problem,” she added.
The OVERCOME study is funded by Lilly. Dr. Shapiro has been compensated by Lilly as a research consultant and as a member of the data monitoring committee for clinical trials for galcanezumab, a Lilly pharmaceutical. Dr. Friedman has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AHS 2022
Autoimmune disorder drugs top list of meds linked to headache
DENVER – in a federal side effect database that anyone can contribute to, according to a new study presented at the annual meeting of the American Headache Society.
“Surprising findings included the significant number of immunosuppressants and immunomodulators present in the data,” study lead author Brett Musialowicz, a medical student at Robert Wood Johnson Medical School, New Brunswich, N.J., said in an interview. “Additionally, our data provides evidence that suggests that several medications belonging to these drug classes were less likely to be associated with medication-induced headaches,” raising questions about the mechanism.
Drugs most frequently linked to headaches
The researchers launched their study to better understand headache as a side effect of medication use, Mr. Musialowicz said. They analyzed entries from the Food and Drug Administration’s Adverse Event Reporting System for the period from July 2018 to March 2020 and listed the top 30 most commonly reported medications linked to headaches and their reported odds ratio. According to a website devoted to pharmacovigilance training, ROR refers to “the odds of a certain event occurring with your medicinal product, compared with the odds of the same event occurring with all other medicinal products in the database.”
After generic and brand name data was consolidated, the drug most frequently linked to headaches was apremilast with 8,672 reports, followed by adalimumab (5,357), tofacitinib (4,276), fingolimod (4,123), and etanercept (4,111). These drugs treat autoimmune disorders such as psoriasis, multiple sclerosis, and Crohn’s disease.
The other drugs in the top 15 ranked by frequency are treatments for hepatitis C (4 drugs), pulmonary arterial hypertension (4 drugs), arthritis (1 drug), and asthma (1 drug).
Of the top 30 drugs most frequently linked to headaches, the pulmonary hypertension drug epoprostenol – ranked 23rd – had the highest ROR at 12.8. The next highest were the hepatitis C drugs glecaprevir and pibrentasvir, tied at 10th in the frequency analysis and both with an ROR of 9.4.
“Pulmonary arterial dilators and vasodilators are believed to cause headaches by sensitizing extracranial arteries. Clinical evidence suggests there a vascular component to some types of headache,” Mr. Musialowicz said. “Monoclonal antibodies are suggested to cause headache by means of an immune response. Several monoclonal antibodies are in trials targeting [the calcitonin gene-related peptide] receptor, which is believed to be involved in migraine headache. These trials will help further elucidate the mechanisms of headache and potential drugs to treat these conditions.”
Is the data useful?
Stewart Tepper, MD, a neurologist at Geisel School of Medicine at Dartmouth, Hanover, N.H., who’s familiar with the study findings, discounted the new research in an interview. He noted that any member of the public can contribute to the federal database of adverse effects (drug manufacturers are required to contribute to it), and the data says nothing about denominators.
“It’s not a reasonable way to evaluate adverse effects, to just have everyone and their uncle saying ‘This particular drug did this to me.’ It’s not in any way useful,” he said. However, he added that the database sometimes “gives you a bit of a signal so you can go back and try to get scientifically collected data.”
When asked to respond, study coauthor and neurologist Pengfei (Phil) Zhang, MD, of Robert Wood Johnson Medical School, noted that the FDA created the database “for a reason.” He also noted that the researchers used a statistical analysis technique – ROR – that was invented to adjust for weaknesses in databases.
No study funding is reported. Mr. Musialowicz reported no disclosures. Dr. Zhang has received honorarium from Alder Biopharmaceuticals, Board Vitals, and Fieve Clinical Research. He collaborates with Headache Science Incorporated without receiving financial support, and he has ownership interest in Cymbeline. Another author reports research grant support from the American Epilepsy Society and the New Jersey Health Foundation. Dr. Tepper reported multiple disclosures.
DENVER – in a federal side effect database that anyone can contribute to, according to a new study presented at the annual meeting of the American Headache Society.
“Surprising findings included the significant number of immunosuppressants and immunomodulators present in the data,” study lead author Brett Musialowicz, a medical student at Robert Wood Johnson Medical School, New Brunswich, N.J., said in an interview. “Additionally, our data provides evidence that suggests that several medications belonging to these drug classes were less likely to be associated with medication-induced headaches,” raising questions about the mechanism.
Drugs most frequently linked to headaches
The researchers launched their study to better understand headache as a side effect of medication use, Mr. Musialowicz said. They analyzed entries from the Food and Drug Administration’s Adverse Event Reporting System for the period from July 2018 to March 2020 and listed the top 30 most commonly reported medications linked to headaches and their reported odds ratio. According to a website devoted to pharmacovigilance training, ROR refers to “the odds of a certain event occurring with your medicinal product, compared with the odds of the same event occurring with all other medicinal products in the database.”
After generic and brand name data was consolidated, the drug most frequently linked to headaches was apremilast with 8,672 reports, followed by adalimumab (5,357), tofacitinib (4,276), fingolimod (4,123), and etanercept (4,111). These drugs treat autoimmune disorders such as psoriasis, multiple sclerosis, and Crohn’s disease.
The other drugs in the top 15 ranked by frequency are treatments for hepatitis C (4 drugs), pulmonary arterial hypertension (4 drugs), arthritis (1 drug), and asthma (1 drug).
Of the top 30 drugs most frequently linked to headaches, the pulmonary hypertension drug epoprostenol – ranked 23rd – had the highest ROR at 12.8. The next highest were the hepatitis C drugs glecaprevir and pibrentasvir, tied at 10th in the frequency analysis and both with an ROR of 9.4.
“Pulmonary arterial dilators and vasodilators are believed to cause headaches by sensitizing extracranial arteries. Clinical evidence suggests there a vascular component to some types of headache,” Mr. Musialowicz said. “Monoclonal antibodies are suggested to cause headache by means of an immune response. Several monoclonal antibodies are in trials targeting [the calcitonin gene-related peptide] receptor, which is believed to be involved in migraine headache. These trials will help further elucidate the mechanisms of headache and potential drugs to treat these conditions.”
Is the data useful?
Stewart Tepper, MD, a neurologist at Geisel School of Medicine at Dartmouth, Hanover, N.H., who’s familiar with the study findings, discounted the new research in an interview. He noted that any member of the public can contribute to the federal database of adverse effects (drug manufacturers are required to contribute to it), and the data says nothing about denominators.
“It’s not a reasonable way to evaluate adverse effects, to just have everyone and their uncle saying ‘This particular drug did this to me.’ It’s not in any way useful,” he said. However, he added that the database sometimes “gives you a bit of a signal so you can go back and try to get scientifically collected data.”
When asked to respond, study coauthor and neurologist Pengfei (Phil) Zhang, MD, of Robert Wood Johnson Medical School, noted that the FDA created the database “for a reason.” He also noted that the researchers used a statistical analysis technique – ROR – that was invented to adjust for weaknesses in databases.
No study funding is reported. Mr. Musialowicz reported no disclosures. Dr. Zhang has received honorarium from Alder Biopharmaceuticals, Board Vitals, and Fieve Clinical Research. He collaborates with Headache Science Incorporated without receiving financial support, and he has ownership interest in Cymbeline. Another author reports research grant support from the American Epilepsy Society and the New Jersey Health Foundation. Dr. Tepper reported multiple disclosures.
DENVER – in a federal side effect database that anyone can contribute to, according to a new study presented at the annual meeting of the American Headache Society.
“Surprising findings included the significant number of immunosuppressants and immunomodulators present in the data,” study lead author Brett Musialowicz, a medical student at Robert Wood Johnson Medical School, New Brunswich, N.J., said in an interview. “Additionally, our data provides evidence that suggests that several medications belonging to these drug classes were less likely to be associated with medication-induced headaches,” raising questions about the mechanism.
Drugs most frequently linked to headaches
The researchers launched their study to better understand headache as a side effect of medication use, Mr. Musialowicz said. They analyzed entries from the Food and Drug Administration’s Adverse Event Reporting System for the period from July 2018 to March 2020 and listed the top 30 most commonly reported medications linked to headaches and their reported odds ratio. According to a website devoted to pharmacovigilance training, ROR refers to “the odds of a certain event occurring with your medicinal product, compared with the odds of the same event occurring with all other medicinal products in the database.”
After generic and brand name data was consolidated, the drug most frequently linked to headaches was apremilast with 8,672 reports, followed by adalimumab (5,357), tofacitinib (4,276), fingolimod (4,123), and etanercept (4,111). These drugs treat autoimmune disorders such as psoriasis, multiple sclerosis, and Crohn’s disease.
