Pam Harrison

The number of children in the United States who unintentionally ingested melatonin supplements over the past 10 years has skyrocketed to the point where, as of 2021, melatonin ingestions by children accounted for almost 5% of all poisonings reported to poison control centers in the United States, data from the National Poison Data System (NPDS) indicate.

This compared with only 0.6% of melatonin ingestions reported to poison control centers in 2012, the authors added.

“Basically the number of pediatric melatonin ingestions increased 530% from 8,337 in 2012 to 52,563 in 2021 so it’s a 6.3-fold increase from the beginning of the study until the end,” Michael Toce, MD, one of the study authors and attending, pediatric emergency medicine/medical toxicology, Boston Children’s Hospital, said in an interview.

“And I think the biggest driver of this increase is simply that sales of melatonin have increased astronomically so there is just more melatonin at home and studies have shown there is a correlation between the amount of an individual medication in the home and the risk of pediatric exposure – so simply put: The more of a single substance in a home, the greater the chance that a child is going to get into it,” he underscored.

The study was published in the Morbidity and Mortality Weekly Report .

Melatonin ingestions

All cases of single substance melatonin ingestions involving children and adolescents between Jan. 1, 2012, and Dec. 31, 2021, were included in the analysis. During the 10-year study interval, 260,435 pediatric melatonin ingestions were reported to the NPDS. Over 94% of the reported ingestions were unintentional and 99% occurred in the home.

Over 88% of them were managed on-site; most involved young male children aged 5 years and under, and almost 83% of children who ingested melatonin supplements remained asymptomatic. On the other hand, 27,795 patients sought care at a health care facility and close to 15% of them were hospitalized. Among all melatonin ingestions, 1.6% resulted in more serious outcomes; more serious outcomes being defined as a moderate or major effects or death. Five children required mechanical ventilation in order to treat their symptoms and 2 patients died.

The largest number of patients who were hospitalized were adolescents who took melatonin intentionally but the largest increase in the rate of exposure was in young, unintentional patients, as Dr. Toce observed. Interestingly, the largest yearly increase in pediatric melatonin ingestions – almost 38% – coincided with the onset of the COVID-19 pandemic.

“This might be related to increased accessibility of melatonin during the pandemic, as children spent more time at home because of stay-at-home orders and school closures,” the authors speculate. Moreover, sleep disturbances were common during the pandemic, leading to a greater likelihood that parents were buying melatonin and thus exposing children to more melatonin at home.

Taken appropriately and at normal does, melatonin in itself is quite safe, as Dr. Toce stressed. However, “for any substance, the dose makes the poison, so taken in any significant quantity, anything is going to be dangerous.” Moreover, it’s important to appreciate that melatonin, at least in the United States, is regulated as a dietary supplement, not as a pharmaceutical.

“Thus, it doesn’t get the same rigorous testing that something like acetaminophen does by the FDA and that means two things,” Dr. Toce noted. First, if the product says that each gummy contains 3 mg of melatonin, no independent body is verifying whether or not that statement is true so there could be 3 mg of melatonin in each gummy or there could be 10 mg,.

Secondly, because there is no impartial oversight for dietary supplements, there may in fact be no melatonin at all in the product or something else may be added to it that might be harmful. “Just because something is sold over-the-counter does not necessarily mean that it’s safe,” Dr. Toce stressed. To keep children safe from pharmaceuticals and supplements, he recommended several generic poison prevention tips. This advice could be passed on to patients who are parents.

• Keep all pharmaceuticals and supplements preferably locked away so there is less risk of children and adolescents taking products either unintentionally or intentionally
• If parents have no place to lock their products up, put them out of reach, high-up so children cannot easily access them
• Keep the product in the original child-resistant packaging as opposed to taking the pills out of the packaging and putting it in a plastic bag bag. “Certainly we’ve seen that when medications are moved into a non–child-resistant container, ingestions go up,” Dr. Toce warned
• Don’t refer to any medicine or supplement a child might take as “candy.” “A lot of children have difficulty taking medications so some families will say: ‘It’s time for your candy,’ ” Dr. Toce explained. Then, if a child does discover the “candy” on a table where they have access to it, they will not recognize it as medication and they’re likely to pop it into their mouth, thinking it is candy.

Lastly, and most importantly, parents who are considering trying a melatonin supplement to help a child sleep better should first establish a stable sleep routine for their child. “They also need to limit caffeinated beverages before bed as well as screen time,” Dr. Toce added.

And they should talk with their primary care provider as to whether or not initiation of a melatonin supplement is appropriate for their child – “and not just jump right into giving them melatonin without first discussing whether it is appropriate to do so,” Dr. Toce stressed.

Remarkable rise

In a comment on his own experience with melatonin poisoning over recent years, toxicology expert Kevin Osterhoudt, MD, of the University of Pennsylvania, Philadelphia and the Children’s Hospital of Philadelphia, noted that it has been their experience that there has been a remarkable rise in poison center reports of children ingesting melatonin in the recent past. For example, the Poison Control Center at CHOP received nearly 4,000 calls involving melatonin ingestion by children 5 years old or younger in the 5 years between 2017 and 2021 with increasing numbers every year.

“The [current study] supports that our regional observation that this has been a national trend,” Dr. Osterhoudt said. Dr. Osterhoudt agreed with Dr. Toce that good sleep is healthy, and it is very important to develop good sleep habits and a regular bedtime routine in order to do so. “In some situations, melatonin may be useful as a short-term sleep aid and that’s a good discussion to have with your child’s health care provider.”

If parents do decide to give their child a melatonin supplement, they need to keep in mind that melatonin may alter how the body handles other drugs such as those used to treat epilepsy or blood clotting. They also need to know experts are still uncertain about how melatonin affects the body over the long term and whether it is safe for mothers to take during pregnancy.

Dr. Osterhoudt offered his own recommendations for safe melatonin use in the home:

• Discuss planned melatonin use with your health care provider.
• Buy only high-quality supplements by looking for the “USP Verified” mark.
• Insist that manufacturers sell products in child-resistant bottles.
• Periodically inspect the medications in your home and dispose of medications that are no longer being used.
• Program the phone number of your regional poison control center into your phone; poison center experts are available 24/7 to answer questions and concerns about ingestions of melatonin (in the United States the number is 1-800-222-1222).

The study authors and neither Dr. Toce nor Dr. Osterhoudt had any relevant conflicts of interest to declare.

The number of children in the United States who unintentionally ingested melatonin supplements over the past 10 years has skyrocketed to the point where, as of 2021, melatonin ingestions by children accounted for almost 5% of all poisonings reported to poison control centers in the United States, data from the National Poison Data System (NPDS) indicate.

This compared with only 0.6% of melatonin ingestions reported to poison control centers in 2012, the authors added.

“Basically the number of pediatric melatonin ingestions increased 530% from 8,337 in 2012 to 52,563 in 2021 so it’s a 6.3-fold increase from the beginning of the study until the end,” Michael Toce, MD, one of the study authors and attending, pediatric emergency medicine/medical toxicology, Boston Children’s Hospital, said in an interview.

“And I think the biggest driver of this increase is simply that sales of melatonin have increased astronomically so there is just more melatonin at home and studies have shown there is a correlation between the amount of an individual medication in the home and the risk of pediatric exposure – so simply put: The more of a single substance in a home, the greater the chance that a child is going to get into it,” he underscored.

The study was published in the Morbidity and Mortality Weekly Report .

Melatonin ingestions

All cases of single substance melatonin ingestions involving children and adolescents between Jan. 1, 2012, and Dec. 31, 2021, were included in the analysis. During the 10-year study interval, 260,435 pediatric melatonin ingestions were reported to the NPDS. Over 94% of the reported ingestions were unintentional and 99% occurred in the home.

Over 88% of them were managed on-site; most involved young male children aged 5 years and under, and almost 83% of children who ingested melatonin supplements remained asymptomatic. On the other hand, 27,795 patients sought care at a health care facility and close to 15% of them were hospitalized. Among all melatonin ingestions, 1.6% resulted in more serious outcomes; more serious outcomes being defined as a moderate or major effects or death. Five children required mechanical ventilation in order to treat their symptoms and 2 patients died.

The largest number of patients who were hospitalized were adolescents who took melatonin intentionally but the largest increase in the rate of exposure was in young, unintentional patients, as Dr. Toce observed. Interestingly, the largest yearly increase in pediatric melatonin ingestions – almost 38% – coincided with the onset of the COVID-19 pandemic.

“This might be related to increased accessibility of melatonin during the pandemic, as children spent more time at home because of stay-at-home orders and school closures,” the authors speculate. Moreover, sleep disturbances were common during the pandemic, leading to a greater likelihood that parents were buying melatonin and thus exposing children to more melatonin at home.

Taken appropriately and at normal does, melatonin in itself is quite safe, as Dr. Toce stressed. However, “for any substance, the dose makes the poison, so taken in any significant quantity, anything is going to be dangerous.” Moreover, it’s important to appreciate that melatonin, at least in the United States, is regulated as a dietary supplement, not as a pharmaceutical.

“Thus, it doesn’t get the same rigorous testing that something like acetaminophen does by the FDA and that means two things,” Dr. Toce noted. First, if the product says that each gummy contains 3 mg of melatonin, no independent body is verifying whether or not that statement is true so there could be 3 mg of melatonin in each gummy or there could be 10 mg,.

Secondly, because there is no impartial oversight for dietary supplements, there may in fact be no melatonin at all in the product or something else may be added to it that might be harmful. “Just because something is sold over-the-counter does not necessarily mean that it’s safe,” Dr. Toce stressed. To keep children safe from pharmaceuticals and supplements, he recommended several generic poison prevention tips. This advice could be passed on to patients who are parents.

• Keep all pharmaceuticals and supplements preferably locked away so there is less risk of children and adolescents taking products either unintentionally or intentionally
• If parents have no place to lock their products up, put them out of reach, high-up so children cannot easily access them
• Keep the product in the original child-resistant packaging as opposed to taking the pills out of the packaging and putting it in a plastic bag bag. “Certainly we’ve seen that when medications are moved into a non–child-resistant container, ingestions go up,” Dr. Toce warned
• Don’t refer to any medicine or supplement a child might take as “candy.” “A lot of children have difficulty taking medications so some families will say: ‘It’s time for your candy,’ ” Dr. Toce explained. Then, if a child does discover the “candy” on a table where they have access to it, they will not recognize it as medication and they’re likely to pop it into their mouth, thinking it is candy.

Lastly, and most importantly, parents who are considering trying a melatonin supplement to help a child sleep better should first establish a stable sleep routine for their child. “They also need to limit caffeinated beverages before bed as well as screen time,” Dr. Toce added.

And they should talk with their primary care provider as to whether or not initiation of a melatonin supplement is appropriate for their child – “and not just jump right into giving them melatonin without first discussing whether it is appropriate to do so,” Dr. Toce stressed.

Remarkable rise

In a comment on his own experience with melatonin poisoning over recent years, toxicology expert Kevin Osterhoudt, MD, of the University of Pennsylvania, Philadelphia and the Children’s Hospital of Philadelphia, noted that it has been their experience that there has been a remarkable rise in poison center reports of children ingesting melatonin in the recent past. For example, the Poison Control Center at CHOP received nearly 4,000 calls involving melatonin ingestion by children 5 years old or younger in the 5 years between 2017 and 2021 with increasing numbers every year.

“The [current study] supports that our regional observation that this has been a national trend,” Dr. Osterhoudt said. Dr. Osterhoudt agreed with Dr. Toce that good sleep is healthy, and it is very important to develop good sleep habits and a regular bedtime routine in order to do so. “In some situations, melatonin may be useful as a short-term sleep aid and that’s a good discussion to have with your child’s health care provider.”

If parents do decide to give their child a melatonin supplement, they need to keep in mind that melatonin may alter how the body handles other drugs such as those used to treat epilepsy or blood clotting. They also need to know experts are still uncertain about how melatonin affects the body over the long term and whether it is safe for mothers to take during pregnancy.

Dr. Osterhoudt offered his own recommendations for safe melatonin use in the home:

• Discuss planned melatonin use with your health care provider.
• Buy only high-quality supplements by looking for the “USP Verified” mark.
• Insist that manufacturers sell products in child-resistant bottles.
• Periodically inspect the medications in your home and dispose of medications that are no longer being used.
• Program the phone number of your regional poison control center into your phone; poison center experts are available 24/7 to answer questions and concerns about ingestions of melatonin (in the United States the number is 1-800-222-1222).

The study authors and neither Dr. Toce nor Dr. Osterhoudt had any relevant conflicts of interest to declare.

The number of children in the United States who unintentionally ingested melatonin supplements over the past 10 years has skyrocketed to the point where, as of 2021, melatonin ingestions by children accounted for almost 5% of all poisonings reported to poison control centers in the United States, data from the National Poison Data System (NPDS) indicate.

This compared with only 0.6% of melatonin ingestions reported to poison control centers in 2012, the authors added.

“Basically the number of pediatric melatonin ingestions increased 530% from 8,337 in 2012 to 52,563 in 2021 so it’s a 6.3-fold increase from the beginning of the study until the end,” Michael Toce, MD, one of the study authors and attending, pediatric emergency medicine/medical toxicology, Boston Children’s Hospital, said in an interview.

“And I think the biggest driver of this increase is simply that sales of melatonin have increased astronomically so there is just more melatonin at home and studies have shown there is a correlation between the amount of an individual medication in the home and the risk of pediatric exposure – so simply put: The more of a single substance in a home, the greater the chance that a child is going to get into it,” he underscored.

The study was published in the Morbidity and Mortality Weekly Report .

Melatonin ingestions

All cases of single substance melatonin ingestions involving children and adolescents between Jan. 1, 2012, and Dec. 31, 2021, were included in the analysis. During the 10-year study interval, 260,435 pediatric melatonin ingestions were reported to the NPDS. Over 94% of the reported ingestions were unintentional and 99% occurred in the home.

Over 88% of them were managed on-site; most involved young male children aged 5 years and under, and almost 83% of children who ingested melatonin supplements remained asymptomatic. On the other hand, 27,795 patients sought care at a health care facility and close to 15% of them were hospitalized. Among all melatonin ingestions, 1.6% resulted in more serious outcomes; more serious outcomes being defined as a moderate or major effects or death. Five children required mechanical ventilation in order to treat their symptoms and 2 patients died.

