Journal of Clinical Outcomes Management

Practicing yoga was associated with improvements in several frailty markers in previously inactive older adults, a multistudy review finds.

“Up to 50% of adults aged 80 years or older are estimated to be frail, and the global prevalence is expected to rise given the aging of our population,” therefore more interventions are needed to help with frailty, corresponding author Julia Loewenthal, MD, said in an interview.

Yoga integrates across multiple body systems including the musculoskeletal system, nervous system, and others, said Dr. Loewenthal of Brigham and Women’s Hospital, Boston. Previous research has shown that yoga has a positive effect on cardiovascular risk factors, mood, and quality of life, but the effects of yoga on frailty have not been well studied.

“We wanted to evaluate whether [yoga] might help with frailty, since it touches on so many systems, as frailty does,” she noted.

In a systematic review published in Annals of Internal Medicine, the researchers identified 33 randomized, controlled trials of yoga-based interventions including 2,384 adults aged 65 years and older. The studies mainly involved Iyengar or chair-based yoga methods. The study population included community-dwelling seniors, nursing home residents, and individuals with chronic diseases.

The studies assessed the effect of a range of yoga practices on frailty markers including gait speed, handgrip strength, balance, lower extremity strength and endurance, and multicomponent measures of physical performance.

Overall, individuals who were randomized to engage in a yoga practice showed improved gait speed and lower extremity strength, compared with controls who were inactive or received an education intervention, with moderate-certainty evidence. The researchers also found low-certainty evidence in favor of yoga for improved balance and for a composite measure of physical function, and low-certainty evidence in favor of yoga for improved handgrip strength.

The findings were limited by several factors, mainly the heterogenous study designs, populations, and yoga styles, the researchers noted. Other limitations included the small sample sizes, variation in descriptions of the studies’ randomizations, and a lack of data on race and ethnicity of the participants.
 

Yoga’s role in healthy aging

“Overall, we were not surprised by the results since we have seen similar findings from other mind-body practices such as tai chi,” Dr. Loewenthal said in an interview. “We were surprised by the degree of improvement many of the participants had with gait speed.

“Yoga practices usually include a mix of poses in the standing, seated, and lying-down positions,” Dr. Loewenthal said. Some of the studies in the review also involved chair-based methods with few standing poses, and some involved gentle or slow-paced practices. “We know that many of the practices helped with leg strength, and perhaps they are also helping with coordination between the brain and body for walking.”

The findings suggest that clinicians can view yoga practice in general as part of a strategy to support healthy aging, Dr. Loewenthal said. “While our work looked at frailty markers and not overall frailty, I think it would be reasonable to offer yoga as a strategy along with already-established interventions such as resistance training and the Mediterranean diet, and if older adults are already practicing yoga, this could help them understand how the practice is impacting the aging process.”

There are many styles of yoga that overlap and are related to one another, so it is hard to make recommendations about a single type, said Dr. Loewenthal. Many of the studies in the review involved Iyengar yoga, named for yoga master B.K.S. Iyengar, which focuses on precise alignment and breath and seems to be conducive for older populations. Iyengar yoga also involves use of props such as blocks, bolsters, straps, and chairs, which makes it well suited for older individuals who may have a chronic condition or other limitations.

“Some styles of yoga are very physical and may reach energy expenditure and cardiovascular effects similar to aerobic exercise, but this is generally not the case for most styles of yoga,” she added.

As for additional research, “I think it is important that trials use a validated definition of frailty as an outcome; all of the trials in our study used markers of frailty but did not look at overall frailty,” said Dr. Loewenthal. In addition, it is important to understand how yoga affects people who have different levels of frailty, since previous research shows that those who are the most frail benefit most from physical activity interventions.
 

Yoga as an entry point for physical activity

With the increasing population of older adults in the United States and around the world, frailty is a major health concern because its association with significant declines in health and potential loss of independence, Amanda Paluch, PhD, said in an interview.

“Therefore, it is important to identify programs that can prevent frailty to support longevity and living independently for older adults. Yoga can be a feasible solution to promote movement and prevent frailty,” said Dr. Paluch, of the University of Massachusetts, Amherst, an assistant professor in the department of kinesiology and Institute for Applied Life Sciences.

“Other studies have demonstrated that light-intensity movement, as in yoga, may be particularly beneficial for older adults,” Dr. Paluch said. “Additionally, research has demonstrated that balance training activities are important to maintain physical function, prevent falls, and maintain their independence for older adults, so it makes sense that yoga was associated with lower likelihood of frailty.”

Although there may be additional benefits with higher intensity activity, “yoga could be a great place to start for older adults who are starting at low activity levels,” she said.

The takeaway for clinicians is to consider encouraging more physical activity for their patients to support healthy aging, including reducing the risk factors for frailty, said Dr. Paluch. “Particularly for older adults, physical activity may not need to be of high intensity for benefits. Activities such as yoga that focus on flexibility, balance, and movement at lower intensities can support healthy aging, and yoga may be a particularly good option for older adults who are least active.”

The study received no outside funding. The researchers and Dr. Paluch had no financial conflicts to disclose.

Practicing yoga was associated with improvements in several frailty markers in previously inactive older adults, a multistudy review finds.

“Up to 50% of adults aged 80 years or older are estimated to be frail, and the global prevalence is expected to rise given the aging of our population,” therefore more interventions are needed to help with frailty, corresponding author Julia Loewenthal, MD, said in an interview.

Yoga integrates across multiple body systems including the musculoskeletal system, nervous system, and others, said Dr. Loewenthal of Brigham and Women’s Hospital, Boston. Previous research has shown that yoga has a positive effect on cardiovascular risk factors, mood, and quality of life, but the effects of yoga on frailty have not been well studied.

“We wanted to evaluate whether [yoga] might help with frailty, since it touches on so many systems, as frailty does,” she noted.

In a systematic review published in Annals of Internal Medicine, the researchers identified 33 randomized, controlled trials of yoga-based interventions including 2,384 adults aged 65 years and older. The studies mainly involved Iyengar or chair-based yoga methods. The study population included community-dwelling seniors, nursing home residents, and individuals with chronic diseases.

The studies assessed the effect of a range of yoga practices on frailty markers including gait speed, handgrip strength, balance, lower extremity strength and endurance, and multicomponent measures of physical performance.

Overall, individuals who were randomized to engage in a yoga practice showed improved gait speed and lower extremity strength, compared with controls who were inactive or received an education intervention, with moderate-certainty evidence. The researchers also found low-certainty evidence in favor of yoga for improved balance and for a composite measure of physical function, and low-certainty evidence in favor of yoga for improved handgrip strength.

The findings were limited by several factors, mainly the heterogenous study designs, populations, and yoga styles, the researchers noted. Other limitations included the small sample sizes, variation in descriptions of the studies’ randomizations, and a lack of data on race and ethnicity of the participants.
 

Yoga’s role in healthy aging

“Overall, we were not surprised by the results since we have seen similar findings from other mind-body practices such as tai chi,” Dr. Loewenthal said in an interview. “We were surprised by the degree of improvement many of the participants had with gait speed.

“Yoga practices usually include a mix of poses in the standing, seated, and lying-down positions,” Dr. Loewenthal said. Some of the studies in the review also involved chair-based methods with few standing poses, and some involved gentle or slow-paced practices. “We know that many of the practices helped with leg strength, and perhaps they are also helping with coordination between the brain and body for walking.”

The findings suggest that clinicians can view yoga practice in general as part of a strategy to support healthy aging, Dr. Loewenthal said. “While our work looked at frailty markers and not overall frailty, I think it would be reasonable to offer yoga as a strategy along with already-established interventions such as resistance training and the Mediterranean diet, and if older adults are already practicing yoga, this could help them understand how the practice is impacting the aging process.”

There are many styles of yoga that overlap and are related to one another, so it is hard to make recommendations about a single type, said Dr. Loewenthal. Many of the studies in the review involved Iyengar yoga, named for yoga master B.K.S. Iyengar, which focuses on precise alignment and breath and seems to be conducive for older populations. Iyengar yoga also involves use of props such as blocks, bolsters, straps, and chairs, which makes it well suited for older individuals who may have a chronic condition or other limitations.

“Some styles of yoga are very physical and may reach energy expenditure and cardiovascular effects similar to aerobic exercise, but this is generally not the case for most styles of yoga,” she added.

As for additional research, “I think it is important that trials use a validated definition of frailty as an outcome; all of the trials in our study used markers of frailty but did not look at overall frailty,” said Dr. Loewenthal. In addition, it is important to understand how yoga affects people who have different levels of frailty, since previous research shows that those who are the most frail benefit most from physical activity interventions.
 

Yoga as an entry point for physical activity

With the increasing population of older adults in the United States and around the world, frailty is a major health concern because its association with significant declines in health and potential loss of independence, Amanda Paluch, PhD, said in an interview.

“Therefore, it is important to identify programs that can prevent frailty to support longevity and living independently for older adults. Yoga can be a feasible solution to promote movement and prevent frailty,” said Dr. Paluch, of the University of Massachusetts, Amherst, an assistant professor in the department of kinesiology and Institute for Applied Life Sciences.

“Other studies have demonstrated that light-intensity movement, as in yoga, may be particularly beneficial for older adults,” Dr. Paluch said. “Additionally, research has demonstrated that balance training activities are important to maintain physical function, prevent falls, and maintain their independence for older adults, so it makes sense that yoga was associated with lower likelihood of frailty.”

Although there may be additional benefits with higher intensity activity, “yoga could be a great place to start for older adults who are starting at low activity levels,” she said.

The takeaway for clinicians is to consider encouraging more physical activity for their patients to support healthy aging, including reducing the risk factors for frailty, said Dr. Paluch. “Particularly for older adults, physical activity may not need to be of high intensity for benefits. Activities such as yoga that focus on flexibility, balance, and movement at lower intensities can support healthy aging, and yoga may be a particularly good option for older adults who are least active.”

The study received no outside funding. The researchers and Dr. Paluch had no financial conflicts to disclose.

Practicing yoga was associated with improvements in several frailty markers in previously inactive older adults, a multistudy review finds.

“Up to 50% of adults aged 80 years or older are estimated to be frail, and the global prevalence is expected to rise given the aging of our population,” therefore more interventions are needed to help with frailty, corresponding author Julia Loewenthal, MD, said in an interview.

Yoga integrates across multiple body systems including the musculoskeletal system, nervous system, and others, said Dr. Loewenthal of Brigham and Women’s Hospital, Boston. Previous research has shown that yoga has a positive effect on cardiovascular risk factors, mood, and quality of life, but the effects of yoga on frailty have not been well studied.

“We wanted to evaluate whether [yoga] might help with frailty, since it touches on so many systems, as frailty does,” she noted.

In a systematic review published in Annals of Internal Medicine, the researchers identified 33 randomized, controlled trials of yoga-based interventions including 2,384 adults aged 65 years and older. The studies mainly involved Iyengar or chair-based yoga methods. The study population included community-dwelling seniors, nursing home residents, and individuals with chronic diseases.

The studies assessed the effect of a range of yoga practices on frailty markers including gait speed, handgrip strength, balance, lower extremity strength and endurance, and multicomponent measures of physical performance.

Overall, individuals who were randomized to engage in a yoga practice showed improved gait speed and lower extremity strength, compared with controls who were inactive or received an education intervention, with moderate-certainty evidence. The researchers also found low-certainty evidence in favor of yoga for improved balance and for a composite measure of physical function, and low-certainty evidence in favor of yoga for improved handgrip strength.

The findings were limited by several factors, mainly the heterogenous study designs, populations, and yoga styles, the researchers noted. Other limitations included the small sample sizes, variation in descriptions of the studies’ randomizations, and a lack of data on race and ethnicity of the participants.
 

Yoga’s role in healthy aging

“Overall, we were not surprised by the results since we have seen similar findings from other mind-body practices such as tai chi,” Dr. Loewenthal said in an interview. “We were surprised by the degree of improvement many of the participants had with gait speed.

“Yoga practices usually include a mix of poses in the standing, seated, and lying-down positions,” Dr. Loewenthal said. Some of the studies in the review also involved chair-based methods with few standing poses, and some involved gentle or slow-paced practices. “We know that many of the practices helped with leg strength, and perhaps they are also helping with coordination between the brain and body for walking.”

The findings suggest that clinicians can view yoga practice in general as part of a strategy to support healthy aging, Dr. Loewenthal said. “While our work looked at frailty markers and not overall frailty, I think it would be reasonable to offer yoga as a strategy along with already-established interventions such as resistance training and the Mediterranean diet, and if older adults are already practicing yoga, this could help them understand how the practice is impacting the aging process.”

