Geriatrics

BARCELONA – Intermittent benzodiazepine use significantly reduces the risk for falls, fractures, and mortality in older adults compared with chronic use of these medications, results of a large-scale study show.

Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.

Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.

Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.

However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.

The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
 

Wide range of adverse outcomes

The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.

“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.

Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.

Moreover, chronic use is more common in older versus younger patients.

Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.

“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”

To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.

They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.

Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.

Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.

The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.

As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.

Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.

Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.

After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
 

Sex differences

In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).

There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).

A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).

Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).

The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”

He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.

“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.

If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.

“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
 

Confirmatory research

In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.

“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.

Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”

In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”

Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”

“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.

The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.

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

BARCELONA – Intermittent benzodiazepine use significantly reduces the risk for falls, fractures, and mortality in older adults compared with chronic use of these medications, results of a large-scale study show.

Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.

Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.

Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.

However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.

The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
 

Wide range of adverse outcomes

The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.

“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.

Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.

Moreover, chronic use is more common in older versus younger patients.

Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.

“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”

To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.

They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.

Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.

Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.

The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.

As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.

Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.

Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.

After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
 

Sex differences

In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).

There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).

A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).

Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).

The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”

He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.

“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.

If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.

“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
 

Confirmatory research

In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.

“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.

Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”

In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”

Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”

“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.

The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.

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

BARCELONA – Intermittent benzodiazepine use significantly reduces the risk for falls, fractures, and mortality in older adults compared with chronic use of these medications, results of a large-scale study show.

Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.

Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.

Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.

However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.

The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
 

Wide range of adverse outcomes

The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.

“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.

Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.

Moreover, chronic use is more common in older versus younger patients.

Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.

“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”

To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.

They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.

Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.

Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.

The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.

As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.

Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.

Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.

After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
 

Sex differences

In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).

There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).

A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).

Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).

The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”

He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.

“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.

If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.

“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
 

Confirmatory research

In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.

“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.

Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”

In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”

Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”

“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.

The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.

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

Two antiamyloid drugs were recently approved by the Food and Drug Administration for treating early-stage Alzheimer’s disease (AD). In trials of both lecanemab (Leqembi) and donanemab, a long-held neuropharmacologic dream was realized: Most amyloid plaques – the primary pathologic marker for AD – were eliminated from the brains of patients with late pre-AD or early AD.

Implications for the amyloid hypothesis

The reduction of amyloid plaques has been argued by many scientists and clinical authorities to be the likely pharmacologic solution for AD. These trials are appropriately viewed as a test of the hypothesis that amyloid bodies are a primary cause of the neurobehavioral symptoms we call AD.

In parallel with that striking reduction in amyloid bodies, drug-treated patients had an initially slower progression of neurobehavioral decline than did placebo-treated control patients. That slowing in symptom progression was accompanied by a modest but statistically significant difference in neurobehavioral ability. After several months in treatment, the rate of decline again paralleled that recorded in the control group. The sustained difference of about a half point on cognitive assessment scores separating treatment and control participants was well short of the 1.5-point difference typically considered clinically significant.

A small number of unexpected and unexplained deaths occurred in the treatment groups. Brain swelling and/or micro-hemorrhages were seen in 20%-30% of treated individuals. Significant brain shrinkage was recorded. These adverse findings are indicative of drug-induced trauma in the target organ for these drugs (i.e., the brain) and were the basis for a boxed warning label for drug usage. Antiamyloid drug treatment was not effective in patients who had higher initial numbers of amyloid plaques, indicating that these drugs would not measurably help the majority of AD patients, who are at more advanced disease stages.

These drugs do not appear to be an “answer” for AD. A modest delay in progression does not mean that we’re on a path to a “cure.” Treatment cost estimates are high – more than $80,000 per year. With requisite PET exams and high copays, patient accessibility issues will be daunting.

Of note, in my view, the trials of these drugs do not support the hypothesis that amyloid is the primary neuropathologic agent underlying the progressive neurobehavioral decline in AD. To the contrary, they add strong support for the counterargument that the emergence of amyloid plaques is an effect and not a fundamental cause of that progressive loss of neurologic function that we ultimately define as “Alzheimer’s disease.”
 

Time to switch gears

The more obvious path to winning the battle against this human scourge is prevention. A recent analysis published in The Lancet argued that about 40% of AD and other dementias are potentially preventable. I disagree. I believe that 80%-90% of prospective cases can be substantially delayed or prevented. Studies have shown that progression to AD or other dementias is driven primarily by the progressive deterioration of organic brain health, expressed by the loss of what psychologists have termed “cognitive reserve.” Cognitive reserve is resilience arising from active brain usage, akin to physical resilience attributable to a physically active life. Scientific studies have shown us that an individual’s cognitive resilience (reserve) is a greater predictor of risk for dementia than are amyloid plaques – indeed, greater than any combination of pathologic markers in dementia patients.

Building up cognitive reserve

It’s increasingly clear to this observer that cognitive reserve is synonymous with organic brain health. The primary factors that underlie cognitive reserve are processing speed in the brain, executive control, response withholding, memory acquisition, reasoning, and attention abilities. Faster, more accurate brains are necessarily more physically optimized. They necessarily sustain brain system connectivity. They are necessarily healthier. Such brains bear a relatively low risk of developing AD or other dementias, just as physically healthier bodies bear a lower risk of being prematurely banished to semi-permanent residence in an easy chair or a bed.

Brain health can be sustained by deploying inexpensive, self-administered, app-based assessments of neurologic performance limits, which inform patients and their medical teams about general brain health status. These assessments can help doctors guide their patients to adopt more intelligent brain-healthy lifestyles, or direct them to the “brain gym” to progressively exercise their brains in ways that contribute to rapid, potentially large-scale, rejuvenating improvements in physical and functional brain health.

Randomized controlled trials incorporating different combinations of physical exercise, diet, and cognitive training have recorded significant improvements in physical and functional neurologic status, indicating substantially advanced brain health. Consistent moderate-to-intense physical exercise, brain- and heart-healthy eating habits, and, particularly, computerized brain training have repeatedly been shown to improve cognitive function and physically rejuvenate the brain. With cognitive training in the right forms, improvements in processing speed and other measures manifest improving brain health and greater safety.

In the National Institutes of Health–funded ACTIVE study with more than 2,800 older adults, just 10-18 hours of a specific speed of processing training (now part of BrainHQ, a program that I was involved in developing) reduced the probability of a progression to dementia over the following 10 years by 29%, and by 48% in those who did the most training.

This approach is several orders of magnitude less expensive than the pricey new AD drugs. It presents less serious issues of accessibility and has no side effects. It delivers far more powerful therapeutic benefits in older normal and at-risk populations.

Sustained wellness supporting prevention is the far more sensible medical way forward to save people from AD and other dementias – at a far lower medical and societal cost.

Dr. Merzenich is professor emeritus, department of neuroscience, University of California, San Francisco. He reported conflicts of interest with Posit Science, Stronger Brains, and the National Institutes of Health.

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

Two antiamyloid drugs were recently approved by the Food and Drug Administration for treating early-stage Alzheimer’s disease (AD). In trials of both lecanemab (Leqembi) and donanemab, a long-held neuropharmacologic dream was realized: Most amyloid plaques – the primary pathologic marker for AD – were eliminated from the brains of patients with late pre-AD or early AD.

Implications for the amyloid hypothesis

The reduction of amyloid plaques has been argued by many scientists and clinical authorities to be the likely pharmacologic solution for AD. These trials are appropriately viewed as a test of the hypothesis that amyloid bodies are a primary cause of the neurobehavioral symptoms we call AD.

In parallel with that striking reduction in amyloid bodies, drug-treated patients had an initially slower progression of neurobehavioral decline than did placebo-treated control patients. That slowing in symptom progression was accompanied by a modest but statistically significant difference in neurobehavioral ability. After several months in treatment, the rate of decline again paralleled that recorded in the control group. The sustained difference of about a half point on cognitive assessment scores separating treatment and control participants was well short of the 1.5-point difference typically considered clinically significant.

A small number of unexpected and unexplained deaths occurred in the treatment groups. Brain swelling and/or micro-hemorrhages were seen in 20%-30% of treated individuals. Significant brain shrinkage was recorded. These adverse findings are indicative of drug-induced trauma in the target organ for these drugs (i.e., the brain) and were the basis for a boxed warning label for drug usage. Antiamyloid drug treatment was not effective in patients who had higher initial numbers of amyloid plaques, indicating that these drugs would not measurably help the majority of AD patients, who are at more advanced disease stages.