The largest number of patients who were hospitalized were adolescents who took melatonin intentionally but the largest increase in the rate of exposure was in young, unintentional patients, as Dr. Toce observed. Interestingly, the largest yearly increase in pediatric melatonin ingestions – almost 38% – coincided with the onset of the COVID-19 pandemic.

“This might be related to increased accessibility of melatonin during the pandemic, as children spent more time at home because of stay-at-home orders and school closures,” the authors speculate. Moreover, sleep disturbances were common during the pandemic, leading to a greater likelihood that parents were buying melatonin and thus exposing children to more melatonin at home.

Taken appropriately and at normal does, melatonin in itself is quite safe, as Dr. Toce stressed. However, “for any substance, the dose makes the poison, so taken in any significant quantity, anything is going to be dangerous.” Moreover, it’s important to appreciate that melatonin, at least in the United States, is regulated as a dietary supplement, not as a pharmaceutical.

“Thus, it doesn’t get the same rigorous testing that something like acetaminophen does by the FDA and that means two things,” Dr. Toce noted. First, if the product says that each gummy contains 3 mg of melatonin, no independent body is verifying whether or not that statement is true so there could be 3 mg of melatonin in each gummy or there could be 10 mg,.

Secondly, because there is no impartial oversight for dietary supplements, there may in fact be no melatonin at all in the product or something else may be added to it that might be harmful. “Just because something is sold over-the-counter does not necessarily mean that it’s safe,” Dr. Toce stressed. To keep children safe from pharmaceuticals and supplements, he recommended several generic poison prevention tips. This advice could be passed on to patients who are parents.

• Keep all pharmaceuticals and supplements preferably locked away so there is less risk of children and adolescents taking products either unintentionally or intentionally
• If parents have no place to lock their products up, put them out of reach, high-up so children cannot easily access them
• Keep the product in the original child-resistant packaging as opposed to taking the pills out of the packaging and putting it in a plastic bag bag. “Certainly we’ve seen that when medications are moved into a non–child-resistant container, ingestions go up,” Dr. Toce warned
• Don’t refer to any medicine or supplement a child might take as “candy.” “A lot of children have difficulty taking medications so some families will say: ‘It’s time for your candy,’ ” Dr. Toce explained. Then, if a child does discover the “candy” on a table where they have access to it, they will not recognize it as medication and they’re likely to pop it into their mouth, thinking it is candy.

Lastly, and most importantly, parents who are considering trying a melatonin supplement to help a child sleep better should first establish a stable sleep routine for their child. “They also need to limit caffeinated beverages before bed as well as screen time,” Dr. Toce added.

And they should talk with their primary care provider as to whether or not initiation of a melatonin supplement is appropriate for their child – “and not just jump right into giving them melatonin without first discussing whether it is appropriate to do so,” Dr. Toce stressed.

Remarkable rise

In a comment on his own experience with melatonin poisoning over recent years, toxicology expert Kevin Osterhoudt, MD, of the University of Pennsylvania, Philadelphia and the Children’s Hospital of Philadelphia, noted that it has been their experience that there has been a remarkable rise in poison center reports of children ingesting melatonin in the recent past. For example, the Poison Control Center at CHOP received nearly 4,000 calls involving melatonin ingestion by children 5 years old or younger in the 5 years between 2017 and 2021 with increasing numbers every year.

“The [current study] supports that our regional observation that this has been a national trend,” Dr. Osterhoudt said. Dr. Osterhoudt agreed with Dr. Toce that good sleep is healthy, and it is very important to develop good sleep habits and a regular bedtime routine in order to do so. “In some situations, melatonin may be useful as a short-term sleep aid and that’s a good discussion to have with your child’s health care provider.”

If parents do decide to give their child a melatonin supplement, they need to keep in mind that melatonin may alter how the body handles other drugs such as those used to treat epilepsy or blood clotting. They also need to know experts are still uncertain about how melatonin affects the body over the long term and whether it is safe for mothers to take during pregnancy.

Dr. Osterhoudt offered his own recommendations for safe melatonin use in the home:

• Discuss planned melatonin use with your health care provider.
• Buy only high-quality supplements by looking for the “USP Verified” mark.
• Insist that manufacturers sell products in child-resistant bottles.
• Periodically inspect the medications in your home and dispose of medications that are no longer being used.
• Program the phone number of your regional poison control center into your phone; poison center experts are available 24/7 to answer questions and concerns about ingestions of melatonin (in the United States the number is 1-800-222-1222).

The study authors and neither Dr. Toce nor Dr. Osterhoudt had any relevant conflicts of interest to declare.

Although breast cancer occurs less frequently in Black women, compared with White women, they have a much higher risk of dying from the disease.

In the United States, age-adjusted breast cancer mortality between 2014 and 2018 was approximately 40% higher among Black women than among non-Hispanic White women.

This mortality gap likely reflects the fact that Black women face substantial barriers to obtaining timely, high-quality medical care, compared with White women, lead author Ismail Jatoi, MD, PhD, University of Texas Health Science Center, San Antonio, and colleagues suggest in a recent opinion piece.

The article was published online  in The New England Journal of Medicine.

When the team examined the statistics for breast cancer mortality, they found a surprise: The mortality gap between races only dates back to 1980.

Prior to 1980, mortality from breast cancer among Black women was slightly lower than White women, Dr. Jatoi and colleagues point out.

That year was a turning point in breast cancer management, as in 1980, both mammography screening and adjuvant endocrine therapy became available.

This was also when the mortality gap between the races started to show up.

It was disparities in access to the two new interventions that precipitated the divergence, as the authors suggest. Why this occurred is fairly self-evident, they comment.

“Black women are more likely than White women to lack health insurance or to have inadequate coverage, which has limited their access to mammography screening and adversely affected therapeutic decisionmaking,” researchers point out.

Moreover, both mammography screening and endocrine therapy primarily benefit patients with hormone receptor (HR)-positive breast cancer, which is equally common in Black and White patients. However, Black women have a 65% higher rate of HR-negative cancers than White women – and HR-negative tumors are often detected during the interval between mammography screening exams as palpable cancers.

Black women also have an 81% higher rate of triple-negative breast cancer, so they have benefited less from mammography screening and adjuvant endocrine therapy, both of which favor the detection and treatment of HR-positive breast cancer, the authors emphasize.

Some have suggested that the excess HR-negative breast cancer in Black women might be explained by hereditary factors. Yet as Dr. Jatoi and colleagues point out, the incidence of HR-negative breast cancer has actually been falling across all races in the United States since 1992.

However, the declines have been slower among Black women, and reductions in its incidence have been smaller among White women living in less affluent regions of the United States compared with White women from more affluent regions.

These patterns suggest that social determinants of health influence not only access to and quality of health care but also the development of HR-negative breast cancers, as the authors observe.

“If all people with breast cancer benefited equally from effective medical interventions, racial differences in mortality for individual tumor subtypes would largely reflect differences in incidence,” Dr. Jatoi and colleagues continue.

Yet the statistics show that the substantial racial disparities in mortality for both HR-positive and HR-negative cancers between Black and White women cannot be explained by differences in the incidence of either tumor alone, they write.

For example, mortality for HR-positive breast cancer is 19% higher among Black women than among White women, yet the incidence of HR-positive breast cancer is 22% lower among Black women.

Similarly, mortality from HR-negative breast cancer is over twice as high among Black women as it is among White women – a substantially larger disparity, compared with the 65% relative difference in the incidence of HR-negative breast cancer between the two races.

“Universal health care coverage could reduce disparities in treatment for cancers of all subtypes, including triple-negative breast cancer,” Dr. Jatoi and colleagues emphasize.

“Ensuring universal access to high-quality medical care can substantially narrow the racial disparity in U.S. breast-cancer mortality,” they conclude. 

The authors have reported no relevant financial relationships.

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

Although breast cancer occurs less frequently in Black women, compared with White women, they have a much higher risk of dying from the disease.

In the United States, age-adjusted breast cancer mortality between 2014 and 2018 was approximately 40% higher among Black women than among non-Hispanic White women.

This mortality gap likely reflects the fact that Black women face substantial barriers to obtaining timely, high-quality medical care, compared with White women, lead author Ismail Jatoi, MD, PhD, University of Texas Health Science Center, San Antonio, and colleagues suggest in a recent opinion piece.

The article was published online  in The New England Journal of Medicine.

When the team examined the statistics for breast cancer mortality, they found a surprise: The mortality gap between races only dates back to 1980.

Prior to 1980, mortality from breast cancer among Black women was slightly lower than White women, Dr. Jatoi and colleagues point out.

That year was a turning point in breast cancer management, as in 1980, both mammography screening and adjuvant endocrine therapy became available.

This was also when the mortality gap between the races started to show up.

It was disparities in access to the two new interventions that precipitated the divergence, as the authors suggest. Why this occurred is fairly self-evident, they comment.

“Black women are more likely than White women to lack health insurance or to have inadequate coverage, which has limited their access to mammography screening and adversely affected therapeutic decisionmaking,” researchers point out.

Moreover, both mammography screening and endocrine therapy primarily benefit patients with hormone receptor (HR)-positive breast cancer, which is equally common in Black and White patients. However, Black women have a 65% higher rate of HR-negative cancers than White women – and HR-negative tumors are often detected during the interval between mammography screening exams as palpable cancers.

Black women also have an 81% higher rate of triple-negative breast cancer, so they have benefited less from mammography screening and adjuvant endocrine therapy, both of which favor the detection and treatment of HR-positive breast cancer, the authors emphasize.

Some have suggested that the excess HR-negative breast cancer in Black women might be explained by hereditary factors. Yet as Dr. Jatoi and colleagues point out, the incidence of HR-negative breast cancer has actually been falling across all races in the United States since 1992.

However, the declines have been slower among Black women, and reductions in its incidence have been smaller among White women living in less affluent regions of the United States compared with White women from more affluent regions.

These patterns suggest that social determinants of health influence not only access to and quality of health care but also the development of HR-negative breast cancers, as the authors observe.

“If all people with breast cancer benefited equally from effective medical interventions, racial differences in mortality for individual tumor subtypes would largely reflect differences in incidence,” Dr. Jatoi and colleagues continue.

Yet the statistics show that the substantial racial disparities in mortality for both HR-positive and HR-negative cancers between Black and White women cannot be explained by differences in the incidence of either tumor alone, they write.

For example, mortality for HR-positive breast cancer is 19% higher among Black women than among White women, yet the incidence of HR-positive breast cancer is 22% lower among Black women.

Similarly, mortality from HR-negative breast cancer is over twice as high among Black women as it is among White women – a substantially larger disparity, compared with the 65% relative difference in the incidence of HR-negative breast cancer between the two races.

“Universal health care coverage could reduce disparities in treatment for cancers of all subtypes, including triple-negative breast cancer,” Dr. Jatoi and colleagues emphasize.

“Ensuring universal access to high-quality medical care can substantially narrow the racial disparity in U.S. breast-cancer mortality,” they conclude. 

The authors have reported no relevant financial relationships.

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

Although breast cancer occurs less frequently in Black women, compared with White women, they have a much higher risk of dying from the disease.

In the United States, age-adjusted breast cancer mortality between 2014 and 2018 was approximately 40% higher among Black women than among non-Hispanic White women.

This mortality gap likely reflects the fact that Black women face substantial barriers to obtaining timely, high-quality medical care, compared with White women, lead author Ismail Jatoi, MD, PhD, University of Texas Health Science Center, San Antonio, and colleagues suggest in a recent opinion piece.

The article was published online  in The New England Journal of Medicine.

When the team examined the statistics for breast cancer mortality, they found a surprise: The mortality gap between races only dates back to 1980.

Prior to 1980, mortality from breast cancer among Black women was slightly lower than White women, Dr. Jatoi and colleagues point out.

That year was a turning point in breast cancer management, as in 1980, both mammography screening and adjuvant endocrine therapy became available.

This was also when the mortality gap between the races started to show up.

It was disparities in access to the two new interventions that precipitated the divergence, as the authors suggest. Why this occurred is fairly self-evident, they comment.

“Black women are more likely than White women to lack health insurance or to have inadequate coverage, which has limited their access to mammography screening and adversely affected therapeutic decisionmaking,” researchers point out.

Moreover, both mammography screening and endocrine therapy primarily benefit patients with hormone receptor (HR)-positive breast cancer, which is equally common in Black and White patients. However, Black women have a 65% higher rate of HR-negative cancers than White women – and HR-negative tumors are often detected during the interval between mammography screening exams as palpable cancers.

Black women also have an 81% higher rate of triple-negative breast cancer, so they have benefited less from mammography screening and adjuvant endocrine therapy, both of which favor the detection and treatment of HR-positive breast cancer, the authors emphasize.

Some have suggested that the excess HR-negative breast cancer in Black women might be explained by hereditary factors. Yet as Dr. Jatoi and colleagues point out, the incidence of HR-negative breast cancer has actually been falling across all races in the United States since 1992.

However, the declines have been slower among Black women, and reductions in its incidence have been smaller among White women living in less affluent regions of the United States compared with White women from more affluent regions.

These patterns suggest that social determinants of health influence not only access to and quality of health care but also the development of HR-negative breast cancers, as the authors observe.

“If all people with breast cancer benefited equally from effective medical interventions, racial differences in mortality for individual tumor subtypes would largely reflect differences in incidence,” Dr. Jatoi and colleagues continue.

Yet the statistics show that the substantial racial disparities in mortality for both HR-positive and HR-negative cancers between Black and White women cannot be explained by differences in the incidence of either tumor alone, they write.

For example, mortality for HR-positive breast cancer is 19% higher among Black women than among White women, yet the incidence of HR-positive breast cancer is 22% lower among Black women.

Similarly, mortality from HR-negative breast cancer is over twice as high among Black women as it is among White women – a substantially larger disparity, compared with the 65% relative difference in the incidence of HR-negative breast cancer between the two races.

“Universal health care coverage could reduce disparities in treatment for cancers of all subtypes, including triple-negative breast cancer,” Dr. Jatoi and colleagues emphasize.

“Ensuring universal access to high-quality medical care can substantially narrow the racial disparity in U.S. breast-cancer mortality,” they conclude. 

The authors have reported no relevant financial relationships.

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

Patients with locally advanced rectal cancer and tumors with deficient mismatch repair (dMMR) have shown a remarkable response to treatment with the programmed cell death-1 (PD-1) inhibitor dostarlimab (Jemperli).

Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.  

The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.

About 5%-10% of patients with rectal cancer have tumors with dMMR.

“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.

The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
 

Single-agent dostarlimab

For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.

Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.

All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.

For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.

As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.

“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”

To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.

In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.

Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.

The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
 

Editorial commentary

In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy. 

For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”

Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.

“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.

“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.

In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.

The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.

The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.

In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”

The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others. 

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

Patients with locally advanced rectal cancer and tumors with deficient mismatch repair (dMMR) have shown a remarkable response to treatment with the programmed cell death-1 (PD-1) inhibitor dostarlimab (Jemperli).

Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.  

The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.

About 5%-10% of patients with rectal cancer have tumors with dMMR.

“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.

The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
 

Single-agent dostarlimab

For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.

Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.

All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.

For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.

As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.

“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”

To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.

In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.

Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.

The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
 

Editorial commentary

In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy. 

For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”

Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.

“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.

“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.

In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.

The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.

The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.

In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”

The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others. 

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

Patients with locally advanced rectal cancer and tumors with deficient mismatch repair (dMMR) have shown a remarkable response to treatment with the programmed cell death-1 (PD-1) inhibitor dostarlimab (Jemperli).

Thus far, the study has involved only 12 patients, but all of them have had a clinical complete response to treatment. They continue to show no signs of cancer (during follow-up ranging from 6 to 25 months) and have not undergone surgery or had radiation and chemotherapy, which are the standard treatment approaches.  

The results were presented (Abstract 16) at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“In our study, the elimination of tumors after 6 months of therapy with PD-1 blockade enabled us to omit both chemoradiotherapy and surgery and to proceed with observation alone,” said the authors, led by Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center, New York.

About 5%-10% of patients with rectal cancer have tumors with dMMR.

“The implications for quality of life are substantial, especially among patients in whom standard treatment would affect child-bearing potential [and] given that the incidence of rectal cancer is rising among young adults of childbearing age, the use of PD-1 blockade to eliminate the need for chemoradiotherapy and surgery may confer a particular benefit in that age group,” the authors wrote.

The results of the current study are cause for “great optimism, but such an approach cannot yet supplant our current curative treatment approach,” Dr. Hanna K. Sanoff, MD, University of North Carolina at Chapel Hill, wrote in an accompanying editorial.
 

Single-agent dostarlimab

For the study, all patients were treated with single-agent dostarlimab every 3 weeks for 6 months.

Dostarlimab is already approved by the Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with dMMR. Rectal cancer is an off-label use.

All patients had mismatch repair-deficient stage 2 or 3 rectal adenocarcinoma. The authors noted that these tumors respond poorly to standard chemotherapy regimens, including neoadjuvant chemotherapy. The median age of enrolled patients was 54 years and 62% were women.

For the study, investigators planned that patients who had a clinical complete response after completion of dostarlimab were to proceed to observation without undergoing either chemoradiotherapy or surgery, while those who did not have a complete response were to have received these standard treatments.

As it turned out, all 12 patients achieved a complete response and have been followed by observation alone. The median follow-up from time of enrollment to data cutoff for the 12 patients was 12 months.

“Therapeutic responses were rapid,” the authors noted, “with resolution of symptoms within 8 weeks after initiation of dostarlimab in 81% of the patients.”

To date, four patients have had 1 year of sustained clinical complete response after completion of the anti-PD-1 course.

In addition to the 12 patients documented in the study, another four patients have received at least one dose of dostarlimab and continue to receive treatment.

Adverse events occurred in most patients but none were grade 3 or higher. The most common grade 1 or 2 adverse events were rash or dermatitis, pruritus, fatigue, nausea and, in one patient, thyroid-function abnormalities.

The authors speculated that in addition to the extremely high tumor mutational burden associated with mismatch-repair deficiency, a tumor cell–extrinsic factor such as the gut microbiome may be driving the exceptionally good response to PD-1 blockade seen in this patient population.
 

Editorial commentary

In the editorial, Dr. Sanoff emphasized that the approach remains experimental and should not replace current curative treatment. She noted that cancer recurrences have been seen in other studies using both chemotherapy and immunotherapy. 

For example, with chemotherapy and radiation, those patients who achieve a clinical complete response have a better prognosis compared with those who do not, but she cautioned that “cancer regrowth occurs in 20% to 30% of such patients when the cancer is managed nonoperatively.”

Dr. Sanoff noted that recurrences were seen when this approach of PD-1 inhibition has been used for metastatic colorectal cancer with dMMR. In the KEYNOTE-177 trial with pembrolizumab (Keytruda), only 55% of patients were reported to be alive without cancer progression at 12 months, and of the patients who initially had a strong response, only 70% had an ongoing response 3 years later.

“These recurrence dynamics may (or may not) differ between immunotherapy and chemoradiotherapy and between early and late-stage disease,” Dr. Sanoff said.

“In fact, very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” she added.

In addition, Dr. Sanoff warned that the decision not to pursue further treatment and to follow patients with observation alone requires very close monitoring.

The current study was conducted at a top U.S. cancer center, Memorial Sloan Kettering Cancer Center. The authors noted that the complete responses (after a minimum of 6 months of follow-up) were measured by the combination of rectal MRI, visual endoscopic inspection, and digital rectal examination.

The completeness of these responses was further supported by the absence of residual tumor on serial endoscopic biopsies and the resolution of 18F-fluorodeoxyglucose uptake on PET scans, the authors added.

In the editorial, Dr. Sanoff said that “safe nonoperative management [also] involves access to specialty care for direct intraluminal visualization and expertise in interpretation of rectal magnetic resonance imaging ... Such expertise is not available in all communities and without it, patients could miss the opportunity for curative resection if tumor regrowth occurred.”

The study was sponsored by the Simon and Eve Colin Foundation, GlaxoSmithKline, and Stand Up to Cancer, among others. 

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

Adagrasib, an investigational drug that acts as a KRASG12C inhibitor, has shown durable clinical benefit in patients with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.

“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.

“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.

New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.

Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.

If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.  

Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
 

Published clinical data

The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.

It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.

Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.

On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.

Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.

Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.

“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.

Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
 

CNS metastases

At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.

As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.

The study was funded by Mirati Therapeutics.

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

Adagrasib, an investigational drug that acts as a KRASG12C inhibitor, has shown durable clinical benefit in patients with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.

“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.

“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.

New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.

Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.

If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.  

Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
 

Published clinical data

The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.

It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.

Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.

On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.

Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.

Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.

“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.

Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
 

CNS metastases

At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.

As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.

The study was funded by Mirati Therapeutics.

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

Adagrasib, an investigational drug that acts as a KRASG12C inhibitor, has shown durable clinical benefit in patients with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.

“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.

“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.

New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.

Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.

If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.  

Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
 

Published clinical data

The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.

It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.

Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.

On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.

Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.

Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.

“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.

Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
 

CNS metastases

At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.

As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.

The study was funded by Mirati Therapeutics.

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

Two doses of either the Pfizer-BioNTech COVID-19 vaccine or the Oxford AstraZeneca alternative provide equal and significant protection against severe disease in patients on hemodialysis who have contracted SARS-CoV-2 infection, results of a multicenter observational study indicate.

Following two doses of either vaccine, the risk of hospital admission was 75% lower among vaccinated patients while the risk of death was 88% lower, compared with those who remained unvaccinated.

No difference was seen between the two vaccine types in terms of outcome severity, and there was no loss of protection in patients over the age of 65 or with increasing time since vaccination, the authors add. The need for oxygen and ventilation was also halved among those who had received two shots, compared with those who had not.

“The coronavirus disease 2019 (COVID-19) pandemic has had a devastating effect on the CKD (chronic kidney disease) community, particularly for individuals receiving maintenance dialysis,” Matthew Oliver, MD, University of Toronto, and Peter Blake, MD, Western University, London, Ont., write in an editorial published with the study.

“Overall, [this and other studies] show that COVID-19 vaccination in the maintenance dialysis population provides moderate protection against acquiring SARS-CoV-2 infection but is highly protective against severe outcomes,” they conclude.

The study was published in the June issue of the Clinical Journal of the American Society of Nephrology.
 

Severe outcomes observed less in patients who tested positive

The cohort included 1,323 patients on hemodialysis who tested positive on PCR testing to SARS-CoV-2 during a surveillance interval between December 2020 and September 2021, report, Damien Ashby, MD, Hammersmith Hospital, London, and colleagues report.

Among those who tested positive, 79% had not been vaccinated, 7% tested positive after their first dose of either vaccine, and 14% tested positive at least 10 days beyond their second dose.

The course of illness was mild in 61% of patients in that they did not require hospital admission, investigators note. Oxygen support was required by 29% of those who tested positive, and 13% died before 28 days, they added. Among those who died within 28 days of testing positive, 90% of the deaths were deemed to be caused by the virus itself.

“Compared with unvaccinated patients, severe COVID-19 outcomes were observed less than half as often in patients testing positive for SARS-Co-V-2 at least 10 days after the second dose,” Dr. Ashby and colleagues emphasize.

“And the protection from severe illness associated with vaccination was most obvious in patients over 65 years, in whom severe COVID-19 outcomes were reduced at least as much after vaccination as in their younger peers,” they add. Following vaccination with the Pfizer-BioNTech vaccine, antibody levels in patients on dialysis were comparable with those of healthy controls.

In contrast, this was not the case for the Oxford AstraZeneca vaccine where neutralizing titers in patients who received the vaccine were less effective against most variants. Despite its ability to produce comparable immunogenicity, the Oxford AstraZeneca vaccine was clearly associated with clinical protection against severe illness, the authors stress.  

They also note that their results are relevant to vaccine uptake in the dialysis population where vaccine hesitancy remains a problem. “This study may, therefore, be useful in reducing vaccine hesitancy, which has resulted in low uptake in some countries (for example, Australia, where almost a quarter of patients on dialysis declined),” Dr. Ashby and colleagues point out.

Although significant vulnerability in the dialysis population remains, “this population has much to gain from vaccination, regardless of age or vaccine type,” the authors underscore.
 

CKD community quick to prioritize vaccine

As the editorialists point out, leaders in the CKD community were quick – and successful – in prioritizing vaccination in the dialysis population right from the beginning of the pandemic. For example, in Ontario, 90% of the maintenance dialysis population had received two doses of a COVID-19 vaccine by September 2021 and 78% had received three doses by January 2022.

Moreover, in Ontario, “our group found that two doses of mRNA vaccine reduced the risk of infection by 69%,” Dr. Oliver and Dr. Blake point out. U.S. researchers also found that the Pfizer mRNA vaccine reduced infection risk from COVID-19 by 79% while the Moderna mRNA vaccine reduced that risk by 73%. Vaccine effectiveness (VE) in the real-world setting indicates that COVID-19 vaccines provide moderate protection against being infected with the SARS-Co-V-2 virus, as the editorialists note.

However, “the VE for preventing severe outcomes is clinically more important for patients on dialysis because their risk of [morbid] events is high,” Dr. Oliver and Dr. Blake write. Indeed, their own study estimated that two doses of an mRNA vaccine reduced severe outcomes by 83%, “a greater benefit than for infection prevention,” they stress.

The editorialists caution that the SARS-CoV-2 virus continues to mutate and serology studies do show that vaccine-induced immunity does wane over time. Thus, while the COVID-19 pandemic is ever-changing, “we should conduct [VE] studies rigorously and expeditiously to bolster the case for prioritizing vaccination in the dialysis population,” Dr. Oliver and Dr. Blake recommend.
 

Need to increase vaccine acceptance

Commenting on the study, Uwe K.H. Korst from Bensheim, Germany, notes that COVID-19 is a daily reminder of how fragile life is for people with CKD. “Daily, the virus continues its horrific and unprecedented course through immunocompromised and immunosuppressed patients with kidney disease,” he writes.

Thus, Mr. Korst continues to call for additional education for health care professionals, patients, and the public to increase vaccine acceptance as well as more research to better understand the virus and its long-term consequences.

“Finally, patients need to express their needs, and physicians need to listen to patients’ voices,” Mr. Korst advises.

Dr. Oliver is a contracted medical lead of Ontario Renal Network and owner of Oliver Medical Management for which he holds patents and has received royalties. He has also reported receiving honoraria for speaking from Baxter Healthcare and participating in advisory boards for Amgen and Janssen. Dr. Blake has reported receiving honoraria from Baxter Global for speaking engagements and serves on the editorial board for the American Journal of Nephrology. Dr. Ashby and Dr. Korst have reported no relevant financial relationships.

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

Two doses of either the Pfizer-BioNTech COVID-19 vaccine or the Oxford AstraZeneca alternative provide equal and significant protection against severe disease in patients on hemodialysis who have contracted SARS-CoV-2 infection, results of a multicenter observational study indicate.

Following two doses of either vaccine, the risk of hospital admission was 75% lower among vaccinated patients while the risk of death was 88% lower, compared with those who remained unvaccinated.

No difference was seen between the two vaccine types in terms of outcome severity, and there was no loss of protection in patients over the age of 65 or with increasing time since vaccination, the authors add. The need for oxygen and ventilation was also halved among those who had received two shots, compared with those who had not.

“The coronavirus disease 2019 (COVID-19) pandemic has had a devastating effect on the CKD (chronic kidney disease) community, particularly for individuals receiving maintenance dialysis,” Matthew Oliver, MD, University of Toronto, and Peter Blake, MD, Western University, London, Ont., write in an editorial published with the study.

“Overall, [this and other studies] show that COVID-19 vaccination in the maintenance dialysis population provides moderate protection against acquiring SARS-CoV-2 infection but is highly protective against severe outcomes,” they conclude.

The study was published in the June issue of the Clinical Journal of the American Society of Nephrology.
 

Severe outcomes observed less in patients who tested positive

The cohort included 1,323 patients on hemodialysis who tested positive on PCR testing to SARS-CoV-2 during a surveillance interval between December 2020 and September 2021, report, Damien Ashby, MD, Hammersmith Hospital, London, and colleagues report.

Among those who tested positive, 79% had not been vaccinated, 7% tested positive after their first dose of either vaccine, and 14% tested positive at least 10 days beyond their second dose.

The course of illness was mild in 61% of patients in that they did not require hospital admission, investigators note. Oxygen support was required by 29% of those who tested positive, and 13% died before 28 days, they added. Among those who died within 28 days of testing positive, 90% of the deaths were deemed to be caused by the virus itself.