There are many styles of yoga that overlap and are related to one another, so it is hard to make recommendations about a single type, said Dr. Loewenthal. Many of the studies in the review involved Iyengar yoga, named for yoga master B.K.S. Iyengar, which focuses on precise alignment and breath and seems to be conducive for older populations. Iyengar yoga also involves use of props such as blocks, bolsters, straps, and chairs, which makes it well suited for older individuals who may have a chronic condition or other limitations.

“Some styles of yoga are very physical and may reach energy expenditure and cardiovascular effects similar to aerobic exercise, but this is generally not the case for most styles of yoga,” she added.

As for additional research, “I think it is important that trials use a validated definition of frailty as an outcome; all of the trials in our study used markers of frailty but did not look at overall frailty,” said Dr. Loewenthal. In addition, it is important to understand how yoga affects people who have different levels of frailty, since previous research shows that those who are the most frail benefit most from physical activity interventions.
 

Yoga as an entry point for physical activity

With the increasing population of older adults in the United States and around the world, frailty is a major health concern because its association with significant declines in health and potential loss of independence, Amanda Paluch, PhD, said in an interview.

“Therefore, it is important to identify programs that can prevent frailty to support longevity and living independently for older adults. Yoga can be a feasible solution to promote movement and prevent frailty,” said Dr. Paluch, of the University of Massachusetts, Amherst, an assistant professor in the department of kinesiology and Institute for Applied Life Sciences.

“Other studies have demonstrated that light-intensity movement, as in yoga, may be particularly beneficial for older adults,” Dr. Paluch said. “Additionally, research has demonstrated that balance training activities are important to maintain physical function, prevent falls, and maintain their independence for older adults, so it makes sense that yoga was associated with lower likelihood of frailty.”

Although there may be additional benefits with higher intensity activity, “yoga could be a great place to start for older adults who are starting at low activity levels,” she said.

The takeaway for clinicians is to consider encouraging more physical activity for their patients to support healthy aging, including reducing the risk factors for frailty, said Dr. Paluch. “Particularly for older adults, physical activity may not need to be of high intensity for benefits. Activities such as yoga that focus on flexibility, balance, and movement at lower intensities can support healthy aging, and yoga may be a particularly good option for older adults who are least active.”

The study received no outside funding. The researchers and Dr. Paluch had no financial conflicts to disclose.

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

Josh struggled for more than a decade with what his doctors had told him was irritable bowel syndrome (IBS). But curiously, the 39-year-old’s flare-ups were caused by some foods that aren’t typical IBS triggers. Peanuts and shellfish caused “stabbing” abdominal pains, and he would feel lightheaded after simply inhaling the scent of them. He also had severe constipation that lasted up to a week and rectal mucous discharges.

So, Josh (not his real name) sought the care of New York gastroenterologist Yevgenia Pashinsky, MD. She conducted a comprehensive nutritional assessment and sent him for allergy testing. The results: Josh had a little-known condition called systemic nickel allergy syndrome (SNAS), which can mimic some of the symptoms of IBS.

Dr. Pashinsky, of the department of medicine at Icahn School of Medicine at Mount Sinai, New York, and a partner with New York Gastroenterology Associates, presented Josh’s case as part of a seminar on SNAS and IBS “mimickers” at the Food and Nutrition Conference and Expo in Orlando last October, sponsored by the Academy of Nutrition and Dietetics.

She and two registered dietitians in her practice, Suzie Finkel, MS, RD, CDN, and Tamara Duker Freuman, MS, RD, CDN, told seminar attendees that SNAS is rarely diagnosed and can be mistaken for IBS. They noted that it probably strikes more people than doctors suspect.

“Systemic nickel allergy is present in at least 10% of the U.S. population (and much higher in some subgroups),” Dr. Pashinsky told this news organization. “But its connection to GI symptoms and functional GI disorders is still being learned about.

“I think of nickel allergy and other allergic disorders when, in addition to GI symptoms, the patient reports skin and mucous membrane involvement along with their abdominal reactions,” she said.

For patients like Josh with SNAS, the diagnosis and treatment of this condition are surprisingly simple and effective.

“Josh had these really [unusual] symptoms and nontraditional IBS food triggers,” Ms. Finkel said in an interview. “So, that’s a situation where, as dietitians we say, ‘Hmm, that’s weird; if you have IBS, then peanuts and shrimp shouldn’t really cause an issue here.’ But this might be something physicians might not be attuned to because it’s not part of their training.”

Ms. Finkel said that Josh was referred to an allergist. Josh tested positive for skin sensitization to nickel, and he was started on a low-nickel diet, which improved his symptoms.

“So, that was this happy ending,” she added.

The upshot?

“Doctors who treat IBS patients [who are not responding to treatment] need to consider the possibility that they have SNAS and send them for allergy testing,” Ms. Finkel said. “If they come back positive, simple dietary changes can address it.”
 

An underrecognized condition

There has been very little research regarding SNAS in patients with IBS, and there are no standard guidelines for diagnosing and treating it.

What’s more, many gastroenterologists aren’t familiar with it. More than a dozen gastroenterologists who were contacted for comment declined to be interviewed because they didn’t know about SNAS – or enough about it to provide useful information for the story.

Ms. Finkel said she’s not surprised that many gastroenterologists don’t know much about how SNAS can mimic IBS, which is why she and her colleagues presented the seminar last October in Orlando. “It’s really an allergy and not a GI disease. It manifests with GI symptoms, but the root is not in the digestive tract; the root is in a true allergy – a clinical allergy – to nickel.”

Complicating the issue is that people who have IBS and those with SNAS typically share some common symptoms.

Like IBS, SNAS can cause GI symptoms – such as cramping, abdominal pain, heartburn, constipation, gaseous distension, and mucus in the stool. It can be triggered by certain fresh, cooked, and canned foods.

But the food triggers that cause SNAS are not usually those that cause IBS symptoms. Rather, SNAS flare-ups are nearly always triggered by foods with high levels of nickel. Examples include apricots, artichokes, asparagus, beans, cauliflower, chickpeas, cocoa/chocolate, figs, lentils, licorice, oats, onions, peas, peanuts, potatoes, spinach, tomatoes, and tea.

According to the American Academy of Allergy, Asthma & Immunology, a distinguishing feature of SNAS is that it can cause allergic contact dermatitis when a person touches something made with nickel. Coins, jewelry, eyeglasses, home fixtures, keys, zippers, dental devices, and even stainless-steel cookware can contain allergy-triggering nickel.

What Ms. Finkel sees the most are skin reactions from touching a surface containing nickel or from ingesting it, she said.

The other immediate symptom is abdominal pain or changes in bowel movements, such as diarrhea, she added.

Christopher Randolph, MD, an allergist based in Connecticut, told this news organization that it’s important for doctors to realize that patients who have a skin reaction to nickel may also have inflammatory GI symptoms.

“We definitely need more controlled studies,” said Dr. Randolph, of the department of allergy and immunology at Yale University, New Haven, Conn. “But the takeaway here is for patients and certainly providers to be mindful that you can have systemic reactions to nickel, even though you implicate only the contact dermatitis.”
 

Diagnosis and treatment recommendations

Skin patch allergy testing – in which a person’s skin is exposed to nickel – can quickly determine whether a patient with IBS is actually experiencing inflammatory reactions to dietary nickel and would benefit from a low-nickel or no-nickel diet, research shows.

For these patients, Dr. Pashinsky recommends the following:

• Avoiding high-nickel foods.
• Limiting canned foods.
• Using nonstainless cookware, especially for acidic foods.
• Boiling foods for potential nickel reduction, especially grains and vegetables.
• Running the tap before using water to drink or cook with first thing in the morning.

Dr. Pashisky and her team also recommend the following guidelines for doctors:

• Ask patients if symptoms occur immediately after eating certain high-nickel foods or worsen with a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet.
• Determine whether a patient is not responding to typical medical and dietary interventions used to treat IBS.
• Conduct a food/symptom history to identify potential nickel allergy triggers.
• Try a low-nickel dietary intervention to see whether a patient’s symptoms improve in a week or two.
• Refer the patient for additional diagnostic skin-patch testing or treatment.

A multidisciplinary approach

Ms. Finkel said it’s important for doctors, particularly gastroenterologists who treat patients for suspected GI disorders to consider nickel allergy as a cause.

“SNAS is this overlooked condition ... and the research is really in its nascency here,” Ms. Finkel said.

“I would say only give [a low- or no-nickel diet] consideration if the high-nickel foods are a possible trigger,” she said. “It is very specific, looking at their diet history, to have a clear hypothesis based on what their triggers are. It’s not something to try out lightly because it’s a very restrictive diet, so I would never put a patient on a diet that I didn’t think was necessary.”

Ms. Finkel added that treatment of SNAS requires a multidisciplinary approach with a gastroenterologist, an allergist, and a dietitian.

Doctors and dietitians have distinct roles in identifying and treating these patients, Ms. Finkel said.

“If there is a suspicion of IBS symptoms and the patient is not responding to first-line treatments, then it is worth having the input of a dietitian and an allergist,” she said.

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

Josh struggled for more than a decade with what his doctors had told him was irritable bowel syndrome (IBS). But curiously, the 39-year-old’s flare-ups were caused by some foods that aren’t typical IBS triggers. Peanuts and shellfish caused “stabbing” abdominal pains, and he would feel lightheaded after simply inhaling the scent of them. He also had severe constipation that lasted up to a week and rectal mucous discharges.

So, Josh (not his real name) sought the care of New York gastroenterologist Yevgenia Pashinsky, MD. She conducted a comprehensive nutritional assessment and sent him for allergy testing. The results: Josh had a little-known condition called systemic nickel allergy syndrome (SNAS), which can mimic some of the symptoms of IBS.

Dr. Pashinsky, of the department of medicine at Icahn School of Medicine at Mount Sinai, New York, and a partner with New York Gastroenterology Associates, presented Josh’s case as part of a seminar on SNAS and IBS “mimickers” at the Food and Nutrition Conference and Expo in Orlando last October, sponsored by the Academy of Nutrition and Dietetics.

She and two registered dietitians in her practice, Suzie Finkel, MS, RD, CDN, and Tamara Duker Freuman, MS, RD, CDN, told seminar attendees that SNAS is rarely diagnosed and can be mistaken for IBS. They noted that it probably strikes more people than doctors suspect.

“Systemic nickel allergy is present in at least 10% of the U.S. population (and much higher in some subgroups),” Dr. Pashinsky told this news organization. “But its connection to GI symptoms and functional GI disorders is still being learned about.

“I think of nickel allergy and other allergic disorders when, in addition to GI symptoms, the patient reports skin and mucous membrane involvement along with their abdominal reactions,” she said.

For patients like Josh with SNAS, the diagnosis and treatment of this condition are surprisingly simple and effective.

“Josh had these really [unusual] symptoms and nontraditional IBS food triggers,” Ms. Finkel said in an interview. “So, that’s a situation where, as dietitians we say, ‘Hmm, that’s weird; if you have IBS, then peanuts and shrimp shouldn’t really cause an issue here.’ But this might be something physicians might not be attuned to because it’s not part of their training.”

Ms. Finkel said that Josh was referred to an allergist. Josh tested positive for skin sensitization to nickel, and he was started on a low-nickel diet, which improved his symptoms.

“So, that was this happy ending,” she added.

The upshot?

“Doctors who treat IBS patients [who are not responding to treatment] need to consider the possibility that they have SNAS and send them for allergy testing,” Ms. Finkel said. “If they come back positive, simple dietary changes can address it.”
 

An underrecognized condition

There has been very little research regarding SNAS in patients with IBS, and there are no standard guidelines for diagnosing and treating it.

What’s more, many gastroenterologists aren’t familiar with it. More than a dozen gastroenterologists who were contacted for comment declined to be interviewed because they didn’t know about SNAS – or enough about it to provide useful information for the story.

Ms. Finkel said she’s not surprised that many gastroenterologists don’t know much about how SNAS can mimic IBS, which is why she and her colleagues presented the seminar last October in Orlando. “It’s really an allergy and not a GI disease. It manifests with GI symptoms, but the root is not in the digestive tract; the root is in a true allergy – a clinical allergy – to nickel.”

Complicating the issue is that people who have IBS and those with SNAS typically share some common symptoms.

Like IBS, SNAS can cause GI symptoms – such as cramping, abdominal pain, heartburn, constipation, gaseous distension, and mucus in the stool. It can be triggered by certain fresh, cooked, and canned foods.

But the food triggers that cause SNAS are not usually those that cause IBS symptoms. Rather, SNAS flare-ups are nearly always triggered by foods with high levels of nickel. Examples include apricots, artichokes, asparagus, beans, cauliflower, chickpeas, cocoa/chocolate, figs, lentils, licorice, oats, onions, peas, peanuts, potatoes, spinach, tomatoes, and tea.

According to the American Academy of Allergy, Asthma & Immunology, a distinguishing feature of SNAS is that it can cause allergic contact dermatitis when a person touches something made with nickel. Coins, jewelry, eyeglasses, home fixtures, keys, zippers, dental devices, and even stainless-steel cookware can contain allergy-triggering nickel.