These drugs do not appear to be an “answer” for AD. A modest delay in progression does not mean that we’re on a path to a “cure.” Treatment cost estimates are high – more than $80,000 per year. With requisite PET exams and high copays, patient accessibility issues will be daunting.

Of note, in my view, the trials of these drugs do not support the hypothesis that amyloid is the primary neuropathologic agent underlying the progressive neurobehavioral decline in AD. To the contrary, they add strong support for the counterargument that the emergence of amyloid plaques is an effect and not a fundamental cause of that progressive loss of neurologic function that we ultimately define as “Alzheimer’s disease.”
 

Time to switch gears

The more obvious path to winning the battle against this human scourge is prevention. A recent analysis published in The Lancet argued that about 40% of AD and other dementias are potentially preventable. I disagree. I believe that 80%-90% of prospective cases can be substantially delayed or prevented. Studies have shown that progression to AD or other dementias is driven primarily by the progressive deterioration of organic brain health, expressed by the loss of what psychologists have termed “cognitive reserve.” Cognitive reserve is resilience arising from active brain usage, akin to physical resilience attributable to a physically active life. Scientific studies have shown us that an individual’s cognitive resilience (reserve) is a greater predictor of risk for dementia than are amyloid plaques – indeed, greater than any combination of pathologic markers in dementia patients.

Building up cognitive reserve

It’s increasingly clear to this observer that cognitive reserve is synonymous with organic brain health. The primary factors that underlie cognitive reserve are processing speed in the brain, executive control, response withholding, memory acquisition, reasoning, and attention abilities. Faster, more accurate brains are necessarily more physically optimized. They necessarily sustain brain system connectivity. They are necessarily healthier. Such brains bear a relatively low risk of developing AD or other dementias, just as physically healthier bodies bear a lower risk of being prematurely banished to semi-permanent residence in an easy chair or a bed.

Brain health can be sustained by deploying inexpensive, self-administered, app-based assessments of neurologic performance limits, which inform patients and their medical teams about general brain health status. These assessments can help doctors guide their patients to adopt more intelligent brain-healthy lifestyles, or direct them to the “brain gym” to progressively exercise their brains in ways that contribute to rapid, potentially large-scale, rejuvenating improvements in physical and functional brain health.

Randomized controlled trials incorporating different combinations of physical exercise, diet, and cognitive training have recorded significant improvements in physical and functional neurologic status, indicating substantially advanced brain health. Consistent moderate-to-intense physical exercise, brain- and heart-healthy eating habits, and, particularly, computerized brain training have repeatedly been shown to improve cognitive function and physically rejuvenate the brain. With cognitive training in the right forms, improvements in processing speed and other measures manifest improving brain health and greater safety.

In the National Institutes of Health–funded ACTIVE study with more than 2,800 older adults, just 10-18 hours of a specific speed of processing training (now part of BrainHQ, a program that I was involved in developing) reduced the probability of a progression to dementia over the following 10 years by 29%, and by 48% in those who did the most training.

This approach is several orders of magnitude less expensive than the pricey new AD drugs. It presents less serious issues of accessibility and has no side effects. It delivers far more powerful therapeutic benefits in older normal and at-risk populations.

Sustained wellness supporting prevention is the far more sensible medical way forward to save people from AD and other dementias – at a far lower medical and societal cost.

Dr. Merzenich is professor emeritus, department of neuroscience, University of California, San Francisco. He reported conflicts of interest with Posit Science, Stronger Brains, and the National Institutes of Health.

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

Two antiamyloid drugs were recently approved by the Food and Drug Administration for treating early-stage Alzheimer’s disease (AD). In trials of both lecanemab (Leqembi) and donanemab, a long-held neuropharmacologic dream was realized: Most amyloid plaques – the primary pathologic marker for AD – were eliminated from the brains of patients with late pre-AD or early AD.

Implications for the amyloid hypothesis

The reduction of amyloid plaques has been argued by many scientists and clinical authorities to be the likely pharmacologic solution for AD. These trials are appropriately viewed as a test of the hypothesis that amyloid bodies are a primary cause of the neurobehavioral symptoms we call AD.

In parallel with that striking reduction in amyloid bodies, drug-treated patients had an initially slower progression of neurobehavioral decline than did placebo-treated control patients. That slowing in symptom progression was accompanied by a modest but statistically significant difference in neurobehavioral ability. After several months in treatment, the rate of decline again paralleled that recorded in the control group. The sustained difference of about a half point on cognitive assessment scores separating treatment and control participants was well short of the 1.5-point difference typically considered clinically significant.

A small number of unexpected and unexplained deaths occurred in the treatment groups. Brain swelling and/or micro-hemorrhages were seen in 20%-30% of treated individuals. Significant brain shrinkage was recorded. These adverse findings are indicative of drug-induced trauma in the target organ for these drugs (i.e., the brain) and were the basis for a boxed warning label for drug usage. Antiamyloid drug treatment was not effective in patients who had higher initial numbers of amyloid plaques, indicating that these drugs would not measurably help the majority of AD patients, who are at more advanced disease stages.

These drugs do not appear to be an “answer” for AD. A modest delay in progression does not mean that we’re on a path to a “cure.” Treatment cost estimates are high – more than $80,000 per year. With requisite PET exams and high copays, patient accessibility issues will be daunting.

Of note, in my view, the trials of these drugs do not support the hypothesis that amyloid is the primary neuropathologic agent underlying the progressive neurobehavioral decline in AD. To the contrary, they add strong support for the counterargument that the emergence of amyloid plaques is an effect and not a fundamental cause of that progressive loss of neurologic function that we ultimately define as “Alzheimer’s disease.”
 

Time to switch gears

The more obvious path to winning the battle against this human scourge is prevention. A recent analysis published in The Lancet argued that about 40% of AD and other dementias are potentially preventable. I disagree. I believe that 80%-90% of prospective cases can be substantially delayed or prevented. Studies have shown that progression to AD or other dementias is driven primarily by the progressive deterioration of organic brain health, expressed by the loss of what psychologists have termed “cognitive reserve.” Cognitive reserve is resilience arising from active brain usage, akin to physical resilience attributable to a physically active life. Scientific studies have shown us that an individual’s cognitive resilience (reserve) is a greater predictor of risk for dementia than are amyloid plaques – indeed, greater than any combination of pathologic markers in dementia patients.

Building up cognitive reserve

It’s increasingly clear to this observer that cognitive reserve is synonymous with organic brain health. The primary factors that underlie cognitive reserve are processing speed in the brain, executive control, response withholding, memory acquisition, reasoning, and attention abilities. Faster, more accurate brains are necessarily more physically optimized. They necessarily sustain brain system connectivity. They are necessarily healthier. Such brains bear a relatively low risk of developing AD or other dementias, just as physically healthier bodies bear a lower risk of being prematurely banished to semi-permanent residence in an easy chair or a bed.

Brain health can be sustained by deploying inexpensive, self-administered, app-based assessments of neurologic performance limits, which inform patients and their medical teams about general brain health status. These assessments can help doctors guide their patients to adopt more intelligent brain-healthy lifestyles, or direct them to the “brain gym” to progressively exercise their brains in ways that contribute to rapid, potentially large-scale, rejuvenating improvements in physical and functional brain health.

Randomized controlled trials incorporating different combinations of physical exercise, diet, and cognitive training have recorded significant improvements in physical and functional neurologic status, indicating substantially advanced brain health. Consistent moderate-to-intense physical exercise, brain- and heart-healthy eating habits, and, particularly, computerized brain training have repeatedly been shown to improve cognitive function and physically rejuvenate the brain. With cognitive training in the right forms, improvements in processing speed and other measures manifest improving brain health and greater safety.

In the National Institutes of Health–funded ACTIVE study with more than 2,800 older adults, just 10-18 hours of a specific speed of processing training (now part of BrainHQ, a program that I was involved in developing) reduced the probability of a progression to dementia over the following 10 years by 29%, and by 48% in those who did the most training.

This approach is several orders of magnitude less expensive than the pricey new AD drugs. It presents less serious issues of accessibility and has no side effects. It delivers far more powerful therapeutic benefits in older normal and at-risk populations.

Sustained wellness supporting prevention is the far more sensible medical way forward to save people from AD and other dementias – at a far lower medical and societal cost.

Dr. Merzenich is professor emeritus, department of neuroscience, University of California, San Francisco. He reported conflicts of interest with Posit Science, Stronger Brains, and the National Institutes of Health.