“Compared with unvaccinated patients, severe COVID-19 outcomes were observed less than half as often in patients testing positive for SARS-Co-V-2 at least 10 days after the second dose,” Dr. Ashby and colleagues emphasize.

“And the protection from severe illness associated with vaccination was most obvious in patients over 65 years, in whom severe COVID-19 outcomes were reduced at least as much after vaccination as in their younger peers,” they add. Following vaccination with the Pfizer-BioNTech vaccine, antibody levels in patients on dialysis were comparable with those of healthy controls.

In contrast, this was not the case for the Oxford AstraZeneca vaccine where neutralizing titers in patients who received the vaccine were less effective against most variants. Despite its ability to produce comparable immunogenicity, the Oxford AstraZeneca vaccine was clearly associated with clinical protection against severe illness, the authors stress.  

They also note that their results are relevant to vaccine uptake in the dialysis population where vaccine hesitancy remains a problem. “This study may, therefore, be useful in reducing vaccine hesitancy, which has resulted in low uptake in some countries (for example, Australia, where almost a quarter of patients on dialysis declined),” Dr. Ashby and colleagues point out.

Although significant vulnerability in the dialysis population remains, “this population has much to gain from vaccination, regardless of age or vaccine type,” the authors underscore.
 

CKD community quick to prioritize vaccine

As the editorialists point out, leaders in the CKD community were quick – and successful – in prioritizing vaccination in the dialysis population right from the beginning of the pandemic. For example, in Ontario, 90% of the maintenance dialysis population had received two doses of a COVID-19 vaccine by September 2021 and 78% had received three doses by January 2022.

Moreover, in Ontario, “our group found that two doses of mRNA vaccine reduced the risk of infection by 69%,” Dr. Oliver and Dr. Blake point out. U.S. researchers also found that the Pfizer mRNA vaccine reduced infection risk from COVID-19 by 79% while the Moderna mRNA vaccine reduced that risk by 73%. Vaccine effectiveness (VE) in the real-world setting indicates that COVID-19 vaccines provide moderate protection against being infected with the SARS-Co-V-2 virus, as the editorialists note.

However, “the VE for preventing severe outcomes is clinically more important for patients on dialysis because their risk of [morbid] events is high,” Dr. Oliver and Dr. Blake write. Indeed, their own study estimated that two doses of an mRNA vaccine reduced severe outcomes by 83%, “a greater benefit than for infection prevention,” they stress.

The editorialists caution that the SARS-CoV-2 virus continues to mutate and serology studies do show that vaccine-induced immunity does wane over time. Thus, while the COVID-19 pandemic is ever-changing, “we should conduct [VE] studies rigorously and expeditiously to bolster the case for prioritizing vaccination in the dialysis population,” Dr. Oliver and Dr. Blake recommend.
 

Need to increase vaccine acceptance

Commenting on the study, Uwe K.H. Korst from Bensheim, Germany, notes that COVID-19 is a daily reminder of how fragile life is for people with CKD. “Daily, the virus continues its horrific and unprecedented course through immunocompromised and immunosuppressed patients with kidney disease,” he writes.

Thus, Mr. Korst continues to call for additional education for health care professionals, patients, and the public to increase vaccine acceptance as well as more research to better understand the virus and its long-term consequences.

“Finally, patients need to express their needs, and physicians need to listen to patients’ voices,” Mr. Korst advises.

Dr. Oliver is a contracted medical lead of Ontario Renal Network and owner of Oliver Medical Management for which he holds patents and has received royalties. He has also reported receiving honoraria for speaking from Baxter Healthcare and participating in advisory boards for Amgen and Janssen. Dr. Blake has reported receiving honoraria from Baxter Global for speaking engagements and serves on the editorial board for the American Journal of Nephrology. Dr. Ashby and Dr. Korst have reported no relevant financial relationships.

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

Two doses of either the Pfizer-BioNTech COVID-19 vaccine or the Oxford AstraZeneca alternative provide equal and significant protection against severe disease in patients on hemodialysis who have contracted SARS-CoV-2 infection, results of a multicenter observational study indicate.

Following two doses of either vaccine, the risk of hospital admission was 75% lower among vaccinated patients while the risk of death was 88% lower, compared with those who remained unvaccinated.

No difference was seen between the two vaccine types in terms of outcome severity, and there was no loss of protection in patients over the age of 65 or with increasing time since vaccination, the authors add. The need for oxygen and ventilation was also halved among those who had received two shots, compared with those who had not.

“The coronavirus disease 2019 (COVID-19) pandemic has had a devastating effect on the CKD (chronic kidney disease) community, particularly for individuals receiving maintenance dialysis,” Matthew Oliver, MD, University of Toronto, and Peter Blake, MD, Western University, London, Ont., write in an editorial published with the study.

“Overall, [this and other studies] show that COVID-19 vaccination in the maintenance dialysis population provides moderate protection against acquiring SARS-CoV-2 infection but is highly protective against severe outcomes,” they conclude.

The study was published in the June issue of the Clinical Journal of the American Society of Nephrology.
 

Severe outcomes observed less in patients who tested positive

The cohort included 1,323 patients on hemodialysis who tested positive on PCR testing to SARS-CoV-2 during a surveillance interval between December 2020 and September 2021, report, Damien Ashby, MD, Hammersmith Hospital, London, and colleagues report.

Among those who tested positive, 79% had not been vaccinated, 7% tested positive after their first dose of either vaccine, and 14% tested positive at least 10 days beyond their second dose.

The course of illness was mild in 61% of patients in that they did not require hospital admission, investigators note. Oxygen support was required by 29% of those who tested positive, and 13% died before 28 days, they added. Among those who died within 28 days of testing positive, 90% of the deaths were deemed to be caused by the virus itself.

“Compared with unvaccinated patients, severe COVID-19 outcomes were observed less than half as often in patients testing positive for SARS-Co-V-2 at least 10 days after the second dose,” Dr. Ashby and colleagues emphasize.

“And the protection from severe illness associated with vaccination was most obvious in patients over 65 years, in whom severe COVID-19 outcomes were reduced at least as much after vaccination as in their younger peers,” they add. Following vaccination with the Pfizer-BioNTech vaccine, antibody levels in patients on dialysis were comparable with those of healthy controls.

In contrast, this was not the case for the Oxford AstraZeneca vaccine where neutralizing titers in patients who received the vaccine were less effective against most variants. Despite its ability to produce comparable immunogenicity, the Oxford AstraZeneca vaccine was clearly associated with clinical protection against severe illness, the authors stress.  

They also note that their results are relevant to vaccine uptake in the dialysis population where vaccine hesitancy remains a problem. “This study may, therefore, be useful in reducing vaccine hesitancy, which has resulted in low uptake in some countries (for example, Australia, where almost a quarter of patients on dialysis declined),” Dr. Ashby and colleagues point out.

Although significant vulnerability in the dialysis population remains, “this population has much to gain from vaccination, regardless of age or vaccine type,” the authors underscore.
 

CKD community quick to prioritize vaccine

As the editorialists point out, leaders in the CKD community were quick – and successful – in prioritizing vaccination in the dialysis population right from the beginning of the pandemic. For example, in Ontario, 90% of the maintenance dialysis population had received two doses of a COVID-19 vaccine by September 2021 and 78% had received three doses by January 2022.

Moreover, in Ontario, “our group found that two doses of mRNA vaccine reduced the risk of infection by 69%,” Dr. Oliver and Dr. Blake point out. U.S. researchers also found that the Pfizer mRNA vaccine reduced infection risk from COVID-19 by 79% while the Moderna mRNA vaccine reduced that risk by 73%. Vaccine effectiveness (VE) in the real-world setting indicates that COVID-19 vaccines provide moderate protection against being infected with the SARS-Co-V-2 virus, as the editorialists note.

However, “the VE for preventing severe outcomes is clinically more important for patients on dialysis because their risk of [morbid] events is high,” Dr. Oliver and Dr. Blake write. Indeed, their own study estimated that two doses of an mRNA vaccine reduced severe outcomes by 83%, “a greater benefit than for infection prevention,” they stress.

The editorialists caution that the SARS-CoV-2 virus continues to mutate and serology studies do show that vaccine-induced immunity does wane over time. Thus, while the COVID-19 pandemic is ever-changing, “we should conduct [VE] studies rigorously and expeditiously to bolster the case for prioritizing vaccination in the dialysis population,” Dr. Oliver and Dr. Blake recommend.
 

Need to increase vaccine acceptance

Commenting on the study, Uwe K.H. Korst from Bensheim, Germany, notes that COVID-19 is a daily reminder of how fragile life is for people with CKD. “Daily, the virus continues its horrific and unprecedented course through immunocompromised and immunosuppressed patients with kidney disease,” he writes.

Thus, Mr. Korst continues to call for additional education for health care professionals, patients, and the public to increase vaccine acceptance as well as more research to better understand the virus and its long-term consequences.

“Finally, patients need to express their needs, and physicians need to listen to patients’ voices,” Mr. Korst advises.

Dr. Oliver is a contracted medical lead of Ontario Renal Network and owner of Oliver Medical Management for which he holds patents and has received royalties. He has also reported receiving honoraria for speaking from Baxter Healthcare and participating in advisory boards for Amgen and Janssen. Dr. Blake has reported receiving honoraria from Baxter Global for speaking engagements and serves on the editorial board for the American Journal of Nephrology. Dr. Ashby and Dr. Korst have reported no relevant financial relationships.

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

Not all patients with chronic obstructive pulmonary disease (COPD) respond equally well to pulmonary rehabilitation (PR).

Now, physicians can better categorize which patients will do well with PR and which ones less well or not well at all based on a new system of clustering of COPD patients according to their response to exercise therapy.

“We identified four clusters of COPD patients and their response to PR in the aim to better understand PR outcome and [adapt] it to patients’ profiles and needs,” lead author Yara Al Chikhanie, MD, of the cardiopulmonary rehabilitation center Dieulefit Sante (France), and colleagues observed.

“Identification of patients likely to show smaller responses to PR may help to target patients benefiting the most and to adapt PR settings for nonresponders to standard PR,” they suggested.

The study was published online in Respiratory Medicine.

Single-center cohort

The cohort consisted of 835 patients from a single center who had been admitted to a cardiopulmonary rehabilitation center over a 6-year period from 2021 to 2017. “The PR program used in the center was the same over the 6-year period,” the authors note – consisting of a 3- to 4-week, inpatient program with activities 5 days a week.

Each day, patients attended a 25-minute aerobic training session on a cycling ergometer or a treadmill; a 30-minute low-intensity gym session; a 30-minute group walk outdoors, and 30 minutes of strength training. “We aimed to cluster patients with COPD admitted to PR based on patients’ clinical characteristics and 6-meter walk test results (6MWT), pulse oxygen saturation (SPO₂), heart rate (HR), and dyspnea,” the authors explained.

They then evaluated patient response to PR in each of these clusters based on the amount of improvement in the 6-meter walk distance (6MWD), lung function, and quality of life observed, they added.

The population consisted of seniors, equally men and women, mostly GOLD II and III patients (a measure of lung function) with a limited walking capacity, some 84% of the cohort having a 6MWD <80% predicted. The characteristics of the four identified clusters were as follows:

• Cluster 1: Consisted of younger men, GOLD I to II, average walkers, obese. The average 6MWD was 430 meters and patients had a large exercise HR response to PR. This cluster had a 76 meter improvement in their 6MWD, although 16% of the same cluster still did not respond to PR.
• Cluster 2: Consisted of older women, GOLD II-III, who were slow walkers. This cluster had a reduced 6MWD of 362 meters, but they also had a significant 97-meter improvement in their 6MWD following PR. Some 18% were still nonresponders to PR.
• Cluster 3: Consisted of older men, GOLD II to III, dyspneic, slow walkers, some 32% of whom responded to PR. This cluster also had a reduced 6MWD at 388 meters, but again, they also had a significant improvement of 79 meters in their 6MWD following the introduction of PR. Some 11% were nonresponders to PR.
• Cluster 4: Consisted of older men, GOLD III to IV, very slow walkers, oxygen-dependent, very dyspneic. This cluster had a severely reduced 6MWD of only 290 meters with severe exercise desaturation and dyspnea, and almost all of them were on long-term oxygen therapy. Nevertheless, this cluster also had a significant, 66-meter improvement in their 6MWD. Twenty-eight percent of them were nonresponders to PR.

Clinical practice

“The highly heterogeneous nature of the enrolled patient population reflects clinical practice,” the authors point out. For example, cluster 1 included patients with the best lung function, compared with those in clusters 2, 3, and 4 – which may be due, at least in part, to the aggravation in disease severity with age given that patients in cluster 1 were the youngest overall.

The fact that those in cluster 4 had the worst performance may also have been because of age and disease severity, the authors note, as those in cluster 4 had the highest proportion of patients on long-term oxygen therapy, again suggestive of disease severity. “Of note, these patients show the most impaired 6MWT responses despite the use of oxygen supplementation during walking,” the researchers added.

The authors also suggest that patients such as those in cluster 4 may require specific PR modalities in order to optimize their functional benefits. In contrast, those in cluster 1 had a significantly higher body mass index, compared with those in the other 3 clusters, which, interestingly enough, was not associated with more severe functional exercise impairment. The fact that older age participants, such as those in cluster 3 as well as those with high BMI in cluster 1, were both able to improve their 6MWD post-PR to the same extent as younger patients without obesity suggests that most older or overweight/obese patients can still show clinically significant improvement in 6MWD post PR, as the authors suggest.

Notably, the 6MWT was the only test available both pre-and post PR, making this an important limitation of the study, because only one aspect of the effect of PR was evaluated, omitting other physical and psychosocial benefits of PR, investigators suggest.

Adds to the literature

Asked to comment on the findings, Sachin Gupta, MD, attending physician, pulmonary & critical care medicine, Alameda Health System, Highland Hospital, Oakland, Calif., felt that these data add to the literature in defining COPD patient profiles, helping to categorize those in whom to expect greater walk distance improvements with PR versus those who will respond less well.

“Because 6MWD is a surrogate marker for quality of life (QOL) and mortality, further analysis in the form of a randomized controlled trial to determine long-term outcomes among the four clusters with adjustment for baseline characteristics would help determine the extent to which certain patient clusters may respond to PR,” Dr. Gupta told this news organization in an email.