What Ms. Finkel sees the most are skin reactions from touching a surface containing nickel or from ingesting it, she said.

The other immediate symptom is abdominal pain or changes in bowel movements, such as diarrhea, she added.

Christopher Randolph, MD, an allergist based in Connecticut, told this news organization that it’s important for doctors to realize that patients who have a skin reaction to nickel may also have inflammatory GI symptoms.

“We definitely need more controlled studies,” said Dr. Randolph, of the department of allergy and immunology at Yale University, New Haven, Conn. “But the takeaway here is for patients and certainly providers to be mindful that you can have systemic reactions to nickel, even though you implicate only the contact dermatitis.”
 

Diagnosis and treatment recommendations

Skin patch allergy testing – in which a person’s skin is exposed to nickel – can quickly determine whether a patient with IBS is actually experiencing inflammatory reactions to dietary nickel and would benefit from a low-nickel or no-nickel diet, research shows.

For these patients, Dr. Pashinsky recommends the following:

• Avoiding high-nickel foods.
• Limiting canned foods.
• Using nonstainless cookware, especially for acidic foods.
• Boiling foods for potential nickel reduction, especially grains and vegetables.
• Running the tap before using water to drink or cook with first thing in the morning.

Dr. Pashisky and her team also recommend the following guidelines for doctors:

• Ask patients if symptoms occur immediately after eating certain high-nickel foods or worsen with a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet.
• Determine whether a patient is not responding to typical medical and dietary interventions used to treat IBS.
• Conduct a food/symptom history to identify potential nickel allergy triggers.
• Try a low-nickel dietary intervention to see whether a patient’s symptoms improve in a week or two.
• Refer the patient for additional diagnostic skin-patch testing or treatment.

A multidisciplinary approach

Ms. Finkel said it’s important for doctors, particularly gastroenterologists who treat patients for suspected GI disorders to consider nickel allergy as a cause.

“SNAS is this overlooked condition ... and the research is really in its nascency here,” Ms. Finkel said.

“I would say only give [a low- or no-nickel diet] consideration if the high-nickel foods are a possible trigger,” she said. “It is very specific, looking at their diet history, to have a clear hypothesis based on what their triggers are. It’s not something to try out lightly because it’s a very restrictive diet, so I would never put a patient on a diet that I didn’t think was necessary.”

Ms. Finkel added that treatment of SNAS requires a multidisciplinary approach with a gastroenterologist, an allergist, and a dietitian.

Doctors and dietitians have distinct roles in identifying and treating these patients, Ms. Finkel said.

“If there is a suspicion of IBS symptoms and the patient is not responding to first-line treatments, then it is worth having the input of a dietitian and an allergist,” she said.

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

Josh struggled for more than a decade with what his doctors had told him was irritable bowel syndrome (IBS). But curiously, the 39-year-old’s flare-ups were caused by some foods that aren’t typical IBS triggers. Peanuts and shellfish caused “stabbing” abdominal pains, and he would feel lightheaded after simply inhaling the scent of them. He also had severe constipation that lasted up to a week and rectal mucous discharges.

So, Josh (not his real name) sought the care of New York gastroenterologist Yevgenia Pashinsky, MD. She conducted a comprehensive nutritional assessment and sent him for allergy testing. The results: Josh had a little-known condition called systemic nickel allergy syndrome (SNAS), which can mimic some of the symptoms of IBS.

Dr. Pashinsky, of the department of medicine at Icahn School of Medicine at Mount Sinai, New York, and a partner with New York Gastroenterology Associates, presented Josh’s case as part of a seminar on SNAS and IBS “mimickers” at the Food and Nutrition Conference and Expo in Orlando last October, sponsored by the Academy of Nutrition and Dietetics.

She and two registered dietitians in her practice, Suzie Finkel, MS, RD, CDN, and Tamara Duker Freuman, MS, RD, CDN, told seminar attendees that SNAS is rarely diagnosed and can be mistaken for IBS. They noted that it probably strikes more people than doctors suspect.

“Systemic nickel allergy is present in at least 10% of the U.S. population (and much higher in some subgroups),” Dr. Pashinsky told this news organization. “But its connection to GI symptoms and functional GI disorders is still being learned about.

“I think of nickel allergy and other allergic disorders when, in addition to GI symptoms, the patient reports skin and mucous membrane involvement along with their abdominal reactions,” she said.

For patients like Josh with SNAS, the diagnosis and treatment of this condition are surprisingly simple and effective.

“Josh had these really [unusual] symptoms and nontraditional IBS food triggers,” Ms. Finkel said in an interview. “So, that’s a situation where, as dietitians we say, ‘Hmm, that’s weird; if you have IBS, then peanuts and shrimp shouldn’t really cause an issue here.’ But this might be something physicians might not be attuned to because it’s not part of their training.”

Ms. Finkel said that Josh was referred to an allergist. Josh tested positive for skin sensitization to nickel, and he was started on a low-nickel diet, which improved his symptoms.

“So, that was this happy ending,” she added.

The upshot?

“Doctors who treat IBS patients [who are not responding to treatment] need to consider the possibility that they have SNAS and send them for allergy testing,” Ms. Finkel said. “If they come back positive, simple dietary changes can address it.”
 

An underrecognized condition

There has been very little research regarding SNAS in patients with IBS, and there are no standard guidelines for diagnosing and treating it.

What’s more, many gastroenterologists aren’t familiar with it. More than a dozen gastroenterologists who were contacted for comment declined to be interviewed because they didn’t know about SNAS – or enough about it to provide useful information for the story.

Ms. Finkel said she’s not surprised that many gastroenterologists don’t know much about how SNAS can mimic IBS, which is why she and her colleagues presented the seminar last October in Orlando. “It’s really an allergy and not a GI disease. It manifests with GI symptoms, but the root is not in the digestive tract; the root is in a true allergy – a clinical allergy – to nickel.”

Complicating the issue is that people who have IBS and those with SNAS typically share some common symptoms.

Like IBS, SNAS can cause GI symptoms – such as cramping, abdominal pain, heartburn, constipation, gaseous distension, and mucus in the stool. It can be triggered by certain fresh, cooked, and canned foods.

But the food triggers that cause SNAS are not usually those that cause IBS symptoms. Rather, SNAS flare-ups are nearly always triggered by foods with high levels of nickel. Examples include apricots, artichokes, asparagus, beans, cauliflower, chickpeas, cocoa/chocolate, figs, lentils, licorice, oats, onions, peas, peanuts, potatoes, spinach, tomatoes, and tea.

According to the American Academy of Allergy, Asthma & Immunology, a distinguishing feature of SNAS is that it can cause allergic contact dermatitis when a person touches something made with nickel. Coins, jewelry, eyeglasses, home fixtures, keys, zippers, dental devices, and even stainless-steel cookware can contain allergy-triggering nickel.

What Ms. Finkel sees the most are skin reactions from touching a surface containing nickel or from ingesting it, she said.

The other immediate symptom is abdominal pain or changes in bowel movements, such as diarrhea, she added.

Christopher Randolph, MD, an allergist based in Connecticut, told this news organization that it’s important for doctors to realize that patients who have a skin reaction to nickel may also have inflammatory GI symptoms.

“We definitely need more controlled studies,” said Dr. Randolph, of the department of allergy and immunology at Yale University, New Haven, Conn. “But the takeaway here is for patients and certainly providers to be mindful that you can have systemic reactions to nickel, even though you implicate only the contact dermatitis.”
 

Diagnosis and treatment recommendations

Skin patch allergy testing – in which a person’s skin is exposed to nickel – can quickly determine whether a patient with IBS is actually experiencing inflammatory reactions to dietary nickel and would benefit from a low-nickel or no-nickel diet, research shows.

For these patients, Dr. Pashinsky recommends the following:

• Avoiding high-nickel foods.
• Limiting canned foods.
• Using nonstainless cookware, especially for acidic foods.
• Boiling foods for potential nickel reduction, especially grains and vegetables.
• Running the tap before using water to drink or cook with first thing in the morning.

Dr. Pashisky and her team also recommend the following guidelines for doctors:

• Ask patients if symptoms occur immediately after eating certain high-nickel foods or worsen with a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet.
• Determine whether a patient is not responding to typical medical and dietary interventions used to treat IBS.
• Conduct a food/symptom history to identify potential nickel allergy triggers.
• Try a low-nickel dietary intervention to see whether a patient’s symptoms improve in a week or two.
• Refer the patient for additional diagnostic skin-patch testing or treatment.

A multidisciplinary approach

Ms. Finkel said it’s important for doctors, particularly gastroenterologists who treat patients for suspected GI disorders to consider nickel allergy as a cause.

“SNAS is this overlooked condition ... and the research is really in its nascency here,” Ms. Finkel said.

“I would say only give [a low- or no-nickel diet] consideration if the high-nickel foods are a possible trigger,” she said. “It is very specific, looking at their diet history, to have a clear hypothesis based on what their triggers are. It’s not something to try out lightly because it’s a very restrictive diet, so I would never put a patient on a diet that I didn’t think was necessary.”

Ms. Finkel added that treatment of SNAS requires a multidisciplinary approach with a gastroenterologist, an allergist, and a dietitian.

Doctors and dietitians have distinct roles in identifying and treating these patients, Ms. Finkel said.

“If there is a suspicion of IBS symptoms and the patient is not responding to first-line treatments, then it is worth having the input of a dietitian and an allergist,” she said.

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

Two U.S. Drug Enforcement Administration proposals on how telehealth can be used going forward to prescribe controlled substances are drawing criticism from mental health and addiction treatment specialists.

The proposed rules – one for Schedule III-V substances, and the other for buprenorphine – are due to go into effect on May 11, when the COVID-19 public health emergency (PHE), and temporary flexibilities, end.

Essentially, both proposals would allow providers to prescribe a 30-day supply of a controlled substance or buprenorphine, but then require a face-to-face meeting for patients to receive additional prescriptions.

The DEA says that the rules are aimed at preventing abuse and diversion of the substances, but clinicians claim they are creating unnecessary hurdles that will probably lead to some patients dropping out of treatment.

“We were happy to see that there is ongoing flexibility to be able to initiate buprenorphine through telehealth, but we were disappointed to see that the DEA set an arbitrary time frame, in this case, a 30-day time frame after which the patient would have to be seen in person before ongoing care with buprenorphine for opioid use disorder could be provided,” Brian Hurley, MD, MBA, the president-elect of the American Society of Addiction Medicine told this news organization.

Dr. Hurley agreed that it is best practice to see patients in person for ongoing care, but he noted they have many reasons why they might not be able to make it into an office every month.

“What this rule would do if instituted as written is prevent me from continuing care for patients unless I can get them in in person,” he said. “And while I’d make every effort as a clinician, it’s not always feasible to do so.”

The addiction specialist noted that only about 20% of Americans with opioid use disorder have access to medications for the disorder. “I would posit that untreated opioid use disorder is a bigger threat to public safety currently than the risk of diversion,” he said.

The DEA is also proposing to allow state laws to supersede its regulations, which concerns Dr. Hurley and other clinicians because some states are more restrictive. “Our position is that state laws that restrict access to medications for opioid use disorder through telehealth means are inconsistent with our policy recommendation. I certainly hope that the DEA hears our concerns and amends the proposal,” said Dr. Hurley.

A potential ‘telehealth cliff’

Shabana Khan, MD, chair of the American Psychiatric Association’s telepsychiatry committee, said that “because of potential overlap with state rules that may be more stringent than these new regulations, APA is concerned that the proposed rules will create a telehealth cliff for those in most need of critical psychiatric and opioid use disorder treatment, particularly in communities where this specialty care is limited or nonexistent.”

NYU Langone Health

Dr. Khan noted that “clarification is necessary on how patients who started treatment during the PHE can continue treatment with a prescribing provider, if at all, through an in-person evaluation with a DEA-registered provider referral.”

Telehealth companies were also disappointed in the DEA proposals.

“The continuity of care for countless Americans will be severed, potentially leaving these patients to fall through the cracks of our health care system without access to needed medications,” said Kyle Zebley, the American Telemedicine Association’s senior vice president of public policy, in a statement.

American Telemedicine Association

“Requiring every patient who has initiated treatment via telemedicine during the pandemic to now visit a provider in person clearly falls on the side of being overly restrictive,” Mr. Zebley added.

The DEA is proposing to allow patients who have been receiving telehealth over the past 3 years to continue to do so for 180 days after the PHE ends.

But the American Telemedicine Association and others said that they still want to see a change in the proposal as written. “Our hope is that the DEA works with us to avoid unnecessary and inappropriate restrictions on the prescription of essential medications for these vulnerable and underserved populations,” Mr. Zebley said in the statement.