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

TOPLINE:

Loneliness is associated with a higher risk of developing Parkinson’s disease (PD) across demographic groups and independent of other risk factors, data from nearly 500,000 U.K. adults suggest.

METHODOLOGY:

• Loneliness is associated with illness and death, including higher risk of neurodegenerative diseases, but no study has examined whether the association between loneliness and detrimental outcomes extends to PD.
• The current analysis included 491,603 U.K. Biobank participants (mean age, 56; 54% women) without a diagnosis of PD at baseline.
• Loneliness was assessed by a single question at baseline and incident PD was ascertained via health records over 15 years.
• Researchers assessed whether the association between loneliness and PD was moderated by age, sex, or genetic risk and whether the association was accounted for by sociodemographic factors; behavioral, mental, physical, or social factors; or genetic risk.

TAKEAWAY:

• Roughly 19% of the cohort reported being lonely. Compared with those who were not lonely, those who did report being lonely were slightly younger and were more likely to be women. They also had fewer resources, more health risk behaviors (current smoker and physically inactive), and worse physical and mental health.
• Over 15+ years of follow-up, 2,822 participants developed PD (incidence rate: 47 per 100,000 person-years). Compared with those who did not develop PD, those who did were older and more likely to be male, former smokers, have higher BMI and PD polygenetic risk score, and to have diabetes, hypertension, myocardial infarction or stroke, anxiety, or depression.
• In the primary analysis, individuals who reported being lonely had a higher risk for PD (hazard ratio, 1.37) – an association that remained after accounting for demographic and socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, BMI, diabetes, hypertension, stroke, myocardial infarction, depression, and having ever seen a psychiatrist (fully adjusted HR, 1.25). 
• The association between loneliness and incident PD was not moderated by sex, age, or polygenetic risk score.
• Contrary to expectations for a prodromal syndrome, loneliness was not associated with incident PD in the first 5 years after baseline but was associated with PD risk in the subsequent 10 years of follow-up (HR, 1.32).

IN PRACTICE:

“Our findings complement other evidence that loneliness is a psychosocial determinant of health associated with increased risk of morbidity and mortality [and] supports recent calls for the protective and healing effects of personally meaningful social connection,” the authors write.

SOURCE:

The study, with first author Antonio Terracciano, PhD, of Florida State University College of Medicine, Tallahassee, was published online  in JAMA Neurology.

LIMITATIONS:

This observational study could not determine causality or whether reverse causality could explain the association. Loneliness was assessed by a single yes/no question. PD diagnosis relied on hospital admission and death records and may have missed early PD diagnoses.

DISCLOSURES:

Funding for the study was provided by the National Institutes of Health and National Institute on Aging. The authors report no relevant financial relationships.

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

TOPLINE:

Loneliness is associated with a higher risk of developing Parkinson’s disease (PD) across demographic groups and independent of other risk factors, data from nearly 500,000 U.K. adults suggest.

METHODOLOGY:

• Loneliness is associated with illness and death, including higher risk of neurodegenerative diseases, but no study has examined whether the association between loneliness and detrimental outcomes extends to PD.
• The current analysis included 491,603 U.K. Biobank participants (mean age, 56; 54% women) without a diagnosis of PD at baseline.
• Loneliness was assessed by a single question at baseline and incident PD was ascertained via health records over 15 years.
• Researchers assessed whether the association between loneliness and PD was moderated by age, sex, or genetic risk and whether the association was accounted for by sociodemographic factors; behavioral, mental, physical, or social factors; or genetic risk.

TAKEAWAY:

• Roughly 19% of the cohort reported being lonely. Compared with those who were not lonely, those who did report being lonely were slightly younger and were more likely to be women. They also had fewer resources, more health risk behaviors (current smoker and physically inactive), and worse physical and mental health.
• Over 15+ years of follow-up, 2,822 participants developed PD (incidence rate: 47 per 100,000 person-years). Compared with those who did not develop PD, those who did were older and more likely to be male, former smokers, have higher BMI and PD polygenetic risk score, and to have diabetes, hypertension, myocardial infarction or stroke, anxiety, or depression.
• In the primary analysis, individuals who reported being lonely had a higher risk for PD (hazard ratio, 1.37) – an association that remained after accounting for demographic and socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, BMI, diabetes, hypertension, stroke, myocardial infarction, depression, and having ever seen a psychiatrist (fully adjusted HR, 1.25). 
• The association between loneliness and incident PD was not moderated by sex, age, or polygenetic risk score.
• Contrary to expectations for a prodromal syndrome, loneliness was not associated with incident PD in the first 5 years after baseline but was associated with PD risk in the subsequent 10 years of follow-up (HR, 1.32).

IN PRACTICE:

“Our findings complement other evidence that loneliness is a psychosocial determinant of health associated with increased risk of morbidity and mortality [and] supports recent calls for the protective and healing effects of personally meaningful social connection,” the authors write.

SOURCE:

The study, with first author Antonio Terracciano, PhD, of Florida State University College of Medicine, Tallahassee, was published online  in JAMA Neurology.

LIMITATIONS:

This observational study could not determine causality or whether reverse causality could explain the association. Loneliness was assessed by a single yes/no question. PD diagnosis relied on hospital admission and death records and may have missed early PD diagnoses.

DISCLOSURES:

Funding for the study was provided by the National Institutes of Health and National Institute on Aging. The authors report no relevant financial relationships.

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

TOPLINE:

Loneliness is associated with a higher risk of developing Parkinson’s disease (PD) across demographic groups and independent of other risk factors, data from nearly 500,000 U.K. adults suggest.

METHODOLOGY:

• Loneliness is associated with illness and death, including higher risk of neurodegenerative diseases, but no study has examined whether the association between loneliness and detrimental outcomes extends to PD.
• The current analysis included 491,603 U.K. Biobank participants (mean age, 56; 54% women) without a diagnosis of PD at baseline.
• Loneliness was assessed by a single question at baseline and incident PD was ascertained via health records over 15 years.
• Researchers assessed whether the association between loneliness and PD was moderated by age, sex, or genetic risk and whether the association was accounted for by sociodemographic factors; behavioral, mental, physical, or social factors; or genetic risk.

TAKEAWAY:

• Roughly 19% of the cohort reported being lonely. Compared with those who were not lonely, those who did report being lonely were slightly younger and were more likely to be women. They also had fewer resources, more health risk behaviors (current smoker and physically inactive), and worse physical and mental health.
• Over 15+ years of follow-up, 2,822 participants developed PD (incidence rate: 47 per 100,000 person-years). Compared with those who did not develop PD, those who did were older and more likely to be male, former smokers, have higher BMI and PD polygenetic risk score, and to have diabetes, hypertension, myocardial infarction or stroke, anxiety, or depression.
• In the primary analysis, individuals who reported being lonely had a higher risk for PD (hazard ratio, 1.37) – an association that remained after accounting for demographic and socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, BMI, diabetes, hypertension, stroke, myocardial infarction, depression, and having ever seen a psychiatrist (fully adjusted HR, 1.25). 
• The association between loneliness and incident PD was not moderated by sex, age, or polygenetic risk score.
• Contrary to expectations for a prodromal syndrome, loneliness was not associated with incident PD in the first 5 years after baseline but was associated with PD risk in the subsequent 10 years of follow-up (HR, 1.32).

IN PRACTICE:

“Our findings complement other evidence that loneliness is a psychosocial determinant of health associated with increased risk of morbidity and mortality [and] supports recent calls for the protective and healing effects of personally meaningful social connection,” the authors write.

SOURCE:

The study, with first author Antonio Terracciano, PhD, of Florida State University College of Medicine, Tallahassee, was published online  in JAMA Neurology.

LIMITATIONS:

This observational study could not determine causality or whether reverse causality could explain the association. Loneliness was assessed by a single yes/no question. PD diagnosis relied on hospital admission and death records and may have missed early PD diagnoses.

DISCLOSURES:

Funding for the study was provided by the National Institutes of Health and National Institute on Aging. The authors report no relevant financial relationships.

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

One in three patients who experience their first bout of atrial fibrillation (AFib) during hospitalization can expect to experience a recurrence of the arrhythmia within the year, new research shows.

The findings, reported in Annals of Internal Medicine, suggest these patients may be good candidates for oral anticoagulants to reduce their risk for stroke.

“Atrial fibrillation is very common in patients for the very first time in their life when they’re sick and in the hospital,” said William F. McIntyre, MD, PhD, a cardiologist at McMaster University, Hamilton, Ont., who led the study. These new insights into AFib management suggest there is a need for primary care physicians to be on the lookout for potential recurrence.