At the same time, he suggested that while patients may not experience much net benefit in their 6MWD, their QOL or mortality risk may still improve with PR. “I cannot recall a patient ever describing their experience with PR as anything other than positive,” Dr. Gupta stressed.

“And as the authors [themselves] note, because PR serves to benefit patients beyond the 6MWD, I would not recommend limiting PR referrals based on the patient clusters identified,” he said.

The authors had no conflicts of interest to declare. Dr. Gupta declared that he is an employee and shareholder at Genentech.

Not all patients with chronic obstructive pulmonary disease (COPD) respond equally well to pulmonary rehabilitation (PR).

Now, physicians can better categorize which patients will do well with PR and which ones less well or not well at all based on a new system of clustering of COPD patients according to their response to exercise therapy.

“We identified four clusters of COPD patients and their response to PR in the aim to better understand PR outcome and [adapt] it to patients’ profiles and needs,” lead author Yara Al Chikhanie, MD, of the cardiopulmonary rehabilitation center Dieulefit Sante (France), and colleagues observed.

“Identification of patients likely to show smaller responses to PR may help to target patients benefiting the most and to adapt PR settings for nonresponders to standard PR,” they suggested.

The study was published online in Respiratory Medicine.

Single-center cohort

The cohort consisted of 835 patients from a single center who had been admitted to a cardiopulmonary rehabilitation center over a 6-year period from 2021 to 2017. “The PR program used in the center was the same over the 6-year period,” the authors note – consisting of a 3- to 4-week, inpatient program with activities 5 days a week.

Each day, patients attended a 25-minute aerobic training session on a cycling ergometer or a treadmill; a 30-minute low-intensity gym session; a 30-minute group walk outdoors, and 30 minutes of strength training. “We aimed to cluster patients with COPD admitted to PR based on patients’ clinical characteristics and 6-meter walk test results (6MWT), pulse oxygen saturation (SPO₂), heart rate (HR), and dyspnea,” the authors explained.

They then evaluated patient response to PR in each of these clusters based on the amount of improvement in the 6-meter walk distance (6MWD), lung function, and quality of life observed, they added.

The population consisted of seniors, equally men and women, mostly GOLD II and III patients (a measure of lung function) with a limited walking capacity, some 84% of the cohort having a 6MWD <80% predicted. The characteristics of the four identified clusters were as follows:

• Cluster 1: Consisted of younger men, GOLD I to II, average walkers, obese. The average 6MWD was 430 meters and patients had a large exercise HR response to PR. This cluster had a 76 meter improvement in their 6MWD, although 16% of the same cluster still did not respond to PR.
• Cluster 2: Consisted of older women, GOLD II-III, who were slow walkers. This cluster had a reduced 6MWD of 362 meters, but they also had a significant 97-meter improvement in their 6MWD following PR. Some 18% were still nonresponders to PR.
• Cluster 3: Consisted of older men, GOLD II to III, dyspneic, slow walkers, some 32% of whom responded to PR. This cluster also had a reduced 6MWD at 388 meters, but again, they also had a significant improvement of 79 meters in their 6MWD following the introduction of PR. Some 11% were nonresponders to PR.
• Cluster 4: Consisted of older men, GOLD III to IV, very slow walkers, oxygen-dependent, very dyspneic. This cluster had a severely reduced 6MWD of only 290 meters with severe exercise desaturation and dyspnea, and almost all of them were on long-term oxygen therapy. Nevertheless, this cluster also had a significant, 66-meter improvement in their 6MWD. Twenty-eight percent of them were nonresponders to PR.

Clinical practice

“The highly heterogeneous nature of the enrolled patient population reflects clinical practice,” the authors point out. For example, cluster 1 included patients with the best lung function, compared with those in clusters 2, 3, and 4 – which may be due, at least in part, to the aggravation in disease severity with age given that patients in cluster 1 were the youngest overall.

The fact that those in cluster 4 had the worst performance may also have been because of age and disease severity, the authors note, as those in cluster 4 had the highest proportion of patients on long-term oxygen therapy, again suggestive of disease severity. “Of note, these patients show the most impaired 6MWT responses despite the use of oxygen supplementation during walking,” the researchers added.

The authors also suggest that patients such as those in cluster 4 may require specific PR modalities in order to optimize their functional benefits. In contrast, those in cluster 1 had a significantly higher body mass index, compared with those in the other 3 clusters, which, interestingly enough, was not associated with more severe functional exercise impairment. The fact that older age participants, such as those in cluster 3 as well as those with high BMI in cluster 1, were both able to improve their 6MWD post-PR to the same extent as younger patients without obesity suggests that most older or overweight/obese patients can still show clinically significant improvement in 6MWD post PR, as the authors suggest.

Notably, the 6MWT was the only test available both pre-and post PR, making this an important limitation of the study, because only one aspect of the effect of PR was evaluated, omitting other physical and psychosocial benefits of PR, investigators suggest.

Adds to the literature

Asked to comment on the findings, Sachin Gupta, MD, attending physician, pulmonary & critical care medicine, Alameda Health System, Highland Hospital, Oakland, Calif., felt that these data add to the literature in defining COPD patient profiles, helping to categorize those in whom to expect greater walk distance improvements with PR versus those who will respond less well.

“Because 6MWD is a surrogate marker for quality of life (QOL) and mortality, further analysis in the form of a randomized controlled trial to determine long-term outcomes among the four clusters with adjustment for baseline characteristics would help determine the extent to which certain patient clusters may respond to PR,” Dr. Gupta told this news organization in an email.

At the same time, he suggested that while patients may not experience much net benefit in their 6MWD, their QOL or mortality risk may still improve with PR. “I cannot recall a patient ever describing their experience with PR as anything other than positive,” Dr. Gupta stressed.

“And as the authors [themselves] note, because PR serves to benefit patients beyond the 6MWD, I would not recommend limiting PR referrals based on the patient clusters identified,” he said.

The authors had no conflicts of interest to declare. Dr. Gupta declared that he is an employee and shareholder at Genentech.

Not all patients with chronic obstructive pulmonary disease (COPD) respond equally well to pulmonary rehabilitation (PR).

Now, physicians can better categorize which patients will do well with PR and which ones less well or not well at all based on a new system of clustering of COPD patients according to their response to exercise therapy.

“We identified four clusters of COPD patients and their response to PR in the aim to better understand PR outcome and [adapt] it to patients’ profiles and needs,” lead author Yara Al Chikhanie, MD, of the cardiopulmonary rehabilitation center Dieulefit Sante (France), and colleagues observed.

“Identification of patients likely to show smaller responses to PR may help to target patients benefiting the most and to adapt PR settings for nonresponders to standard PR,” they suggested.

The study was published online in Respiratory Medicine.

Single-center cohort

The cohort consisted of 835 patients from a single center who had been admitted to a cardiopulmonary rehabilitation center over a 6-year period from 2021 to 2017. “The PR program used in the center was the same over the 6-year period,” the authors note – consisting of a 3- to 4-week, inpatient program with activities 5 days a week.

Each day, patients attended a 25-minute aerobic training session on a cycling ergometer or a treadmill; a 30-minute low-intensity gym session; a 30-minute group walk outdoors, and 30 minutes of strength training. “We aimed to cluster patients with COPD admitted to PR based on patients’ clinical characteristics and 6-meter walk test results (6MWT), pulse oxygen saturation (SPO₂), heart rate (HR), and dyspnea,” the authors explained.

They then evaluated patient response to PR in each of these clusters based on the amount of improvement in the 6-meter walk distance (6MWD), lung function, and quality of life observed, they added.

The population consisted of seniors, equally men and women, mostly GOLD II and III patients (a measure of lung function) with a limited walking capacity, some 84% of the cohort having a 6MWD <80% predicted. The characteristics of the four identified clusters were as follows:

• Cluster 1: Consisted of younger men, GOLD I to II, average walkers, obese. The average 6MWD was 430 meters and patients had a large exercise HR response to PR. This cluster had a 76 meter improvement in their 6MWD, although 16% of the same cluster still did not respond to PR.
• Cluster 2: Consisted of older women, GOLD II-III, who were slow walkers. This cluster had a reduced 6MWD of 362 meters, but they also had a significant 97-meter improvement in their 6MWD following PR. Some 18% were still nonresponders to PR.
• Cluster 3: Consisted of older men, GOLD II to III, dyspneic, slow walkers, some 32% of whom responded to PR. This cluster also had a reduced 6MWD at 388 meters, but again, they also had a significant improvement of 79 meters in their 6MWD following the introduction of PR. Some 11% were nonresponders to PR.
• Cluster 4: Consisted of older men, GOLD III to IV, very slow walkers, oxygen-dependent, very dyspneic. This cluster had a severely reduced 6MWD of only 290 meters with severe exercise desaturation and dyspnea, and almost all of them were on long-term oxygen therapy. Nevertheless, this cluster also had a significant, 66-meter improvement in their 6MWD. Twenty-eight percent of them were nonresponders to PR.

Clinical practice

“The highly heterogeneous nature of the enrolled patient population reflects clinical practice,” the authors point out. For example, cluster 1 included patients with the best lung function, compared with those in clusters 2, 3, and 4 – which may be due, at least in part, to the aggravation in disease severity with age given that patients in cluster 1 were the youngest overall.

The fact that those in cluster 4 had the worst performance may also have been because of age and disease severity, the authors note, as those in cluster 4 had the highest proportion of patients on long-term oxygen therapy, again suggestive of disease severity. “Of note, these patients show the most impaired 6MWT responses despite the use of oxygen supplementation during walking,” the researchers added.

The authors also suggest that patients such as those in cluster 4 may require specific PR modalities in order to optimize their functional benefits. In contrast, those in cluster 1 had a significantly higher body mass index, compared with those in the other 3 clusters, which, interestingly enough, was not associated with more severe functional exercise impairment. The fact that older age participants, such as those in cluster 3 as well as those with high BMI in cluster 1, were both able to improve their 6MWD post-PR to the same extent as younger patients without obesity suggests that most older or overweight/obese patients can still show clinically significant improvement in 6MWD post PR, as the authors suggest.

Notably, the 6MWT was the only test available both pre-and post PR, making this an important limitation of the study, because only one aspect of the effect of PR was evaluated, omitting other physical and psychosocial benefits of PR, investigators suggest.

Adds to the literature

Asked to comment on the findings, Sachin Gupta, MD, attending physician, pulmonary & critical care medicine, Alameda Health System, Highland Hospital, Oakland, Calif., felt that these data add to the literature in defining COPD patient profiles, helping to categorize those in whom to expect greater walk distance improvements with PR versus those who will respond less well.

“Because 6MWD is a surrogate marker for quality of life (QOL) and mortality, further analysis in the form of a randomized controlled trial to determine long-term outcomes among the four clusters with adjustment for baseline characteristics would help determine the extent to which certain patient clusters may respond to PR,” Dr. Gupta told this news organization in an email.

At the same time, he suggested that while patients may not experience much net benefit in their 6MWD, their QOL or mortality risk may still improve with PR. “I cannot recall a patient ever describing their experience with PR as anything other than positive,” Dr. Gupta stressed.

“And as the authors [themselves] note, because PR serves to benefit patients beyond the 6MWD, I would not recommend limiting PR referrals based on the patient clusters identified,” he said.

The authors had no conflicts of interest to declare. Dr. Gupta declared that he is an employee and shareholder at Genentech.

Sildenafil (Viagra, Pfizer), a phosphodieterase-5 (PDE-5) inhibitor and a pulmonary-selective vasodilator, may reduce mortality in patients with idiopathic pulmonary fibrosis (IPF), compared with placebo or standard of care but it does not reduce hospitalizations or acute exacerbations from the disorder, a small meta-analysis suggests.

“There have only been four trials investigating sildenafil [in IPF] and the results were very close to being statistically significant so the addition of a few events would cause that to be true,” Tyler Pitre, MD, McMaster University, Hamilton, Ont., and Dena Zeraatkar, PhD, Harvard Medical School, Boston, told this news organization in a joint email.

“So lack of statistical significance does not preclude benefit,” they added, “and we think these results warrant additional trials and, if results remain consistent, [we] suspect the next update of the analysis may demonstrate statistical significance.”

The study was published online in Pulmonary Pharmacology & Therapeutics.
 

Reanalysis necessary

As the investigators pointed out, the most recent international guidelines have a conditional recommendation against the use of sildenafil in IPF patients so reanalysis of the data was felt to be necessary in order to inform upcoming guidelines. The purpose of the review was to provide an update of the evidence as to whether sildenafil not only provides mortality benefit in this patient population but also whether it improves overall lung function, reduces exacerbations and hospitalizations along with adverse events (AEs) leading to drug discontinuation.

The four studies included in the meta-analysis were all randomized, controlled trials in which either standalone PDE-5 inhibitors were compared with placebo or with standard IPF care with either pirfenidone (Esbroef ) or nintedanib (Ofev). The age of participants across the trials ranged from 68.6 years to 70.4 years and participants were predominantly male.

Follow-up ranged from just 12 weeks to 52 weeks. “Four trials including 659 patients and 88 deaths, reported on mortality,” the investigators noted. At a relative risk reduction of 0.73 (95% confidence interval, 0.51-1.04), the investigators concluded with moderate certainty that sildenafil probably reduces mortality in IPF patients.

Four trials including 659 patients reported on acute exacerbations and hospitalizations. At a RR of 1.10 (95% CI, 0.61-1.67), pooled results showed sildenafil may not reduce hospitalizations or acute exacerbations, compared with controls, although this conclusion was reached with low certainty. Four trials containing slightly more patients at 661 participants reported on AEs leading to drug discontinuation.

Again with moderate certainty, the authors concluded there is probably no difference in drug discontinuation rates because of AEs when comparing sildenafil to controls, at a RR of 0.79 (95% CI, 0.56-1.10). Four trials including 602 patients reported on lung function changes while diffusion capacity of carbon monoxide (DLCO) results were available for 487 patients. Based on these four trials, sildenafil may not change the decline of forced vital capacity (FVC) at a mean difference of 0.61% (95% CI, –0.29 to 1.59), compared with standard of care or placebo.