DEA Administrator Anne Milgram said in a statement that the agency believes that “the telemedicine regulations would continue to expand access to buprenorphine for patients with opioid use disorder,” and that the DEA “is committed to the expansion of telemedicine with guardrails that prevent the online overprescribing of controlled medications that can cause harm.”

Rahul Gupta, MD, director of the White House Office of National Drug Control Policy, said in a statement that “This proposed rule builds on President Biden’s historic move to eliminate the X-waiver that prevented many prescribers from treating patients with buprenorphine.” He added, “Thanks to these changes, millions of Americans will be able to access the lifesaving care they need.”

The DEA estimated that there were 15.7 million prescriptions for buprenorphine in 2021 and that about 67,000 were for initial prescriptions.

Ketamine confusion

The rule on controlled substances has also caused some consternation, especially given that it does not differentiate between racemic ketamine and esketamine, said Lisa Marie Harding, MD, vice president of the board of the American Society of Ketamine Physicians, Psychotherapists & Practitioners.

Lisa Harding

Esketamine (Spravato) is approved by the Food and Drug Administration and, under a Risk Evaluation and Mitigation Strategy, can only be administered in FDA-monitored treatment facilities. Racemic ketamine is being prescribed – often for home use – with almost no regulatory oversight.

Dr. Harding, who is an approved Spravato provider and also administers intravenous ketamine in her practice, does not believe that ketamine should be used at home without supervision.

“I had a patient who had a very powerful dissociative experience in my office earlier this week,” Dr. Harding said in an interview. One of her staff asked what would happen if the patient had experienced that at home. “We don’t know. Nor do we want this to happen,” said Dr. Harding.

However, the DEA proposal would continue to allow for home use, at least initially. “If it’s open to interpretation, those people that prescribe ketamine for home use can use that leeway to then continue to do it,” she said. “That is not safe.”

Dr. Harding approves of the proposed DEA requirement for face-to-face visits. “It’s good patient care,” she said. But she wants the administration to adjust the rules to make it harder to offer home ketamine therapy.

“Lots of people are using racemic ketamine off-label for treating depression with success but doing it in treatment settings that are appropriate,” said Dr. Harding.

Dr. Hurley and Dr. Harding report no relevant financial relationships.

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

Two U.S. Drug Enforcement Administration proposals on how telehealth can be used going forward to prescribe controlled substances are drawing criticism from mental health and addiction treatment specialists.

The proposed rules – one for Schedule III-V substances, and the other for buprenorphine – are due to go into effect on May 11, when the COVID-19 public health emergency (PHE), and temporary flexibilities, end.

Essentially, both proposals would allow providers to prescribe a 30-day supply of a controlled substance or buprenorphine, but then require a face-to-face meeting for patients to receive additional prescriptions.

The DEA says that the rules are aimed at preventing abuse and diversion of the substances, but clinicians claim they are creating unnecessary hurdles that will probably lead to some patients dropping out of treatment.

“We were happy to see that there is ongoing flexibility to be able to initiate buprenorphine through telehealth, but we were disappointed to see that the DEA set an arbitrary time frame, in this case, a 30-day time frame after which the patient would have to be seen in person before ongoing care with buprenorphine for opioid use disorder could be provided,” Brian Hurley, MD, MBA, the president-elect of the American Society of Addiction Medicine told this news organization.

Dr. Hurley agreed that it is best practice to see patients in person for ongoing care, but he noted they have many reasons why they might not be able to make it into an office every month.

“What this rule would do if instituted as written is prevent me from continuing care for patients unless I can get them in in person,” he said. “And while I’d make every effort as a clinician, it’s not always feasible to do so.”

The addiction specialist noted that only about 20% of Americans with opioid use disorder have access to medications for the disorder. “I would posit that untreated opioid use disorder is a bigger threat to public safety currently than the risk of diversion,” he said.

The DEA is also proposing to allow state laws to supersede its regulations, which concerns Dr. Hurley and other clinicians because some states are more restrictive. “Our position is that state laws that restrict access to medications for opioid use disorder through telehealth means are inconsistent with our policy recommendation. I certainly hope that the DEA hears our concerns and amends the proposal,” said Dr. Hurley.

A potential ‘telehealth cliff’

Shabana Khan, MD, chair of the American Psychiatric Association’s telepsychiatry committee, said that “because of potential overlap with state rules that may be more stringent than these new regulations, APA is concerned that the proposed rules will create a telehealth cliff for those in most need of critical psychiatric and opioid use disorder treatment, particularly in communities where this specialty care is limited or nonexistent.”

NYU Langone Health

Dr. Khan noted that “clarification is necessary on how patients who started treatment during the PHE can continue treatment with a prescribing provider, if at all, through an in-person evaluation with a DEA-registered provider referral.”

Telehealth companies were also disappointed in the DEA proposals.

“The continuity of care for countless Americans will be severed, potentially leaving these patients to fall through the cracks of our health care system without access to needed medications,” said Kyle Zebley, the American Telemedicine Association’s senior vice president of public policy, in a statement.

American Telemedicine Association

“Requiring every patient who has initiated treatment via telemedicine during the pandemic to now visit a provider in person clearly falls on the side of being overly restrictive,” Mr. Zebley added.

The DEA is proposing to allow patients who have been receiving telehealth over the past 3 years to continue to do so for 180 days after the PHE ends.

But the American Telemedicine Association and others said that they still want to see a change in the proposal as written. “Our hope is that the DEA works with us to avoid unnecessary and inappropriate restrictions on the prescription of essential medications for these vulnerable and underserved populations,” Mr. Zebley said in the statement.

DEA Administrator Anne Milgram said in a statement that the agency believes that “the telemedicine regulations would continue to expand access to buprenorphine for patients with opioid use disorder,” and that the DEA “is committed to the expansion of telemedicine with guardrails that prevent the online overprescribing of controlled medications that can cause harm.”

Rahul Gupta, MD, director of the White House Office of National Drug Control Policy, said in a statement that “This proposed rule builds on President Biden’s historic move to eliminate the X-waiver that prevented many prescribers from treating patients with buprenorphine.” He added, “Thanks to these changes, millions of Americans will be able to access the lifesaving care they need.”

The DEA estimated that there were 15.7 million prescriptions for buprenorphine in 2021 and that about 67,000 were for initial prescriptions.

Ketamine confusion

The rule on controlled substances has also caused some consternation, especially given that it does not differentiate between racemic ketamine and esketamine, said Lisa Marie Harding, MD, vice president of the board of the American Society of Ketamine Physicians, Psychotherapists & Practitioners.

Lisa Harding

Esketamine (Spravato) is approved by the Food and Drug Administration and, under a Risk Evaluation and Mitigation Strategy, can only be administered in FDA-monitored treatment facilities. Racemic ketamine is being prescribed – often for home use – with almost no regulatory oversight.

Dr. Harding, who is an approved Spravato provider and also administers intravenous ketamine in her practice, does not believe that ketamine should be used at home without supervision.

“I had a patient who had a very powerful dissociative experience in my office earlier this week,” Dr. Harding said in an interview. One of her staff asked what would happen if the patient had experienced that at home. “We don’t know. Nor do we want this to happen,” said Dr. Harding.

However, the DEA proposal would continue to allow for home use, at least initially. “If it’s open to interpretation, those people that prescribe ketamine for home use can use that leeway to then continue to do it,” she said. “That is not safe.”

Dr. Harding approves of the proposed DEA requirement for face-to-face visits. “It’s good patient care,” she said. But she wants the administration to adjust the rules to make it harder to offer home ketamine therapy.

“Lots of people are using racemic ketamine off-label for treating depression with success but doing it in treatment settings that are appropriate,” said Dr. Harding.

Dr. Hurley and Dr. Harding report no relevant financial relationships.

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

Two U.S. Drug Enforcement Administration proposals on how telehealth can be used going forward to prescribe controlled substances are drawing criticism from mental health and addiction treatment specialists.

The proposed rules – one for Schedule III-V substances, and the other for buprenorphine – are due to go into effect on May 11, when the COVID-19 public health emergency (PHE), and temporary flexibilities, end.

Essentially, both proposals would allow providers to prescribe a 30-day supply of a controlled substance or buprenorphine, but then require a face-to-face meeting for patients to receive additional prescriptions.

The DEA says that the rules are aimed at preventing abuse and diversion of the substances, but clinicians claim they are creating unnecessary hurdles that will probably lead to some patients dropping out of treatment.

“We were happy to see that there is ongoing flexibility to be able to initiate buprenorphine through telehealth, but we were disappointed to see that the DEA set an arbitrary time frame, in this case, a 30-day time frame after which the patient would have to be seen in person before ongoing care with buprenorphine for opioid use disorder could be provided,” Brian Hurley, MD, MBA, the president-elect of the American Society of Addiction Medicine told this news organization.

Dr. Hurley agreed that it is best practice to see patients in person for ongoing care, but he noted they have many reasons why they might not be able to make it into an office every month.

“What this rule would do if instituted as written is prevent me from continuing care for patients unless I can get them in in person,” he said. “And while I’d make every effort as a clinician, it’s not always feasible to do so.”

The addiction specialist noted that only about 20% of Americans with opioid use disorder have access to medications for the disorder. “I would posit that untreated opioid use disorder is a bigger threat to public safety currently than the risk of diversion,” he said.

The DEA is also proposing to allow state laws to supersede its regulations, which concerns Dr. Hurley and other clinicians because some states are more restrictive. “Our position is that state laws that restrict access to medications for opioid use disorder through telehealth means are inconsistent with our policy recommendation. I certainly hope that the DEA hears our concerns and amends the proposal,” said Dr. Hurley.

A potential ‘telehealth cliff’

Shabana Khan, MD, chair of the American Psychiatric Association’s telepsychiatry committee, said that “because of potential overlap with state rules that may be more stringent than these new regulations, APA is concerned that the proposed rules will create a telehealth cliff for those in most need of critical psychiatric and opioid use disorder treatment, particularly in communities where this specialty care is limited or nonexistent.”

NYU Langone Health

Dr. Khan noted that “clarification is necessary on how patients who started treatment during the PHE can continue treatment with a prescribing provider, if at all, through an in-person evaluation with a DEA-registered provider referral.”

Telehealth companies were also disappointed in the DEA proposals.

“The continuity of care for countless Americans will be severed, potentially leaving these patients to fall through the cracks of our health care system without access to needed medications,” said Kyle Zebley, the American Telemedicine Association’s senior vice president of public policy, in a statement.

American Telemedicine Association

“Requiring every patient who has initiated treatment via telemedicine during the pandemic to now visit a provider in person clearly falls on the side of being overly restrictive,” Mr. Zebley added.

The DEA is proposing to allow patients who have been receiving telehealth over the past 3 years to continue to do so for 180 days after the PHE ends.

But the American Telemedicine Association and others said that they still want to see a change in the proposal as written. “Our hope is that the DEA works with us to avoid unnecessary and inappropriate restrictions on the prescription of essential medications for these vulnerable and underserved populations,” Mr. Zebley said in the statement.

DEA Administrator Anne Milgram said in a statement that the agency believes that “the telemedicine regulations would continue to expand access to buprenorphine for patients with opioid use disorder,” and that the DEA “is committed to the expansion of telemedicine with guardrails that prevent the online overprescribing of controlled medications that can cause harm.”

Rahul Gupta, MD, director of the White House Office of National Drug Control Policy, said in a statement that “This proposed rule builds on President Biden’s historic move to eliminate the X-waiver that prevented many prescribers from treating patients with buprenorphine.” He added, “Thanks to these changes, millions of Americans will be able to access the lifesaving care they need.”

The DEA estimated that there were 15.7 million prescriptions for buprenorphine in 2021 and that about 67,000 were for initial prescriptions.

Ketamine confusion

The rule on controlled substances has also caused some consternation, especially given that it does not differentiate between racemic ketamine and esketamine, said Lisa Marie Harding, MD, vice president of the board of the American Society of Ketamine Physicians, Psychotherapists & Practitioners.

Lisa Harding

Esketamine (Spravato) is approved by the Food and Drug Administration and, under a Risk Evaluation and Mitigation Strategy, can only be administered in FDA-monitored treatment facilities. Racemic ketamine is being prescribed – often for home use – with almost no regulatory oversight.

Dr. Harding, who is an approved Spravato provider and also administers intravenous ketamine in her practice, does not believe that ketamine should be used at home without supervision.

“I had a patient who had a very powerful dissociative experience in my office earlier this week,” Dr. Harding said in an interview. One of her staff asked what would happen if the patient had experienced that at home. “We don’t know. Nor do we want this to happen,” said Dr. Harding.

However, the DEA proposal would continue to allow for home use, at least initially. “If it’s open to interpretation, those people that prescribe ketamine for home use can use that leeway to then continue to do it,” she said. “That is not safe.”

Dr. Harding approves of the proposed DEA requirement for face-to-face visits. “It’s good patient care,” she said. But she wants the administration to adjust the rules to make it harder to offer home ketamine therapy.