AFib is strongly linked to stroke, and patients at greater risk for stroke may be prescribed oral anticoagulants. Although the arrhythmia can be reversed before the patient is discharged from the hospital, risk for recurrence was unclear, Dr. McIntyre said.

“We wanted to know if the patient was in atrial fibrillation because of the physiologic stress that they were under, or if they just have the disease called atrial fibrillation, which should usually be followed lifelong by a specialist,” Dr. McIntyre said.

Dr. McIntyre and colleagues followed 139 patients (mean age, 71 years) at three medical centers in Ontario who experienced new-onset AFib during their hospital stay, along with an equal number of patients who had no history of AFib and who served as controls. The research team used a Holter monitor to record study participants’ heart rhythm for 14 days to detect incident AFib at 1 and 6 months after discharge. They also followed up with periodic phone calls for up to 12 months. Among the study participants, half were admitted for noncardiac surgeries, and the other half were admitted for medical illnesses, including infections and pneumonia. Participants with a prior history of AFib were excluded from the analysis.

The primary outcome of the study was an episode of AFib that lasted at least 30 seconds on the monitor or one detected during routine care at the 12-month mark.

Patients who experienced AFib for the first time in the hospital had roughly a 33% risk for recurrence within a year, nearly sevenfold higher than their age- and sex-matched counterparts who had not had an arrhythmia during their hospital stay (3%; confidence interval, 0%-6.4%).

“This study has important implications for management of patients who have a first presentation of AFib that is concurrent with a reversible physiologic stressor,” the authors wrote. “An AFib recurrence risk of 33.1% at 1 year is neither low enough to conclude that transient new-onset AFib in the setting of another illness is benign nor high enough that all such transient new-onset AFib can be assumed to be paroxysmal AFib. Instead, these results call for risk stratification and follow-up in these patients.”

The researchers reported that among people with recurrent AFib in the study, the median total time in arrhythmia was 9 hours. “This far exceeds the cutoff of 6 minutes that was established as being associated with stroke using simulated AFib screening in patients with implanted continuous monitors,” they wrote. “These results suggest that the patients in our study who had AFib detected in follow-up are similar to contemporary patients with AFib for whom evidence-based therapies, including oral anticoagulation, are warranted.”

Dr. McIntyre and colleagues were able to track outcomes and treatments for the patients in the study. In the group with recurrent AFib, 1 had a stroke, 2 experienced systemic embolism, 3 had a heart failure event, 6 experienced bleeding, and 11 died. In the other group, there was one case of stroke, one of heart failure, four cases involving bleeding, and seven deaths. “The proportion of participants with new-onset AFib during their initial hospitalization who were taking oral anticoagulants was 47.1% at 6 months and 49.2% at 12 months. This included 73% of participants with AFib detected during follow-up and 39% who did not have AFib detected during follow-up,” they wrote.

The uncertain nature of AFib recurrence complicates predictions about patients’ posthospitalization experiences within the following year. “We cannot just say: ‘Hey, this is just a reversible illness, and now we can forget about it,’ ” Dr. McIntyre said. “Nor is the risk of recurrence so strong in the other direction that you can give patients a lifelong diagnosis of atrial fibrillation.”
 

Role for primary care

Without that certainty, physicians cannot refer everyone who experiences new-onset AFib to a cardiologist for long-term care. The variability in recurrence rates necessitates a more nuanced and personalized approach. Here, primary care physicians step in, offering tailored care based on their established, long-term patient relationships, Dr. McIntyre said.

The study participants already have chronic health conditions that bring them into regular contact with their family physician. This gives primary care physicians a golden opportunity to be on lookout and to recommend care from a cardiologist at the appropriate time if it becomes necessary, he said.

“I have certainly seen cases of recurrent atrial fibrillation in patients who had an episode while hospitalized, and consistent with this study, this is a common clinical occurrence,” said Deepak L. Bhatt, MD, MPH, director of Mount Sinai Heart, New York. Primary care physicians must remain vigilant and avoid the temptation to attribute AFib solely to illness or surgery

“Ideally, we would have randomized clinical trial data to guide the decision about whether to use prophylactic anticoagulation,” said Dr. Bhatt, who added that a cardiology consultation may also be appropriate.

Dr. McIntyre reported no relevant financial relationships. Dr. Bhatt reported numerous relationships with industry.

A version of this article appeared on Medscape.com.

One in three patients who experience their first bout of atrial fibrillation (AFib) during hospitalization can expect to experience a recurrence of the arrhythmia within the year, new research shows.

The findings, reported in Annals of Internal Medicine, suggest these patients may be good candidates for oral anticoagulants to reduce their risk for stroke.

“Atrial fibrillation is very common in patients for the very first time in their life when they’re sick and in the hospital,” said William F. McIntyre, MD, PhD, a cardiologist at McMaster University, Hamilton, Ont., who led the study. These new insights into AFib management suggest there is a need for primary care physicians to be on the lookout for potential recurrence.

AFib is strongly linked to stroke, and patients at greater risk for stroke may be prescribed oral anticoagulants. Although the arrhythmia can be reversed before the patient is discharged from the hospital, risk for recurrence was unclear, Dr. McIntyre said.

“We wanted to know if the patient was in atrial fibrillation because of the physiologic stress that they were under, or if they just have the disease called atrial fibrillation, which should usually be followed lifelong by a specialist,” Dr. McIntyre said.

Dr. McIntyre and colleagues followed 139 patients (mean age, 71 years) at three medical centers in Ontario who experienced new-onset AFib during their hospital stay, along with an equal number of patients who had no history of AFib and who served as controls. The research team used a Holter monitor to record study participants’ heart rhythm for 14 days to detect incident AFib at 1 and 6 months after discharge. They also followed up with periodic phone calls for up to 12 months. Among the study participants, half were admitted for noncardiac surgeries, and the other half were admitted for medical illnesses, including infections and pneumonia. Participants with a prior history of AFib were excluded from the analysis.

The primary outcome of the study was an episode of AFib that lasted at least 30 seconds on the monitor or one detected during routine care at the 12-month mark.

Patients who experienced AFib for the first time in the hospital had roughly a 33% risk for recurrence within a year, nearly sevenfold higher than their age- and sex-matched counterparts who had not had an arrhythmia during their hospital stay (3%; confidence interval, 0%-6.4%).

“This study has important implications for management of patients who have a first presentation of AFib that is concurrent with a reversible physiologic stressor,” the authors wrote. “An AFib recurrence risk of 33.1% at 1 year is neither low enough to conclude that transient new-onset AFib in the setting of another illness is benign nor high enough that all such transient new-onset AFib can be assumed to be paroxysmal AFib. Instead, these results call for risk stratification and follow-up in these patients.”

The researchers reported that among people with recurrent AFib in the study, the median total time in arrhythmia was 9 hours. “This far exceeds the cutoff of 6 minutes that was established as being associated with stroke using simulated AFib screening in patients with implanted continuous monitors,” they wrote. “These results suggest that the patients in our study who had AFib detected in follow-up are similar to contemporary patients with AFib for whom evidence-based therapies, including oral anticoagulation, are warranted.”

Dr. McIntyre and colleagues were able to track outcomes and treatments for the patients in the study. In the group with recurrent AFib, 1 had a stroke, 2 experienced systemic embolism, 3 had a heart failure event, 6 experienced bleeding, and 11 died. In the other group, there was one case of stroke, one of heart failure, four cases involving bleeding, and seven deaths. “The proportion of participants with new-onset AFib during their initial hospitalization who were taking oral anticoagulants was 47.1% at 6 months and 49.2% at 12 months. This included 73% of participants with AFib detected during follow-up and 39% who did not have AFib detected during follow-up,” they wrote.

The uncertain nature of AFib recurrence complicates predictions about patients’ posthospitalization experiences within the following year. “We cannot just say: ‘Hey, this is just a reversible illness, and now we can forget about it,’ ” Dr. McIntyre said. “Nor is the risk of recurrence so strong in the other direction that you can give patients a lifelong diagnosis of atrial fibrillation.”
 

Role for primary care

Without that certainty, physicians cannot refer everyone who experiences new-onset AFib to a cardiologist for long-term care. The variability in recurrence rates necessitates a more nuanced and personalized approach. Here, primary care physicians step in, offering tailored care based on their established, long-term patient relationships, Dr. McIntyre said.