Nor may it change the rate of DLCO decline at a MD of 0.97 (95% CI, 0.04-1.90), both outcomes again being rated with moderate certainty. Asked if the combination of either nintedanib plus sildenafil or pirfenidone plus sildenafil led to a mortality benefit in IPF patients, Dr. Pitre and Dr. Zeraatkar noted that there was no mortality benefit in either the INSTAGE trial or in another recent study published in Lancet Respiratory Medicine.

“However, both of these trials were quite small and therefore unlikely to detect a mortality benefit,” Dr. Pitre and Dr. Zeraatkar noted. Indeed, the benefit of doing a systematic review is the ability to pool event rates across trials to see if a benefit emerges as well as to evaluate the consistency of the direction of these effects.

“Our review presented the most up-to-date and comprehensive summary of the evidence on sildenafil therapy for IPF patients,” the authors stated.

While they did acknowledge that the mortality benefit seen with sildenafil over placebo or standard of care did not reach statistical significance, this was likely because of too few patients and events. For example, in a systematic review published in the New England Journal of Medicine in 1988, the authors were able to show a statistically significant benefit on 5-year mortality risk with the combination of tamoxifen and cytotoxic therapy whereas none of the individual trials analyzed were able to detect a mortality benefit because they were underpowered.

“Similarly, we suggest that something like this is possible with sildenafil, as the three major trials addressing sildenafil show the same direction toward benefit with little inconsistency,” Dr. Pitre and Dr. Zeraatkar noted.

“We should not exclude benefits based on P values alone,” they said, adding: “Clearly out systematic review is not going to change clinical practice given the uncertainty of the results but I do think that in a disease such as IPF, further research is warranted in targeted patient populations [and] for clinicians, we suggest they keep an open mind to sildenafil.”

Commentary

Asked to comment on the findings, Krishna Thavarajah, MD, director of the interstitial lung disease program at Henry Ford Hospital and clinical assistant professor at Wayne State University, both in Detroit, agreed with the authors that the lack of a statistically significant mortality benefit seen in the meta-analysis does not necessarily translate into a lack of benefit from the use of sildenafil in IPF patients. “As the authors point out, there are simply not enough data available to know if there is a mortality benefit, limited by the variable follow-up times and IPF patients targeted with or without pulmonary hypertension.”

Indeed, Dr. Thavarajah felt that a mortality benefit might be difficult to show in IPF patients, especially those on antifibrotics, given the duration of the studies analyzed and the number of patients needed to be able to show a statistically significant difference. “I myself have not prescribed sildenafil for IPF patients given the lack of clear data,” Dr. Thavarajah acknowledged.

“[But] the meta-analysis shows that sildenafil could have a mortality benefit in IPF patients without evidence of a benefit in FVC, DLCO, or acute exacerbations,” she confirmed, agreeing that further study would be helpful in assessing the potential for sildenafil to provide a mortality benefit in IPF patients.

No funding for the study was reported. Neither the authors nor Dr. Thavarajah had any conflicts of interest to declare.

Sildenafil (Viagra, Pfizer), a phosphodieterase-5 (PDE-5) inhibitor and a pulmonary-selective vasodilator, may reduce mortality in patients with idiopathic pulmonary fibrosis (IPF), compared with placebo or standard of care but it does not reduce hospitalizations or acute exacerbations from the disorder, a small meta-analysis suggests.

“There have only been four trials investigating sildenafil [in IPF] and the results were very close to being statistically significant so the addition of a few events would cause that to be true,” Tyler Pitre, MD, McMaster University, Hamilton, Ont., and Dena Zeraatkar, PhD, Harvard Medical School, Boston, told this news organization in a joint email.

“So lack of statistical significance does not preclude benefit,” they added, “and we think these results warrant additional trials and, if results remain consistent, [we] suspect the next update of the analysis may demonstrate statistical significance.”

The study was published online in Pulmonary Pharmacology & Therapeutics.
 

Reanalysis necessary

As the investigators pointed out, the most recent international guidelines have a conditional recommendation against the use of sildenafil in IPF patients so reanalysis of the data was felt to be necessary in order to inform upcoming guidelines. The purpose of the review was to provide an update of the evidence as to whether sildenafil not only provides mortality benefit in this patient population but also whether it improves overall lung function, reduces exacerbations and hospitalizations along with adverse events (AEs) leading to drug discontinuation.

The four studies included in the meta-analysis were all randomized, controlled trials in which either standalone PDE-5 inhibitors were compared with placebo or with standard IPF care with either pirfenidone (Esbroef ) or nintedanib (Ofev). The age of participants across the trials ranged from 68.6 years to 70.4 years and participants were predominantly male.

Follow-up ranged from just 12 weeks to 52 weeks. “Four trials including 659 patients and 88 deaths, reported on mortality,” the investigators noted. At a relative risk reduction of 0.73 (95% confidence interval, 0.51-1.04), the investigators concluded with moderate certainty that sildenafil probably reduces mortality in IPF patients.

Four trials including 659 patients reported on acute exacerbations and hospitalizations. At a RR of 1.10 (95% CI, 0.61-1.67), pooled results showed sildenafil may not reduce hospitalizations or acute exacerbations, compared with controls, although this conclusion was reached with low certainty. Four trials containing slightly more patients at 661 participants reported on AEs leading to drug discontinuation.

Again with moderate certainty, the authors concluded there is probably no difference in drug discontinuation rates because of AEs when comparing sildenafil to controls, at a RR of 0.79 (95% CI, 0.56-1.10). Four trials including 602 patients reported on lung function changes while diffusion capacity of carbon monoxide (DLCO) results were available for 487 patients. Based on these four trials, sildenafil may not change the decline of forced vital capacity (FVC) at a mean difference of 0.61% (95% CI, –0.29 to 1.59), compared with standard of care or placebo.

Nor may it change the rate of DLCO decline at a MD of 0.97 (95% CI, 0.04-1.90), both outcomes again being rated with moderate certainty. Asked if the combination of either nintedanib plus sildenafil or pirfenidone plus sildenafil led to a mortality benefit in IPF patients, Dr. Pitre and Dr. Zeraatkar noted that there was no mortality benefit in either the INSTAGE trial or in another recent study published in Lancet Respiratory Medicine.

“However, both of these trials were quite small and therefore unlikely to detect a mortality benefit,” Dr. Pitre and Dr. Zeraatkar noted. Indeed, the benefit of doing a systematic review is the ability to pool event rates across trials to see if a benefit emerges as well as to evaluate the consistency of the direction of these effects.

“Our review presented the most up-to-date and comprehensive summary of the evidence on sildenafil therapy for IPF patients,” the authors stated.

While they did acknowledge that the mortality benefit seen with sildenafil over placebo or standard of care did not reach statistical significance, this was likely because of too few patients and events. For example, in a systematic review published in the New England Journal of Medicine in 1988, the authors were able to show a statistically significant benefit on 5-year mortality risk with the combination of tamoxifen and cytotoxic therapy whereas none of the individual trials analyzed were able to detect a mortality benefit because they were underpowered.

“Similarly, we suggest that something like this is possible with sildenafil, as the three major trials addressing sildenafil show the same direction toward benefit with little inconsistency,” Dr. Pitre and Dr. Zeraatkar noted.

“We should not exclude benefits based on P values alone,” they said, adding: “Clearly out systematic review is not going to change clinical practice given the uncertainty of the results but I do think that in a disease such as IPF, further research is warranted in targeted patient populations [and] for clinicians, we suggest they keep an open mind to sildenafil.”

Commentary

Asked to comment on the findings, Krishna Thavarajah, MD, director of the interstitial lung disease program at Henry Ford Hospital and clinical assistant professor at Wayne State University, both in Detroit, agreed with the authors that the lack of a statistically significant mortality benefit seen in the meta-analysis does not necessarily translate into a lack of benefit from the use of sildenafil in IPF patients. “As the authors point out, there are simply not enough data available to know if there is a mortality benefit, limited by the variable follow-up times and IPF patients targeted with or without pulmonary hypertension.”

Indeed, Dr. Thavarajah felt that a mortality benefit might be difficult to show in IPF patients, especially those on antifibrotics, given the duration of the studies analyzed and the number of patients needed to be able to show a statistically significant difference. “I myself have not prescribed sildenafil for IPF patients given the lack of clear data,” Dr. Thavarajah acknowledged.

“[But] the meta-analysis shows that sildenafil could have a mortality benefit in IPF patients without evidence of a benefit in FVC, DLCO, or acute exacerbations,” she confirmed, agreeing that further study would be helpful in assessing the potential for sildenafil to provide a mortality benefit in IPF patients.

No funding for the study was reported. Neither the authors nor Dr. Thavarajah had any conflicts of interest to declare.

Sildenafil (Viagra, Pfizer), a phosphodieterase-5 (PDE-5) inhibitor and a pulmonary-selective vasodilator, may reduce mortality in patients with idiopathic pulmonary fibrosis (IPF), compared with placebo or standard of care but it does not reduce hospitalizations or acute exacerbations from the disorder, a small meta-analysis suggests.

“There have only been four trials investigating sildenafil [in IPF] and the results were very close to being statistically significant so the addition of a few events would cause that to be true,” Tyler Pitre, MD, McMaster University, Hamilton, Ont., and Dena Zeraatkar, PhD, Harvard Medical School, Boston, told this news organization in a joint email.

“So lack of statistical significance does not preclude benefit,” they added, “and we think these results warrant additional trials and, if results remain consistent, [we] suspect the next update of the analysis may demonstrate statistical significance.”

The study was published online in Pulmonary Pharmacology & Therapeutics.
 

Reanalysis necessary

As the investigators pointed out, the most recent international guidelines have a conditional recommendation against the use of sildenafil in IPF patients so reanalysis of the data was felt to be necessary in order to inform upcoming guidelines. The purpose of the review was to provide an update of the evidence as to whether sildenafil not only provides mortality benefit in this patient population but also whether it improves overall lung function, reduces exacerbations and hospitalizations along with adverse events (AEs) leading to drug discontinuation.

The four studies included in the meta-analysis were all randomized, controlled trials in which either standalone PDE-5 inhibitors were compared with placebo or with standard IPF care with either pirfenidone (Esbroef ) or nintedanib (Ofev). The age of participants across the trials ranged from 68.6 years to 70.4 years and participants were predominantly male.

Follow-up ranged from just 12 weeks to 52 weeks. “Four trials including 659 patients and 88 deaths, reported on mortality,” the investigators noted. At a relative risk reduction of 0.73 (95% confidence interval, 0.51-1.04), the investigators concluded with moderate certainty that sildenafil probably reduces mortality in IPF patients.

Four trials including 659 patients reported on acute exacerbations and hospitalizations. At a RR of 1.10 (95% CI, 0.61-1.67), pooled results showed sildenafil may not reduce hospitalizations or acute exacerbations, compared with controls, although this conclusion was reached with low certainty. Four trials containing slightly more patients at 661 participants reported on AEs leading to drug discontinuation.

Again with moderate certainty, the authors concluded there is probably no difference in drug discontinuation rates because of AEs when comparing sildenafil to controls, at a RR of 0.79 (95% CI, 0.56-1.10). Four trials including 602 patients reported on lung function changes while diffusion capacity of carbon monoxide (DLCO) results were available for 487 patients. Based on these four trials, sildenafil may not change the decline of forced vital capacity (FVC) at a mean difference of 0.61% (95% CI, –0.29 to 1.59), compared with standard of care or placebo.

Nor may it change the rate of DLCO decline at a MD of 0.97 (95% CI, 0.04-1.90), both outcomes again being rated with moderate certainty. Asked if the combination of either nintedanib plus sildenafil or pirfenidone plus sildenafil led to a mortality benefit in IPF patients, Dr. Pitre and Dr. Zeraatkar noted that there was no mortality benefit in either the INSTAGE trial or in another recent study published in Lancet Respiratory Medicine.

“However, both of these trials were quite small and therefore unlikely to detect a mortality benefit,” Dr. Pitre and Dr. Zeraatkar noted. Indeed, the benefit of doing a systematic review is the ability to pool event rates across trials to see if a benefit emerges as well as to evaluate the consistency of the direction of these effects.

“Our review presented the most up-to-date and comprehensive summary of the evidence on sildenafil therapy for IPF patients,” the authors stated.

While they did acknowledge that the mortality benefit seen with sildenafil over placebo or standard of care did not reach statistical significance, this was likely because of too few patients and events. For example, in a systematic review published in the New England Journal of Medicine in 1988, the authors were able to show a statistically significant benefit on 5-year mortality risk with the combination of tamoxifen and cytotoxic therapy whereas none of the individual trials analyzed were able to detect a mortality benefit because they were underpowered.

“Similarly, we suggest that something like this is possible with sildenafil, as the three major trials addressing sildenafil show the same direction toward benefit with little inconsistency,” Dr. Pitre and Dr. Zeraatkar noted.

“We should not exclude benefits based on P values alone,” they said, adding: “Clearly out systematic review is not going to change clinical practice given the uncertainty of the results but I do think that in a disease such as IPF, further research is warranted in targeted patient populations [and] for clinicians, we suggest they keep an open mind to sildenafil.”

Commentary

Asked to comment on the findings, Krishna Thavarajah, MD, director of the interstitial lung disease program at Henry Ford Hospital and clinical assistant professor at Wayne State University, both in Detroit, agreed with the authors that the lack of a statistically significant mortality benefit seen in the meta-analysis does not necessarily translate into a lack of benefit from the use of sildenafil in IPF patients. “As the authors point out, there are simply not enough data available to know if there is a mortality benefit, limited by the variable follow-up times and IPF patients targeted with or without pulmonary hypertension.”

Indeed, Dr. Thavarajah felt that a mortality benefit might be difficult to show in IPF patients, especially those on antifibrotics, given the duration of the studies analyzed and the number of patients needed to be able to show a statistically significant difference. “I myself have not prescribed sildenafil for IPF patients given the lack of clear data,” Dr. Thavarajah acknowledged.

“[But] the meta-analysis shows that sildenafil could have a mortality benefit in IPF patients without evidence of a benefit in FVC, DLCO, or acute exacerbations,” she confirmed, agreeing that further study would be helpful in assessing the potential for sildenafil to provide a mortality benefit in IPF patients.

No funding for the study was reported. Neither the authors nor Dr. Thavarajah had any conflicts of interest to declare.

An alarming increase in both esophageal cancer (EC) and the primary precursor lesion for esophageal adenocarcinoma known as Barrett’s esophagus (BE) has been observed among middle-aged adults over the past 5 years, and it’s not because of better or more frequent screening, warn the authors of a new study from Florida.