The other drugs in the top 15 ranked by frequency are treatments for hepatitis C (4 drugs), pulmonary arterial hypertension (4 drugs), arthritis (1 drug), and asthma (1 drug).
Of the top 30 drugs most frequently linked to headaches, the pulmonary hypertension drug epoprostenol – ranked 23rd – had the highest ROR at 12.8. The next highest were the hepatitis C drugs glecaprevir and pibrentasvir, tied at 10th in the frequency analysis and both with an ROR of 9.4.
“Pulmonary arterial dilators and vasodilators are believed to cause headaches by sensitizing extracranial arteries. Clinical evidence suggests there a vascular component to some types of headache,” Mr. Musialowicz said. “Monoclonal antibodies are suggested to cause headache by means of an immune response. Several monoclonal antibodies are in trials targeting [the calcitonin gene-related peptide] receptor, which is believed to be involved in migraine headache. These trials will help further elucidate the mechanisms of headache and potential drugs to treat these conditions.”
Is the data useful?
Stewart Tepper, MD, a neurologist at Geisel School of Medicine at Dartmouth, Hanover, N.H., who’s familiar with the study findings, discounted the new research in an interview. He noted that any member of the public can contribute to the federal database of adverse effects (drug manufacturers are required to contribute to it), and the data says nothing about denominators.
“It’s not a reasonable way to evaluate adverse effects, to just have everyone and their uncle saying ‘This particular drug did this to me.’ It’s not in any way useful,” he said. However, he added that the database sometimes “gives you a bit of a signal so you can go back and try to get scientifically collected data.”
When asked to respond, study coauthor and neurologist Pengfei (Phil) Zhang, MD, of Robert Wood Johnson Medical School, noted that the FDA created the database “for a reason.” He also noted that the researchers used a statistical analysis technique – ROR – that was invented to adjust for weaknesses in databases.
No study funding is reported. Mr. Musialowicz reported no disclosures. Dr. Zhang has received honorarium from Alder Biopharmaceuticals, Board Vitals, and Fieve Clinical Research. He collaborates with Headache Science Incorporated without receiving financial support, and he has ownership interest in Cymbeline. Another author reports research grant support from the American Epilepsy Society and the New Jersey Health Foundation. Dr. Tepper reported multiple disclosures.
AT AHS 2022
Recommended headache treatments get mixed reception in EDs
DENVER – a new study finds. But the use of diphenhydramine (Benadryl) more than doubled even though guidelines caution against it, while recommended drugs such triptans and corticosteroids were rarely prescribed.
From 2007-2010 to 2015-2018, researchers reported at the annual meeting of the American Headache Society, a database reveals that opioid use in headache cases at EDs fell from 54% to 28%. Diphenhydramine use grew from 17% to 36% (both (P < .001). The percentage of cases in which EDs sought neuroimaging stayed stable at about 36%, a number that the study authors described as too high.
“Future studies are warranted to identify strategies to promote evidence-based treatments for headaches and appropriate outpatient referrals for follow-up and to reduce unnecessary neuroimaging orders in EDs,” lead author Seonkyeong Yang, MS, of the University of Florida, Gainesville, said in an interview.
Ms. Yang said researchers launched the study to update previous data in light of changes in opioid prescribing and the 2016 release of American Headache Society guidelines for the treatment of acute migraines in the ED setting. The research was published in the Journal of Clinical Medicine.
Headache treatment in the ED
For the study, researchers analyzed data from the U.S. National Hospital Ambulatory Medical Care survey and focused on adults who had a primary discharge diagnosis of headache.
For the 2015-2018 period, per weighted numbers, the survey encompassed 10.2 million headaches mostly among people younger than 50 (71%), female (73%), and White (73%). Migraines made up 33% of the total, with nonspecified headache accounting for almost all of the remainder (63%).
In 68% of cases, two or more medications were administered in the ED. This number rose to 83% among patients with migraine. But most of the time (54%), no medications were prescribed at discharge.
Among recommended medications, antiemetics – the most commonly used class of drugs in these patients – were prescribed 59% of the time in both 2007-2010 and 2015-2018 (P = .88). Usage of acetaminophens and NSAIDs grew from 37% to 52% over that time period.
Despite recommendations, the use of ergot alkaloids/triptans and corticosteroids remained low (less than 6% of the time).
“Several factors may contribute to the underuse of triptans in EDs, including their cardiovascular contraindications, ED physicians’ unfamiliarity with injectable triptans, higher costs, and treatment failures with triptans before ED visits,” Ms. Yang said. “We observed an upward trend in dexamethasone use over time. However, it was still underutilized. [The corticosteroid was only used 3.5% of the time from 2015-2018.] The 2016 AHS guideline strongly recommends dexamethasone use to prevent migraine recurrence after ED discharge. Identifying patients at high risk of headache recurrence for dexamethasone use may further improve patient outcomes of acute headache management in ED settings.”
Ms. Yang also reported that the use of diphenhydramine grew even though it’s not recommended. “Diphenhydramine is more likely to be used to prevent akathisia, a side effect of some antiemetics [that is, dopamine receptor antagonists] in headache-related ED visits,” she said. “However, the 2016 AHS guideline recommends against diphenhydramine use due to its limited efficacy in relieving headache pain. In addition, there is also conflicting evidence on diphenhydramine’s efficacy in preventing akathisia when coadministered with antiemetics. Diphenhydramine use requires caution due to its sedative effect and abuse potential.”
As for medication combinations, Ms. Yang said “the most broadly used therapy among headache-related ED visits in 2007-2010 was an opioid with an antiemetic (21.0%), which decreased to 6.6% in 2015-2018. Meanwhile, the combined use of acetaminophen/NSAIDs with antiemetic and diphenhydramine increased substantially from 3.9% to 15.7% and became the most prevalent therapy in 2015-2018. Opioid monotherapy use gradually decreased during the study period [from 8.8% to 1.9%].”
Evidence-based treatments underutilized
Commenting on the findings, New York University Langone neurologist and headache researcher Mia Tova Minen, MD, MPH, noted in an interview that AHS guidelines do not indicate acetaminophen/NSAIDs, diphenhydramine, and corticosteroids for the acute treatment of migraine. “The recommended treatments are sumatriptan subcutaneous, IV metoclopramide, and IV prochlorperazine. Steroids can be helpful in the prevention of migraine recurrence but not for the acute treatment of the migraine itself,” she said. “We need to ensure that patients with migraine get the top evidence-based treatments for migraine.”
As for diphenhydramine, she said it “is not a treatment for headache disorders. It does not have proven efficacy. It is sometimes given to reduce side effects of more acute treatments of headache, but it can make patients fatigued and keep them in the ED longer.”
Overuse of neuroimaging
Ms. Yang also highlighted study data about the frequency of neuroimaging. “Understandably, ED physicians do not want to miss any life-threatening secondary headaches like stroke,” she said. “However, other factors also contribute to the overuse of neuroimaging in headache-related ED visits: patient demands, financial incentives, a busy ED practice where clinical evaluation is replaced by tests, and ED physicians’ unfamiliarity with ICHD-3 diagnostic criteria for primary headache disorders. There is still much room for improvement in neuroimaging use for headaches in ED settings.”
For her part, Dr. Minen said scans are often performed reflexively and can be overused. “A CT scan is really only good in the case of acute trauma to rule out a fracture or a bleed or if there are signs of an emergent neurologic emergency like herniation or if a MRI is contraindicated. An MRI of the brain is typically the best test to examine brain tissue, though sometimes vessel imaging is also warranted. In the case of no red flags and a normal neurologic exam, the use of neuroimaging is low yield.”
The research has no funding. Ms. Yang and two other authors disclosed research funding from Merck. Dr. Minen reports no disclosures.
DENVER – a new study finds. But the use of diphenhydramine (Benadryl) more than doubled even though guidelines caution against it, while recommended drugs such triptans and corticosteroids were rarely prescribed.
From 2007-2010 to 2015-2018, researchers reported at the annual meeting of the American Headache Society, a database reveals that opioid use in headache cases at EDs fell from 54% to 28%. Diphenhydramine use grew from 17% to 36% (both (P < .001). The percentage of cases in which EDs sought neuroimaging stayed stable at about 36%, a number that the study authors described as too high.
“Future studies are warranted to identify strategies to promote evidence-based treatments for headaches and appropriate outpatient referrals for follow-up and to reduce unnecessary neuroimaging orders in EDs,” lead author Seonkyeong Yang, MS, of the University of Florida, Gainesville, said in an interview.
Ms. Yang said researchers launched the study to update previous data in light of changes in opioid prescribing and the 2016 release of American Headache Society guidelines for the treatment of acute migraines in the ED setting. The research was published in the Journal of Clinical Medicine.