The study participants already have chronic health conditions that bring them into regular contact with their family physician. This gives primary care physicians a golden opportunity to be on lookout and to recommend care from a cardiologist at the appropriate time if it becomes necessary, he said.

“I have certainly seen cases of recurrent atrial fibrillation in patients who had an episode while hospitalized, and consistent with this study, this is a common clinical occurrence,” said Deepak L. Bhatt, MD, MPH, director of Mount Sinai Heart, New York. Primary care physicians must remain vigilant and avoid the temptation to attribute AFib solely to illness or surgery

“Ideally, we would have randomized clinical trial data to guide the decision about whether to use prophylactic anticoagulation,” said Dr. Bhatt, who added that a cardiology consultation may also be appropriate.

Dr. McIntyre reported no relevant financial relationships. Dr. Bhatt reported numerous relationships with industry.

A version of this article appeared on Medscape.com.

One in three patients who experience their first bout of atrial fibrillation (AFib) during hospitalization can expect to experience a recurrence of the arrhythmia within the year, new research shows.

The findings, reported in Annals of Internal Medicine, suggest these patients may be good candidates for oral anticoagulants to reduce their risk for stroke.

“Atrial fibrillation is very common in patients for the very first time in their life when they’re sick and in the hospital,” said William F. McIntyre, MD, PhD, a cardiologist at McMaster University, Hamilton, Ont., who led the study. These new insights into AFib management suggest there is a need for primary care physicians to be on the lookout for potential recurrence.

AFib is strongly linked to stroke, and patients at greater risk for stroke may be prescribed oral anticoagulants. Although the arrhythmia can be reversed before the patient is discharged from the hospital, risk for recurrence was unclear, Dr. McIntyre said.

“We wanted to know if the patient was in atrial fibrillation because of the physiologic stress that they were under, or if they just have the disease called atrial fibrillation, which should usually be followed lifelong by a specialist,” Dr. McIntyre said.

Dr. McIntyre and colleagues followed 139 patients (mean age, 71 years) at three medical centers in Ontario who experienced new-onset AFib during their hospital stay, along with an equal number of patients who had no history of AFib and who served as controls. The research team used a Holter monitor to record study participants’ heart rhythm for 14 days to detect incident AFib at 1 and 6 months after discharge. They also followed up with periodic phone calls for up to 12 months. Among the study participants, half were admitted for noncardiac surgeries, and the other half were admitted for medical illnesses, including infections and pneumonia. Participants with a prior history of AFib were excluded from the analysis.

The primary outcome of the study was an episode of AFib that lasted at least 30 seconds on the monitor or one detected during routine care at the 12-month mark.

Patients who experienced AFib for the first time in the hospital had roughly a 33% risk for recurrence within a year, nearly sevenfold higher than their age- and sex-matched counterparts who had not had an arrhythmia during their hospital stay (3%; confidence interval, 0%-6.4%).

“This study has important implications for management of patients who have a first presentation of AFib that is concurrent with a reversible physiologic stressor,” the authors wrote. “An AFib recurrence risk of 33.1% at 1 year is neither low enough to conclude that transient new-onset AFib in the setting of another illness is benign nor high enough that all such transient new-onset AFib can be assumed to be paroxysmal AFib. Instead, these results call for risk stratification and follow-up in these patients.”

The researchers reported that among people with recurrent AFib in the study, the median total time in arrhythmia was 9 hours. “This far exceeds the cutoff of 6 minutes that was established as being associated with stroke using simulated AFib screening in patients with implanted continuous monitors,” they wrote. “These results suggest that the patients in our study who had AFib detected in follow-up are similar to contemporary patients with AFib for whom evidence-based therapies, including oral anticoagulation, are warranted.”

Dr. McIntyre and colleagues were able to track outcomes and treatments for the patients in the study. In the group with recurrent AFib, 1 had a stroke, 2 experienced systemic embolism, 3 had a heart failure event, 6 experienced bleeding, and 11 died. In the other group, there was one case of stroke, one of heart failure, four cases involving bleeding, and seven deaths. “The proportion of participants with new-onset AFib during their initial hospitalization who were taking oral anticoagulants was 47.1% at 6 months and 49.2% at 12 months. This included 73% of participants with AFib detected during follow-up and 39% who did not have AFib detected during follow-up,” they wrote.

The uncertain nature of AFib recurrence complicates predictions about patients’ posthospitalization experiences within the following year. “We cannot just say: ‘Hey, this is just a reversible illness, and now we can forget about it,’ ” Dr. McIntyre said. “Nor is the risk of recurrence so strong in the other direction that you can give patients a lifelong diagnosis of atrial fibrillation.”
 

Role for primary care

Without that certainty, physicians cannot refer everyone who experiences new-onset AFib to a cardiologist for long-term care. The variability in recurrence rates necessitates a more nuanced and personalized approach. Here, primary care physicians step in, offering tailored care based on their established, long-term patient relationships, Dr. McIntyre said.

The study participants already have chronic health conditions that bring them into regular contact with their family physician. This gives primary care physicians a golden opportunity to be on lookout and to recommend care from a cardiologist at the appropriate time if it becomes necessary, he said.

“I have certainly seen cases of recurrent atrial fibrillation in patients who had an episode while hospitalized, and consistent with this study, this is a common clinical occurrence,” said Deepak L. Bhatt, MD, MPH, director of Mount Sinai Heart, New York. Primary care physicians must remain vigilant and avoid the temptation to attribute AFib solely to illness or surgery

“Ideally, we would have randomized clinical trial data to guide the decision about whether to use prophylactic anticoagulation,” said Dr. Bhatt, who added that a cardiology consultation may also be appropriate.

Dr. McIntyre reported no relevant financial relationships. Dr. Bhatt reported numerous relationships with industry.

A version of this article appeared on Medscape.com.

TOPLINE:

Use of a novel clinical-decision support tool and shared decision-making in elderly patients with type 2 diabetes managed in a primary care practice and at high risk for hypoglycemic episodes led to a 46% decrease in the number of at-risk patients and discontinuation of hypoglycemic agents in 20% in a prospective, 6-month, single-arm study with 94 patients.

METHODOLOGY:

• The HypoPrevent study enrolled 94 people from a Pennsylvania primary care practice who were at least 65 years old with type 2 diabetes and at risk for hypoglycemia because of treatment with insulin or sulfonylureas, and having a hemoglobin A1c of less than 7.0%.
• Clinicians and patients used a newly devised hypoglycemia reduction clinical-decision support tool developed by the Endocrine Society and a health care consulting company to help guide shared decision-making for a goal A1c level, potential changes to treatment, and other steps to reduce the risk of hypoglycemia.
• Primary outcomes during 6-month follow-up were impact of the intervention on A1c, changes in use of insulin or sulfonylureas, change in the number of study patients at risk for hypoglycemia, and impact on the incidence of nonsevere hypoglycemic events (NSHEs) measured with the Treatment-Related Impact Measure–Non-severe Hypoglycemic Events (TRIM-HYPO) survey.

TAKEAWAY:

• Patients averaged 74 years old, 57% were women, 95% were White, 61% had diabetes for more than 10 years, 48% had chronic kidney disease, 51% were on insulin, 47% on a sulfonylurea, and 80 of the 94 enrolled patients completed all three study visits.
• Nineteen patients (20%) reduced their dose of or discontinued insulin or sulfonylurea.
• In patients with both baseline and follow-up A1c measures, A1c rose from 6.29% at baseline to 6.82%.
• Fifty patients set an A1c goal and had a timely follow-up A1c measurement, and in this subgroup the number of patients at risk for hypoglycemia decreased by 46%, a significant change.
• Patients who reported at least one NSHE at baseline had a significant reduction between the baseline survey and follow-up visits in both the total score as well as each of the five scored domains.

IN PRACTICE:

The HypoPrevent study results “show the potential of a decision support tool and shared decision making to reduce the risk of hypoglycemia in older persons with type 2 diabetes,” and that “the tested decision tool can be effectively used by a busy primary care practice with positive results,” concluded the researchers in their report.

SOURCE:

The HypoPrevent study was funded and organized by the Endocrine Society in collaboration with a multicenter team of researchers. The report appeared in the Journal of the American Geriatrics Society.

LIMITATIONS:

Lack of a control group makes it impossible to conclusively determine whether the intervention led to the observed increases in A1c levels, nor can the study exclude regression to the mean as the cause for lowered A1c levels.

DISCLOSURES:

The study received funding from Abbott, Lilly, Merck, Novo Nordisk, and Sanofi. Two coauthors had individual disclosures listed in the report; the other six coauthors had no disclosures.