“Lots of people are using racemic ketamine off-label for treating depression with success but doing it in treatment settings that are appropriate,” said Dr. Harding.

Dr. Hurley and Dr. Harding report no relevant financial relationships.

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

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS - The antipsychotic brexpiprazole effectively improves agitation associated with Alzheimer’s disease (AD) with favorable tolerability, results of a phase 3 study suggest.

“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.

Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.

Agitation common, distressing

With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.

Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.

The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.

Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.

Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).

The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).

Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).

Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).

Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).

“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.

Boxed warnings

Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.

Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.

One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.

This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.

Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.

“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.

In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.

In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.

“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.

Caution still warranted

Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”

He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.

Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”

Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”

“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said. 

The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.

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

This article was updated 3/14/23.

NEW ORLEANS - The antipsychotic brexpiprazole effectively improves agitation associated with Alzheimer’s disease (AD) with favorable tolerability, results of a phase 3 study suggest.

“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.

Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.

Agitation common, distressing

With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.

Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.

The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.

Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.

Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).

The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).

Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).

Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).

Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).

“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.

Boxed warnings

Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.

Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.

One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.

This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.

Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.

“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.

In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.

In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.

“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.

Caution still warranted

Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”

He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.

Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”

Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”

“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said. 

The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.

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

This article was updated 3/14/23.

NEW ORLEANS - The antipsychotic brexpiprazole effectively improves agitation associated with Alzheimer’s disease (AD) with favorable tolerability, results of a phase 3 study suggest.

“In this phase 3 trial of patients with agitation in Alzheimer’s dementia, treatment with brexpiprazole 2 or 3 mg/day resulted in statistically significantly greater improvements in agitation versus placebo on the primary and key secondary endpoints,” said study investigator George Grossberg, MD, professor and director of the division of geriatric psychiatry, department of psychiatry & behavioral neuroscience, Saint Louis University.

Dr. Grossberg presented the findings as part of the annual meeting of the American Association for Geriatric Psychiatry.

Agitation common, distressing

With two previous studies also showing efficacy of brexpiprazole in AD-related agitation, Dr. Grossberg speculated that brexpiprazole will become the first drug to be approved for agitation in AD.

Agitation is one of the most common AD symptoms and is arguably the most distressing for patients and caregivers alike, Dr. Grossberg noted.

The drug was approved by the Food and Drug Administration in 2015 as an adjunctive therapy to antidepressants for adults with major depressive disorder and for adults with schizophrenia.

To investigate the drug at effective doses for AD-related agitation, the researchers conducted a phase 3 multicenter trial that included 345 patients with AD who met criteria for agitation and aggression.

Study participants had a mean Mini-Mental State Examination (MMSE) score between 5 and 22 at screening and baseline and a mean Cohen-Mansfield Agitation Inventory (CMAI) total score of about 79. A score above 45 is considered clinically significant agitation. Use of AD medications were permitted.

Patients had a mean age of 74 years and were randomly assigned in a 2:1 ratio to receive treatment with brexpiprazole 2 mg (n = 75) or 3 mg (n = 153) per day, or placebo (n = 117).

The study’s primary endpoint was improvement as assessed by the CMAI. Over 12 weeks, participants in the brexpiprazole group experienced greater improvement in agitation, with a mean change of –22.6 with brexpiprazole vs. –17.3 with placebo (P = .0026).

Brexpiprazole was also associated with significantly greater improvement in the secondary outcome of change from baseline to week 12 in agitation severity, as assessed using the Clinical Global Impression-Severity of Illness (CGI-S) score (mean change, –1.20 with brexpiprazole vs. –0.93 with placebo; P = .0078).

Specifically, treatment with the drug resulted in improvements in three key subscales of agitation, including aggressive behavior, such as physically striking out (P < .01 vs. placebo); physically nonaggressive; and verbally agitated, such as screaming or cursing (both P < .05).

Treatment-emergent adverse events (TEAEs) associated with brexpiprazole vs. placebo included somnolence (3.5% vs. 0.9%), nasopharyngitis (3.1% vs. 1.7%), dizziness (2.7% vs. 1.7%), diarrhea (2.2% vs. 0.9%), urinary tract infection (2.2% vs. 0.9%), and asthenia (2.2% vs. 0.0%).

“Aside from headache, no other TEAEs had an incidence of more than 5% in the brexpiprazole (2 or 3 mg) group, or in either dose group,” Dr. Grossberg said. “Cognition also remained stable,” he added.

Boxed warnings

Adverse events commonly associated with brexpiprazole include weight change, extrapyramidal events, falls, cardiovascular events, and sedation. In the study, all occurred at an incidence of less than 2% in both study groups, he noted.

Compared with the antipsychotic aripiprazole, brexpiprazole is associated with lower weight gain and akathisia, or motor restlessness.

One death occurred in the brexpiprazole 3 mg group in a patient who had heart failure, pneumonia, and cachexia. At autopsy, it was found the patient had cerebral and coronary atherosclerosis. The death was considered to be unrelated to brexpiprazole, said Dr. Grossberg.

This finding is notable because a caveat is that brexpiprazole, like aripiprazole and other typical and atypical antipsychotics, carries an FDA boxed warning related to an increased risk for death in older patients when used for dementia-related psychosis.

Noting that a black box warning about mortality risk is not a minor issue, Dr. Grossberg added that the risks are relatively low, whereas the risks associated with agitation in dementia can be high.

“If it’s an emergency situation, you have to treat the patient because otherwise they may harm someone else, or harm the staff, or harm their loved ones or themselves, and in those cases, we want to treat the patient first, get them under control, and then we worry about the black box,” he said.

In addition, “the No. 1 reason for getting kicked out of a nursing home is agitation or severe behaviors in the context of a dementia or a major neurocognitive disorder that the facility cannot control,” Dr. Grossberg added.

In such cases, patients may wind up in an emergency department and may not be welcome back at the nursing home.

“There’s always a risk/benefit ratio, and I have that discussion with patients and their families, but I can tell you that I’ve never had a family ask me not to use a medication because of the black box warning, because they see how miserable and how out of control their loved one is and they’re miserable because they see the suffering and will ask that we do anything that we can to get this behavior under control,” Dr. Grossberg said.

Caution still warranted

Commenting on the study, Rajesh R. Tampi, MD, professor and chairman of the department of psychiatry and the Bhatia Family Endowed Chair in Psychiatry at Creighton University, Omaha, Neb., underscored that, owing to the concerns behind the FDA warnings, “nonpharmacologic management is the cornerstone of treating agitation in Alzheimer’s dementia.”

He noted that the lack of an FDA-approved drug for agitation with AD is the result of “the overall benefits of any of the drug classes or drugs trialed to treat agitation in Alzheimer’s dementia vs. their adverse effect profile,” he said.

Therefore, he continued, “any medication or medication class should be used with caution among these individuals who often have polymorbidity.”

Dr. Tampi agreed that “the use of each drug for agitation in AD should be on a case-by-case basis with a clear and documented risk/benefit discussion with the patient and their families.”

“These medications should only be used for refractory symptoms or emergency situations where the agitation is not managed adequately with nonpharmacologic techniques and with a clear and documented risk/benefit discussion with patients and their families,” Dr. Tampi said. 

The study was supported by Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck. Dr. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. Dr. Tampi had no disclosures to report.

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

This article was updated 3/14/23.

Response to buprenorphine among emergency department patients using fentanyl was similar to that in patients using other opioids, based on data from nearly 900 individuals.

California EDs include a facilitation program known as CA Bridge for the treatment of opioid use disorder. Guidelines for CA Bridge call for high-dose buprenorphine to treat patients in drug withdrawal, with doses starting at 8-16 mg, Hannah Snyder, MD, of the University of California, San Francisco, and colleagues wrote.

“Buprenorphine has been repeatedly shown to save lives and prevent overdoses,” Dr. Snyder said in an interview. “We know that emergency department–initiated buprenorphine is an essential tool for increasing access. In the era of fentanyl, both patients and providers have expressed concerns that buprenorphine may not work as well as it did when patients were more likely to be using heroin or opioid pills.

“This retrospective cohort study provides additional information about emergency department buprenorphine as fentanyl becomes increasingly prevalent.” 

In a research letter published in JAMA Network Open, the investigators reviewed data from the electronic health records of 896 patients who presented with opioid use disorder (OUD) at 16 CA Bridge EDs between Jan. 1, 2020, and April 30, 2020. All patients with OUD were included regardless of chief concern, current treatment, treatment desires, or withdrawal. A total of 87 individuals reported fentanyl use; if no fentanyl use was reported, the patient was classified as not using fentanyl. The median age of the patients was 35 years, two thirds were male, approximately 46% were White and non-Hispanic, and 30% had unstable housing.

The primary outcome was follow-up engagement at 7-14 days and 25-37 days.

A total of 492 patients received buprenorphine, including 44 fentanyl users, and 439 initiated high doses of 8-32 mg. At a 30-day follow-up, eight patients had precipitated withdrawal, including two cases in fentanyl users; none of these cases required hospital admission.

The follow-up engagement was similar for both groups, with adjusted odds ratios of 0.60 for administered buprenorphine at the initial ED encounter, 1.09 for 7-day follow-up, and 1.33 for 30-day follow-up.

The findings were limited by the retrospective design and use of clinical documentation, which likely resulted in underreporting of fentanyl use and follow-up, the researchers noted. However, the results supported the effectiveness of buprenorphine for ED patients in withdrawal with a history of fentanyl exposure.

“We were pleased to see that precipitated withdrawal was relatively uncommon in this study, and that patients who did and did not use fentanyl followed up at similar rates,” said Dr. Snyder. “This aligns with our clinical experience and prior research showing that emergency department buprenorphine starts continue to be an essential tool.”

The message for clinicians: “If a patient presents to the emergency department in objective opioid withdrawal and desires buprenorphine, they should be offered treatment in that moment,” Dr. Snyder said. “Treatment protocols used by hospitals in this study are available online. Emergency departments can offer compassionate and evidence-based treatment initiation 24 hours a day, 7 days a week, 365 days a year.”
 

More data needed on dosing strategies

“We need additional research to determine best practices for patients who use fentanyl and want to start buprenorphine, but are not yet in withdrawal,” Dr. Snyder said. “Doses of buprenorphine like those in this study are only appropriate for patients who are in withdrawal with objective signs, so some patients may struggle to wait long enough after their last use to go into sufficient withdrawal.”

Precipitated withdrawal does occur in some cases, said Dr. Snyder. “If it does, the emergency department is a very good place to manage it. We need additional research to determine best practices in management to make patients as comfortable as possible, including additional high-dose buprenorphine as well as additional adjunctive agents.”
 

Findings support buprenorphine

“The classic approach to buprenorphine initiation, which emerged from psychiatry outpatient office visits, is to start with very small doses of buprenorphine [2-4 mg] and titrate up slowly,” Reuben J. Strayer, MD, said in an interview.

“This dose range turns out to be the ‘sour spot’ most likely to cause the most important complication around buprenorphine initiation–precipitated withdrawal,” said Dr. Strayer, the director of addiction medicine in the emergency medicine department at Maimonides Medical Center, New York.

“One of the current focus areas of OUD treatment research is determining how to initiate buprenorphine without entailing a period of spontaneous withdrawal and without causing precipitated withdrawal,” Strayer explained. “The two primary strategies are low-dose buprenorphine initiation [LDBI, less than 2 mg, sometimes called microdosing] and high-dose [HDBI, ≥ 16 mg] buprenorphine initiation. HDBI is attractive because the primary treatment of buprenorphine-precipitated withdrawal is more buprenorphine.

“Additionally, using a high dose up front immediately transitions the patient to therapeutic blood levels, which protects the patient from withdrawal, cravings, and overdose from dangerous opioids (heroin, fentanyl, oxycodone).”

However, “the contamination and now replacement of heroin with fentanyl in the street drug supply has challenged buprenorphine initiation, because fentanyl, when used chronically, accumulates in the body and leaks into the bloodstream slowly over time, preventing the opioid washout that is required to eliminate the risk of precipitated withdrawal when buprenorphine is administered,” said Dr. Strayer.

The current study demonstrates that patients who are initiated with a first dose of 8-16 mg buprenorphine are unlikely to experience precipitated withdrawal and are successfully transitioned to buprenorphine maintenance and clinic follow-up, Dr. Snyder said, but he was surprised by the low rate of precipitated withdrawal in the current study, “which is discordant with what is being anecdotally reported across the country.”

However, the take-home message for clinicians is the support for the initiation of buprenorphine in emergency department settings at a starting dose of 8-16 mg, regardless of reported fentanyl use, he said. “Given the huge impact buprenorphine therapy has on OUD-related mortality, clinicians should make every effort to initiate buprenorphine for OUD patients at every opportunity, and precipitated withdrawal is very unlikely in appropriately selected patients.