“We found that the [prevalence of] esophageal cancer and Barrett’s esophagus may have in fact plateaued in the elderly, but there is a concerning increase in their prevalence in middle-aged adults despite the fact that there has been no increase in the use of endoscopy in this population,” Bashar Qumseya, MD, MPH, associate professor of medicine and chief of endoscopy, University of Florida, Gainesville, told a press briefing.

“This should be of great concern to physicians and to patients, and it is our suggestion that maybe we should consider screening middle-aged patients or even those at younger ages for both conditions,” he added.

The study was highlighted during a press briefing in advance of the annual Digestive Disease Week® (DDW).
 

Research network

The analysis was carried out using electronic health records from the OneFlorida Clinical Data Research Network, a database that covers over 40% of residents living in Florida. The researchers identified patients who had been diagnosed with EC or BE between 2012 and 2019. “The primary outcome of interest was the adjusted prevalence of EC and BE in the population,” they stated.

The cohort was categorized by age: those aged 18-44 years (young); those aged 45-64 years (middle-aged), and those older than 65 (elderly). The number of patients included in the database varied by year and ranged from 4,238,884 to 5,411,838 patients per year, the investigators noted. Interestingly, in the most recent year, 2019, more women, at over 57%, were diagnosed with EC than were men.

Over the study interval, the prevalence of EC remained stable among the elderly but nearly doubled among middle-aged patients, from a rate of 49 per 100,000 in 2012 to a rate of 94 per 100,000 in 2019.

Similarly, there was a 50% increase in BE over the same study interval, from 304 per 100,000 in 2012 to 466 per 100,000 in 2019, again in the middle-aged group. The increase in the prevalence of BE was highest in those aged 51-60 years, followed by those aged 61-70 years and then by those aged 41-50.

Data from the same cohort also indicated that the great majority of patients with multiple risk factors for EC or BE – obesity, diet, and gastroesophageal reflux disease – had never undergone endoscopy, “so we can definitely do better,” Dr. Qumseya said. One simple way to “do better” is to offer patients an endoscopy when they undergo their first colonoscopy at the recommended age of 45 years.

“I am not in a position to make the guidelines,”Dr. Qumseya commented. “But we do [already] have guidelines that suggest that patients with multiple risk factors [for EC and BE] be screened, and since we know from our data that this is not happening, I believe that if a patient has multiple risk factors, they should have at least one screening endoscopy at the time of colonoscopy. Otherwise, we are missing a good opportunity to do so, and personally, I think this is something that we should be considering.”

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

An alarming increase in both esophageal cancer (EC) and the primary precursor lesion for esophageal adenocarcinoma known as Barrett’s esophagus (BE) has been observed among middle-aged adults over the past 5 years, and it’s not because of better or more frequent screening, warn the authors of a new study from Florida.

“We found that the [prevalence of] esophageal cancer and Barrett’s esophagus may have in fact plateaued in the elderly, but there is a concerning increase in their prevalence in middle-aged adults despite the fact that there has been no increase in the use of endoscopy in this population,” Bashar Qumseya, MD, MPH, associate professor of medicine and chief of endoscopy, University of Florida, Gainesville, told a press briefing.

“This should be of great concern to physicians and to patients, and it is our suggestion that maybe we should consider screening middle-aged patients or even those at younger ages for both conditions,” he added.

The study was highlighted during a press briefing in advance of the annual Digestive Disease Week® (DDW).
 

Research network

The analysis was carried out using electronic health records from the OneFlorida Clinical Data Research Network, a database that covers over 40% of residents living in Florida. The researchers identified patients who had been diagnosed with EC or BE between 2012 and 2019. “The primary outcome of interest was the adjusted prevalence of EC and BE in the population,” they stated.

The cohort was categorized by age: those aged 18-44 years (young); those aged 45-64 years (middle-aged), and those older than 65 (elderly). The number of patients included in the database varied by year and ranged from 4,238,884 to 5,411,838 patients per year, the investigators noted. Interestingly, in the most recent year, 2019, more women, at over 57%, were diagnosed with EC than were men.

Over the study interval, the prevalence of EC remained stable among the elderly but nearly doubled among middle-aged patients, from a rate of 49 per 100,000 in 2012 to a rate of 94 per 100,000 in 2019.

Similarly, there was a 50% increase in BE over the same study interval, from 304 per 100,000 in 2012 to 466 per 100,000 in 2019, again in the middle-aged group. The increase in the prevalence of BE was highest in those aged 51-60 years, followed by those aged 61-70 years and then by those aged 41-50.

Data from the same cohort also indicated that the great majority of patients with multiple risk factors for EC or BE – obesity, diet, and gastroesophageal reflux disease – had never undergone endoscopy, “so we can definitely do better,” Dr. Qumseya said. One simple way to “do better” is to offer patients an endoscopy when they undergo their first colonoscopy at the recommended age of 45 years.

“I am not in a position to make the guidelines,”Dr. Qumseya commented. “But we do [already] have guidelines that suggest that patients with multiple risk factors [for EC and BE] be screened, and since we know from our data that this is not happening, I believe that if a patient has multiple risk factors, they should have at least one screening endoscopy at the time of colonoscopy. Otherwise, we are missing a good opportunity to do so, and personally, I think this is something that we should be considering.”

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

An alarming increase in both esophageal cancer (EC) and the primary precursor lesion for esophageal adenocarcinoma known as Barrett’s esophagus (BE) has been observed among middle-aged adults over the past 5 years, and it’s not because of better or more frequent screening, warn the authors of a new study from Florida.

“We found that the [prevalence of] esophageal cancer and Barrett’s esophagus may have in fact plateaued in the elderly, but there is a concerning increase in their prevalence in middle-aged adults despite the fact that there has been no increase in the use of endoscopy in this population,” Bashar Qumseya, MD, MPH, associate professor of medicine and chief of endoscopy, University of Florida, Gainesville, told a press briefing.

“This should be of great concern to physicians and to patients, and it is our suggestion that maybe we should consider screening middle-aged patients or even those at younger ages for both conditions,” he added.

The study was highlighted during a press briefing in advance of the annual Digestive Disease Week® (DDW).
 

Research network

The analysis was carried out using electronic health records from the OneFlorida Clinical Data Research Network, a database that covers over 40% of residents living in Florida. The researchers identified patients who had been diagnosed with EC or BE between 2012 and 2019. “The primary outcome of interest was the adjusted prevalence of EC and BE in the population,” they stated.

The cohort was categorized by age: those aged 18-44 years (young); those aged 45-64 years (middle-aged), and those older than 65 (elderly). The number of patients included in the database varied by year and ranged from 4,238,884 to 5,411,838 patients per year, the investigators noted. Interestingly, in the most recent year, 2019, more women, at over 57%, were diagnosed with EC than were men.

Over the study interval, the prevalence of EC remained stable among the elderly but nearly doubled among middle-aged patients, from a rate of 49 per 100,000 in 2012 to a rate of 94 per 100,000 in 2019.

Similarly, there was a 50% increase in BE over the same study interval, from 304 per 100,000 in 2012 to 466 per 100,000 in 2019, again in the middle-aged group. The increase in the prevalence of BE was highest in those aged 51-60 years, followed by those aged 61-70 years and then by those aged 41-50.

Data from the same cohort also indicated that the great majority of patients with multiple risk factors for EC or BE – obesity, diet, and gastroesophageal reflux disease – had never undergone endoscopy, “so we can definitely do better,” Dr. Qumseya said. One simple way to “do better” is to offer patients an endoscopy when they undergo their first colonoscopy at the recommended age of 45 years.

“I am not in a position to make the guidelines,”Dr. Qumseya commented. “But we do [already] have guidelines that suggest that patients with multiple risk factors [for EC and BE] be screened, and since we know from our data that this is not happening, I believe that if a patient has multiple risk factors, they should have at least one screening endoscopy at the time of colonoscopy. Otherwise, we are missing a good opportunity to do so, and personally, I think this is something that we should be considering.”

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

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

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

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

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

The transition from perimenopause to menopause is accompanied by a proatherogenic shift in lipids and other circulating metabolites that potentially predispose women to cardiovascular disease (CVD). Now, for the first time, a new prospective cohort study quantifies the link between hormonal shifts and these lipid changes.

However, hormone therapy (HT) somewhat mitigates the shift and may help protect menopausal women from some elevated CVD risk, the same study suggests.

“Menopause is not avoidable, but perhaps the negative metabolite shift can be diminished by lifestyle choices such as eating healthily and being physically active,” senior author Eija Laakkonen, MD, University of Jyväskylä, Finland, told this news organization in an email.

“And women should especially pay attention to the quality of dietary fats and amount of exercise [they get] to maintain cardiorespiratory fitness,” she said, adding that women should discuss the option of HT with their health care providers.

Asked to comment, JoAnn Manson, MD, of Harvard Medical School, Boston, and past president of the North American Menopause Society, said there is strong evidence that women undergo negative cardiometabolic changes during the menopausal transition.

Changes include those in body composition (an increase in visceral fat and waist circumference), as well as unfavorable shifts in the lipid profile, as reflected by increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides and a decrease in high-density lipoprotein cholesterol (HDL-C).

It’s also clear from a variety of cohort studies that HT blunts menopausal-related increases in body weight, percentage of body fat, as well as visceral fat, she said.

So the new findings do seem to “parallel” those of other perimenopausal to menopausal transition studies, which include HT having “favorable effects on lipids,” Dr. Manson said. HT “lowers LDL-C and increases HDL-C, and this is especially true when it is given orally,” but even transdermal delivery has shown some benefits, she observed.
 

Shift in hormones causes 10% of lipid changes after menopause

The new study, by Jari E. Karppinen, also of the University of Jyväskylä, and colleagues, was recently published in the European Journal of Preventive Cardiology. The data are from the Estrogenic Regulation of Muscle Apoptosis (ERMA) prospective cohort study.

In total, 218 women were tracked from perimenopause through to early postmenopause, 35 of whom started HT, mostly oral preparations. The women were followed for a median of 14 months. Their mean age was 51.7 years when their hormone and metabolite profiles were first measured.

Previous studies have shown that menopause is associated with levels of metabolites that promote CVD, but this study is the first to specifically link this shift with changes in female sex hormones, the researchers stress.

“Menopause was associated with a statistically significant change in 85 metabolite measures,” Mr. Karppinen and colleagues report.

Analyses showed that the menopausal hormonal shift directly explained the change in 64 of the 85 metabolites, with effect sizes ranging from 2.1% to 11.2%. 

These included increases in LDL-C, triglycerides, and fatty acids. Analyses were adjusted for age at baseline, duration of follow-up, education level, smoking status, alcohol use, physical activity, and diet quality.

More specifically, investigators found that all apoB-containing particle counts as well as particle diameters increased over follow-up, although no change occurred in HDL particles.

They also found cholesterol concentrations in all apoB-containing lipoprotein classes to increase and triglyceride concentrations to increase in very low-density lipoprotein and HDL particles.

“These findings, including HDL triglycerides, can be interpreted as signs of poor metabolic health since, despite higher HDL-C being good for health, high HDL triglyceride levels are associated with a higher risk of coronary heart disease,” Dr. Laakkonen emphasized.

Among the 35 women who initiated HT on study enrollment, investigators did note, on exploratory analysis, increases in HDL-C and reductions in LDL-C.

“The number of women starting HT was small, and the type of HT was not controlled,” Dr. Laakkonen cautioned, however.

“Nevertheless, our observations support clinical guidelines to initiate HT early into menopause, as this timing offers the greatest cardioprotective effect,” she added.

The study was supported by the Academy of Finland. The authors and Dr. Manson have reported no relevant financial relationships. Dr. Manson is a contributor to Medscape.

This article was updated on 5/20/2022.

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

Twelve years after the human papillomavirus (HPV) vaccination program was introduced in the United States, the overall prevalence of cancer-causing HPV strains covered by the vaccine dropped by 85% among females – 90% among vaccinated females and 74% among unvaccinated females – a strong sign of herd immunity, a new analysis of a nationally representative database is showing.

“HPV vaccination is working well,” Hannah Rosenblum, MD, Centers for Disease Control and Prevention, Atlanta, told this news organization in an email.

“Twelve years after introduction of HPV vaccination in the United States, national data demonstrate increasing impact among females and strong herd effects among unvaccinated females,” she added. “[Although] vaccination coverage and completion of the recommended dose in the United States is lower than coverage with other adolescent vaccinations, HPV vaccination is the best way to prevent HPV infections that can lead to several cancers in both females and males.”

The study was published online in Annals of Internal Medicine.
 

NHANES survey

The authors used data from the National Health and Nutrition Examination Survey (NHANES) to examine the four HPV types in the quadrivalent vaccine before 2003 and 2006 (the pre-vaccine era) and then again between 2007-2010, 2011-2014, and 2015-2018 (the vaccine era). For females, they analyzed demographic and HPV prevalence data across each 4-year era.

“Analyses were limited to sexually experienced participants, to ensure that all those included had an opportunity for HPV exposure, and to participants aged 14-24 years with adequate self-collected cervicovaginal specimens,” the authors explain.

This resulted in a sample size of 3,197 females. Demographic and HPV prevalence data were also collected from males but only during the 2013-2016 era, because those are the only years for which male HPV typing data are available in NHANES. Again, analyses were limited to sexually experienced males aged 14-24 years with adequate self-collected penile specimens, which resulted in a sample size of 661 males.

Over the 12 years of follow-up for females, there was a steady increase in females reporting having received at least one dose of the HPV vaccine – from slightly over 25% during 2007-12 to 59% during 2015-2018. The percentage of males who reported having at least one HPV dose also increased, from 29.5% in 2016 to 34.5% in 2018.

During the earliest vaccine era (2007-2010), the prevalence of the four HPV strains covered by the vaccine was 7.3% among vaccinated females, compared with 20.4% among unvaccinated females. “By 2015 to 2018, the prevalence was 2.8% (prevalence ratio, 0.16; 95% confidence interval, 0.07-0.39). The prevalence of the four vaccine-covered types was only 1.9% in vaccinated females, compared with 4.8% in unvaccinated females (PR, 0.40; 95% CI, 0.11-1.41).