Headache treatment in the ED
For the study, researchers analyzed data from the U.S. National Hospital Ambulatory Medical Care survey and focused on adults who had a primary discharge diagnosis of headache.
For the 2015-2018 period, per weighted numbers, the survey encompassed 10.2 million headaches mostly among people younger than 50 (71%), female (73%), and White (73%). Migraines made up 33% of the total, with nonspecified headache accounting for almost all of the remainder (63%).
In 68% of cases, two or more medications were administered in the ED. This number rose to 83% among patients with migraine. But most of the time (54%), no medications were prescribed at discharge.
Among recommended medications, antiemetics – the most commonly used class of drugs in these patients – were prescribed 59% of the time in both 2007-2010 and 2015-2018 (P = .88). Usage of acetaminophens and NSAIDs grew from 37% to 52% over that time period.
Despite recommendations, the use of ergot alkaloids/triptans and corticosteroids remained low (less than 6% of the time).
“Several factors may contribute to the underuse of triptans in EDs, including their cardiovascular contraindications, ED physicians’ unfamiliarity with injectable triptans, higher costs, and treatment failures with triptans before ED visits,” Ms. Yang said. “We observed an upward trend in dexamethasone use over time. However, it was still underutilized. [The corticosteroid was only used 3.5% of the time from 2015-2018.] The 2016 AHS guideline strongly recommends dexamethasone use to prevent migraine recurrence after ED discharge. Identifying patients at high risk of headache recurrence for dexamethasone use may further improve patient outcomes of acute headache management in ED settings.”
Ms. Yang also reported that the use of diphenhydramine grew even though it’s not recommended. “Diphenhydramine is more likely to be used to prevent akathisia, a side effect of some antiemetics [that is, dopamine receptor antagonists] in headache-related ED visits,” she said. “However, the 2016 AHS guideline recommends against diphenhydramine use due to its limited efficacy in relieving headache pain. In addition, there is also conflicting evidence on diphenhydramine’s efficacy in preventing akathisia when coadministered with antiemetics. Diphenhydramine use requires caution due to its sedative effect and abuse potential.”
As for medication combinations, Ms. Yang said “the most broadly used therapy among headache-related ED visits in 2007-2010 was an opioid with an antiemetic (21.0%), which decreased to 6.6% in 2015-2018. Meanwhile, the combined use of acetaminophen/NSAIDs with antiemetic and diphenhydramine increased substantially from 3.9% to 15.7% and became the most prevalent therapy in 2015-2018. Opioid monotherapy use gradually decreased during the study period [from 8.8% to 1.9%].”
Evidence-based treatments underutilized
Commenting on the findings, New York University Langone neurologist and headache researcher Mia Tova Minen, MD, MPH, noted in an interview that AHS guidelines do not indicate acetaminophen/NSAIDs, diphenhydramine, and corticosteroids for the acute treatment of migraine. “The recommended treatments are sumatriptan subcutaneous, IV metoclopramide, and IV prochlorperazine. Steroids can be helpful in the prevention of migraine recurrence but not for the acute treatment of the migraine itself,” she said. “We need to ensure that patients with migraine get the top evidence-based treatments for migraine.”
As for diphenhydramine, she said it “is not a treatment for headache disorders. It does not have proven efficacy. It is sometimes given to reduce side effects of more acute treatments of headache, but it can make patients fatigued and keep them in the ED longer.”
Overuse of neuroimaging
Ms. Yang also highlighted study data about the frequency of neuroimaging. “Understandably, ED physicians do not want to miss any life-threatening secondary headaches like stroke,” she said. “However, other factors also contribute to the overuse of neuroimaging in headache-related ED visits: patient demands, financial incentives, a busy ED practice where clinical evaluation is replaced by tests, and ED physicians’ unfamiliarity with ICHD-3 diagnostic criteria for primary headache disorders. There is still much room for improvement in neuroimaging use for headaches in ED settings.”
For her part, Dr. Minen said scans are often performed reflexively and can be overused. “A CT scan is really only good in the case of acute trauma to rule out a fracture or a bleed or if there are signs of an emergent neurologic emergency like herniation or if a MRI is contraindicated. An MRI of the brain is typically the best test to examine brain tissue, though sometimes vessel imaging is also warranted. In the case of no red flags and a normal neurologic exam, the use of neuroimaging is low yield.”
The research has no funding. Ms. Yang and two other authors disclosed research funding from Merck. Dr. Minen reports no disclosures.
DENVER – a new study finds. But the use of diphenhydramine (Benadryl) more than doubled even though guidelines caution against it, while recommended drugs such triptans and corticosteroids were rarely prescribed.
From 2007-2010 to 2015-2018, researchers reported at the annual meeting of the American Headache Society, a database reveals that opioid use in headache cases at EDs fell from 54% to 28%. Diphenhydramine use grew from 17% to 36% (both (P < .001). The percentage of cases in which EDs sought neuroimaging stayed stable at about 36%, a number that the study authors described as too high.
“Future studies are warranted to identify strategies to promote evidence-based treatments for headaches and appropriate outpatient referrals for follow-up and to reduce unnecessary neuroimaging orders in EDs,” lead author Seonkyeong Yang, MS, of the University of Florida, Gainesville, said in an interview.
Ms. Yang said researchers launched the study to update previous data in light of changes in opioid prescribing and the 2016 release of American Headache Society guidelines for the treatment of acute migraines in the ED setting. The research was published in the Journal of Clinical Medicine.
Headache treatment in the ED
For the study, researchers analyzed data from the U.S. National Hospital Ambulatory Medical Care survey and focused on adults who had a primary discharge diagnosis of headache.
For the 2015-2018 period, per weighted numbers, the survey encompassed 10.2 million headaches mostly among people younger than 50 (71%), female (73%), and White (73%). Migraines made up 33% of the total, with nonspecified headache accounting for almost all of the remainder (63%).
In 68% of cases, two or more medications were administered in the ED. This number rose to 83% among patients with migraine. But most of the time (54%), no medications were prescribed at discharge.
Among recommended medications, antiemetics – the most commonly used class of drugs in these patients – were prescribed 59% of the time in both 2007-2010 and 2015-2018 (P = .88). Usage of acetaminophens and NSAIDs grew from 37% to 52% over that time period.
Despite recommendations, the use of ergot alkaloids/triptans and corticosteroids remained low (less than 6% of the time).
“Several factors may contribute to the underuse of triptans in EDs, including their cardiovascular contraindications, ED physicians’ unfamiliarity with injectable triptans, higher costs, and treatment failures with triptans before ED visits,” Ms. Yang said. “We observed an upward trend in dexamethasone use over time. However, it was still underutilized. [The corticosteroid was only used 3.5% of the time from 2015-2018.] The 2016 AHS guideline strongly recommends dexamethasone use to prevent migraine recurrence after ED discharge. Identifying patients at high risk of headache recurrence for dexamethasone use may further improve patient outcomes of acute headache management in ED settings.”
Ms. Yang also reported that the use of diphenhydramine grew even though it’s not recommended. “Diphenhydramine is more likely to be used to prevent akathisia, a side effect of some antiemetics [that is, dopamine receptor antagonists] in headache-related ED visits,” she said. “However, the 2016 AHS guideline recommends against diphenhydramine use due to its limited efficacy in relieving headache pain. In addition, there is also conflicting evidence on diphenhydramine’s efficacy in preventing akathisia when coadministered with antiemetics. Diphenhydramine use requires caution due to its sedative effect and abuse potential.”
As for medication combinations, Ms. Yang said “the most broadly used therapy among headache-related ED visits in 2007-2010 was an opioid with an antiemetic (21.0%), which decreased to 6.6% in 2015-2018. Meanwhile, the combined use of acetaminophen/NSAIDs with antiemetic and diphenhydramine increased substantially from 3.9% to 15.7% and became the most prevalent therapy in 2015-2018. Opioid monotherapy use gradually decreased during the study period [from 8.8% to 1.9%].”
Evidence-based treatments underutilized
Commenting on the findings, New York University Langone neurologist and headache researcher Mia Tova Minen, MD, MPH, noted in an interview that AHS guidelines do not indicate acetaminophen/NSAIDs, diphenhydramine, and corticosteroids for the acute treatment of migraine. “The recommended treatments are sumatriptan subcutaneous, IV metoclopramide, and IV prochlorperazine. Steroids can be helpful in the prevention of migraine recurrence but not for the acute treatment of the migraine itself,” she said. “We need to ensure that patients with migraine get the top evidence-based treatments for migraine.”
As for diphenhydramine, she said it “is not a treatment for headache disorders. It does not have proven efficacy. It is sometimes given to reduce side effects of more acute treatments of headache, but it can make patients fatigued and keep them in the ED longer.”