“Many clinicians remain reluctant to initiate buprenorphine in ED settings for unfamiliarity with the drug, fear of precipitated withdrawal, or concerns around the certainty of outpatient follow-up,” Dr. Snyder said. “Education, encouragement, systems programming, such as including decision support within the electronic health record, and role-modeling from local champions will promote wider adoption of this lifesaving practice.”

Looking ahead, “more research, including prospective research, is needed to refine best practices around buprenorphine administration,” said Dr. Snyder. Questions to address include which patients are most at risk for precipitated withdrawal and whether there are alternatives to standard initiation dosing that are sufficiently unlikely to cause precipitated withdrawal. “Possibly effective alternatives include buprenorphine initiation by administration of long-acting injectable depot buprenorphine, which accumulates slowly, potentially avoiding precipitated withdrawal, as well as a slow intravenous buprenorphine infusion such as 9 mg given over 12 hours.”

The study received no outside funding. Dr. Snyder disclosed grants from the Substance Abuse and Mental Health Services Administration and the California Department of Health Care Services during the study. Dr. Strayer reported no relevant financial relationships.

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

Response to buprenorphine among emergency department patients using fentanyl was similar to that in patients using other opioids, based on data from nearly 900 individuals.

California EDs include a facilitation program known as CA Bridge for the treatment of opioid use disorder. Guidelines for CA Bridge call for high-dose buprenorphine to treat patients in drug withdrawal, with doses starting at 8-16 mg, Hannah Snyder, MD, of the University of California, San Francisco, and colleagues wrote.

“Buprenorphine has been repeatedly shown to save lives and prevent overdoses,” Dr. Snyder said in an interview. “We know that emergency department–initiated buprenorphine is an essential tool for increasing access. In the era of fentanyl, both patients and providers have expressed concerns that buprenorphine may not work as well as it did when patients were more likely to be using heroin or opioid pills.

“This retrospective cohort study provides additional information about emergency department buprenorphine as fentanyl becomes increasingly prevalent.” 

In a research letter published in JAMA Network Open, the investigators reviewed data from the electronic health records of 896 patients who presented with opioid use disorder (OUD) at 16 CA Bridge EDs between Jan. 1, 2020, and April 30, 2020. All patients with OUD were included regardless of chief concern, current treatment, treatment desires, or withdrawal. A total of 87 individuals reported fentanyl use; if no fentanyl use was reported, the patient was classified as not using fentanyl. The median age of the patients was 35 years, two thirds were male, approximately 46% were White and non-Hispanic, and 30% had unstable housing.

The primary outcome was follow-up engagement at 7-14 days and 25-37 days.

A total of 492 patients received buprenorphine, including 44 fentanyl users, and 439 initiated high doses of 8-32 mg. At a 30-day follow-up, eight patients had precipitated withdrawal, including two cases in fentanyl users; none of these cases required hospital admission.

The follow-up engagement was similar for both groups, with adjusted odds ratios of 0.60 for administered buprenorphine at the initial ED encounter, 1.09 for 7-day follow-up, and 1.33 for 30-day follow-up.

The findings were limited by the retrospective design and use of clinical documentation, which likely resulted in underreporting of fentanyl use and follow-up, the researchers noted. However, the results supported the effectiveness of buprenorphine for ED patients in withdrawal with a history of fentanyl exposure.

“We were pleased to see that precipitated withdrawal was relatively uncommon in this study, and that patients who did and did not use fentanyl followed up at similar rates,” said Dr. Snyder. “This aligns with our clinical experience and prior research showing that emergency department buprenorphine starts continue to be an essential tool.”

The message for clinicians: “If a patient presents to the emergency department in objective opioid withdrawal and desires buprenorphine, they should be offered treatment in that moment,” Dr. Snyder said. “Treatment protocols used by hospitals in this study are available online. Emergency departments can offer compassionate and evidence-based treatment initiation 24 hours a day, 7 days a week, 365 days a year.”
 

More data needed on dosing strategies

“We need additional research to determine best practices for patients who use fentanyl and want to start buprenorphine, but are not yet in withdrawal,” Dr. Snyder said. “Doses of buprenorphine like those in this study are only appropriate for patients who are in withdrawal with objective signs, so some patients may struggle to wait long enough after their last use to go into sufficient withdrawal.”

Precipitated withdrawal does occur in some cases, said Dr. Snyder. “If it does, the emergency department is a very good place to manage it. We need additional research to determine best practices in management to make patients as comfortable as possible, including additional high-dose buprenorphine as well as additional adjunctive agents.”
 

Findings support buprenorphine

“The classic approach to buprenorphine initiation, which emerged from psychiatry outpatient office visits, is to start with very small doses of buprenorphine [2-4 mg] and titrate up slowly,” Reuben J. Strayer, MD, said in an interview.

“This dose range turns out to be the ‘sour spot’ most likely to cause the most important complication around buprenorphine initiation–precipitated withdrawal,” said Dr. Strayer, the director of addiction medicine in the emergency medicine department at Maimonides Medical Center, New York.

“One of the current focus areas of OUD treatment research is determining how to initiate buprenorphine without entailing a period of spontaneous withdrawal and without causing precipitated withdrawal,” Strayer explained. “The two primary strategies are low-dose buprenorphine initiation [LDBI, less than 2 mg, sometimes called microdosing] and high-dose [HDBI, ≥ 16 mg] buprenorphine initiation. HDBI is attractive because the primary treatment of buprenorphine-precipitated withdrawal is more buprenorphine.

“Additionally, using a high dose up front immediately transitions the patient to therapeutic blood levels, which protects the patient from withdrawal, cravings, and overdose from dangerous opioids (heroin, fentanyl, oxycodone).”

However, “the contamination and now replacement of heroin with fentanyl in the street drug supply has challenged buprenorphine initiation, because fentanyl, when used chronically, accumulates in the body and leaks into the bloodstream slowly over time, preventing the opioid washout that is required to eliminate the risk of precipitated withdrawal when buprenorphine is administered,” said Dr. Strayer.

The current study demonstrates that patients who are initiated with a first dose of 8-16 mg buprenorphine are unlikely to experience precipitated withdrawal and are successfully transitioned to buprenorphine maintenance and clinic follow-up, Dr. Snyder said, but he was surprised by the low rate of precipitated withdrawal in the current study, “which is discordant with what is being anecdotally reported across the country.”

However, the take-home message for clinicians is the support for the initiation of buprenorphine in emergency department settings at a starting dose of 8-16 mg, regardless of reported fentanyl use, he said. “Given the huge impact buprenorphine therapy has on OUD-related mortality, clinicians should make every effort to initiate buprenorphine for OUD patients at every opportunity, and precipitated withdrawal is very unlikely in appropriately selected patients.

“Many clinicians remain reluctant to initiate buprenorphine in ED settings for unfamiliarity with the drug, fear of precipitated withdrawal, or concerns around the certainty of outpatient follow-up,” Dr. Snyder said. “Education, encouragement, systems programming, such as including decision support within the electronic health record, and role-modeling from local champions will promote wider adoption of this lifesaving practice.”

Looking ahead, “more research, including prospective research, is needed to refine best practices around buprenorphine administration,” said Dr. Snyder. Questions to address include which patients are most at risk for precipitated withdrawal and whether there are alternatives to standard initiation dosing that are sufficiently unlikely to cause precipitated withdrawal. “Possibly effective alternatives include buprenorphine initiation by administration of long-acting injectable depot buprenorphine, which accumulates slowly, potentially avoiding precipitated withdrawal, as well as a slow intravenous buprenorphine infusion such as 9 mg given over 12 hours.”

The study received no outside funding. Dr. Snyder disclosed grants from the Substance Abuse and Mental Health Services Administration and the California Department of Health Care Services during the study. Dr. Strayer reported no relevant financial relationships.

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

Response to buprenorphine among emergency department patients using fentanyl was similar to that in patients using other opioids, based on data from nearly 900 individuals.

California EDs include a facilitation program known as CA Bridge for the treatment of opioid use disorder. Guidelines for CA Bridge call for high-dose buprenorphine to treat patients in drug withdrawal, with doses starting at 8-16 mg, Hannah Snyder, MD, of the University of California, San Francisco, and colleagues wrote.

“Buprenorphine has been repeatedly shown to save lives and prevent overdoses,” Dr. Snyder said in an interview. “We know that emergency department–initiated buprenorphine is an essential tool for increasing access. In the era of fentanyl, both patients and providers have expressed concerns that buprenorphine may not work as well as it did when patients were more likely to be using heroin or opioid pills.

“This retrospective cohort study provides additional information about emergency department buprenorphine as fentanyl becomes increasingly prevalent.” 

In a research letter published in JAMA Network Open, the investigators reviewed data from the electronic health records of 896 patients who presented with opioid use disorder (OUD) at 16 CA Bridge EDs between Jan. 1, 2020, and April 30, 2020. All patients with OUD were included regardless of chief concern, current treatment, treatment desires, or withdrawal. A total of 87 individuals reported fentanyl use; if no fentanyl use was reported, the patient was classified as not using fentanyl. The median age of the patients was 35 years, two thirds were male, approximately 46% were White and non-Hispanic, and 30% had unstable housing.

The primary outcome was follow-up engagement at 7-14 days and 25-37 days.

A total of 492 patients received buprenorphine, including 44 fentanyl users, and 439 initiated high doses of 8-32 mg. At a 30-day follow-up, eight patients had precipitated withdrawal, including two cases in fentanyl users; none of these cases required hospital admission.

The follow-up engagement was similar for both groups, with adjusted odds ratios of 0.60 for administered buprenorphine at the initial ED encounter, 1.09 for 7-day follow-up, and 1.33 for 30-day follow-up.

The findings were limited by the retrospective design and use of clinical documentation, which likely resulted in underreporting of fentanyl use and follow-up, the researchers noted. However, the results supported the effectiveness of buprenorphine for ED patients in withdrawal with a history of fentanyl exposure.

“We were pleased to see that precipitated withdrawal was relatively uncommon in this study, and that patients who did and did not use fentanyl followed up at similar rates,” said Dr. Snyder. “This aligns with our clinical experience and prior research showing that emergency department buprenorphine starts continue to be an essential tool.”

The message for clinicians: “If a patient presents to the emergency department in objective opioid withdrawal and desires buprenorphine, they should be offered treatment in that moment,” Dr. Snyder said. “Treatment protocols used by hospitals in this study are available online. Emergency departments can offer compassionate and evidence-based treatment initiation 24 hours a day, 7 days a week, 365 days a year.”
 

More data needed on dosing strategies

“We need additional research to determine best practices for patients who use fentanyl and want to start buprenorphine, but are not yet in withdrawal,” Dr. Snyder said. “Doses of buprenorphine like those in this study are only appropriate for patients who are in withdrawal with objective signs, so some patients may struggle to wait long enough after their last use to go into sufficient withdrawal.”

Precipitated withdrawal does occur in some cases, said Dr. Snyder. “If it does, the emergency department is a very good place to manage it. We need additional research to determine best practices in management to make patients as comfortable as possible, including additional high-dose buprenorphine as well as additional adjunctive agents.”
 

Findings support buprenorphine

“The classic approach to buprenorphine initiation, which emerged from psychiatry outpatient office visits, is to start with very small doses of buprenorphine [2-4 mg] and titrate up slowly,” Reuben J. Strayer, MD, said in an interview.

“This dose range turns out to be the ‘sour spot’ most likely to cause the most important complication around buprenorphine initiation–precipitated withdrawal,” said Dr. Strayer, the director of addiction medicine in the emergency medicine department at Maimonides Medical Center, New York.

“One of the current focus areas of OUD treatment research is determining how to initiate buprenorphine without entailing a period of spontaneous withdrawal and without causing precipitated withdrawal,” Strayer explained. “The two primary strategies are low-dose buprenorphine initiation [LDBI, less than 2 mg, sometimes called microdosing] and high-dose [HDBI, ≥ 16 mg] buprenorphine initiation. HDBI is attractive because the primary treatment of buprenorphine-precipitated withdrawal is more buprenorphine.

“Additionally, using a high dose up front immediately transitions the patient to therapeutic blood levels, which protects the patient from withdrawal, cravings, and overdose from dangerous opioids (heroin, fentanyl, oxycodone).”

However, “the contamination and now replacement of heroin with fentanyl in the street drug supply has challenged buprenorphine initiation, because fentanyl, when used chronically, accumulates in the body and leaks into the bloodstream slowly over time, preventing the opioid washout that is required to eliminate the risk of precipitated withdrawal when buprenorphine is administered,” said Dr. Strayer.

The current study demonstrates that patients who are initiated with a first dose of 8-16 mg buprenorphine are unlikely to experience precipitated withdrawal and are successfully transitioned to buprenorphine maintenance and clinic follow-up, Dr. Snyder said, but he was surprised by the low rate of precipitated withdrawal in the current study, “which is discordant with what is being anecdotally reported across the country.”