In contrast, the prevalence of HPV types that were not covered by the vaccine showed little change – from 51.1% in the pre-vaccine era to 47.6% during 2015-2018 (PR, 0.93; 95% CI, 0.80-1.08). The authors considered this a good sign because it indicates that vaccine-type HPV infections are not being replaced with other oncogenic HPV infections. Between 2013 and 2016, the difference in the prevalence of the four HPV vaccine types was smaller at 1.8% among vaccinated males and 3.5% among unvaccinated males (PR, 0.49; 95% CI, 0.11-2.20).

Again, the prevalence of non-HPV vaccine types was not significantly different between vaccinated and unvaccinated males: 30.7% versus 34.3%.

During the vaccine era, effectiveness for females ranged from 60% to 84%. For males, vaccine effectiveness could only be evaluated for the single 4-year period from 2013 to 2016, and it was estimated at 51%. Dr. Rosenblum noted that vaccine efficacy estimates were lower on this national survey than the almost 100% efficacy rates observed in clinical trials in both males and females.

“This might be due in part to many participants receiving the vaccine at an older age than is recommended when they could have been infected [with HPV] at the time of vaccination,” Dr. Rosenblum said. She also noted that because males were incorporated into the HPV vaccination program years after females, they likely also experienced strong herd effects from the vaccine, making it challenging to estimate vaccine effectiveness.

Dr. Rosenblum also noted that there have already been documented declines in cervical precancers and high-grade vulvar and vaginal precancers, as well as genital warts and juvenile-onset recurrent respiratory papillomatosis. At the same time, the incidence of cervical precancers has recently declined among U.S. females in their late teens and early 20s – “likely reflecting the impact of vaccination,” she said.

“This study is good news for the United States HPV vaccination program, and all efforts are needed to ensure that children and adolescents receive routinely recommended vaccinations [including vaccination against HPV],” Dr. Rosenblum added.
 

Editorial comment

Commenting on the findings, Rebecca Perkins, MD, Boston University School of Medicine, and colleagues point out that the COVID-19 pandemic has led to disruptions in HPV vaccination programs and has reversed much of the progress made in recent years. “During the pandemic, providers and health systems have deprioritized adolescent vaccination and particularly HPV vaccination, which in turn has led to more severe drops for HPV vaccination than for other adolescent vaccinations, and for adolescent vaccination, compared with early childhood and adult vaccinations,” Dr. Perkins and colleagues write in an accompanying editorial.

Thus, the need to compensate for the cumulative deficit of missed vaccinations over the past 2 years has created a “serious and urgent threat” to cancer prevention efforts – “a shortfall from which it may take a decade to recover,” the editorialists predict. To try and reverse this trend, several practices have been shown to improve HPV vaccination rates.

The first is a strong provider recommendation such as, “Your child is due for an HPV vaccine today.” The second is to give standing orders to allow nurses and medical assistants to administer vaccinations without requiring intervention by a physician. Lastly, programs to remind patients when vaccines are due and to recall them for appointments also work well.

“Using evidence-based methods and redoubling our efforts to prioritize HPV vaccination will be crucial to ensuring that we do not lose a generation to preventable HPV-associated cancer,” write Dr. Perkins and colleagues.

The study authors and editorialists have disclosed no relevant financial relationships.

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

Twelve years after the human papillomavirus (HPV) vaccination program was introduced in the United States, the overall prevalence of cancer-causing HPV strains covered by the vaccine dropped by 85% among females – 90% among vaccinated females and 74% among unvaccinated females – a strong sign of herd immunity, a new analysis of a nationally representative database is showing.

“HPV vaccination is working well,” Hannah Rosenblum, MD, Centers for Disease Control and Prevention, Atlanta, told this news organization in an email.

“Twelve years after introduction of HPV vaccination in the United States, national data demonstrate increasing impact among females and strong herd effects among unvaccinated females,” she added. “[Although] vaccination coverage and completion of the recommended dose in the United States is lower than coverage with other adolescent vaccinations, HPV vaccination is the best way to prevent HPV infections that can lead to several cancers in both females and males.”

The study was published online in Annals of Internal Medicine.
 

NHANES survey

The authors used data from the National Health and Nutrition Examination Survey (NHANES) to examine the four HPV types in the quadrivalent vaccine before 2003 and 2006 (the pre-vaccine era) and then again between 2007-2010, 2011-2014, and 2015-2018 (the vaccine era). For females, they analyzed demographic and HPV prevalence data across each 4-year era.

“Analyses were limited to sexually experienced participants, to ensure that all those included had an opportunity for HPV exposure, and to participants aged 14-24 years with adequate self-collected cervicovaginal specimens,” the authors explain.

This resulted in a sample size of 3,197 females. Demographic and HPV prevalence data were also collected from males but only during the 2013-2016 era, because those are the only years for which male HPV typing data are available in NHANES. Again, analyses were limited to sexually experienced males aged 14-24 years with adequate self-collected penile specimens, which resulted in a sample size of 661 males.

Over the 12 years of follow-up for females, there was a steady increase in females reporting having received at least one dose of the HPV vaccine – from slightly over 25% during 2007-12 to 59% during 2015-2018. The percentage of males who reported having at least one HPV dose also increased, from 29.5% in 2016 to 34.5% in 2018.

During the earliest vaccine era (2007-2010), the prevalence of the four HPV strains covered by the vaccine was 7.3% among vaccinated females, compared with 20.4% among unvaccinated females. “By 2015 to 2018, the prevalence was 2.8% (prevalence ratio, 0.16; 95% confidence interval, 0.07-0.39). The prevalence of the four vaccine-covered types was only 1.9% in vaccinated females, compared with 4.8% in unvaccinated females (PR, 0.40; 95% CI, 0.11-1.41).

In contrast, the prevalence of HPV types that were not covered by the vaccine showed little change – from 51.1% in the pre-vaccine era to 47.6% during 2015-2018 (PR, 0.93; 95% CI, 0.80-1.08). The authors considered this a good sign because it indicates that vaccine-type HPV infections are not being replaced with other oncogenic HPV infections. Between 2013 and 2016, the difference in the prevalence of the four HPV vaccine types was smaller at 1.8% among vaccinated males and 3.5% among unvaccinated males (PR, 0.49; 95% CI, 0.11-2.20).

Again, the prevalence of non-HPV vaccine types was not significantly different between vaccinated and unvaccinated males: 30.7% versus 34.3%.

During the vaccine era, effectiveness for females ranged from 60% to 84%. For males, vaccine effectiveness could only be evaluated for the single 4-year period from 2013 to 2016, and it was estimated at 51%. Dr. Rosenblum noted that vaccine efficacy estimates were lower on this national survey than the almost 100% efficacy rates observed in clinical trials in both males and females.

“This might be due in part to many participants receiving the vaccine at an older age than is recommended when they could have been infected [with HPV] at the time of vaccination,” Dr. Rosenblum said. She also noted that because males were incorporated into the HPV vaccination program years after females, they likely also experienced strong herd effects from the vaccine, making it challenging to estimate vaccine effectiveness.

Dr. Rosenblum also noted that there have already been documented declines in cervical precancers and high-grade vulvar and vaginal precancers, as well as genital warts and juvenile-onset recurrent respiratory papillomatosis. At the same time, the incidence of cervical precancers has recently declined among U.S. females in their late teens and early 20s – “likely reflecting the impact of vaccination,” she said.

“This study is good news for the United States HPV vaccination program, and all efforts are needed to ensure that children and adolescents receive routinely recommended vaccinations [including vaccination against HPV],” Dr. Rosenblum added.
 

Editorial comment

Commenting on the findings, Rebecca Perkins, MD, Boston University School of Medicine, and colleagues point out that the COVID-19 pandemic has led to disruptions in HPV vaccination programs and has reversed much of the progress made in recent years. “During the pandemic, providers and health systems have deprioritized adolescent vaccination and particularly HPV vaccination, which in turn has led to more severe drops for HPV vaccination than for other adolescent vaccinations, and for adolescent vaccination, compared with early childhood and adult vaccinations,” Dr. Perkins and colleagues write in an accompanying editorial.

Thus, the need to compensate for the cumulative deficit of missed vaccinations over the past 2 years has created a “serious and urgent threat” to cancer prevention efforts – “a shortfall from which it may take a decade to recover,” the editorialists predict. To try and reverse this trend, several practices have been shown to improve HPV vaccination rates.

The first is a strong provider recommendation such as, “Your child is due for an HPV vaccine today.” The second is to give standing orders to allow nurses and medical assistants to administer vaccinations without requiring intervention by a physician. Lastly, programs to remind patients when vaccines are due and to recall them for appointments also work well.

“Using evidence-based methods and redoubling our efforts to prioritize HPV vaccination will be crucial to ensuring that we do not lose a generation to preventable HPV-associated cancer,” write Dr. Perkins and colleagues.

The study authors and editorialists have disclosed no relevant financial relationships.

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

Twelve years after the human papillomavirus (HPV) vaccination program was introduced in the United States, the overall prevalence of cancer-causing HPV strains covered by the vaccine dropped by 85% among females – 90% among vaccinated females and 74% among unvaccinated females – a strong sign of herd immunity, a new analysis of a nationally representative database is showing.

“HPV vaccination is working well,” Hannah Rosenblum, MD, Centers for Disease Control and Prevention, Atlanta, told this news organization in an email.

“Twelve years after introduction of HPV vaccination in the United States, national data demonstrate increasing impact among females and strong herd effects among unvaccinated females,” she added. “[Although] vaccination coverage and completion of the recommended dose in the United States is lower than coverage with other adolescent vaccinations, HPV vaccination is the best way to prevent HPV infections that can lead to several cancers in both females and males.”

The study was published online in Annals of Internal Medicine.
 

NHANES survey

The authors used data from the National Health and Nutrition Examination Survey (NHANES) to examine the four HPV types in the quadrivalent vaccine before 2003 and 2006 (the pre-vaccine era) and then again between 2007-2010, 2011-2014, and 2015-2018 (the vaccine era). For females, they analyzed demographic and HPV prevalence data across each 4-year era.

“Analyses were limited to sexually experienced participants, to ensure that all those included had an opportunity for HPV exposure, and to participants aged 14-24 years with adequate self-collected cervicovaginal specimens,” the authors explain.

This resulted in a sample size of 3,197 females. Demographic and HPV prevalence data were also collected from males but only during the 2013-2016 era, because those are the only years for which male HPV typing data are available in NHANES. Again, analyses were limited to sexually experienced males aged 14-24 years with adequate self-collected penile specimens, which resulted in a sample size of 661 males.

Over the 12 years of follow-up for females, there was a steady increase in females reporting having received at least one dose of the HPV vaccine – from slightly over 25% during 2007-12 to 59% during 2015-2018. The percentage of males who reported having at least one HPV dose also increased, from 29.5% in 2016 to 34.5% in 2018.

During the earliest vaccine era (2007-2010), the prevalence of the four HPV strains covered by the vaccine was 7.3% among vaccinated females, compared with 20.4% among unvaccinated females. “By 2015 to 2018, the prevalence was 2.8% (prevalence ratio, 0.16; 95% confidence interval, 0.07-0.39). The prevalence of the four vaccine-covered types was only 1.9% in vaccinated females, compared with 4.8% in unvaccinated females (PR, 0.40; 95% CI, 0.11-1.41).

In contrast, the prevalence of HPV types that were not covered by the vaccine showed little change – from 51.1% in the pre-vaccine era to 47.6% during 2015-2018 (PR, 0.93; 95% CI, 0.80-1.08). The authors considered this a good sign because it indicates that vaccine-type HPV infections are not being replaced with other oncogenic HPV infections. Between 2013 and 2016, the difference in the prevalence of the four HPV vaccine types was smaller at 1.8% among vaccinated males and 3.5% among unvaccinated males (PR, 0.49; 95% CI, 0.11-2.20).

Again, the prevalence of non-HPV vaccine types was not significantly different between vaccinated and unvaccinated males: 30.7% versus 34.3%.

During the vaccine era, effectiveness for females ranged from 60% to 84%. For males, vaccine effectiveness could only be evaluated for the single 4-year period from 2013 to 2016, and it was estimated at 51%. Dr. Rosenblum noted that vaccine efficacy estimates were lower on this national survey than the almost 100% efficacy rates observed in clinical trials in both males and females.

“This might be due in part to many participants receiving the vaccine at an older age than is recommended when they could have been infected [with HPV] at the time of vaccination,” Dr. Rosenblum said. She also noted that because males were incorporated into the HPV vaccination program years after females, they likely also experienced strong herd effects from the vaccine, making it challenging to estimate vaccine effectiveness.

Dr. Rosenblum also noted that there have already been documented declines in cervical precancers and high-grade vulvar and vaginal precancers, as well as genital warts and juvenile-onset recurrent respiratory papillomatosis. At the same time, the incidence of cervical precancers has recently declined among U.S. females in their late teens and early 20s – “likely reflecting the impact of vaccination,” she said.

“This study is good news for the United States HPV vaccination program, and all efforts are needed to ensure that children and adolescents receive routinely recommended vaccinations [including vaccination against HPV],” Dr. Rosenblum added.
 

Editorial comment

Commenting on the findings, Rebecca Perkins, MD, Boston University School of Medicine, and colleagues point out that the COVID-19 pandemic has led to disruptions in HPV vaccination programs and has reversed much of the progress made in recent years. “During the pandemic, providers and health systems have deprioritized adolescent vaccination and particularly HPV vaccination, which in turn has led to more severe drops for HPV vaccination than for other adolescent vaccinations, and for adolescent vaccination, compared with early childhood and adult vaccinations,” Dr. Perkins and colleagues write in an accompanying editorial.

Thus, the need to compensate for the cumulative deficit of missed vaccinations over the past 2 years has created a “serious and urgent threat” to cancer prevention efforts – “a shortfall from which it may take a decade to recover,” the editorialists predict. To try and reverse this trend, several practices have been shown to improve HPV vaccination rates.

The first is a strong provider recommendation such as, “Your child is due for an HPV vaccine today.” The second is to give standing orders to allow nurses and medical assistants to administer vaccinations without requiring intervention by a physician. Lastly, programs to remind patients when vaccines are due and to recall them for appointments also work well.

“Using evidence-based methods and redoubling our efforts to prioritize HPV vaccination will be crucial to ensuring that we do not lose a generation to preventable HPV-associated cancer,” write Dr. Perkins and colleagues.

The study authors and editorialists have disclosed no relevant financial relationships.

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