Overuse of neuroimaging
Ms. Yang also highlighted study data about the frequency of neuroimaging. “Understandably, ED physicians do not want to miss any life-threatening secondary headaches like stroke,” she said. “However, other factors also contribute to the overuse of neuroimaging in headache-related ED visits: patient demands, financial incentives, a busy ED practice where clinical evaluation is replaced by tests, and ED physicians’ unfamiliarity with ICHD-3 diagnostic criteria for primary headache disorders. There is still much room for improvement in neuroimaging use for headaches in ED settings.”
For her part, Dr. Minen said scans are often performed reflexively and can be overused. “A CT scan is really only good in the case of acute trauma to rule out a fracture or a bleed or if there are signs of an emergent neurologic emergency like herniation or if a MRI is contraindicated. An MRI of the brain is typically the best test to examine brain tissue, though sometimes vessel imaging is also warranted. In the case of no red flags and a normal neurologic exam, the use of neuroimaging is low yield.”
The research has no funding. Ms. Yang and two other authors disclosed research funding from Merck. Dr. Minen reports no disclosures.
AT AHS 2022
COVID vaccination in DMT-treated MS patients: New data
NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.
However, vaccine antibody response remains lower with anti-CD20 therapies.
One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.
Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).
Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
Vaccine response
The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.
The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).
The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.
Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.
“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.
“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.
Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.
“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.
He added that he reassures patients who need high-efficacy therapies that “they should use them.”
That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.
“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
Favorable findings
Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.
The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.
“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.
In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.
To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.
Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.
“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
Ponesimod results
In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.
The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.
Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.
Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.
A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.
None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.
“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.
“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.
In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.
“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
Concerns remain
In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.
“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.
“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.
Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”
Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.
“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.
Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.
However, vaccine antibody response remains lower with anti-CD20 therapies.
One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.
Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).
Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
Vaccine response
The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.
The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).
The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.
Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.
“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.
“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.
Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.
“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.
He added that he reassures patients who need high-efficacy therapies that “they should use them.”
That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.
“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
Favorable findings
Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.
The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.
“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.
In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.
To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.
Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.
“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
Ponesimod results
In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.
The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.
Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.
Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.
A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.
None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.
“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.
“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.
In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.
“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
Concerns remain
In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.
“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.
“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.
Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”
Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.
“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.
Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – The latest updates on COVID-19 vaccination response among patients with multiple sclerosis (MS) who are treated with disease-modifying therapy (DMT) show that, if patients do contract the virus, cases are mild and serious infections are rare.
However, vaccine antibody response remains lower with anti-CD20 therapies.
One of several late-breaking studies on these issues that were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers included more than 100 patients with MS who were treated with a variety of DMTs.
Results showed that the rate of antibody response was just 55% among those treated with anti-CD20 therapies versus 83% for those treated with other DMTs, including sphingosine-1-phosphate receptor modulators (S1Ps).
Consistent with what has been observed in other studies, “vaccine antibody responses were slightly lower in B cell–depleted patients than with other therapies,” senior author Rahul Dave, MD, director of the INOVA MS and Neuroimmunology Center, Inova Neurosciences Institute, the University of Virginia, Fairfax, said in an interview.
Vaccine response
The investigators sought to assess detailed vaccine responses in 134 patients with MS. Serum COVID antibody measures were conducted approximately 3 weeks to 4 months after vaccination – and mostly after the initial vaccination.
The antibody response rate was significantly lower with anti-CD20 treatments (55%) than with all other DMTs examined (83%), including S1Ps, immunomodulators, immunosuppressive drugs, interferon B, anti-CD52, and natalizumab (P < .01).
The highest prevalence of antibody response was observed among those taking immunomodulators; responses occurred among 91% of patients taking teriflunomide and among 93% of those taking fumarates.
Among those treated with anti-CD20 therapy, antibody responses correlated with higher baseline immunoglobulin levels (P = .01) and shorter durations of therapy.
“We found that longer total duration of therapy and lower immunoglobulin levels tended to correlate with decreases in immune responses,” said Dr. Dave.
“Interestingly, the timing between vaccination versus administration of [anti-CD20 drug] ocrelizumab did not seem to be impactful with regards to antibody responses,” Dr. Dave noted. He added that this is contrary to some past studies that showed benefits if the vaccination could be completed prior to starting ocrelizumab.
Sixteen participants tested polymerase chain reaction positive for COVID during the previous 12 months. Although most infections were described as mild and self-limited, four of the patients received outpatient monoclonal antibody therapy, and one required hospitalization because of COVID.
“I think it is notable and reassuring that, overall, our patients had mild courses. This is consistent with the vaccines ‘working,’ and is true even in patients on high-efficacy immunosuppressants that partially abrogate antibody responses,” Dr. Dave said.
He added that he reassures patients who need high-efficacy therapies that “they should use them.”
That being said, as in the general population, even vaccinated patients can get COVID. “You can be sick and feel terrible, but in general, hospitalization numbers are way down compared to 2 years ago. We are seeing the same trends in MS patients, including the B cell–depleted patients,” he said.
“To get at the question whether B cell–depleted patients behave exactly the same as the general population, or even [with] other DMTs, we will need large, multicenter, prospective datasets,” said Dr. Dave.
Favorable findings
Two other late-breaking posters at the meeting provided updates regarding antibody responses among patients receiving S1Ps. There has been concern that S1Ps may blunt antibody responses to COVID vaccinations.
The concern is in regard to their unique mechanisms of sequestering circulating lymphocytes, particularly the older, nonselective S1P receptor modulator fingolimod, said the author of one of the studies, Daniel Kantor, MD, president emeritus of the Florida Society of Neurology and founding president of the Medical Partnership 4 MS+.
“It appears the issues with fingolimod might relate to the level of white blood cell sequestration, [which is] greater in fingolimod than the newer S1P receptor modulators, and/or the result of S1P4 receptor modulation, which is not seen with the newer, selective medications,” Dr. Kantor said in an interview.
In a prospective observational trial of patients with relapsing MS, among 30 participants who were treated with ozanimod, the mean increase in IgG antibody titer 4 weeks after either of the two available mRNA vaccines was 232.73 AU/mL versus a mean increase of 526.59 AU/mL among 30 non–ozanimod/DMT-treated patients.
To date, only three patients in the study were taking ocrelizumab; for those patients, the mean increase in IgG titers was 0.633.
Despite the lower antibody titers in the ozanimod-treated patients, which Dr. Kantor noted are generally regarded as protective, all but one of the patients had positive results on T-Detect, which was indicative of vaccine protection.
“In this study, [relapsing] MS patients treated with ozanimod had an antibody and T-cell response to the mRNA COVID-19 vaccines,” he reported. “This trial is ongoing, with 48 weeks of follow-up expected in December 2022.”
Ponesimod results
In the other S1P modulator-related late-breaking study, Janssen Research and Development reported on antibody responses of patients who were treated with the S1P drug ponesimod in the phase 2 AC-058B202 study.
The median exposure to ponesimod at time of vaccination was 10.7 years (range, 9.8-11.8 years). There were 134 patients in the study. Of those, both prevaccination and postvaccination blood samples from 49 patients were tested for spike antibody concentrations.
Among those participants, 40 (81.6%) met the definition of response to the COVID-19 vaccination, defined as seroconversion in the case of negative prevaccination antibody testing or a fourfold antibody concentration increase in the case of a positive prevaccination antibody result.
Of the 38 antibody-negative participants, 33 (86.8%) achieved seroconversion post vaccination.
A total of 20 participants reported having had prevaccine COVID, while 17 had postvaccination COVID.
None of the cases were serious, severe, or fatal, and none led to permanent treatment discontinuation.
“In patients with RMS on ponesimod, the majority (> 80%) appear to develop a measurable SARS-CoV-2 humoral response after COVID-19 vaccination,” the authors, led by Janice Wong, of Janssen Research and Development, wrote.
“Further investigations on the efficacy and safety of COVID-19 vaccination in MS patients on ponesimod are warranted,” they added.
In a final study from Genentech, of 4848 patients with MS who were fully vaccinated during the Delta and Omicron waves, 1.3% had a COVID-related hospitalization. In addition, rate of severe SARS-CoV-2 infections was very low (0.6%); there were fewer than 10 infections in each subgroup of DMTs. These patients included 585 (17%) who were treated with ocrelizumab, 238 (7%) who were treated with S1P receptor modulators, 33 (1%) who were treated with interferons, 1,004 (29%) who were treated with other DMTs, and 1,574 (46%) for whom no DMTs were recorded.
“We can conclude from this study that the characteristics of people with MS with more severe COVID-19 outcomes resemble those observed in the general population,” such as in those who are older or have higher rates of comorbidities, Preeti Bajaj, team lead of HEOR, Neuroscience, at Genentech, said in an interview. “We believe [ocrelizumab] treatment decisions should be made between a patient and their treating neurologist or other medical professional based on a benefit-risk assessment specific to the individual patient.”