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

TOPLINE:

Use of a novel clinical-decision support tool and shared decision-making in elderly patients with type 2 diabetes managed in a primary care practice and at high risk for hypoglycemic episodes led to a 46% decrease in the number of at-risk patients and discontinuation of hypoglycemic agents in 20% in a prospective, 6-month, single-arm study with 94 patients.

METHODOLOGY:

• The HypoPrevent study enrolled 94 people from a Pennsylvania primary care practice who were at least 65 years old with type 2 diabetes and at risk for hypoglycemia because of treatment with insulin or sulfonylureas, and having a hemoglobin A1c of less than 7.0%.
• Clinicians and patients used a newly devised hypoglycemia reduction clinical-decision support tool developed by the Endocrine Society and a health care consulting company to help guide shared decision-making for a goal A1c level, potential changes to treatment, and other steps to reduce the risk of hypoglycemia.
• Primary outcomes during 6-month follow-up were impact of the intervention on A1c, changes in use of insulin or sulfonylureas, change in the number of study patients at risk for hypoglycemia, and impact on the incidence of nonsevere hypoglycemic events (NSHEs) measured with the Treatment-Related Impact Measure–Non-severe Hypoglycemic Events (TRIM-HYPO) survey.

TAKEAWAY:

• Patients averaged 74 years old, 57% were women, 95% were White, 61% had diabetes for more than 10 years, 48% had chronic kidney disease, 51% were on insulin, 47% on a sulfonylurea, and 80 of the 94 enrolled patients completed all three study visits.
• Nineteen patients (20%) reduced their dose of or discontinued insulin or sulfonylurea.
• In patients with both baseline and follow-up A1c measures, A1c rose from 6.29% at baseline to 6.82%.
• Fifty patients set an A1c goal and had a timely follow-up A1c measurement, and in this subgroup the number of patients at risk for hypoglycemia decreased by 46%, a significant change.
• Patients who reported at least one NSHE at baseline had a significant reduction between the baseline survey and follow-up visits in both the total score as well as each of the five scored domains.

IN PRACTICE:

The HypoPrevent study results “show the potential of a decision support tool and shared decision making to reduce the risk of hypoglycemia in older persons with type 2 diabetes,” and that “the tested decision tool can be effectively used by a busy primary care practice with positive results,” concluded the researchers in their report.

SOURCE:

The HypoPrevent study was funded and organized by the Endocrine Society in collaboration with a multicenter team of researchers. The report appeared in the Journal of the American Geriatrics Society.

LIMITATIONS:

Lack of a control group makes it impossible to conclusively determine whether the intervention led to the observed increases in A1c levels, nor can the study exclude regression to the mean as the cause for lowered A1c levels.

DISCLOSURES:

The study received funding from Abbott, Lilly, Merck, Novo Nordisk, and Sanofi. Two coauthors had individual disclosures listed in the report; the other six coauthors had no disclosures.

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

TOPLINE:

Use of a novel clinical-decision support tool and shared decision-making in elderly patients with type 2 diabetes managed in a primary care practice and at high risk for hypoglycemic episodes led to a 46% decrease in the number of at-risk patients and discontinuation of hypoglycemic agents in 20% in a prospective, 6-month, single-arm study with 94 patients.

METHODOLOGY:

• The HypoPrevent study enrolled 94 people from a Pennsylvania primary care practice who were at least 65 years old with type 2 diabetes and at risk for hypoglycemia because of treatment with insulin or sulfonylureas, and having a hemoglobin A1c of less than 7.0%.
• Clinicians and patients used a newly devised hypoglycemia reduction clinical-decision support tool developed by the Endocrine Society and a health care consulting company to help guide shared decision-making for a goal A1c level, potential changes to treatment, and other steps to reduce the risk of hypoglycemia.
• Primary outcomes during 6-month follow-up were impact of the intervention on A1c, changes in use of insulin or sulfonylureas, change in the number of study patients at risk for hypoglycemia, and impact on the incidence of nonsevere hypoglycemic events (NSHEs) measured with the Treatment-Related Impact Measure–Non-severe Hypoglycemic Events (TRIM-HYPO) survey.

TAKEAWAY:

• Patients averaged 74 years old, 57% were women, 95% were White, 61% had diabetes for more than 10 years, 48% had chronic kidney disease, 51% were on insulin, 47% on a sulfonylurea, and 80 of the 94 enrolled patients completed all three study visits.
• Nineteen patients (20%) reduced their dose of or discontinued insulin or sulfonylurea.
• In patients with both baseline and follow-up A1c measures, A1c rose from 6.29% at baseline to 6.82%.
• Fifty patients set an A1c goal and had a timely follow-up A1c measurement, and in this subgroup the number of patients at risk for hypoglycemia decreased by 46%, a significant change.
• Patients who reported at least one NSHE at baseline had a significant reduction between the baseline survey and follow-up visits in both the total score as well as each of the five scored domains.

IN PRACTICE:

The HypoPrevent study results “show the potential of a decision support tool and shared decision making to reduce the risk of hypoglycemia in older persons with type 2 diabetes,” and that “the tested decision tool can be effectively used by a busy primary care practice with positive results,” concluded the researchers in their report.

SOURCE:

The HypoPrevent study was funded and organized by the Endocrine Society in collaboration with a multicenter team of researchers. The report appeared in the Journal of the American Geriatrics Society.

LIMITATIONS:

Lack of a control group makes it impossible to conclusively determine whether the intervention led to the observed increases in A1c levels, nor can the study exclude regression to the mean as the cause for lowered A1c levels.

DISCLOSURES:

The study received funding from Abbott, Lilly, Merck, Novo Nordisk, and Sanofi. Two coauthors had individual disclosures listed in the report; the other six coauthors had no disclosures.

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

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

TOPLINE:

Women who continue breast cancer screening after age 70 face a considerable risk for overdiagnosis.

METHODOLOGY:

• Overdiagnosis – the risk of detecting and treating cancers that would never have caused issues in a person’s lifetime – is increasingly recognized as a harm of breast cancer screening; however, the scope of the problem among older women remains uncertain. 
• To get an idea, investigators linked Medicare claims data with Surveillance, Epidemiology, and End Results (SEER) data for 54,635 women 70 years or older to compare the incidence of breast cancer and breast cancer–specific death among women who continued screening mammography with those who did not.
• The women all had undergone recent screening mammograms and had no history of breast cancer at study entry. Those who had a subsequent mammogram within 3 years were classified as undergoing continued screening while those who did not were classified as not undergoing continued screening.
• Overdiagnosis was defined as the difference in cumulative incidence of breast cancer between screened and unscreened women divided by the cumulative incidence among screened women. 
• Results were adjusted for potential confounders, including age, race, and ethnicity.

TAKEAWAY:

• Over 80% of women 70-84 years old and more than 60% of women 85 years or older continued screening.
• Among women 70-74 years old, the adjusted cumulative incidence of breast cancer was 6.1 cases per 100 screened women vs. 4.2 cases per 100 unscreened women; for women aged 75-84 years old, the cumulative incidence was 4.9 per 100 screened women vs. 2.6 per 100 unscreened women, and for women 85 years and older, the cumulative incidence was 2.8 vs. 1.3 per 100, respectively.
• Estimates of overdiagnosis ranged from 31% of breast cancer cases among screened women in the 70-74 age group to 54% of cases in the 85 and older group.
• The researchers found no statistically significant reduction in breast cancer–specific death associated with screening in any age or life-expectancy group. Overdiagnosis appeared to be driven by in situ and localized invasive breast cancer, not advanced breast cancer.

IN PRACTICE:

The proportion of older women who continue to receive screening mammograms and may experience breast cancer overdiagnosis is “considerable” and “increases with advancing age and with decreasing life expectancy,” the authors conclude. Given potential benefits and harms of screening in this population, “patient preferences, including risk tolerance, comfort with uncertainty, and willingness to undergo treatment, are important for informing screening decisions.”

SOURCE:

The study was led by Ilana Richman, MD, MHS, of the Yale School of Medicine, New Haven, Connecticut, and published in the Annals of Internal Medicine.

LIMITATIONS:

The definition of screening mammography in the study may have misclassified some diagnostic mammograms as screening. Using a more conservative definition of screening mammogram, which largely accounted for this misclassification, estimates for overdiagnosis were smaller, ranging from 15% of cases in the 70-74 age group to 44% of cases in the 85 and older group. Results could not be adjusted for breast density, family history, and other breast cancer risk factors not captured by the data.