However, the take-home message for clinicians is the support for the initiation of buprenorphine in emergency department settings at a starting dose of 8-16 mg, regardless of reported fentanyl use, he said. “Given the huge impact buprenorphine therapy has on OUD-related mortality, clinicians should make every effort to initiate buprenorphine for OUD patients at every opportunity, and precipitated withdrawal is very unlikely in appropriately selected patients.

“Many clinicians remain reluctant to initiate buprenorphine in ED settings for unfamiliarity with the drug, fear of precipitated withdrawal, or concerns around the certainty of outpatient follow-up,” Dr. Snyder said. “Education, encouragement, systems programming, such as including decision support within the electronic health record, and role-modeling from local champions will promote wider adoption of this lifesaving practice.”

Looking ahead, “more research, including prospective research, is needed to refine best practices around buprenorphine administration,” said Dr. Snyder. Questions to address include which patients are most at risk for precipitated withdrawal and whether there are alternatives to standard initiation dosing that are sufficiently unlikely to cause precipitated withdrawal. “Possibly effective alternatives include buprenorphine initiation by administration of long-acting injectable depot buprenorphine, which accumulates slowly, potentially avoiding precipitated withdrawal, as well as a slow intravenous buprenorphine infusion such as 9 mg given over 12 hours.”

The study received no outside funding. Dr. Snyder disclosed grants from the Substance Abuse and Mental Health Services Administration and the California Department of Health Care Services during the study. Dr. Strayer reported no relevant financial relationships.

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

In what some call a “disturbing trend,” efforts are being made to broaden the definition of “family members” who can sue physicians for wrongful death. In addition, the types of emotional damage that physicians can be sued for is expanding in pockets across the nation. The latest effort to expand the capacity to sue, a bill in New York state, failed when it was not signed by the governor – but a toned-down bill is in the works.

The impact of New York’s proposed expansion of wrongful death lawsuits would have been widespread. The New York legislation would have expanded the definition of “close family members” to include spouses, domestic partners, children, parents, stepparents, siblings, grandparents, and perhaps more. Additionally, lawsuits could have allowed juries to determine “close family members” of the deceased patient on the basis of specific circumstances of the person’s relationship with the decedent.

Currently, every state allows a wrongful death claim to be filed by immediate family members. If the patient who died was married, a surviving spouse could bring the lawsuit. If the patient had been unmarried, an adult child could bring the lawsuit in some states. A parent typically brings a lawsuit if their minor child has died from alleged wrongful death. In some states, one member of a civil union or domestic partnership may bring a wrongful death lawsuit. And if a single adult has no children or spouse/partner, more distant family members, including aunts, uncles, siblings, or grandparents, may file the suit.

The New York bill would also have expanded compensable damages to include loss of affection and companionship, and it would have expanded emotional damages, which are not currently included in New York. It would also have extended the statute of limitations of a wrongful death claim from 2 years to 3.5 years.

In general, in states that allow emotional distress to be included in wrongful death lawsuits, attorneys must demonstrate that survivors have suffered mental harm, such as depression, loss of sleep, fear, and anger, says Russ Haven, JD, general counsel for the New York Public Interest Research Group. While mental harm is not particularly easy to prove, attorneys must show that survivors have ongoing distress that is the direct result of the loss of the loved one and that the distress is significant enough to severely affect their quality of life.

Mr. Haven gives an example of emotional distress: “We worked with a woman who lost her fiancé in a motor vehicle accident,” he says. “The funeral ended up on the day she had scheduled her wedding dress fitting. A situation like that causes a good deal of lasting emotional distress.”
 

Expanding family members who can bring the lawsuit

The fact that a fiancé could be included in a wrongful death settlement is another aspect of the New York bill that was central to arguments both for and against the expansion of family members who can make claims. “We think a modern society includes unmarried partners, grandparents, siblings, and others,” says Mr. Haven.

“The language of who is a close family member might seem clear, but to a defense attorney, it isn’t,” says Tom Stebbins, executive director of the Lawsuit Reform Alliance of New York. “This could end up being a situation where someone has 40 grandchildren, and all could be considered close family members.”

Many states currently allow damages for claims of grief and mental anguish resulting from a wrongful death.

In her recent veto of the Grieving Families Act, New York Gov. Kathy Hochul took fire for her choices. The bill represented years of effort by the state legislature to expand the qualifiers for wrongful death lawsuits. Those supporting what ultimately became Senate Bill S74A believed they finally had the law over the finish line. Those opposed breathed a sigh of relief when the bill was vetoed.

Had Gov. Hochul signed Bill 274A, the effect on costs would have been enormous for physicians. New York already has the highest cumulative medical liability payouts in the nation, according to the Medical Society of the State of New York.

The MSSNY was among many parties that fought against the law. The Greater New York Hospital Association, insurance companies, the Defense Association of New York, and the New York Conference of Mayors all joined in lobbying against the bill.

“Gov. Hochul, in her veto message, correctly noted that the proposed New York legislation represented an extraordinary departure from New York’s wrongful death jurisprudence,” says Remi Stone, director of government relations at The Doctors Company, part of the TDC Group. “I would add that while there are some other states that allow grief damages, none are as wide-ranging as the proposed legislation.”

The NYPIRG, the AARP, and the New York Immigration Coalition supported the bill. In a statement following the veto, the New York State Trial Lawyers Association said: “By vetoing the Grieving Families Act, Gov. Hochul has sided with insurance companies, the health care industry, big corporations, and anyone else who doesn’t want to be held accountable for the negligent killing of a person. This bill passed with overwhelming bipartisan support and would rectify over a century of injustice.”

Following Gov. Hochul’s veto, the bill’s proponents and the state legislature vowed to return to the drawing board and construct a bill that the governor would eventually approve. For now, however, the controversial legislation has been put to rest.

Mr. Haven and the NYPIRG argue that New York lags behind many other states in allowing survivors to claim loss for their emotional distress. “When there is relationship loss, it has a great impact on your life,” Mr. Haven says, “and this goes beyond simply the financial impact.”

“The bill was well intended but completely vague on who could bring lawsuits and would have increased medical malpractice insurance by far too much,” says MSSNY President Parag Mehta, MD. “For safety net hospitals, one lawsuit would halt their ability to provide many programs aimed at underserved populations.”

Peter Kolbert, JD, senior vice president of claim and litigation services at Healthcare Risk Advisors (part of the TDC Group), had this to say: “The current ‘recoverable’ damages in New York in a wrongful death case include loss of guidance and support for minor children of a decedent. Those damages have been sustained at $2 million per child. It is rationally very challenging, if not impossible, to distinguish between those damages and the proposed damages that the very same people would have been entitled to under the proposed statute.”
 

What will happen in the future?

While the veto has stalled New York’s wrongful death expansion for now, supporters in and out of the legislature remain determined to continue their fight. “Advocates argue that the bill would have brought the state in line with wrongful death law in others,” says Brian Whitelaw, JD, a partner at Michigan’s Foley, Baron, Metzger & Juip. “But if the bill had become law as written, the economic impact would have been substantial.”

Mr. Whitelaw says that such wide-ranging lawsuits can have consequences that extend far beyond physicians’ insurance premiums. “This could impact the average person on the street’s ability to obtain the medical care they need, because doctors will go elsewhere to practice,” he says. “Beyond impacting the health care system, it can hurt small businesses as well.”

Mr. Haven says supporters of the expansion are far from finished with their efforts. “New York’s current law dates back to 1847, and it was cutting edge then,” he says. “It was designed for an agrarian society where if the husband died, his widow and children wouldn’t become destitute. Now, 175 years later, we realize that the law has biases, and tort law has evolved. The state needs to evolve as well.”

For his part, Dr. Mehta is open to a dialogue with lawmakers to revise the law in a manner agreeable to all parties. “We want to work together to make the system right,” he says. “The liability system in New York needs an overall holistic change, and we are available at any time to have discussions. The vetoed bill was a Band-Aid and didn’t address the main, underlying issues in the state.”

Mr. Stebbins, too, says he would like to continue the debate over how an expansion should look. “We hope to go through a discussion on caps to these suits,” he explains. “We have already seen the cap of $10 million broken four times in the past few years through nuclear verdicts. That’s something we need to address.”

Given the legislature’s overwhelming support for the bill, some version of it will likely make another appearance in the coming session. Whether or not it can strike the middle ground that will make all parties happy – including the governor – is yet to be seen. “Is it wrong to seek compensation for pain and suffering from a wrongful death?” asks Mr. Whitelaw. “No. But there must be limits to such laws, or where does it end?”

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

In what some call a “disturbing trend,” efforts are being made to broaden the definition of “family members” who can sue physicians for wrongful death. In addition, the types of emotional damage that physicians can be sued for is expanding in pockets across the nation. The latest effort to expand the capacity to sue, a bill in New York state, failed when it was not signed by the governor – but a toned-down bill is in the works.

The impact of New York’s proposed expansion of wrongful death lawsuits would have been widespread. The New York legislation would have expanded the definition of “close family members” to include spouses, domestic partners, children, parents, stepparents, siblings, grandparents, and perhaps more. Additionally, lawsuits could have allowed juries to determine “close family members” of the deceased patient on the basis of specific circumstances of the person’s relationship with the decedent.

Currently, every state allows a wrongful death claim to be filed by immediate family members. If the patient who died was married, a surviving spouse could bring the lawsuit. If the patient had been unmarried, an adult child could bring the lawsuit in some states. A parent typically brings a lawsuit if their minor child has died from alleged wrongful death. In some states, one member of a civil union or domestic partnership may bring a wrongful death lawsuit. And if a single adult has no children or spouse/partner, more distant family members, including aunts, uncles, siblings, or grandparents, may file the suit.

The New York bill would also have expanded compensable damages to include loss of affection and companionship, and it would have expanded emotional damages, which are not currently included in New York. It would also have extended the statute of limitations of a wrongful death claim from 2 years to 3.5 years.

In general, in states that allow emotional distress to be included in wrongful death lawsuits, attorneys must demonstrate that survivors have suffered mental harm, such as depression, loss of sleep, fear, and anger, says Russ Haven, JD, general counsel for the New York Public Interest Research Group. While mental harm is not particularly easy to prove, attorneys must show that survivors have ongoing distress that is the direct result of the loss of the loved one and that the distress is significant enough to severely affect their quality of life.

Mr. Haven gives an example of emotional distress: “We worked with a woman who lost her fiancé in a motor vehicle accident,” he says. “The funeral ended up on the day she had scheduled her wedding dress fitting. A situation like that causes a good deal of lasting emotional distress.”
 

Expanding family members who can bring the lawsuit

The fact that a fiancé could be included in a wrongful death settlement is another aspect of the New York bill that was central to arguments both for and against the expansion of family members who can make claims. “We think a modern society includes unmarried partners, grandparents, siblings, and others,” says Mr. Haven.

“The language of who is a close family member might seem clear, but to a defense attorney, it isn’t,” says Tom Stebbins, executive director of the Lawsuit Reform Alliance of New York. “This could end up being a situation where someone has 40 grandchildren, and all could be considered close family members.”

Many states currently allow damages for claims of grief and mental anguish resulting from a wrongful death.

In her recent veto of the Grieving Families Act, New York Gov. Kathy Hochul took fire for her choices. The bill represented years of effort by the state legislature to expand the qualifiers for wrongful death lawsuits. Those supporting what ultimately became Senate Bill S74A believed they finally had the law over the finish line. Those opposed breathed a sigh of relief when the bill was vetoed.

Had Gov. Hochul signed Bill 274A, the effect on costs would have been enormous for physicians. New York already has the highest cumulative medical liability payouts in the nation, according to the Medical Society of the State of New York.

The MSSNY was among many parties that fought against the law. The Greater New York Hospital Association, insurance companies, the Defense Association of New York, and the New York Conference of Mayors all joined in lobbying against the bill.

“Gov. Hochul, in her veto message, correctly noted that the proposed New York legislation represented an extraordinary departure from New York’s wrongful death jurisprudence,” says Remi Stone, director of government relations at The Doctors Company, part of the TDC Group. “I would add that while there are some other states that allow grief damages, none are as wide-ranging as the proposed legislation.”

The NYPIRG, the AARP, and the New York Immigration Coalition supported the bill. In a statement following the veto, the New York State Trial Lawyers Association said: “By vetoing the Grieving Families Act, Gov. Hochul has sided with insurance companies, the health care industry, big corporations, and anyone else who doesn’t want to be held accountable for the negligent killing of a person. This bill passed with overwhelming bipartisan support and would rectify over a century of injustice.”

Following Gov. Hochul’s veto, the bill’s proponents and the state legislature vowed to return to the drawing board and construct a bill that the governor would eventually approve. For now, however, the controversial legislation has been put to rest.