Concerns remain
In a comment, Bruce A. C. Cree, MD, PhD, professor of clinical neurology and clinical research director at the Weill Institute for Neurosciences, University of California, San Francisco, described the overall data on vaccine efficacy on anti-CD20s as “discouraging” and said he is adjusting his own recommendations for these patients.
“Repeated vaccinations do not seem to stimulate humoral responses in B cell–depleted patients,” said Dr. Cree, who was not involved with the research.
“In my personal practice, I have been suspending dosing in my patients to allow for B-cell reconstitution to occur followed by revaccination,” he added.
Regarding the S1P drugs, he noted that, aside from fingolimod, “the antibody response frequency seems to be better than initial reports. However, the index values are low and may not be protective.”
Overall, the take-home message for patients with MS who are taking DMTs should be, “all patients treated with S1P modulators or anti-C20 antibodies should be vaccinated and boosted,” Dr. Cree said.
“In some cases, temporary interruption of treatment might be useful to help develop robust responses to vaccinations,” he added.
Dr. Dave reported no financial relationships regarding the poster but is a paid speaker/consultant for Novartis, Bristol-Myers Squibb, EMD Serono, Biogen, Alexion, Genentech, Horizon, and Sanofi for their MS & NMO therapies. Dr. Kantor’s research was supported by a grant from BMS; he is a consultant for Biogen, BMS, and Janssen. Dr. Cree reported that he is an unpaid consultant for BMS, the manufacturer of ozanimod.
A version of this article first appeared on Medscape.com.
AT CMSC 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.
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.
Psychedelic drugs ‘truly have potential’ in headache care
DENVER – Psychedelics such as psilocybin “truly have the potential to transform how we treat a number of neuropsychiatric diseases, including headaches,” a neuropharmacologist told colleagues at the annual meeting of the American Headache Society.
However, Bryan Roth, MD, PhD, professor of pharmacology at the University of North Carolina at Chapel Hill, also offered a major cautionary note: There have been no randomized, phase 3 trials of psychedelics, and he bluntly said that “I do not recommend the use of psychedelics for any medical condition.”
The potential disease-altering powers of psychedelics have received a tremendous amount of research and media attention over the past several years. A landmark randomized, double-blind study released in 2016 triggered much of the interest, Dr. Roth said, when it suggested that high-dose psilocybin significantly lowered levels of depressed mood/anxiety in patients with life-threatening cancer. At 6 months, 80% of patients who took the dose reported moderate or greater improvement in well-being/life satisfaction.
“You have the potential – unprecedented in psychiatry – that a single dose of a therapeutic agent may induce a rapid, robust, and sustained antidepressant action,” he said. Also of note: The “vast majority” of subjects say their encounter with a psychedelic was “one of the most meaningful experiences of their lives.”
Dr. Roth said his own research suggests that psychedelics cause a “huge increase” in the asynchronous firing of neurons. “Noise is being injected into the system and is interpreted by the brain or the mind, which always likes to make a story about what’s going on. The story it makes up is idiosyncratic to every person and memorable for reasons that are not understood.”
Now, Dr. Roth said, he and colleagues are working to “create drugs that have this potential remarkable therapeutic efficacy in psychiatric and neurologic disorders without the psychedelic effects.” A $27 million grant from the Defense Advanced Research Projects Agency is providing support for their efforts, he said.
For the moment, he said, there’s no way to know if “the psychedelic experience is essential to the therapeutic action of these drugs. But it’s a testable hypothesis.”
As he noted, a tiny 2010 study of 2-bromo-lysergic acid diethylamide (LSD), which doesn’t cause hallucinations, showed promise as a treatment for cluster headaches.
For now, Dr. Roth said, his lab is synthesizing and testing new compounds that interact with the crucial 5-HT2A receptor.
Additional research
In another presentation at the AHS annual meeting, neurologist Emmanuelle A. D. Schindler, MD, PhD, of Yale School of Medicine, highlighted her 2021 study of an exploratory double-blind, placebo-controlled, cross-over study of psilocybin versus placebo for migraine headache. A single oral dose of the drug, the researchers found, reduced headache frequency and pain over 2 weeks. The study is small, with just 10 subjects, and multiple exclusion criteria.
She also revealed preliminary findings from an ongoing randomized, double-blind, placebo-controlled study of psilocybin versus placebo in cluster headaches. In 14 subjects, a psilocybin pulse was linked to fewer cluster attacks over 3 weeks, although the effect wasn’t statistically significant. However, there was a statistically significant reduction over 8 weeks in patients with chronic headache.
Dr. Schindler noted that “with these early studies, we only looked out to 2 weeks for migraine, and we only looked out to 2 months for cluster.” There are multiple other limitations, she acknowledged. “We have to do a lot more research and consider safety as well.”
However, “there is a really unique capacity for lasting effects after limited dosing,” she added, and the studies do show reductions in headache burden “that do not correlate with acute psychedelic effects.”
Moving forward, Dr. Roth cautioned that while U.S. states are allowing the use of psychedelics for medical purposes, “we don’t know if they ultimately are therapeutic. And we have strong reason to believe that microdosing or chronic dosing of these compounds is ultimately going to be deleterious to the health of our patients.”
Dr. Roth did not provide disclosure information. Dr. Schindler discloses research funding (Ceruvia Lifesciences, Wallace Research Foundation, Clusterbusters, Department of Veterans Affairs), serves on advisory boards (Ceruvia Lifesciences, Clusterbusters), and has a patent.
DENVER – Psychedelics such as psilocybin “truly have the potential to transform how we treat a number of neuropsychiatric diseases, including headaches,” a neuropharmacologist told colleagues at the annual meeting of the American Headache Society.
However, Bryan Roth, MD, PhD, professor of pharmacology at the University of North Carolina at Chapel Hill, also offered a major cautionary note: There have been no randomized, phase 3 trials of psychedelics, and he bluntly said that “I do not recommend the use of psychedelics for any medical condition.”
The potential disease-altering powers of psychedelics have received a tremendous amount of research and media attention over the past several years. A landmark randomized, double-blind study released in 2016 triggered much of the interest, Dr. Roth said, when it suggested that high-dose psilocybin significantly lowered levels of depressed mood/anxiety in patients with life-threatening cancer. At 6 months, 80% of patients who took the dose reported moderate or greater improvement in well-being/life satisfaction.
“You have the potential – unprecedented in psychiatry – that a single dose of a therapeutic agent may induce a rapid, robust, and sustained antidepressant action,” he said. Also of note: The “vast majority” of subjects say their encounter with a psychedelic was “one of the most meaningful experiences of their lives.”
Dr. Roth said his own research suggests that psychedelics cause a “huge increase” in the asynchronous firing of neurons. “Noise is being injected into the system and is interpreted by the brain or the mind, which always likes to make a story about what’s going on. The story it makes up is idiosyncratic to every person and memorable for reasons that are not understood.”
Now, Dr. Roth said, he and colleagues are working to “create drugs that have this potential remarkable therapeutic efficacy in psychiatric and neurologic disorders without the psychedelic effects.” A $27 million grant from the Defense Advanced Research Projects Agency is providing support for their efforts, he said.
For the moment, he said, there’s no way to know if “the psychedelic experience is essential to the therapeutic action of these drugs. But it’s a testable hypothesis.”
As he noted, a tiny 2010 study of 2-bromo-lysergic acid diethylamide (LSD), which doesn’t cause hallucinations, showed promise as a treatment for cluster headaches.
For now, Dr. Roth said, his lab is synthesizing and testing new compounds that interact with the crucial 5-HT2A receptor.
Additional research
In another presentation at the AHS annual meeting, neurologist Emmanuelle A. D. Schindler, MD, PhD, of Yale School of Medicine, highlighted her 2021 study of an exploratory double-blind, placebo-controlled, cross-over study of psilocybin versus placebo for migraine headache. A single oral dose of the drug, the researchers found, reduced headache frequency and pain over 2 weeks. The study is small, with just 10 subjects, and multiple exclusion criteria.
She also revealed preliminary findings from an ongoing randomized, double-blind, placebo-controlled study of psilocybin versus placebo in cluster headaches. In 14 subjects, a psilocybin pulse was linked to fewer cluster attacks over 3 weeks, although the effect wasn’t statistically significant. However, there was a statistically significant reduction over 8 weeks in patients with chronic headache.
Dr. Schindler noted that “with these early studies, we only looked out to 2 weeks for migraine, and we only looked out to 2 months for cluster.” There are multiple other limitations, she acknowledged. “We have to do a lot more research and consider safety as well.”