DISCLOSURES:

The work was funded by the National Cancer Institute. One author reported funding from Genentech and Johnson & Johnson.

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

TOPLINE:

Women who continue breast cancer screening after age 70 face a considerable risk for overdiagnosis.

METHODOLOGY:

• Overdiagnosis – the risk of detecting and treating cancers that would never have caused issues in a person’s lifetime – is increasingly recognized as a harm of breast cancer screening; however, the scope of the problem among older women remains uncertain. 
• To get an idea, investigators linked Medicare claims data with Surveillance, Epidemiology, and End Results (SEER) data for 54,635 women 70 years or older to compare the incidence of breast cancer and breast cancer–specific death among women who continued screening mammography with those who did not.
• The women all had undergone recent screening mammograms and had no history of breast cancer at study entry. Those who had a subsequent mammogram within 3 years were classified as undergoing continued screening while those who did not were classified as not undergoing continued screening.
• Overdiagnosis was defined as the difference in cumulative incidence of breast cancer between screened and unscreened women divided by the cumulative incidence among screened women. 
• Results were adjusted for potential confounders, including age, race, and ethnicity.

TAKEAWAY:

• Over 80% of women 70-84 years old and more than 60% of women 85 years or older continued screening.
• Among women 70-74 years old, the adjusted cumulative incidence of breast cancer was 6.1 cases per 100 screened women vs. 4.2 cases per 100 unscreened women; for women aged 75-84 years old, the cumulative incidence was 4.9 per 100 screened women vs. 2.6 per 100 unscreened women, and for women 85 years and older, the cumulative incidence was 2.8 vs. 1.3 per 100, respectively.
• Estimates of overdiagnosis ranged from 31% of breast cancer cases among screened women in the 70-74 age group to 54% of cases in the 85 and older group.
• The researchers found no statistically significant reduction in breast cancer–specific death associated with screening in any age or life-expectancy group. Overdiagnosis appeared to be driven by in situ and localized invasive breast cancer, not advanced breast cancer.

IN PRACTICE:

The proportion of older women who continue to receive screening mammograms and may experience breast cancer overdiagnosis is “considerable” and “increases with advancing age and with decreasing life expectancy,” the authors conclude. Given potential benefits and harms of screening in this population, “patient preferences, including risk tolerance, comfort with uncertainty, and willingness to undergo treatment, are important for informing screening decisions.”

SOURCE:

The study was led by Ilana Richman, MD, MHS, of the Yale School of Medicine, New Haven, Connecticut, and published in the Annals of Internal Medicine.

LIMITATIONS:

The definition of screening mammography in the study may have misclassified some diagnostic mammograms as screening. Using a more conservative definition of screening mammogram, which largely accounted for this misclassification, estimates for overdiagnosis were smaller, ranging from 15% of cases in the 70-74 age group to 44% of cases in the 85 and older group. Results could not be adjusted for breast density, family history, and other breast cancer risk factors not captured by the data.

DISCLOSURES:

The work was funded by the National Cancer Institute. One author reported funding from Genentech and Johnson & Johnson.

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

TOPLINE:

Women who continue breast cancer screening after age 70 face a considerable risk for overdiagnosis.

METHODOLOGY:

• Overdiagnosis – the risk of detecting and treating cancers that would never have caused issues in a person’s lifetime – is increasingly recognized as a harm of breast cancer screening; however, the scope of the problem among older women remains uncertain. 
• To get an idea, investigators linked Medicare claims data with Surveillance, Epidemiology, and End Results (SEER) data for 54,635 women 70 years or older to compare the incidence of breast cancer and breast cancer–specific death among women who continued screening mammography with those who did not.
• The women all had undergone recent screening mammograms and had no history of breast cancer at study entry. Those who had a subsequent mammogram within 3 years were classified as undergoing continued screening while those who did not were classified as not undergoing continued screening.
• Overdiagnosis was defined as the difference in cumulative incidence of breast cancer between screened and unscreened women divided by the cumulative incidence among screened women. 
• Results were adjusted for potential confounders, including age, race, and ethnicity.

TAKEAWAY:

• Over 80% of women 70-84 years old and more than 60% of women 85 years or older continued screening.
• Among women 70-74 years old, the adjusted cumulative incidence of breast cancer was 6.1 cases per 100 screened women vs. 4.2 cases per 100 unscreened women; for women aged 75-84 years old, the cumulative incidence was 4.9 per 100 screened women vs. 2.6 per 100 unscreened women, and for women 85 years and older, the cumulative incidence was 2.8 vs. 1.3 per 100, respectively.
• Estimates of overdiagnosis ranged from 31% of breast cancer cases among screened women in the 70-74 age group to 54% of cases in the 85 and older group.
• The researchers found no statistically significant reduction in breast cancer–specific death associated with screening in any age or life-expectancy group. Overdiagnosis appeared to be driven by in situ and localized invasive breast cancer, not advanced breast cancer.

IN PRACTICE:

The proportion of older women who continue to receive screening mammograms and may experience breast cancer overdiagnosis is “considerable” and “increases with advancing age and with decreasing life expectancy,” the authors conclude. Given potential benefits and harms of screening in this population, “patient preferences, including risk tolerance, comfort with uncertainty, and willingness to undergo treatment, are important for informing screening decisions.”

SOURCE:

The study was led by Ilana Richman, MD, MHS, of the Yale School of Medicine, New Haven, Connecticut, and published in the Annals of Internal Medicine.

LIMITATIONS:

The definition of screening mammography in the study may have misclassified some diagnostic mammograms as screening. Using a more conservative definition of screening mammogram, which largely accounted for this misclassification, estimates for overdiagnosis were smaller, ranging from 15% of cases in the 70-74 age group to 44% of cases in the 85 and older group. Results could not be adjusted for breast density, family history, and other breast cancer risk factors not captured by the data.

DISCLOSURES:

The work was funded by the National Cancer Institute. One author reported funding from Genentech and Johnson & Johnson.

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

A new study published in Annals of Internal Medicine found atypical antipsychotics were not safer than haloperidol when it comes to treating postoperative delirium in older patients.

Dae Hyun Kim, MD, ScD, associate professor of medicine at Harvard Medical School, in Boston, who is the lead author of the study, said the findings were especially relevant, as the use of atypical antipsychotics, such as quetiapine, olanzapine, and risperidone, has increased while use of haloperidol has fallen.

A separate but related study led by Dr. Kim, which was recently published in the Journal of the American Geriatrics Society, showed that between 2008 and 2018, use of haloperidol and benzodiazepines in community hospitals and academic medical centers decreased while use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine rose (P < .01).

“Clinicians should not think atypical antipsychotics are the safer option to haloperidol,” Dr. Kim said. “We should focus on reducing prescriptions.”
 

Postoperative delirium

Postoperative delirium is the among the most common complications of surgery in older adults, affecting between 15% and 50% of those patients who undergo major operations. Postoperative delirium is associated with longer hospital stays, poor functional recovery, institutionalization, dementia, and death.

According to research from Harvard Medical School, postoperative delirium is linked to a 40% faster rate of cognitive decline among patients who develop the condition, compared with those who do not experience the complication.

While older patients often feel tired or a bit off after surgery, marked changes in mental function, such as confusion, disorientation, agitation, aggression, hallucinations, or persistent sleepiness, could indicate postoperative delirium.

“Antipsychotic medications are most commonly used off label for managing those symptoms of delirium,” Dr. Kim said. “What we’ve done is look at the comparative safety of two other drugs.”
 

Results

In the retrospective cohort study, researchers analyzed data from 17,115 patients aged 65 years and older who were without psychiatric disorders and who received oral antipsychotics after major surgery requiring general anesthesia.

“These results don’t apply to people in emergent situations where there is severe behavior that threatens their safety and others,” Dr. Kim noted.

There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%), olanzapine (2.8%; relative risk, 0.74; 95% confidence interval, 0.42-1.27), quetiapine (2.6%; RR, 0.70; 95% CI, 0.47-1.04), or risperidone (3.3%; RR, 0.90; CI, 0.53-1.41).

The study also found statistically insignificant differences in the risk for nonfatal clinical events. Those risks ranged from 2% to 2.6% for a cardiac arrhythmia, from 4.2% to 4.6% for pneumonia, and from 0.6% to 1.2% for strokes or transient ischemic attacks.

Esther Oh, MD, PhD, an associate professor at Johns Hopkins University, Baltimore, said that caring for patients who experience acute changes in mental status or behaviors during hospitalization can be difficult.