Mr. Haven and the NYPIRG argue that New York lags behind many other states in allowing survivors to claim loss for their emotional distress. “When there is relationship loss, it has a great impact on your life,” Mr. Haven says, “and this goes beyond simply the financial impact.”

“The bill was well intended but completely vague on who could bring lawsuits and would have increased medical malpractice insurance by far too much,” says MSSNY President Parag Mehta, MD. “For safety net hospitals, one lawsuit would halt their ability to provide many programs aimed at underserved populations.”

Peter Kolbert, JD, senior vice president of claim and litigation services at Healthcare Risk Advisors (part of the TDC Group), had this to say: “The current ‘recoverable’ damages in New York in a wrongful death case include loss of guidance and support for minor children of a decedent. Those damages have been sustained at $2 million per child. It is rationally very challenging, if not impossible, to distinguish between those damages and the proposed damages that the very same people would have been entitled to under the proposed statute.”
 

What will happen in the future?

While the veto has stalled New York’s wrongful death expansion for now, supporters in and out of the legislature remain determined to continue their fight. “Advocates argue that the bill would have brought the state in line with wrongful death law in others,” says Brian Whitelaw, JD, a partner at Michigan’s Foley, Baron, Metzger & Juip. “But if the bill had become law as written, the economic impact would have been substantial.”

Mr. Whitelaw says that such wide-ranging lawsuits can have consequences that extend far beyond physicians’ insurance premiums. “This could impact the average person on the street’s ability to obtain the medical care they need, because doctors will go elsewhere to practice,” he says. “Beyond impacting the health care system, it can hurt small businesses as well.”

Mr. Haven says supporters of the expansion are far from finished with their efforts. “New York’s current law dates back to 1847, and it was cutting edge then,” he says. “It was designed for an agrarian society where if the husband died, his widow and children wouldn’t become destitute. Now, 175 years later, we realize that the law has biases, and tort law has evolved. The state needs to evolve as well.”

For his part, Dr. Mehta is open to a dialogue with lawmakers to revise the law in a manner agreeable to all parties. “We want to work together to make the system right,” he says. “The liability system in New York needs an overall holistic change, and we are available at any time to have discussions. The vetoed bill was a Band-Aid and didn’t address the main, underlying issues in the state.”

Mr. Stebbins, too, says he would like to continue the debate over how an expansion should look. “We hope to go through a discussion on caps to these suits,” he explains. “We have already seen the cap of $10 million broken four times in the past few years through nuclear verdicts. That’s something we need to address.”

Given the legislature’s overwhelming support for the bill, some version of it will likely make another appearance in the coming session. Whether or not it can strike the middle ground that will make all parties happy – including the governor – is yet to be seen. “Is it wrong to seek compensation for pain and suffering from a wrongful death?” asks Mr. Whitelaw. “No. But there must be limits to such laws, or where does it end?”

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

In what some call a “disturbing trend,” efforts are being made to broaden the definition of “family members” who can sue physicians for wrongful death. In addition, the types of emotional damage that physicians can be sued for is expanding in pockets across the nation. The latest effort to expand the capacity to sue, a bill in New York state, failed when it was not signed by the governor – but a toned-down bill is in the works.

The impact of New York’s proposed expansion of wrongful death lawsuits would have been widespread. The New York legislation would have expanded the definition of “close family members” to include spouses, domestic partners, children, parents, stepparents, siblings, grandparents, and perhaps more. Additionally, lawsuits could have allowed juries to determine “close family members” of the deceased patient on the basis of specific circumstances of the person’s relationship with the decedent.

Currently, every state allows a wrongful death claim to be filed by immediate family members. If the patient who died was married, a surviving spouse could bring the lawsuit. If the patient had been unmarried, an adult child could bring the lawsuit in some states. A parent typically brings a lawsuit if their minor child has died from alleged wrongful death. In some states, one member of a civil union or domestic partnership may bring a wrongful death lawsuit. And if a single adult has no children or spouse/partner, more distant family members, including aunts, uncles, siblings, or grandparents, may file the suit.

The New York bill would also have expanded compensable damages to include loss of affection and companionship, and it would have expanded emotional damages, which are not currently included in New York. It would also have extended the statute of limitations of a wrongful death claim from 2 years to 3.5 years.

In general, in states that allow emotional distress to be included in wrongful death lawsuits, attorneys must demonstrate that survivors have suffered mental harm, such as depression, loss of sleep, fear, and anger, says Russ Haven, JD, general counsel for the New York Public Interest Research Group. While mental harm is not particularly easy to prove, attorneys must show that survivors have ongoing distress that is the direct result of the loss of the loved one and that the distress is significant enough to severely affect their quality of life.

Mr. Haven gives an example of emotional distress: “We worked with a woman who lost her fiancé in a motor vehicle accident,” he says. “The funeral ended up on the day she had scheduled her wedding dress fitting. A situation like that causes a good deal of lasting emotional distress.”
 

Expanding family members who can bring the lawsuit

The fact that a fiancé could be included in a wrongful death settlement is another aspect of the New York bill that was central to arguments both for and against the expansion of family members who can make claims. “We think a modern society includes unmarried partners, grandparents, siblings, and others,” says Mr. Haven.

“The language of who is a close family member might seem clear, but to a defense attorney, it isn’t,” says Tom Stebbins, executive director of the Lawsuit Reform Alliance of New York. “This could end up being a situation where someone has 40 grandchildren, and all could be considered close family members.”

Many states currently allow damages for claims of grief and mental anguish resulting from a wrongful death.

In her recent veto of the Grieving Families Act, New York Gov. Kathy Hochul took fire for her choices. The bill represented years of effort by the state legislature to expand the qualifiers for wrongful death lawsuits. Those supporting what ultimately became Senate Bill S74A believed they finally had the law over the finish line. Those opposed breathed a sigh of relief when the bill was vetoed.

Had Gov. Hochul signed Bill 274A, the effect on costs would have been enormous for physicians. New York already has the highest cumulative medical liability payouts in the nation, according to the Medical Society of the State of New York.

The MSSNY was among many parties that fought against the law. The Greater New York Hospital Association, insurance companies, the Defense Association of New York, and the New York Conference of Mayors all joined in lobbying against the bill.

“Gov. Hochul, in her veto message, correctly noted that the proposed New York legislation represented an extraordinary departure from New York’s wrongful death jurisprudence,” says Remi Stone, director of government relations at The Doctors Company, part of the TDC Group. “I would add that while there are some other states that allow grief damages, none are as wide-ranging as the proposed legislation.”

The NYPIRG, the AARP, and the New York Immigration Coalition supported the bill. In a statement following the veto, the New York State Trial Lawyers Association said: “By vetoing the Grieving Families Act, Gov. Hochul has sided with insurance companies, the health care industry, big corporations, and anyone else who doesn’t want to be held accountable for the negligent killing of a person. This bill passed with overwhelming bipartisan support and would rectify over a century of injustice.”

Following Gov. Hochul’s veto, the bill’s proponents and the state legislature vowed to return to the drawing board and construct a bill that the governor would eventually approve. For now, however, the controversial legislation has been put to rest.

Mr. Haven and the NYPIRG argue that New York lags behind many other states in allowing survivors to claim loss for their emotional distress. “When there is relationship loss, it has a great impact on your life,” Mr. Haven says, “and this goes beyond simply the financial impact.”

“The bill was well intended but completely vague on who could bring lawsuits and would have increased medical malpractice insurance by far too much,” says MSSNY President Parag Mehta, MD. “For safety net hospitals, one lawsuit would halt their ability to provide many programs aimed at underserved populations.”

Peter Kolbert, JD, senior vice president of claim and litigation services at Healthcare Risk Advisors (part of the TDC Group), had this to say: “The current ‘recoverable’ damages in New York in a wrongful death case include loss of guidance and support for minor children of a decedent. Those damages have been sustained at $2 million per child. It is rationally very challenging, if not impossible, to distinguish between those damages and the proposed damages that the very same people would have been entitled to under the proposed statute.”
 

What will happen in the future?

While the veto has stalled New York’s wrongful death expansion for now, supporters in and out of the legislature remain determined to continue their fight. “Advocates argue that the bill would have brought the state in line with wrongful death law in others,” says Brian Whitelaw, JD, a partner at Michigan’s Foley, Baron, Metzger & Juip. “But if the bill had become law as written, the economic impact would have been substantial.”

Mr. Whitelaw says that such wide-ranging lawsuits can have consequences that extend far beyond physicians’ insurance premiums. “This could impact the average person on the street’s ability to obtain the medical care they need, because doctors will go elsewhere to practice,” he says. “Beyond impacting the health care system, it can hurt small businesses as well.”

Mr. Haven says supporters of the expansion are far from finished with their efforts. “New York’s current law dates back to 1847, and it was cutting edge then,” he says. “It was designed for an agrarian society where if the husband died, his widow and children wouldn’t become destitute. Now, 175 years later, we realize that the law has biases, and tort law has evolved. The state needs to evolve as well.”

For his part, Dr. Mehta is open to a dialogue with lawmakers to revise the law in a manner agreeable to all parties. “We want to work together to make the system right,” he says. “The liability system in New York needs an overall holistic change, and we are available at any time to have discussions. The vetoed bill was a Band-Aid and didn’t address the main, underlying issues in the state.”

Mr. Stebbins, too, says he would like to continue the debate over how an expansion should look. “We hope to go through a discussion on caps to these suits,” he explains. “We have already seen the cap of $10 million broken four times in the past few years through nuclear verdicts. That’s something we need to address.”

Given the legislature’s overwhelming support for the bill, some version of it will likely make another appearance in the coming session. Whether or not it can strike the middle ground that will make all parties happy – including the governor – is yet to be seen. “Is it wrong to seek compensation for pain and suffering from a wrongful death?” asks Mr. Whitelaw. “No. But there must be limits to such laws, or where does it end?”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

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

The Food and Drug Administration has made changes to existing mammography regulations.

A final rule, updating the regulations issued under the Mammography Quality Standards Act of 1992, requires that mammography facilities notify patients about the density of their breasts, strengthens the FDA’s oversight of facilities, and provides guidance to help physicians better categorize and assess mammograms, according to a March 9 press release.

The rule requires implementation of the changes within 18 months.

According to the final rule document, the updates are “intended to improve the delivery of mammography services” in ways that reflect changes in mammography technology, quality standards, and the way results are categorized, reported, and communicated to patients and providers.

For instance, mammography reports must include an assessment of breast density to provide greater detail on the potential limitations of the mammogram results and allow patients and physicians to make more informed decisions, such as the possibility of additional imaging for women with dense breast tissue.

“Today’s action represents the agency’s broader commitment to support innovation to prevent, detect and treat cancer,” said Hilary Marston, MD, MPH, FDA’s chief medical officer, in the agency’s press release. The FDA remains “committed to advancing efforts to improve the health of women and strengthen the fight against breast cancer.”

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

The Food and Drug Administration has made changes to existing mammography regulations.

A final rule, updating the regulations issued under the Mammography Quality Standards Act of 1992, requires that mammography facilities notify patients about the density of their breasts, strengthens the FDA’s oversight of facilities, and provides guidance to help physicians better categorize and assess mammograms, according to a March 9 press release.

The rule requires implementation of the changes within 18 months.

According to the final rule document, the updates are “intended to improve the delivery of mammography services” in ways that reflect changes in mammography technology, quality standards, and the way results are categorized, reported, and communicated to patients and providers.

For instance, mammography reports must include an assessment of breast density to provide greater detail on the potential limitations of the mammogram results and allow patients and physicians to make more informed decisions, such as the possibility of additional imaging for women with dense breast tissue.

“Today’s action represents the agency’s broader commitment to support innovation to prevent, detect and treat cancer,” said Hilary Marston, MD, MPH, FDA’s chief medical officer, in the agency’s press release. The FDA remains “committed to advancing efforts to improve the health of women and strengthen the fight against breast cancer.”

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

The Food and Drug Administration has made changes to existing mammography regulations.

A final rule, updating the regulations issued under the Mammography Quality Standards Act of 1992, requires that mammography facilities notify patients about the density of their breasts, strengthens the FDA’s oversight of facilities, and provides guidance to help physicians better categorize and assess mammograms, according to a March 9 press release.

The rule requires implementation of the changes within 18 months.

According to the final rule document, the updates are “intended to improve the delivery of mammography services” in ways that reflect changes in mammography technology, quality standards, and the way results are categorized, reported, and communicated to patients and providers.

For instance, mammography reports must include an assessment of breast density to provide greater detail on the potential limitations of the mammogram results and allow patients and physicians to make more informed decisions, such as the possibility of additional imaging for women with dense breast tissue.

“Today’s action represents the agency’s broader commitment to support innovation to prevent, detect and treat cancer,” said Hilary Marston, MD, MPH, FDA’s chief medical officer, in the agency’s press release. The FDA remains “committed to advancing efforts to improve the health of women and strengthen the fight against breast cancer.”

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