However, “there is a really unique capacity for lasting effects after limited dosing,” she added, and the studies do show reductions in headache burden “that do not correlate with acute psychedelic effects.”
Moving forward, Dr. Roth cautioned that while U.S. states are allowing the use of psychedelics for medical purposes, “we don’t know if they ultimately are therapeutic. And we have strong reason to believe that microdosing or chronic dosing of these compounds is ultimately going to be deleterious to the health of our patients.”
Dr. Roth did not provide disclosure information. Dr. Schindler discloses research funding (Ceruvia Lifesciences, Wallace Research Foundation, Clusterbusters, Department of Veterans Affairs), serves on advisory boards (Ceruvia Lifesciences, Clusterbusters), and has a patent.
DENVER – Psychedelics such as psilocybin “truly have the potential to transform how we treat a number of neuropsychiatric diseases, including headaches,” a neuropharmacologist told colleagues at the annual meeting of the American Headache Society.
However, Bryan Roth, MD, PhD, professor of pharmacology at the University of North Carolina at Chapel Hill, also offered a major cautionary note: There have been no randomized, phase 3 trials of psychedelics, and he bluntly said that “I do not recommend the use of psychedelics for any medical condition.”
The potential disease-altering powers of psychedelics have received a tremendous amount of research and media attention over the past several years. A landmark randomized, double-blind study released in 2016 triggered much of the interest, Dr. Roth said, when it suggested that high-dose psilocybin significantly lowered levels of depressed mood/anxiety in patients with life-threatening cancer. At 6 months, 80% of patients who took the dose reported moderate or greater improvement in well-being/life satisfaction.
“You have the potential – unprecedented in psychiatry – that a single dose of a therapeutic agent may induce a rapid, robust, and sustained antidepressant action,” he said. Also of note: The “vast majority” of subjects say their encounter with a psychedelic was “one of the most meaningful experiences of their lives.”
Dr. Roth said his own research suggests that psychedelics cause a “huge increase” in the asynchronous firing of neurons. “Noise is being injected into the system and is interpreted by the brain or the mind, which always likes to make a story about what’s going on. The story it makes up is idiosyncratic to every person and memorable for reasons that are not understood.”
Now, Dr. Roth said, he and colleagues are working to “create drugs that have this potential remarkable therapeutic efficacy in psychiatric and neurologic disorders without the psychedelic effects.” A $27 million grant from the Defense Advanced Research Projects Agency is providing support for their efforts, he said.
For the moment, he said, there’s no way to know if “the psychedelic experience is essential to the therapeutic action of these drugs. But it’s a testable hypothesis.”
As he noted, a tiny 2010 study of 2-bromo-lysergic acid diethylamide (LSD), which doesn’t cause hallucinations, showed promise as a treatment for cluster headaches.
For now, Dr. Roth said, his lab is synthesizing and testing new compounds that interact with the crucial 5-HT2A receptor.
Additional research
In another presentation at the AHS annual meeting, neurologist Emmanuelle A. D. Schindler, MD, PhD, of Yale School of Medicine, highlighted her 2021 study of an exploratory double-blind, placebo-controlled, cross-over study of psilocybin versus placebo for migraine headache. A single oral dose of the drug, the researchers found, reduced headache frequency and pain over 2 weeks. The study is small, with just 10 subjects, and multiple exclusion criteria.
She also revealed preliminary findings from an ongoing randomized, double-blind, placebo-controlled study of psilocybin versus placebo in cluster headaches. In 14 subjects, a psilocybin pulse was linked to fewer cluster attacks over 3 weeks, although the effect wasn’t statistically significant. However, there was a statistically significant reduction over 8 weeks in patients with chronic headache.
Dr. Schindler noted that “with these early studies, we only looked out to 2 weeks for migraine, and we only looked out to 2 months for cluster.” There are multiple other limitations, she acknowledged. “We have to do a lot more research and consider safety as well.”
However, “there is a really unique capacity for lasting effects after limited dosing,” she added, and the studies do show reductions in headache burden “that do not correlate with acute psychedelic effects.”
Moving forward, Dr. Roth cautioned that while U.S. states are allowing the use of psychedelics for medical purposes, “we don’t know if they ultimately are therapeutic. And we have strong reason to believe that microdosing or chronic dosing of these compounds is ultimately going to be deleterious to the health of our patients.”
Dr. Roth did not provide disclosure information. Dr. Schindler discloses research funding (Ceruvia Lifesciences, Wallace Research Foundation, Clusterbusters, Department of Veterans Affairs), serves on advisory boards (Ceruvia Lifesciences, Clusterbusters), and has a patent.
FROM AHS 2022
Disappointing results for investigational Alzheimer’s drug
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
, new research suggests.
Top-line results for a phase 2 trial showed the novel drug, a monoclonal antibody designed to neutralize neurotoxic oligomers (a form of beta-amyloid), was not statistically superior to placebo in terms of cognitive ability or episodic memory function among cognitively unimpaired individuals with a genetic mutation for early-onset AD.
Genentech announced the negative results on June 16 together with Banner Alzheimer’s Institute, Phoenix.
During a press briefing, company representatives and researchers expressed disappointment with the initial results – but stressed numerous ongoing analyses have yet to be completed.
“This is the beginning of the story, but by no means the end of it,” Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, and one of the study leaders, said at the briefing.
API ADAD trial
The prospective, double-blind parallel-group Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) phase 2 trial enrolled 252 members of the world’s largest extended family with ADAD in Colombia. A total of 94% of the participants completed the study.
Two-thirds of participants carried the Presenilin 1 (PSEN1) E280A mutation, which virtually guarantees that carriers will develop AD at an average age of 44 years and dementia at an average age of 49 years.
Study participants were randomly assigned to receive crenezumab or placebo over a period of 5-8 years. The dose of crenezumab was increased at different time points during the trial as knowledge about potential treatment approaches for AD evolved.
Dr. Tariot noted the maximum dose was not provided for the entire treatment period. “The longest people received the highest dose was about 2 years,” he added.
Coprimary endpoints were rate of change in cognitive abilities, as measured by the API ADAD composite cognitive score, or episodic memory function, measured by the Free and Cued Selective Reminding Test Cueing Index.
Results showed these outcomes were not statistically significant for those receiving the active medication.
In addition to a range of cognitive measures, researchers also assessed amyloid PET and, later in the study, tau PET. MRI and cerebrospinal fluid (CSF) measures were also examined.
The investigators did find small numerical differences favoring crenezumab across the coprimary and multiple secondary and exploratory endpoints, but these were also not statistically significant.
Finally, no new safety issues were identified with crenezumab during the study.
Further analyses of data are ongoing and additional brain imaging and CSF biomarker results will be presented at the Alzheimer’s Association International Conference on Aug. 2.
While the study was not positive, it demonstrated that prevention trials are possible, even in less-than-ideal circumstances and generated a wealth of useful data, the investigators note.
“There were some differences between the treated and untreated patients, and we still need to understand which patients were most likely to experience those differences,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech, told briefing attendees.
“We need to understand the biomarkers involved and what [they’re] telling us about the disease and the timing of the intervention,” Dr. Doody said.
Prevention “needs to be one of our targeted therapeutic approaches but probably not our only one,” she added.
Beyond amyloid?
Commenting on the negative results, Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said they demonstrate the need to focus beyond amyloid and more on the biology of aging.
“This broader approach coupled with advances in novel biomarkers is bringing us closer to the day when physicians will be able to zero in on the root causes of each patient’s Alzheimer’s – and tailor combinations of drug therapies to provide precision medicine,” Dr. Fillit, who was not involved with the research, said in statement.
Genentech is also evaluating the potential of gantenerumab for ADAD and for the prevention of sporadic AD and treatment of early Alzheimer’s in late-stage clinical trials. Results from the phase 3 GRADUATE studies of gantenerumab in early AD are expected by the end of the year.
The study was supported by the National Institute on Aging, contributions to Banner Alzheimer’s Foundation, and Genentech.
A version of this article first appeared on Medscape.com.
Don’t overlook this cause of falls
I enjoyed reading “How to identify balance disorders and reduce fall risk” (J Fam Pract. 2022;71:20-30) from the January/February issue. I was, however, disappointed to see that normal pressure hydrocephalus (NPH) was not discussed in the article or tables.
Recently, I took care of a 72-year-old patient who presented after multiple falls. In conjunction with Neurology, the presumptive diagnosis of Parkinson disease was made. However, the patient continued to experience a health decline that included cognitive changes, nocturia, and the classic “magnetic gait” of NPH (mnemonic for diagnosing this triad of symptoms: weird, wet, wobbly). The presumptive diagnosis was then changed when the results of a fluorodopa F18 positron emission tomography scan (also known as a DaT scan) returned as normal, essentially excluding the diagnosis of Parkinson disease.