“Although there is a lot of evidence in the literature that nonpharmacological methods to address these problems are effective, staff shortages of recent years have made it even more difficult for the care team to institute these methods,” Dr. Oh said in an interview.
 

Prevention

Dr. Oh and Dr. Kim agreed that nonpharmacologic strategies, such as ensuring good nutrition and hydration, daily walking, cognitive-stimulating activities, and good sleep hygiene, are effective and safe in preventing postoperative delirium.

“These are common sense interventions, but they require a lot of staffing and training,” Dr. Kim said. “It’s a resource-intensive intervention that requires really changing the way hospital staff interacts with older patients in the hospital.”

Second-generation antipsychotic medications often are thought to be safer than haloperidol in terms of side effects, Dr. Oh said, but the new findings challenge that assumption.

“Based on the findings from this study and on prior studies of antipsychotic use for older adults, use of all antipsychotics, both first and second generation, should be reviewed carefully to ensure they are being administered at the lowest effective dose for the shortest duration possible,” she said.

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Kim and Dr. Oh disclosed no relevant financial relationships.

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

A new study published in Annals of Internal Medicine found atypical antipsychotics were not safer than haloperidol when it comes to treating postoperative delirium in older patients.

Dae Hyun Kim, MD, ScD, associate professor of medicine at Harvard Medical School, in Boston, who is the lead author of the study, said the findings were especially relevant, as the use of atypical antipsychotics, such as quetiapine, olanzapine, and risperidone, has increased while use of haloperidol has fallen.

A separate but related study led by Dr. Kim, which was recently published in the Journal of the American Geriatrics Society, showed that between 2008 and 2018, use of haloperidol and benzodiazepines in community hospitals and academic medical centers decreased while use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine rose (P < .01).

“Clinicians should not think atypical antipsychotics are the safer option to haloperidol,” Dr. Kim said. “We should focus on reducing prescriptions.”
 

Postoperative delirium

Postoperative delirium is the among the most common complications of surgery in older adults, affecting between 15% and 50% of those patients who undergo major operations. Postoperative delirium is associated with longer hospital stays, poor functional recovery, institutionalization, dementia, and death.

According to research from Harvard Medical School, postoperative delirium is linked to a 40% faster rate of cognitive decline among patients who develop the condition, compared with those who do not experience the complication.

While older patients often feel tired or a bit off after surgery, marked changes in mental function, such as confusion, disorientation, agitation, aggression, hallucinations, or persistent sleepiness, could indicate postoperative delirium.

“Antipsychotic medications are most commonly used off label for managing those symptoms of delirium,” Dr. Kim said. “What we’ve done is look at the comparative safety of two other drugs.”
 

Results

In the retrospective cohort study, researchers analyzed data from 17,115 patients aged 65 years and older who were without psychiatric disorders and who received oral antipsychotics after major surgery requiring general anesthesia.

“These results don’t apply to people in emergent situations where there is severe behavior that threatens their safety and others,” Dr. Kim noted.

There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%), olanzapine (2.8%; relative risk, 0.74; 95% confidence interval, 0.42-1.27), quetiapine (2.6%; RR, 0.70; 95% CI, 0.47-1.04), or risperidone (3.3%; RR, 0.90; CI, 0.53-1.41).

The study also found statistically insignificant differences in the risk for nonfatal clinical events. Those risks ranged from 2% to 2.6% for a cardiac arrhythmia, from 4.2% to 4.6% for pneumonia, and from 0.6% to 1.2% for strokes or transient ischemic attacks.

Esther Oh, MD, PhD, an associate professor at Johns Hopkins University, Baltimore, said that caring for patients who experience acute changes in mental status or behaviors during hospitalization can be difficult.

“Although there is a lot of evidence in the literature that nonpharmacological methods to address these problems are effective, staff shortages of recent years have made it even more difficult for the care team to institute these methods,” Dr. Oh said in an interview.
 

Prevention

Dr. Oh and Dr. Kim agreed that nonpharmacologic strategies, such as ensuring good nutrition and hydration, daily walking, cognitive-stimulating activities, and good sleep hygiene, are effective and safe in preventing postoperative delirium.

“These are common sense interventions, but they require a lot of staffing and training,” Dr. Kim said. “It’s a resource-intensive intervention that requires really changing the way hospital staff interacts with older patients in the hospital.”

Second-generation antipsychotic medications often are thought to be safer than haloperidol in terms of side effects, Dr. Oh said, but the new findings challenge that assumption.

“Based on the findings from this study and on prior studies of antipsychotic use for older adults, use of all antipsychotics, both first and second generation, should be reviewed carefully to ensure they are being administered at the lowest effective dose for the shortest duration possible,” she said.

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Kim and Dr. Oh disclosed no relevant financial relationships.

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

A new study published in Annals of Internal Medicine found atypical antipsychotics were not safer than haloperidol when it comes to treating postoperative delirium in older patients.

Dae Hyun Kim, MD, ScD, associate professor of medicine at Harvard Medical School, in Boston, who is the lead author of the study, said the findings were especially relevant, as the use of atypical antipsychotics, such as quetiapine, olanzapine, and risperidone, has increased while use of haloperidol has fallen.

A separate but related study led by Dr. Kim, which was recently published in the Journal of the American Geriatrics Society, showed that between 2008 and 2018, use of haloperidol and benzodiazepines in community hospitals and academic medical centers decreased while use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine rose (P < .01).

“Clinicians should not think atypical antipsychotics are the safer option to haloperidol,” Dr. Kim said. “We should focus on reducing prescriptions.”
 

Postoperative delirium

Postoperative delirium is the among the most common complications of surgery in older adults, affecting between 15% and 50% of those patients who undergo major operations. Postoperative delirium is associated with longer hospital stays, poor functional recovery, institutionalization, dementia, and death.

According to research from Harvard Medical School, postoperative delirium is linked to a 40% faster rate of cognitive decline among patients who develop the condition, compared with those who do not experience the complication.

While older patients often feel tired or a bit off after surgery, marked changes in mental function, such as confusion, disorientation, agitation, aggression, hallucinations, or persistent sleepiness, could indicate postoperative delirium.

“Antipsychotic medications are most commonly used off label for managing those symptoms of delirium,” Dr. Kim said. “What we’ve done is look at the comparative safety of two other drugs.”
 

Results

In the retrospective cohort study, researchers analyzed data from 17,115 patients aged 65 years and older who were without psychiatric disorders and who received oral antipsychotics after major surgery requiring general anesthesia.

“These results don’t apply to people in emergent situations where there is severe behavior that threatens their safety and others,” Dr. Kim noted.

There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%), olanzapine (2.8%; relative risk, 0.74; 95% confidence interval, 0.42-1.27), quetiapine (2.6%; RR, 0.70; 95% CI, 0.47-1.04), or risperidone (3.3%; RR, 0.90; CI, 0.53-1.41).

The study also found statistically insignificant differences in the risk for nonfatal clinical events. Those risks ranged from 2% to 2.6% for a cardiac arrhythmia, from 4.2% to 4.6% for pneumonia, and from 0.6% to 1.2% for strokes or transient ischemic attacks.

Esther Oh, MD, PhD, an associate professor at Johns Hopkins University, Baltimore, said that caring for patients who experience acute changes in mental status or behaviors during hospitalization can be difficult.

“Although there is a lot of evidence in the literature that nonpharmacological methods to address these problems are effective, staff shortages of recent years have made it even more difficult for the care team to institute these methods,” Dr. Oh said in an interview.
 

Prevention

Dr. Oh and Dr. Kim agreed that nonpharmacologic strategies, such as ensuring good nutrition and hydration, daily walking, cognitive-stimulating activities, and good sleep hygiene, are effective and safe in preventing postoperative delirium.

“These are common sense interventions, but they require a lot of staffing and training,” Dr. Kim said. “It’s a resource-intensive intervention that requires really changing the way hospital staff interacts with older patients in the hospital.”

Second-generation antipsychotic medications often are thought to be safer than haloperidol in terms of side effects, Dr. Oh said, but the new findings challenge that assumption.

“Based on the findings from this study and on prior studies of antipsychotic use for older adults, use of all antipsychotics, both first and second generation, should be reviewed carefully to ensure they are being administered at the lowest effective dose for the shortest duration possible,” she said.

The study was supported by the National Institute on Aging of the National Institutes of Health. Dr. Kim and Dr. Oh disclosed no relevant financial relationships.

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