The patient has since seen a dramatic improvement in gait and cognitive and urinary symptoms following a high-volume lumbar puncture and placement of a ventriculoperitoneal shunt.
This case demonstrates the importance of considering NPH in the differential diagnosis for patients with balance disorders. Prompt diagnosis and management can result in a variable, but at times dramatic, reversal of symptoms.
Ernestine Lee, MD, MPH
Austin, TX
I enjoyed reading “How to identify balance disorders and reduce fall risk” (J Fam Pract. 2022;71:20-30) from the January/February issue. I was, however, disappointed to see that normal pressure hydrocephalus (NPH) was not discussed in the article or tables.
Recently, I took care of a 72-year-old patient who presented after multiple falls. In conjunction with Neurology, the presumptive diagnosis of Parkinson disease was made. However, the patient continued to experience a health decline that included cognitive changes, nocturia, and the classic “magnetic gait” of NPH (mnemonic for diagnosing this triad of symptoms: weird, wet, wobbly). The presumptive diagnosis was then changed when the results of a fluorodopa F18 positron emission tomography scan (also known as a DaT scan) returned as normal, essentially excluding the diagnosis of Parkinson disease.
The patient has since seen a dramatic improvement in gait and cognitive and urinary symptoms following a high-volume lumbar puncture and placement of a ventriculoperitoneal shunt.
This case demonstrates the importance of considering NPH in the differential diagnosis for patients with balance disorders. Prompt diagnosis and management can result in a variable, but at times dramatic, reversal of symptoms.
Ernestine Lee, MD, MPH
Austin, TX
I enjoyed reading “How to identify balance disorders and reduce fall risk” (J Fam Pract. 2022;71:20-30) from the January/February issue. I was, however, disappointed to see that normal pressure hydrocephalus (NPH) was not discussed in the article or tables.
Recently, I took care of a 72-year-old patient who presented after multiple falls. In conjunction with Neurology, the presumptive diagnosis of Parkinson disease was made. However, the patient continued to experience a health decline that included cognitive changes, nocturia, and the classic “magnetic gait” of NPH (mnemonic for diagnosing this triad of symptoms: weird, wet, wobbly). The presumptive diagnosis was then changed when the results of a fluorodopa F18 positron emission tomography scan (also known as a DaT scan) returned as normal, essentially excluding the diagnosis of Parkinson disease.
The patient has since seen a dramatic improvement in gait and cognitive and urinary symptoms following a high-volume lumbar puncture and placement of a ventriculoperitoneal shunt.
This case demonstrates the importance of considering NPH in the differential diagnosis for patients with balance disorders. Prompt diagnosis and management can result in a variable, but at times dramatic, reversal of symptoms.
Ernestine Lee, MD, MPH
Austin, TX
Findings raise questions about migraine and sleep
CHARLOTTE, N.C. – What may be the largest case-based study of patients with migraine and sleep-disordered breathing to date has found that, counter to prevailing thought, they may not be at higher risk of having obstructive sleep apnea (OSA) than nonmigraine patients, although further prospective studies are needed to validate that finding.
“This in no way for me changes the fact that, for patients that complain of headaches, sleep apnea remains to be something that should be considered as possible cause of their headaches,” neurologist and Cleveland Clinic postdoctoral fellow Eric Gruenthal, MD, said in an interview after he presented his results at the annual meeting of the Associated Professional Sleep Societies.
The study suggested that patients with migraine may have an OSA risk that “may be a little lower” than their nonmigraine counterparts, Dr. Gruenthal said. “But we have really yet to determine whether that’s true or not.”
Large case-based study
The retrospective case study included 4,783 migraine cases from the Cleveland Clinic electronic health record database who were case matched on a 1:3 basis with 14,287 controls. Patients with migraine had an average age of 47.5 years (±13.3) and body mass index of 33.7 kg/m2 (±8.6), and 76.4% were White. All patients had polysomnography (PSG) at a Cleveland Clinic facility from 1998 to 2021.
The analysis evaluated the collected data in two domains: sleep architecture, consisting of arousal index (AI), total sleep time (TST) and percentage of sleep stage time; and sleep-disordered breathing, including apnea hypopnea index (AHI) and mean oxygen saturation. The key findings of the migraine patients versus controls include:
- Lower AI, 19.6 (95% confidence interval, 12.8-30.9) versus 22.6 (95% CI, 14.7-34.9; P < .001).
- Shorter TST, 359 (95% CI, 307-421) versus 363 (95% CI, 306-432.5) minutes (P = .01).
- With regard to sleep stage, the percentage of N2 sleep was higher, 67.8% (95% CI, 59.6%-75.6%) versus 67% (95% CI, 58.4%-74.8%; P < .001); but the percentage of REM was lower at 16.7% (95% CI, 10%-22%) versus 17% (95% CI, 11.1%-22.2%; P = .012).
- Lower AHI, 7.4 (95% CI, 2.6-17) versus 9.5 (95% CI, 3.7-22.1, P < .001).
- Higher mean oxygen saturation, 93.7 (±2.4) versus 93.3% (±2.6; P < .001).
“Also,” Dr. Gruenthal added, “we found that the percentage of sleep time with oxygen saturation below 90% was lower among patients with migraine, at 1.3% versus 2.4%” (P < .001).
A unique profile?
The goal of the study was to determine whether migraine patients would have a unique PSG profile, Dr. Gruenthal said. “We were trying to overcome some of the limitations of previous studies, most notably those that use small sample sizes, and in some cases a lack of controls.”
The findings that migraine patients would have higher AI and elevated AHI ran counter to the study’s hypotheses, but fell in line with the expectation that they would have reduced TST, Dr. Gruenthal said.
Patients with migraine “may, in fact, exhibit a lower burden of sleep-disordered breathing, and that’s based on our findings such as the lower AHI and decreased burden of hypoxemia,” he said. “We theorized that this may be related to patients with migraine having a unique CGRP [calcitonin gene-related peptide] and serotonin physiology.” He noted that previously published research has shown that sleep CGRP and serotonin have a central role in causing arousal in response to rising CO2 levels during sleep, which can occur during apneas and hypopneas.
Dr. Gruenthal noted that the researchers are still analyzing the findings. “We theorized that possible indication bias may be present in our study,” he said. “It may be the case that patients with migraine are more likely to get their PSG done because of their headache and not for things like snoring and witnessed apneas, which may be more predictive of significant sleep apnea.” They’re also evaluating the “question of medicine confounding.”
Dr. Gruenthal added that “the big unanswered question out there is, if you have a patient with migraine who also has sleep apnea, by treating the sleep apnea will that improve their migraine?”
More questions than answers
Commenting on the study, Donald Bliwise, PhD, professor of neurology at Emory Sleep Center, Atlanta, said the study findings shouldn’t change how clinicians approach migraine in relation to sleep.
“It’s a case series, it’s retrospective,” said Dr. Bliwise, who was not involved in the study. “It’s the largest study that I know of that has ever looked at the diagnosis of migraine in relation to polysomnographic measures of sleep, but it’s imprecise to the extent that migraine is a clinical diagnosis, so not everyone that carries the diagnosis of migraine has the diagnosis made by a neurologist.”
The study raises more questions than it answers, he said, “but that’s not necessarily a bad thing. I think we need more prospective studies.” Those studies should be more granular in how they analyze sleep in migraine patients “Since migraine is an intermittent event, and sleep quality and length, and percentage of REM sleep and even sleep apnea can vary from night to night, it would be fascinating to look at headaches over a month in relation to sleep over a month.”
Dr. Gruenthal and Dr. Bliwise have no disclosures. The Association of Migraine Disorders provided funding for the study.
CHARLOTTE, N.C. – What may be the largest case-based study of patients with migraine and sleep-disordered breathing to date has found that, counter to prevailing thought, they may not be at higher risk of having obstructive sleep apnea (OSA) than nonmigraine patients, although further prospective studies are needed to validate that finding.
“This in no way for me changes the fact that, for patients that complain of headaches, sleep apnea remains to be something that should be considered as possible cause of their headaches,” neurologist and Cleveland Clinic postdoctoral fellow Eric Gruenthal, MD, said in an interview after he presented his results at the annual meeting of the Associated Professional Sleep Societies.
The study suggested that patients with migraine may have an OSA risk that “may be a little lower” than their nonmigraine counterparts, Dr. Gruenthal said. “But we have really yet to determine whether that’s true or not.”
Large case-based study
The retrospective case study included 4,783 migraine cases from the Cleveland Clinic electronic health record database who were case matched on a 1:3 basis with 14,287 controls. Patients with migraine had an average age of 47.5 years (±13.3) and body mass index of 33.7 kg/m2 (±8.6), and 76.4% were White. All patients had polysomnography (PSG) at a Cleveland Clinic facility from 1998 to 2021.
The analysis evaluated the collected data in two domains: sleep architecture, consisting of arousal index (AI), total sleep time (TST) and percentage of sleep stage time; and sleep-disordered breathing, including apnea hypopnea index (AHI) and mean oxygen saturation. The key findings of the migraine patients versus controls include:
- Lower AI, 19.6 (95% confidence interval, 12.8-30.9) versus 22.6 (95% CI, 14.7-34.9; P < .001).
- Shorter TST, 359 (95% CI, 307-421) versus 363 (95% CI, 306-432.5) minutes (P = .01).
- With regard to sleep stage, the percentage of N2 sleep was higher, 67.8% (95% CI, 59.6%-75.6%) versus 67% (95% CI, 58.4%-74.8%; P < .001); but the percentage of REM was lower at 16.7% (95% CI, 10%-22%) versus 17% (95% CI, 11.1%-22.2%; P = .012).
- Lower AHI, 7.4 (95% CI, 2.6-17) versus 9.5 (95% CI, 3.7-22.1, P < .001).
- Higher mean oxygen saturation, 93.7 (±2.4) versus 93.3% (±2.6; P < .001).
“Also,” Dr. Gruenthal added, “we found that the percentage of sleep time with oxygen saturation below 90% was lower among patients with migraine, at 1.3% versus 2.4%” (P < .001).
A unique profile?
The goal of the study was to determine whether migraine patients would have a unique PSG profile, Dr. Gruenthal said. “We were trying to overcome some of the limitations of previous studies, most notably those that use small sample sizes, and in some cases a lack of controls.”
The findings that migraine patients would have higher AI and elevated AHI ran counter to the study’s hypotheses, but fell in line with the expectation that they would have reduced TST, Dr. Gruenthal said.
Patients with migraine “may, in fact, exhibit a lower burden of sleep-disordered breathing, and that’s based on our findings such as the lower AHI and decreased burden of hypoxemia,” he said. “We theorized that this may be related to patients with migraine having a unique CGRP [calcitonin gene-related peptide] and serotonin physiology.” He noted that previously published research has shown that sleep CGRP and serotonin have a central role in causing arousal in response to rising CO2 levels during sleep, which can occur during apneas and hypopneas.
Dr. Gruenthal noted that the researchers are still analyzing the findings. “We theorized that possible indication bias may be present in our study,” he said. “It may be the case that patients with migraine are more likely to get their PSG done because of their headache and not for things like snoring and witnessed apneas, which may be more predictive of significant sleep apnea.” They’re also evaluating the “question of medicine confounding.”
Dr. Gruenthal added that “the big unanswered question out there is, if you have a patient with migraine who also has sleep apnea, by treating the sleep apnea will that improve their migraine?”
More questions than answers
Commenting on the study, Donald Bliwise, PhD, professor of neurology at Emory Sleep Center, Atlanta, said the study findings shouldn’t change how clinicians approach migraine in relation to sleep.
“It’s a case series, it’s retrospective,” said Dr. Bliwise, who was not involved in the study. “It’s the largest study that I know of that has ever looked at the diagnosis of migraine in relation to polysomnographic measures of sleep, but it’s imprecise to the extent that migraine is a clinical diagnosis, so not everyone that carries the diagnosis of migraine has the diagnosis made by a neurologist.”
The study raises more questions than it answers, he said, “but that’s not necessarily a bad thing. I think we need more prospective studies.” Those studies should be more granular in how they analyze sleep in migraine patients “Since migraine is an intermittent event, and sleep quality and length, and percentage of REM sleep and even sleep apnea can vary from night to night, it would be fascinating to look at headaches over a month in relation to sleep over a month.”
Dr. Gruenthal and Dr. Bliwise have no disclosures. The Association of Migraine Disorders provided funding for the study.
CHARLOTTE, N.C. – What may be the largest case-based study of patients with migraine and sleep-disordered breathing to date has found that, counter to prevailing thought, they may not be at higher risk of having obstructive sleep apnea (OSA) than nonmigraine patients, although further prospective studies are needed to validate that finding.
“This in no way for me changes the fact that, for patients that complain of headaches, sleep apnea remains to be something that should be considered as possible cause of their headaches,” neurologist and Cleveland Clinic postdoctoral fellow Eric Gruenthal, MD, said in an interview after he presented his results at the annual meeting of the Associated Professional Sleep Societies.
The study suggested that patients with migraine may have an OSA risk that “may be a little lower” than their nonmigraine counterparts, Dr. Gruenthal said. “But we have really yet to determine whether that’s true or not.”
Large case-based study
The retrospective case study included 4,783 migraine cases from the Cleveland Clinic electronic health record database who were case matched on a 1:3 basis with 14,287 controls. Patients with migraine had an average age of 47.5 years (±13.3) and body mass index of 33.7 kg/m2 (±8.6), and 76.4% were White. All patients had polysomnography (PSG) at a Cleveland Clinic facility from 1998 to 2021.
The analysis evaluated the collected data in two domains: sleep architecture, consisting of arousal index (AI), total sleep time (TST) and percentage of sleep stage time; and sleep-disordered breathing, including apnea hypopnea index (AHI) and mean oxygen saturation. The key findings of the migraine patients versus controls include:
- Lower AI, 19.6 (95% confidence interval, 12.8-30.9) versus 22.6 (95% CI, 14.7-34.9; P < .001).
- Shorter TST, 359 (95% CI, 307-421) versus 363 (95% CI, 306-432.5) minutes (P = .01).
- With regard to sleep stage, the percentage of N2 sleep was higher, 67.8% (95% CI, 59.6%-75.6%) versus 67% (95% CI, 58.4%-74.8%; P < .001); but the percentage of REM was lower at 16.7% (95% CI, 10%-22%) versus 17% (95% CI, 11.1%-22.2%; P = .012).
- Lower AHI, 7.4 (95% CI, 2.6-17) versus 9.5 (95% CI, 3.7-22.1, P < .001).
- Higher mean oxygen saturation, 93.7 (±2.4) versus 93.3% (±2.6; P < .001).
“Also,” Dr. Gruenthal added, “we found that the percentage of sleep time with oxygen saturation below 90% was lower among patients with migraine, at 1.3% versus 2.4%” (P < .001).
A unique profile?
The goal of the study was to determine whether migraine patients would have a unique PSG profile, Dr. Gruenthal said. “We were trying to overcome some of the limitations of previous studies, most notably those that use small sample sizes, and in some cases a lack of controls.”
The findings that migraine patients would have higher AI and elevated AHI ran counter to the study’s hypotheses, but fell in line with the expectation that they would have reduced TST, Dr. Gruenthal said.
Patients with migraine “may, in fact, exhibit a lower burden of sleep-disordered breathing, and that’s based on our findings such as the lower AHI and decreased burden of hypoxemia,” he said. “We theorized that this may be related to patients with migraine having a unique CGRP [calcitonin gene-related peptide] and serotonin physiology.” He noted that previously published research has shown that sleep CGRP and serotonin have a central role in causing arousal in response to rising CO2 levels during sleep, which can occur during apneas and hypopneas.
Dr. Gruenthal noted that the researchers are still analyzing the findings. “We theorized that possible indication bias may be present in our study,” he said. “It may be the case that patients with migraine are more likely to get their PSG done because of their headache and not for things like snoring and witnessed apneas, which may be more predictive of significant sleep apnea.” They’re also evaluating the “question of medicine confounding.”
Dr. Gruenthal added that “the big unanswered question out there is, if you have a patient with migraine who also has sleep apnea, by treating the sleep apnea will that improve their migraine?”
More questions than answers
Commenting on the study, Donald Bliwise, PhD, professor of neurology at Emory Sleep Center, Atlanta, said the study findings shouldn’t change how clinicians approach migraine in relation to sleep.
“It’s a case series, it’s retrospective,” said Dr. Bliwise, who was not involved in the study. “It’s the largest study that I know of that has ever looked at the diagnosis of migraine in relation to polysomnographic measures of sleep, but it’s imprecise to the extent that migraine is a clinical diagnosis, so not everyone that carries the diagnosis of migraine has the diagnosis made by a neurologist.”
The study raises more questions than it answers, he said, “but that’s not necessarily a bad thing. I think we need more prospective studies.” Those studies should be more granular in how they analyze sleep in migraine patients “Since migraine is an intermittent event, and sleep quality and length, and percentage of REM sleep and even sleep apnea can vary from night to night, it would be fascinating to look at headaches over a month in relation to sleep over a month.”
Dr. Gruenthal and Dr. Bliwise have no disclosures. The Association of Migraine Disorders provided funding for the study.
AT SLEEP 2022